ASHP COVID 19 Evidence Table

Assessment of Evidence for COVID-19-Related Treatments: Updated 6/18/2020
The information contained in this evidence table is emerging and rapidly evolving because of ongoing research and is subject to the professional judgment and interpretation of the practi-
tioner due to the uniqueness of each medical facility’s approach to the care of patients with COVID-19 and the needs of individual patients. ASHP provides this evidence table to help practi-
tioners better understand current approaches related to treatment and care. ASHP has made reasonable efforts to ensure the accuracy and appropriateness of the information presented.
However, any reader of this information is advised ASHP is not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising
from the use of the information in the evidence table in any and all practice settings. Any reader of this document is cautioned that ASHP makes no representation, guarantee, or warranty,
express or implied, as to the accuracy and appropriateness of the information contained in this evidence table and will bear no responsibility or liability for the results or consequences of its
use.
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Select entries were updated on 6/18/2020; these can be identified by the date that appears in the Drug(s) column.
TABLE OF CONTENTS
ANTIVIRAL AGENTS SUPPORTING AGENTS OTHER

 BALOXAVIR  ANAKINRA UPDATED  ACE INHIBITORS, ANGIOTENSIN II
 CHLOROQUINE PHOSPHATE  ASCORBIC ACID RECEPTOR BLOCKERS (ARBs)
  ANTICOAGULANTS
FAVIPIRAVIR  AZITHROMYCIN
(Avigan®, Favilavir) UPDATED  COVID-19 CONVALESCENT PLASMA
 BARICITINIB (Olumiant®)
UPDATED  HIV PROTEASE INHIBITORS UPDATED  FAMOTIDINE
 COLCHICINE
(e.g., LPV/RTV, Kaletra®) UPDATED  HMG-CoA REDUCTASE INHIBITORS
 CORTICOSTEROIDS (general)
 HYDROXYCHLOROQUINE (statins)
(Plaquenil®)  EPOPROSTENOL (inhaled) UPDATED  IMMUNE GLOBULIN
 UPDATED 
NEURAMINIDASE INHIBITORS INTERFERONS  IVERMECTIN
(e.g., oseltamivir)  METHYLPREDNISOLONE  NEBULIZED DRUGS
UPDATED  REMDESIVIR (DEPO-Medrol®, SOLU-Medrol®)  NICLOSAMIDE
 UMIFENOVIR (Arbidol®)  NITRIC OXIDE (inhaled)  NITAZOXANIDE
 RUXOLITINIB (Jakafi®) UPDATED  NONSTEROIDAL ANTI-INFLAMMATORY
UPDATED  SARILUMAB (Kefzara®) AGENTS (NSAIAs)
 SILTUXIMAB (Sylvant®)  TISSUE PLASMINOGEN ACTIVATOR
(t-PA; alteplase)
 SIROLIMUS (Rapamune®)
 TOCILIZUMAB (Actemra®)
Updated 6-18-20. The current version of this document can be found on the ASHP COVID-19 Resource Center. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License
ANTIVIRAL AGENTS
Drug(s) AHFS Class Rationale Trials or Clinical Experience Dosagea Comments
Baloxavir 8:18.92 Antiviral active against Only limited clinical trial data available to Protocol for two registered Chinese No data to date support use in the
Antiviral influenza viruses date to evaluate use of baloxavir for treat- trials (ChiCTR2000029544, treatment of COVID-19
Updated ment of COVID-19 ChiCTR2000029548) specifies an oral
5/13/20 In vitro antiviral activity baloxavir marboxil dosage of 80 mg
against SARS-CoV-2 demon- Exploratory, open-label, randomized con- on day 1 and on day 4, and another
strated in one trial 3 trolled study at a single center in China dose of 80 mg on day 7 (as needed);
(ChiCTR2000029544): 29 adults hospital- not to exceed 3 total doses. 1, 3
ized with COVID-19 receiving antiviral
treatment with lopinavir/ritonavir, da-
runavir/cobicistat, or umifenovir
(Arbidol®), in combination with inhaled
interferon-α, were randomized to treat-
ment with baloxavir marboxil (80 mg orally
on day 1 and on day 4, and 80 mg orally on
day 7 as needed) (n=10), favipiravir (1600
or 2200 mg orally on day 1, followed by
600 mg three times daily for up to 14 days)
(n=9), or control (standard antiviral treat-
ment) (n=10). Percentage of pts with viral
conversion (2 consecutive tests with unde-
tectable viral RNA results) after 14 days of
treatment was 70, 77, and 100% in the
baloxavir, favipiravir, and control groups,
respectively, with median time to clinical
improvement of 14, 14, and 15 days, re-
spectively. 3
Another randomized controlled trial regis-

tered in China: 1
CHiCTR2000029548
Chloroquine 8:30.08 In vitro activity against Only limited clinical trial data available to Optimal dosage and duration of Efficacy and safety of chloroquine for
Phosphate Antimalarial various viruses, including date to evaluate use of chloroquine for treatment not known 25 treatment or prevention of COVID-19
(4- coronaviruses 1-3, 13, 14 treatment or prevention of COVID-19 not established 10, 24, 39
Updated aminoquino- Consider: 500 mg of chloroquine
6/16/20 line deriva- In vitro activity against Clinical experience in treating pts with phosphate is equivalent to 300 mg of No data to date indicating that in vitro
tive) SARS-CoV-2 in infected COVID-19: Majority of data to date in- chloroquine base 17 activity against SARS-CoV-2 corresponds
Vero E6 cells reported; volves use in pts with mild or moderate with clinical efficacy for treatment or
some evidence it may block COVID-19; 35 only limited clinical data on Oral chloroquine phosphate dosage prevention of COVID-19
infection in Vero E6 cells use in pts with severe and critical disease. suggested in the EUA (now re-
exposed to SARS-CoV-2 1, 4, 35
voked): For treatment of hospital- Data from randomized, controlled clini-
12
ized adults and adolescents weighing cal trials needed to substantiate initial
50 kg or more when a clinical trial is reports of efficacy of 4-aminoquinoline
Active in vitro against SARS- Small, randomized study in hospitalized not available or participation not antimalarials for treatment of COVID-
CoV-1 and MERS-CoV 2, 3, 5, 9 adults in China compared chloroquine feasible, suggested dosage was 1 g 19, guide decisions regarding the most
with LPV/RTV (Huang et al): 10 pts (7 with on day 1, then 500 mg daily for 4-7 appropriate pts for treatment with such
Has immunomodulatory moderate and 3 with severe COVID-19) days of total treatment based on drugs, and identify optimal dose and
activity that theoretically received chloroquine (500 mg twice daily clinical evaluation. 25 FDA now states treatment duration
could contribute to an for 10 days) and 12 pts (7 with moderate that this dosage is unlikely to have
anti-inflammatory response and 5 with severe COVID-19) received LPV/ an antiviral effect in pts with COVID- Additional data needed regarding toxici-
in patients with viral infec- RTV (lopinavir 400 mg/ritonavir 100 mg 19 based on a reassessment of in ty profile when used in patients with
tions 1-3, 13, 15-16 twice daily for 10 days). All 10 pts treated vitro EC50/EC90 data and calculated COVID-19
with chloroquine had negative RT-PCR re- lung concentrations; it is unclear
Known pharmacokinetics sults for SARS-CoV-2 by day 13 and were whether this dosage would provide Chloroquine suggested as possible op-
and toxicity profile based on discharged from the hospital by day 14; any beneficial immunomodulatory tion and included in Chinese guidelines
use for other indications 13, 11/12 pts (92%) treated with LPV/RTV were effects. 57 for treatment of COVID-19. 11
17
negative for SARS-CoV-2 at day 14 and only
6/12 (50%) were discharged from the hos- Oral chloroquine phosphate dosage NIH COVID-19 Treatment Guidelines
pital by day 14. Note: Results suggest that in Chinese guidelines: 500 mg twice Panel recommends against use of chlo-
chloroquine was associated with shorter daily for 7 days (adults 18-65 years roquine for the treatment of COVID-19,
time to RT-PCR conversion and quicker weighing >50 kg); 500 mg twice daily except in a clinical trial; the panel rec-
recovery than LPV/RTV; however, this on days 1 and 2, then 500 mg once ommends against use of high-dose chlo-
study included a limited number of pts and daily on days 3-7 (adults weighing roquine (i.e., 600 mg twice daily for 10
the median time from onset of symptoms <50 kg) 11 days) for the treatment of COVID-19
to initiation of treatment was shorter in because such dosage has been associat-
those treated with chloroquine than in Oral chloroquine phosphate dosage ed with more severe toxicities com-
those treated with LPV/RTV (2.5 vs 6.5 used in some clinical trials: Initial pared with lower-dose chloroquine. 35
days, respectively).20 dose of 600 mg (of chloroquine)
followed by 300 mg (of chloroquine) IDSA recommends that chloroquine be
Double-blind randomized phase 2b study 12 hours later on day 1, then 300 mg used for the treatment of COVID-19 in
in Brazil, (Borba et al) to evaluate two (of chloroquine) twice daily on days the context of a clinical trial. 38 IDSA
different chloroquine dosages as adjunctive 2-5 4 recommends that a combined regimen
therapy in hospitalized adults with severe of chloroquine and azithromycin be
COVID-19 (NCT04323527): The first 81 en- used for the treatment of COVID-19
rolled pts were randomized 1:1 to receive only in the context of a clinical trial. 38
high-dose chloroquine (600 mg twice daily
for 10 days) or lower-dose chloroquine
(450 mg twice daily on day 1, then 450 mg NIH COVID-19 Treatment Guidelines
once daily on days 2-5); all pts also received Panel does not recommend the use of
azithromycin and ceftriaxone and some any agents, including chloroquine, for
also received oseltamivir. An unplanned preexposure prophylaxis (PrEP) or post-
interim analysis was performed and the exposure prophylaxis (PEP) for preven-
high-dose arm of the study was halted be- tion of SARS-CoV-2 infection outside of
cause of toxicity concerns, particularly QTc clinical trials. The panel states that, to
prolongation and ventricular tachycardia, date, no agent is known to be effective
and because more deaths were reported in for preventing SARS-CoV-2 infection
this arm. By day 13, 16/41 pts (39%) treat- when given before or after an exposure.
35
ed with the high-dose regimen had died vs
6/40 (15%) treated with the lower-dose
regimen. QTc >500 msec occurred more Because 4-aminoquinolines
frequently in the high-dose group (18.9%) (chloroquine, hydroxychloroquine) are
than in the lower-dose group (11.1%). The associated with QT prolongation, cau-
high-dose arm included more pts prone to tion is advised if considering use of the
cardiac complications than the lower-dose drugs in pts with COVID-19 at risk for QT
arm. Data were insufficient to evaluate prolongation or receiving other drugs
efficacy. Study continuing using only the associated with arrhythmias; 13, 17, 36, 39
lower dosage. 37 diagnostic testing and monitoring rec-
ommended to minimize risk of adverse
See Hydroxychloroquine in this Evidence effects, including drug-induced cardiac
Table for additional information on clinical effects. 35, 36, 39 (See Hydroxychloro-
quine in this Evidence Table.)
trials and experience with 4- NIH panel states that 4-aminoquinolines
aminoquinoline antimalarials in the man- (chloroquine, hydroxychloroquine)
agement of COVID-19. should be used concomitantly with
drugs that pose a moderate to high risk
Multiple clinical trials to evaluate chloro- for QTc prolongation (e.g., antiarrhyth-
quine for the treatment of COVID-19 are mics, antipsychotics, antifungals, fluoro-
registered at clinicaltrials.gov (some listed quinolones, macrolides [including
below): 10 azithromycin]) only if necessary. The
NCT04323527 panel states that use of doxycycline
NCT04328493 (instead of azithromycin) should be
NCT04331600 considered for empiric therapy of atypi-
NCT04362332 cal pneumonia in COVID-19 pts receiv-
NCT04428268 ing chloroquine (or hydroxychloro-
quine). 35
Several clinical trials to evaluate chloro- FDA issued a safety alert regarding ad-
quine for prevention of COVID-19 in the verse cardiac effects (e.g., prolonged QT
healthcare setting are registered at clinical- interval, ventricular tachycardia, ven-
trials.gov: 10 tricular fibrillation) reported with use of
NCT04303507 chloroquine or hydroxychloroquine
NCT04333732 (either alone or in conjunction with
NCT04349371 azithromycin or other drugs known to
prolong QT interval) in hospital and
outpatient settings; FDA cautions
against use of chloroquine or hy-
droxychloroquine outside of a clinical
trial or hospital setting and urges
healthcare professionals and pts to
report adverse effects involving these
drugs to FDA MedWatch. 39
Emergency use authorization (EUA) for

chloroquine (now revoked): Effective
June 15, 2020, FDA has revoked the EUA
for chloroquine and hydroxychloroquine
57
previously issued on March 28, 2020
that permitted distribution of the drugs
from the strategic national stockpile
(SNS) for use in adults and adolescents
weighing 50 kg or more hospitalized
with COVID-19 for whom a clinical trial
was not available or participation not
feasible. 24, 57 Based on a review of new
information and reevaluation of infor-
mation available at the time the EUA
was issued, FDA concluded that the
original criteria for issuance of the EUA
for these drugs are no longer met. 57
Based on the totality of scientific evi-
dence available, FDA concluded that it is
unlikely that chloroquine and hy-
droxychloroquine may be effective in
treating COVID-19 and, in light of ongo-
ing reports of serious cardiac adverse
events and several newly reported cas-
es of methemoglobinemia in COVID-19
patients, the known and potential bene-
fits of chloroquine and hydroxychloro-
quine do not outweigh the known and
potential risks associated with the use
authorized by the EUA. 57 (See Hy-
droxychloroquine in this Evidence Ta-
ble.)
Favipiravir 8:18.32 Broad-spectrum antiviral Only very limited clinical trial data availa- A favipiravir dosage of 1600 mg twice Not commercially available in the US
(Avigan®, Antiviral with in vitro activity ble to date to evaluate use of favipiravir in daily on day 1, then 600 mg twice
Favilavir) against various viruses, the treatment of COVID-19 daily thereafter for 7–10 or 14 days Efficacy and safety of favipiravir for
including coronaviruses 1–5 was used in several open-label treatment of COVID-19 not established
Updated Open-label, prospective, randomized, COVID-19 studies in China 6, 15
6/3/20 In vitro evidence of activity multicenter study in 236 adults with Additional data needed to substantiate
against SARS-CoV-2 in in- COVID-19 pneumonia in China Protocol in one ongoing trial initial reports of efficacy for treatment
fected Vero E6 cells report- (ChiCTR2000030254): Favipiravir (1600 mg (NCT04346628) for treatment of mild of COVID-19 and identify optimal dos-
ed with high concentra- orally twice daily on day 1, then 600 mg COVID-19 specifies a favipiravir dosage and treatment duration
tions of the drug 1, 5, 16 orally twice daily thereafter for 7–10 days) age of 1800 mg on day 1, then 800
was associated with greater clinical recov- mg twice daily on days 2–10 7 Given the lack of pharmacokinetic and
Licensed in Japan and Chi- ery rate at 7 days (61 vs 52%) compared safety data for the high favipiravir dos-
na for treatment of influ- with the control group treated with Protocol in one ongoing trial ages proposed for treatment of COVID-
enza 2, 4, 6 umifenovir (Arbidol®; 200 mg 3 times daily NCT04358549 for treatment of 19, the drug should be used with cau-
for 7–10 days). Stratified by disease severi- COVID-19 specifies a favipiravir dos- tion at such dosages. 19, 20 Favipiravir is
ty, clinical recovery rate at day 7 in pts with age of 1800 mg twice daily on day 1, associated with QT prolongation. 21
moderate COVID-19 pneumonia was 71% in then 1000 mg twice daily on days 2– Some have suggested close cardiac and
the favipiravir group vs 56% in the 14 7 hepatic monitoring during treatment, as
umifenovir group; clinical recovery rate in well as monitoring of plasma and tissue
those with severe to critical COVID-19 Protocol in one ongoing trial concentrations of the drug and, if possi-
pneumonia was 6% vs 0%, respectively. (NCT04373733; PIONEER) for early ble, the active metabolite. 19, 20, 21 Some
Twice as many pts in the favipiravir group treatment of suspected or confirmed data suggest that favipiravir exposure
had severe to critical disease compared COVID-19 specified a favipiravir dos- may be greater in Asian populations. 17,
with the group receiving umifenovir. 6 age of 1800 mg twice daily on day 1, 19
followed by 800 mg twice daily on

In a small, open-label, nonrandomized days 2–10 7 Early embryonic deaths and teratogen-
study in patients with non-severe COVID- icity observed in animal studies. Favipi-
19 in China (ChiCTR2000029600), favipi- Because high favipiravir concentra- ravir is contraindicated in women with
ravir (1600 mg orally twice daily on day 1, tions are required for in vitro activity known or suspected pregnancy and
then 600 mg orally twice daily on days 2– against SARS-CoV-2, 1, 5, 13 it has been precautions should be taken to avoid
14) (n=35) was associated with decreased suggested that high favipiravir dosag- pregnancy during treatment with the
median time to viral clearance (4 vs 11 es, like those used in the treatment drug. 14
days) and higher improvement rate on of Ebola virus disease, should be
chest CT imaging on day 14 (91 vs 62%) considered for the treatment of If favipiravir is used in pts receiving ac-
compared with the control group receiving COVID-19. 11, 19, 20 One such favipi- etaminophen, the maximum recom-
lopinavir/ritonavir (n=45); both groups also ravir regimen used in the treatment mended daily dosage of acetaminophen
received aerosolized interferon α-1b. 15 of Ebola virus disease includes a is 3 g. 17, 18
loading dosage of 6000 mg (doses of
US: Randomized, controlled open-label 2400 mg, 2400 mg, and 1200 mg
proof-of-concept trial (NCT04358549) of given 8 hours apart on day 1), then a
favipiravir for the treatment of COVID-19 7, maintenance dosage of 1200 mg
10
every 12 hours on days 2–10. 12, 13
US: Randomized, open-label trial For the treatment of COVID-19, one

(NCT04346628) to evaluate efficacy of pharmacokinetic simulation model
favipiravir in pts with mild, uncomplicated suggested that a dosage of 2400 mg
COVID-19 7 twice daily on day 1, followed by
1600 mg twice daily on days 2–10
Multiple clinical trials initiated in pts with should achieve adequate favipiravir
COVID-19 in China, Japan, and other coun- trough plasma concentrations and
tries to evaluate favipiravir alone or in may be more pharmacologically
conjunction with other antivirals or other relevant than lower dosages 19
agents (some listed below): 7-9
NCT04310228 Pharmacokinetic data are available
NCT04319900 from a study in critically ill pts with
NCT04333589 COVID-19 requiring mechanical
NCT04358549 ventilation who received a favipi-
NCT04373733 ravir dosage of 1600 mg twice daily
NCT04376814 on day 1, then 600 mg twice daily
ChiCTR2000030113 on days 2–5 (or longer if needed)
ChiCTR2000030894 via NG tube. Trough serum concen-
ChiCTR2000030987 trations of the drug in most samples
ChiCTR2000029996 were lower than the lower limit of
JapicCTI-205238 quantification and lower than the in
JPRN-jRCTs031190226 vitro EC50 of the drug reported for
JPRN-jRCTs041190120 SARS-CoV-2; trough concentrations
in these critically ill pts also were
much lower than those previously
reported in healthy individuals who
received the same dosage 22
HIV Protease 8:18.08.08 Lopinavir (LPV): In vitro Lopinavir and Ritonavir (LPV/RTV; Kalet- LPV/RTV (COVID-19): LPV 400 mg/ LPV/RTV: Efficacy for the treatment of
Inhibitors HIV Protease activity against SARS-CoV-2 ra®) randomized, open-label trial in China RTV 100 mg orally twice daily for 10- COVID-19, with or without other antivi-
Inhibitors in Vero E6 cells; 19 also has (Cao et al) in hospitalized adults with se- 14 days 3, 16, 24 rals, not definitely established
Updated in vitro activity against SARS vere COVID-19 compared LPV/RTV in con-
6/18/20 -CoV-1 and MERS-CoV; 1, 2, 9 junction with standard care (99 pts) vs LPV/RTV (COVID-19): LPV 400 mg/ Darunavir: No data to date to support
some evidence of benefit in standard care alone (100 pts). Primary end RTV 100 mg orally twice daily with use in the treatment of COVID-19. Man-
animal studies for treatment point was time to clinical improvement or without umifenovir (Arbidol® 200 ufacturer states they have no clinical or
of MERS-CoV 2, 7, 9, 11 (time from randomization to improvement mg every 8 hours) 6 pharmacologic evidence to support use
of two points on a seven-category ordinal of DRV/cobicistat for treatment of
Atazanavir (ATV): ATV scale or hospital discharge, whichever LPV/RTV (COVID-19): LPV 400 mg/ COVID-19 and initial unpublished results
alone or with ritonavir (ATV/ came first). In ITT population, time to clini- RTV 100 mg orally twice daily for no from a study in China indicated that a 5-
RTV) has in vitro activity cal improvement was not shorter with longer than 10 days 13 with or with- day regimen of DRV/cobicistat was not
against SARS-CoV-2 in Vero LPV/RTV compared with standard care out interferon (5 million units of effective for treatment of COVID-19 21
E6 cells, 17, 19 human epithe- (median time to clinical improvement 16 interferon-α or equivalent twice
lial pulmonary cells (A549), days in both groups); in modified ITT popu- daily given in 2 mL of sterile water Atazanavir, Nelfinavir, Saquinavir,
17
and human monocytes 17 lation, median time to clinical improve- by nebulization) and with or without Tipranavir: No data to date to support
ment 15 days in LPV/RTV group and 16 ribavirin for up to 10 days 5, 13 use in the treatment of COVID-19
Darunavir (DRV): In one days in standard care only group. The 28-
study, DRV with cobicistat day mortality rate was numerically lower in LPV/RTV (SARS): LPV 400 mg/RTV NIH COVID-19 Treatment Guidelines
had no in vitro activity LPV/RTV group (19.2% vs 25% in ITT 100 mg orally twice daily for 14 days Panel recommends against the use of
against SARS-CoV-2 at population; 16.7% vs 25% in modified ITT with ribavirin (4-g oral loading dose, LPV/RTV or other HIV protease inhibi-
clinically relevant concen- population). Some evidence that LPV/RTV then 1.2 g orally every 8 hours or 8 tors for the treatment of COVID-19,
trations in Caco-2 cells; 18 initiation within 12 days after symptom mg/kg IV every 8 hours) 1 except in the context of a clinical trial.
in another study, high DRV onset is associated with shorter time to The panel states that there are concerns
concentrations were re- clinical improvement. No significant differ- LPV/RTV (MERS): LPV 400 mg/RTV whether drug concentrations achieved
quired for in vitro inhibi- ences in reduction of viral RNA load, dura- 100 mg orally twice daily with ribavi- with oral doses of HIV protease inhibi-
tion of SARS-CoV-2 in Vero tion of viral RNA detectability, duration of rin (various regimens) and/or inter- tors are adequate to inhibit SARS-CoV-2
E6 cells 19 oxygen therapy, duration of hospitaliza- feron-α ; LPV 400 mg/RTV 100 mg and clinical trials using LPV/RTV have
tion, or time from randomization to death. orally twice daily with interferon β- not demonstrated a clinical benefit in
Nelfinavir (NFV), LPV/RTV stopped early in 13 pts because of 1b (0.25 mg/mL sub-Q on alternate patients with COVID-19. 22
Saquinavir (SQV), and adverse effects. 3 days) for 14 days 1, 4, 8
Tipranavir (TPV): In vitro IDSA recommends that LPV/RTV be
activity against SARS-CoV-2 LPV/RTV vs chloroquine in small, random- used for the treatment of COVID-19
in Vero E6 cells 19 ized study in hospitalized adults with only in the context of a clinical trial 23
COVID-19 in China (Huang et al): 10 pts (7
with moderate and 3 with severe disease)
received chloroquine (500 mg twice daily
for 10 days) and 12 pts (7 with moderate
and 5 with severe disease) received LPV/
RTV (lopinavir 400 mg/ritonavir 100 mg
twice daily for 10 days). All 10 pts treated
with chloroquine had negative RT-PCR re-
sults for SARS-CoV-2 by day 13 and were
discharged from the hospital by day 14;
11/12 pts (92%) treated with LPV/RTV were
negative for SARS-CoV-2 at day 14 and only
6/12 (50%) were discharged from the hos-
pital by day 14. Note: Results suggest that
chloroquine was associated with shorter
time to RT-PCR conversion and quicker
recovery than LPV/RTV; however, this
study included a limited number of pts and
the median time from onset of symptoms
to initiation of treatment was shorter in
those treated with chloroquine than in
those treated with LPV/RTV (2.5 vs 6.5
days, respectively). 24
LPV/RTV with ribavirin and interferon β-

1b vs LPV/RTV alone in open-label, ran-
domized trial in adults with mild to mod-
erate COVID-19 in Hong Kong (Hung et al;
NCT04276688): 127 pts were randomized
2:1 to receive LPV/RTV (LPV 400 mg/RTV
100 mg) twice daily for 14 days) with ribavi-
rin (400 mg twice daily) and interferon β-1b
(8 million IU sub-Q on alternate days for up
to 3 doses depending on how soon treat-
ment initiated after symptom onset) or a
14-day regimen of LPV/RTV alone. Median
time to negative RT-PCR results for SARS-
CoV-2 in nasopharyngeal samples was 7
days in pts treated with the 3-drug regimen
vs 12 days in those treated with LPV/RTV
alone; median duration of hospitalization
was 9 or 14.5 days, respectively. Adverse
effects reported in 48% of those treated
with the 3-drug regimen and in 49% of
those treated with LPV/RTV alone. Note:
Results indicate a 3-drug regimen that in-
cluded LPV/RTV, ribavirin, and interferon β-
1b was more effective than LPV/RTV alone
in pts with mild to moderate COVID-19,
especially when treatment was initiated
within 7 days of symptom onset. 25
LPV/RTV retrospective cohort study in

China (Deng et al) evaluated use of LPV/
RTV with or without umifenovir (Arbidol®)
in adults. Primary end point was negative
conversion in nasopharyngeal samples and
progression or improvement of pneumo-
nia. At 7 days, SARS-CoV-2 undetectable in
nasopharyngeal specimens in 6/17 pts
(35%) treated with LPV/RTV alone vs 12/16
(75%) treated with both drugs; chest CT
scans were improving in 29% of pts treated
with LPV/RTV alone vs 69% of pts treated
with both drugs. 6 (See Umifenovir in this
Evidence Table.)
LPV/RTV Clinical Experience (COVID-19):

Only limited data on LPV/RTV used with or
without interferon in pts with COVID-19
outside of clinical trials. 5, 12, 14. 16
LPV/RTV Clinical Experience (SARS and

MERS): Evidence of some clinical benefit
when used in conjunction with ribavirin
and/or interferon. 1, 8-11
LPV/RTV COVID-19 Clinical Trials: Multiple

trials registered at clinicaltrials.gov (some
listed below): 15
NCT04307693 (LPV/RTV vs hydroxychloro-
quine in pts with mild disease)
NCT04255017 (LPV/RTV vs umifenovir vs
oseltamivir)
quine vs placebo)
quine vs losartan vs placebo) 15
quine vs LPV/RTV plus hydroxychloroquine
vs placebo in pts with mild disease)
NCT04315948 (LPV/RTV plus interferon β-
1a vs LPV/RTV vs remdesivir [each regimen
given with standard care] vs standard care
NCT04425382 (LPV/RTV vs DRV/cobicistat)
Darunavir COVID-19 Clinical Trials:

A few trials registered at clinicaltrials.gov:15
NCT04252274 (Open-label randomized trial
to evaluate DRV/cobicistat)
NTC04303299 (Open-label randomized trial
includes treatment arms to evaluate DRV/
RTV in conjunction with chloroquine or
oseltamivir)
NCT04425382 (DRV/cobicistat vs LPV/RTV)
Hydroxychlo- 8:30.08 In vitro activity against Only limited clinical trial data available to Optimal dosage and duration of Efficacy and safety of hydroxychloro-
roquine Antimalarial various viruses, including date to evaluate use of hydroxychloroquine treatment not known 26 quine for treatment or prevention of
(Plaquenil®) coronaviruses 5, 8. 12-14 for treatment or prevention of COVID-19 COVID-19 not established 10, 24, 39
(4- Oral hydroxychloroquine sulfate
Updated aminoquino- In vitro activity against Clinical experience in treating pts with dosage suggested in the EUA (now No data to date indicating that in vitro
6/16/20 line deriva- SARS-CoV-2 in infected COVID-19: Majority of data to date involves revoked): For treatment of hospital- activity against SARS-CoV-2 corresponds
tive) Vero E6 cells reported; use in pts with mild or moderate COVID-19; ized adults and adolescents weighing with clinical efficacy for treatment or
7, 18, 31, 35, 47, 49
may be more potent than only limited clinical data on 50 kg or more when a clinical trial is prevention of COVID-19
chloroquine in vitro, but use in pts with severe and critical disease.35 not available or participation not
some data are conflicting feasible, suggested dosage was 800 Data from randomized, controlled clini-
and additional study need- Hydroxychloroquine small pilot study con- mg on day 1, then 400 mg daily for 4- cal trials needed to substantiate initial
ed 8, 12 ducted in China: 15 treatment-naive pts 7 days of total treatment based on reports of efficacy of 4-aminoquinoline
received hydroxychloroquine sulfate (400 clinical evaluation. 26 FDA now states antimalarials for treatment of COVID-
Has immunomodulatory mg daily for 5 days) with conventional that this dosage is unlikely to have an 19, guide decisions regarding the most
activity that theoretically treatments and 15 pts received convention- antiviral effect in pts with COVID-19 appropriate pts for treatment with such
could contribute to an anti- al treatments alone; 18 both groups re- based on a reassessment of in vitro drugs, and identify optimal dose and
inflammatory response in ceived interferon and most pts also re- EC50/EC90 data and calculated lung treatment duration
patients with viral infec- ceived umifenovir (Arbidol®) or LPV/RTV. concentrations; it is unclear whether
tions 3, 8, 13, 15, 16 30
Primary end point was conversion to this dosage would provide any bene- Additional data needed from random-
negative PCR in pharyngeal swabs on day 7. ficial immunomodulatory effects. 57 ized, controlled clinical trials before any
Known pharmacokinetics Negative PCR reported at day 7 in 13 pts conclusions can be made regarding
and toxicity profile based (86.7%) treated with hydroxychloroquine possible benefits and safety of using
on use for other indica- and 14 pts (93.3%) not treated with the Oral hydroxychloroquine sulfate hydroxychloroquine with azithromycin.
tions 13 drug (data unclear for 3 pts); median dura- dosage used or being investigated in (See Azithromycin in this Evidence Ta-
tion from hospitalization to negative con- clinical trials: 400 mg once or twice ble.)
Hydroxyl analog of chloro- version and to temperature normalization daily for 5-10 days 10, 18
quine with similar mecha- were similar in both groups; evidence of Additional data needed regarding toxici-
nisms of action and ad- radiologic progression on CT in 5 pts treat- Oral hydroxychloroquine sulfate ty profile when used in patients with
verse effects; 13, 14 may ed with the drug and 7 pts not treated with with azithromycin (NIAID trial COVID-19
have more favorable dose- the drug (all pts showed improvement at A5395; NCT04358068): 400 mg twice
related toxicity profile than follow-up). 18 daily on day 1, then 200 mg twice NIH COVID-19 Treatment Guidelines
chloroquine, 13-16 but cardi- daily for 6 days) with azithromycin Panel recommends against use of hy-
otoxicity (e.g., prolonged Hydroxychloroquine randomized, parallel- (500 mg on day 1, then 250 mg once droxychloroquine for the treatment of
QT interval) is a concern group study in adults in China daily for 4 days) 10, 48 COVID-19, except in a clinical trial. 35
with both drugs 13, 35 (ChiCTR2000029559): 31 pts with COVID-
19 and pneumonia received hydroxychloro- Oral hydroxychloroquine sulfate IDSA recommends that hydroxychloro-
quine sulfate (200 mg twice daily for 5 with azithromycin (France): 200 mg quine be used for the treatment of
days) and standard treatment (O2, antiviral COVID-19 in the context of a clinical
trial. 38
agents, antibacterial agents, immuno- 3 times daily for 10 days with or
globulin, with or without corticosteroids) without azithromycin (500 mg on day NIH COVID-19 Treatment Guidelines
and 31 other pts received standard treat- 1, then 250 mg once daily on days 2- Panel recommends against the use of a
ment alone (control group). Exclusion 5) 7, 34, 47 combined regimen of hydroxychloro-
criteria included severe and critical illness. quine and azithromycin for the treat-
Pts assessed at baseline and 5 days after ment of COVID-19, except in the context
treatment initiation for time to clinical re- of a clinical trial, because of the poten-
covery (TTCR; defined as normalization of tial for toxicities. 35
fever and cough relief maintained for >72
hours), clinical characteristics, and changes IDSA recommends that a combined
on chest CT. It was concluded that hy- regimen of hydroxychloroquine and
droxychloroquine was associated with azithromycin be used for the treatment
symptom relief since time to fever normali- of COVID-19 only in the context of a
zation was shorter in hydroxychloroquine clinical trial. 38
group (2.2 days) vs control group (3.2
days), time to cough remission was shorter NIH COVID-19 Treatment Guidelines
in hydroxychloroquine group, and pneumo- Panel does not recommend the use of
nia improved in 25/31 pts (80.6%) in hy- any agents, including hydroxychloro-
droxychloroquine group vs 17/31 pts quine, for preexposure prophylaxis
(54.8%) in control group. Total of 4 pts (PrEP) or postexposure prophylaxis
progressed to severe illness (all in the con- (PEP) for prevention of SARS-CoV-2
trol group). 31 Note: This study did not infection outside of clinical trials. 35 The
include pts with severe disease and pts panel states that, to date, no agent is
received other anti-infectives in addition to known to be effective for preventing
hydroxychloroquine. At study entry, 9 pts SARS-CoV-2 infection when given before
without fever and 9 pts without cough or after an exposure. 35
were included in hydroxychloroquine group Because 4-aminoquinolines
and 14 pts without fever and 16 pts with- (hydroxychloroquine, chloroquine) and
out cough were included in control group; azithromycin are independently associ-
unclear how these pts were addressed in ated with QT prolongation and because
TTCR calculations. Although initial regis- concomitant use of the drugs may fur-
tered study protocol specified 2 different ther increase the risk of QT prolonga-
hydroxychloroquine treatment groups and tion, caution is advised if considering
a placebo group (each with 100 pts) and use of hydroxychloroquine (with or
primary end points of time to negative without azithromycin) in pts with COVID
nucleic acid and T-cell recovery, 32 data -19, especially in outpatients who may
provided only for certain clinical symptoms not receive close monitoring and in
in 62 pts without severe disease and PCR those at risk for QT prolongation or
results not reported. 31 receiving other drugs associated with
arrhythmias. 35, 36, 38, 39, 41-44
Hydroxychloroquine randomized, parallel-
group, open-label study in hospitalized NIH panel states that 4-aminoquinolines
adults with mild to moderate COVID-19 in (hydroxychloroquine, chloroquine)
China (ChiCTR2000029868): 150 pts (148 should be used concomitantly with
with mild to moderate disease and 2 with drugs that pose a moderate to high risk
severe disease) were randomized 1:1 to for QTc prolongation (e.g., antiarrhyth-
receive hydroxychloroquine (1200 mg daily mics, antipsychotics, antifungals, fluoro-
for 3 days, then 800 mg daily for total treat- quinolones, macrolides [including
ment duration of 2-3 weeks) with standard azithromycin]) only if necessary. In addi-
of care or standard of care alone. Mean tion, because of the long half-lives of
time from onset of symptoms to randomi- both hydroxychloroquine (up to 40
zation was 16.6 days (range: 3-41 days). days) and azithromycin (up to 72
hours),
Standard of care included IV fluids, O2, vari- caution is warranted even when these
ous antivirals (e.g., umifenovir, LPV/RTV), drugs are used sequentially. The panel
antibiotics, and/or glucocorticoid therapy. states that use of doxycycline (instead
By day 28, 73% of pts (53 treated with hy- of azithromycin) should be considered
droxychloroquine with standard of care for empiric therapy of atypical pneumo-
and 56 treated with standard of care alone) nia in COVID-19 pts receiving hy-
had converted to negative for SARS-CoV-2. droxychloroquine (or chloroquine). 35
The probability of negative conversion by
day 28 in those treated with hydroxychlo- The benefits and risks of hydroxychloro-
roquine was similar to that in those treated quine (with or without azithromycin)
with standard of care alone; the median should be carefully assessed; diagnostic
time to negative seroconversion (6 and 7 testing and monitoring are recommend-
days) also was similar in both groups. Ad- ed to minimize risk of adverse effects,
verse effects reported in 30% of those including drug-induced cardiac effects.
35, 36, 38, 39, 41-44
treated with hydroxychloroquine and 9% of
those treated with standard of care alone.
Note: Results indicate that use of hy- FDA issued a safety alert regarding ad-
droxychloroquine in pts with mild to mod- verse cardiac effects (e.g., prolonged QT
erate COVID-19 did not provide additional interval, ventricular tachycardia, ven-
benefits compared with use of standard of tricular fibrillation) reported with use of
care alone. 49 chloroquine or hydroxychloroquine
(either alone or in conjunction with
Hydroxychloroquine with azithromycin azithromycin or other drugs known to
open-label, nonrandomized study in prolong QT interval) in hospital and
France (Gautret et al): Preliminary data outpatient settings; FDA cautions
from an ongoing study in hospitalized pts against use of chloroquine or hy-
with confirmed COVID-19 was used to as- droxychloroquine outside of a clinical
sess efficacy of hydroxychloroquine used trial or hospital setting and urges
alone or with azithromycin; untreated pts healthcare professionals and pts to
were used as a negative control. The prima- report adverse effects involving these
ry end point was negative PCR results in drugs to FDA MedWatch. 39
nasopharyngeal samples at day 6. Data
from 14 pts treated with hydroxychloro- Emergency use authorization (EUA) for
quine sulfate (200 mg 3 times daily for 10 hydroxychloroquine (now revoked):
days), 6 pts treated with hydroxychloro- Effective June 15, 2020, FDA has re-
quine and azithromycin (500 mg on day 1, voked the EUA for hydroxychloroquine
then 250 mg daily on days 2-5), and 16 pts and chloroquine 57 previously issued on
in the control group were analyzed. At day March 28, 2020 that permitted distribu-
6, 8/14 (57%) in the hydroxychloroquine tion of the drugs from the strategic
group, 6/6 (100%) in the hydroxychloro- national stockpile (SNS) for use in adults
quine and azithromycin group, and 2/16 and adolescents weighing 50 kg or more
(12.5%) in the control group had negative hospitalized with COVID-19 for whom a
PCR results. At day 8, a positive PCR was clinical trial was not available or partici-
reported in a pt treated with both drugs pation not feasible. 24, 57 Based on a
who had tested negative at day 6.7 Note: review of new information and reeval-
This was a small nonrandomized study that uation of information available at the
didn’t appear to be designed to compare time the EUA was issued, FDA conclud-
hydroxychloroquine vs hydroxychloroquine ed that the original criteria for issuance
and azithromycin (pts received antibiotics of the EUA for these drugs are no long-
to prevent bacterial superinfection based er met. Based on the totality of scien-
on clinical judgment). Data on disease se- tific evidence available, FDA concluded
verity were unclear (some asymptomatic that it is unlikely that hydroxychloro-
quine and chloroquine may be effective
pts were included when study initiated) in treating COVID-19 and, in light of
and information on disease progression ongoing reports of serious cardiac ad-
and clinical outcomes was not presented. verse events and several newly report-
ed cases of methemoglobinemia in
Hydroxychloroquine with azithromycin COVID-19 patients, the known and po-
open-label, uncontrolled study in France tential benefits of hydroxychloroquine
(Molina et al): 11 adults hospitalized with and chloroquine do not outweigh the
COVID-19 received hydroxychloroquine known and potential risks associated
(600 mg daily for 10 days) and azithromycin with the use authorized by the EUA. 57
(500 mg on day 1, then 250 mg daily on
days 2-5). At time of treatment initiation, The basis for the FDA decision to re-
8/11 pts had significant comorbidities asso- voke the EUA for hydroxychloroquine
ciated with poor outcomes and 10/11 had and chloroquine is summarized below:
fever and received O2. Within 5 days, 1 pt
died and 2 transferred to ICU; the regimen 1) Suggested hydroxychloroquine and
was discontinued in 1 pt after 4 days be- chloroquine dosage regimens as de-
cause of prolonged QT interval. Nasopha- tailed in the EUA fact sheets for
ryngeal samples were still PCR positive at healthcare providers are unlikely to
days 5 and 6 in 8/10 pts tested. 33 Note: In produce an antiviral effect. 57
this small uncontrolled study, hydroxychlo-
roquine and azithromycin regimen did not 2) Earlier observations of decreased
result in rapid viral clearance or provide viral shedding with hydroxychloroquine
clinical benefit. or chloroquine treatment have not been
consistently replicated and recent data
Hydroxychloroquine with azithromycin from a randomized controlled trial as-
uncontrolled, retrospective, observational sessing probability of negative conver-
study in France (Gautret et al): 80 adults sion showed no difference between
with confirmed COVID-19 (including 6 pts hydroxychloroquine and standard of
included in a previous study by the same care alone. 57
group) were treated with hydroxychloro-
quine sulfate (200 mg 3 times daily for 10 3) Current US treatment guidelines do
days) and azithromycin (500 mg on day 1, not recommend the use of chloroquine
then 250 mg daily on days 2-5). Majority or hydroxychloroquine in hospitalized
(92%) were considered low risk for clinical patients with COVID-19 outside of a
deterioration (low national early warning clinical trial and the NIH guidelines now
score for COVID-19 based on age, respira- recommend against such use outside of
tory rate, O2 saturation, temperature, BP, a clinical trial. 57
pulse, level of consciousness); only 15%
had fever; 4 pts were asymptomatic carri- 4) Recent data from a large, random-
ers; mean time from onset of symptoms to ized, controlled trial showed no evi-
treatment initiation was 4.9 days. Clinical dence of benefit in mortality or other
outcome, contagiousness as assessed by outcomes such as hospital length of stay
nasopharyngeal PCR assay and culture, and or need for mechanical ventilation for
length of stay in infectious disease (ID) unit hydroxychloroquine treatment in hospi-
were evaluated in pts who were treated for talized patients with COVID-19. 57
at least 3 days and followed for at least 6
days. Favorable outcome was reported for Consult the FDA letter regarding the
81.3%; 15% required O2; 3 pts transferred revocation of the EUA for hydroxychlo-
to ICU; 1 pt died; mean time to discharge roquine and chloroquine and the FDA
from ID unit was 4.1 days. At day 8, PCR memorandum explaining the basis for
results were negative in 93% of those test- the revocation for additional infor-
ed; at day 5, viral cultures were negative in mation. 57
34
97.5% of those tested. Note: Almost all
pts were considered low risk for clinical
deterioration (including 4 pts described as
asymptomatic carriers) and it is unclear
how many would have had spontaneous
conversion to negative nasopharyngeal
samples during same time frame. Although
80 pts were enrolled, PCR results available
for fewer pts beginning on day 3 and only
60 pts represented in day 6 data. This was
an uncontrolled study and data presented
cannot be used to determine whether a
regimen of hydroxychloroquine with
azithromycin provides benefits in terms of
disease progression or decreased infec-
tiousness, especially for pts with more se-
vere disease.
Hydroxychloroquine with azithromycin

uncontrolled, observational, retrospective
analysis in France (Million et al): Data for
1061 pts with PCR-documented SARS-CoV-
2 RNA who were treated with a regimen of
hydroxychloroquine sulfate (200 mg 3
times daily for 10 days) and azithromycin
(500 mg on day 1, then 250 mg daily on
days 2-5) were analyzed for clinical out-
comes and persistence of viral shedding.
Pts were included in the analysis if they
received the combined regimen for at least
3 days and were clinically assessable at day
9. There were 56 asymptomatic and 1005
symptomatic pts; the majority (95%) had
relatively mild disease and were considered
low risk for clinical deterioration; median
age was 43.6 years (range: 14-95 years) and
mean time between onset of symptoms
and initiation of treatment was 6.4 days.
Within 10 days of treatment, good clinical
outcome reported in 973 pts (91.7%) and
poor clinical outcome reported in 46 pts
(4.3%). Persistent nasal carriage of SARS-
CoV-2 reported at completion of treatment
in 47 pts (4.4%); 8 pts died.47
Hydroxychloroquine (with or without

azithromycin) in a retrospective analysis of
patients hospitalized with COVID-19 in US
Veterans Health Administration medical
centers (Magagnoli et al): Data for 368
males (median age >65 years) treated with
hydroxychloroquine in addition to standard
supportive management were analyzed for

death rate and need for mechanical ventila-
tion. Death rate was 27.8% (27/97) in those
treated with hydroxychloroquine, 22.1%
(25/113) in those treated with hydroxychlo-
roquine and azithromycin, and 11.4%
(18/158) in those not treated with hy-
droxychloroquine; rate of ventilation was
13.3, 6.9, and 14.1%, respectively. Use of
hydroxychloroquine alone (but not use of
hydroxychloroquine and azithromycin) was
associated with increased overall mortality
compared with no hydroxychloroquine; use
of hydroxychloroquine with or without
azithromycin did not reduce the risk of
mechanical ventilation. 40 Note: The pt
population included only elderly males 59-
75 years of age, many with significant
comorbidities. This analysis did not look at
efficacy measures.
Two different retrospective studies ana-

lyzed outcome data for hospitalized pts
with confirmed COVID-19 in New York to
assess the effects of treatment with hy-
droxychloroquine with or without azithro-
mycin (Rosenberg et al, Geleris et al):
Results of these studies suggest that use of
hydroxychloroquine with or without
azithromycin is not associated with de-
creased in-hospital mortality. 45, 46
Rosenberg et al analyzed data for 1438 pts

(735 received hydroxychloroquine with
azithromycin, 271 received hydroxychloro-
quine alone, 211 received azithromycin
alone, 221 received neither drug) and as-
sessed in-hospital mortality (primary out-
come). Overall, in-hospital mortality was
20.3%; in-hospital mortality was 25.7, 19.9,
10, or 12.7% in those treated with hy-
droxychloroquine with azithromycin, hy-
droxychloroquine alone, azithromycin
alone, or neither drug, respectively. 45
Geleris et al analyzed data for 1376 pts

(811 received hydroxychloroquine [486 of
these also received azithromycin] and 565
did not receive hydroxychloroquine [127 of
these received azithromycin]) and assessed
the primary end point of time from study
baseline to intubation or death. Overall,
346 pts (25.1%) progressed to a primary
end point of intubation and/or death and
the composite end point of intubation or
death was not affected by hydroxychloro-
quine treatment (intubation or death re-
ported in 32.3% of pts treated with hy-
droxychloroquine and 14.9% of pts not
treated with the drug). 46
Large, randomized, controlled, adaptive

trial evaluating efficacy of 6 different
treatments for prevention of death in
hospitalized pts with COVID-19 compared
with usual care alone (NCT04381936; RE-
COVERY): Study protocol included a treat-
ment arm to evaluate efficacy of hy-
droxychloroquine sulfate (two 800-mg
doses given 6 hours apart followed by two
400-mg doses given 12 and 24 hours after
the initial dose on day 1, then 400 mg every
12 hours thereafter for 9 days). 53, 54 The
investigators announced preliminary re-
sults for the hydroxychloroquine treat-
ment arm. A total of 1542 pts were ran-
domized to receive hydroxychloroquine
with usual care and 3132 pts were random-
ized to usual care alone. Data for these pts
indicate that hydroxychloroquine did not
provide a significant difference in the pri-
mary end point of 28-day mortality (25.7%
in those treated with hydroxychloroquine
with usual care compared with 23.5% in
those treated with usual care alone). In
addition, there was no evidence of benefi-
cial effects on duration of hospitalization or
other outcomes. 53 Note: Data regarding pt
demographics and clinical characteristics
(e.g., age, disease severity, comorbidities)
and time from diagnosis to study enroll-
ment have not been provided to date.
Large, multinational, retrospective study

analyzed outcome data for hospitalized
pts with confirmed COVID-19 to assess the
effects of hydroxychloroquine or chloro-
quine used with or without a macrolide
(Mehra et al; now retracted): Original
publication included data obtained world-
wide for 96,032 pts hospitalized with
COVID-19 between Dec 20, 2019 and Apr
14, 2020, including 14,888 pts who re-
ceived chloroquine or hydroxychloroquine
with or without a macrolide (azithromycin
or clarithromycin) initiated within 48 hours
of diagnosis (treatment group) and 81,144
pts who did not receive these drugs
(control group). Based on those data, in-
hospital mortality rate in the control group
was 9.3% compared with 18% in those
treated with hydroxychloroquine alone
(n=3016), 23.8% in those treated with hy-
droxychloroquine and a macrolide
(n=6221), 16.4% in those treated with chlo-
roquine alone (n=1868), and 22.2% in those
treated with chloroquine and a macrolide
(n=3783). 50 Note: This published study has
now been retracted by the publisher at
the request of 3 of the original authors. 52
Concerns were raised with respect to the
veracity of the data and analyses conduct-
ed by a global healthcare data collabora-
tive. 51, 52
Hydroxychloroquine for postexposure

prophylaxis of COVID-19 randomized,
placebo-controlled trial in the US and Can-
ada (NCT04308668): Asymptomatic adults
with occupational or household exposure
to an individual with COVID-19 were ran-
domly assigned 1:1 to receive postexposure
prophylaxis with a 5-day regimen of hy-
droxychloroquine sulfate (initial 800-mg
dose followed by a 600-mg dose given 6-8
hours after first dose on day 1, then 600 mg
once daily for 4 additional days) or placebo
(folate tablets). A total of 821 asympto-
matic adults were enrolled within 4 days
after COVID-19 exposure (414 randomized
to hydroxychloroquine and 407 random-
ized to placebo); 66% were healthcare
workers. Overall, 88% of participants re-
ported high-risk exposures (occurred at a
distance of <6 feet for >10 minutes while
not wearing a face mask or eye shield) and
the others reported moderate-risk expo-
sures (occurred at a distance of <6 feet for
>10 minutes while wearing a face mask but
no eye shield). Note: Participants were
recruited primarily through social media
outreach and traditional media platforms
and were enrolled using an internet-based
survey. The exposure event and subse-
quent onset of new symptoms and illness
compatible with COVID-19 after
enrollment were self-reported using email
surveys on days 1, 5, 10, and 14 and at 4-6
weeks. Results of these surveys and infor-
mation obtained using additional forms of
follow-up indicated that confirmed or prob-
able COVID-19 (based on self-reported
symptoms or PCR testing) developed in
13% of participants overall (107/821) and
did not differ significantly between those
who received hydroxychloroquine prophy-
laxis (11.8%) and those who received place-
bo (14.3%). 55 Note: The various limita-
tions of the trial design should be consid-
ered when interpreting the results. Expo-
sure to someone with confirmed COVID-19,
time from the exposure event to initiation
of prophylaxis, and all outcome data
(including possible COVID-19 symptoms
and PCR test results) were self-reported by
study participants. COVID-19 was con-
firmed with PCR testing in only a small per-
centage (<3%) of participants who self-
reported COVID-19 symptoms. Survey re-
sults indicated that full adherence to the 5-
day prophylaxis regimen was reported by
only 75% of patients randomized to hy-
droxychloroquine and 83% of those ran-
domized to placebo. In addition, a total of
52 participants did not complete any sur-
veys after study enrollment. 55, 56
Efficacy measures: Initial studies evalu-

ating hydroxychloroquine based efficacy of
the drug on negative conversion in naso-
pharyngeal samples at day 6 or 7. 7, 18 RT-
PCR tests using upper and lower respiratory
specimens (including nasopharyngeal and
oropharyngeal swabs) are recommended
for diagnosis of COVID-19; 19, 21 however,
dynamics of SARS-Cov-2 in infected pa-
tients (untreated or treated) and presence
of the virus at various body sites over the
course of infection have not been fully
determined. 22, 23
Hydroxychloroquine with azithromycin

randomized, double-blind, placebo-
controlled trial sponsored by NIAID
(A5395; NCT04358068): Symptomatic
adults with COVID-19 not currently requir-
ing hospitalization will be randomized to
receive hydroxychloroquine (400 mg twice
daily on day 1, then 200 mg twice daily for

6 days) and azithromycin (500 mg on day 1,
then 250 mg once daily for 4 days) or place-
bo and followed for 23 weeks to determine
whether the combined regimen will pre-
vent hospitalization and death. 10, 48
Multiple clinical trials to evaluate hy-

droxychloroquine for treatment of COVID-
19 are registered at clinicaltrials.gov (some
listed below): 10
NCT04329923
NCT04332991
NCT04334967
NCT04335552
NCT04341727
NCT04345692
NCT04350450
NCT04351620
NCT04353037
NCT04362332
Multiple clinical trials to evaluate hy-

droxychloroquine for prevention of COVID-
19 in the healthcare setting or in household
contacts of pts with the disease are regis-
tered at clinicaltrials.gov (some listed be-
low): 10
NCT04318015
NCT04318444
NCT04328961
NCT04331834
NCT04334148
NCT04341441
NCT04363450
NCT04372017
Neuramini- 8:18.28 Antivirals active against In a retrospective case series of 99 patients Dosage of oseltamivir in the case No data to date support use in the
dase inhibi- influenza viruses with COVID-19 at single center in Wuhan series of 99 patients was 75 mg oral- treatment of COVID-19
tors (e.g., from 1/1/20 to 1/20/20, 76% of patients ly every 12 hours. 1
oseltamivir) received antiviral treatment, including osel-
tamivir (75 mg orally every 12 hours). At Dosages of oseltamivir from regis-
Updated the time of evaluation, 58% of patients tered trials (either recruiting, or not
5/8/20 remained hospitalized, 31% had been dis- yet recruiting) vary, but include 300
charged, and 11% had died. 1 mg orally daily, 75 mg orally once or
twice daily, and 4–6 mg/kg orally
While oseltamivir is noted to have been (frequency not specified). 5
widely used for confirmed or suspected
COVID-19 cases in hospitals in China, there
has been no exact evidence to date that
oseltamivir is effective in the treatment of
COVID-19. 2
Neither oseltamivir nor zanamivir has

demonstrated inhibition of cytopathic
effect against SARS-CoV in in vitro cell cul-
ture. 4
Clinicaltrials.gov trials for COVID-19 that

include oseltamivir5:
NCT04303299
NCT04261270
NCT04255017
NCT04338698
Remdesivir 8:18.32 Broad-spectrum antiviral Various clinical trials initiated in US, China, Optimal dosage and duration of Not commercially available; most prom-
Antiviral (nucleotide analog pro- and other countries treatment not known 25, 26 ising direct-acting antiviral (DAA) cur-
Updated drug) with activity against rently being investigated for COVID-19
6/18/20 various viruses, including Randomized, double-blind, placebo- Emergency use authorization (EUA)
coronaviruses 24 controlled trial in hospitalized adults with dosage recommended for adults Efficacy and safety of remdesivir for
severe COVID-19 in China (NCT04257656; and children weighing 40 kg or treatment of COVID-19 not established
In vitro evidence of activity Wang et al): Pts were randomized 2:1 to more: Loading dose of 200 mg by IV
against SARS-CoV-2 in Vero receive remdesivir (200 mg IV on day 1, infusion on day 1, followed by FDA warns that concomitant use of
E6 cells 1, 18 then 100 mg IV once daily on days 2-10) or maintenance doses of 100 mg by IV remdesivir and chloroquine or hy-
placebo initiated within 12 days of symp- infusion once daily from day 2. Opti- droxychloroquine is not recommended;
26,33
In Rhesus macaques infect- tom onset. Primary outcome was time to mal duration of treatment not there is in vitro evidence that chlo-
ed with SARS-CoV-2, treat- clinical improvement within 28 days after known. For pts requiring invasive roquine antagonizes intracellular meta-
ment with a 6-day regimen randomization or hospital discharge, which- mechanical ventilation and/or bolic activation and antiviral activity of
of IV remdesivir initiated ever came first. ITT population included ECMO, recommended total treat- remdesivir. 26
12 hours after virus inocu- 158 pts treated with remdesivir and 78 pts ment duration is 10 days. For those
lation was associated with treated with placebo; 32% of pts also re- not requiring invasive mechanical NIH COVID-19 Treatment Guidelines
some benefits (lower dis- ceived interferon α-2b, 28% also received ventilation and/or ECMO, recom- Panel recommends use of remdesivir for
ease severity scores, fewer LPV/RTV, and 66% also received cortico- mended total treatment duration is the treatment of severe COVID-19 in
pulmonary infiltrates, low- steroids during hospitalization. Median 5 days; if pt does not demonstrate hospitalized patients who have oxygen
er virus titers in bron- time to clinical improvement was not sig- clinical improvement, treatment may saturation (SpO2) of 94% or lower on
choalveolar lavage sam- nificantly different in remdesivir group (21 be extended for up to 5 additional room air, require supplemental oxygen,
ples) compared with vehi- days) vs placebo group (23 days); 28-day days (i.e., up to a total treatment or are on mechanical ventilation or
cle control; remdesivir mortality rate was similar in both groups duration of 10 days). 26 ECMO. The panel recommends a 5-day
treatment did not reduce (14 vs 13%). When remdesivir was initiat- remdesivir regimen in hospitalized pa-
viral loads or infectious ed within 10 days of symptom onset, medi- Emergency use authorization (EUA) tients with severe COVID-19 who are
virus titers in nose, throat, an time to clinical improvement was nu- dosage recommended for children not intubated. The panel states that
or rectal swabs compared merically shorter (but not statistically sig- weighing 3.5 to less than 40 kg data are insufficient regarding optimal
with vehicle control 19 nificant) compared with placebo group (18 (using the lyophilized powder for- duration of remdesivir treatment for
vs 23 days). Duration of invasive mechani- mulation only): Loading dose of 5 patients on mechanical ventilation or
In vitro activity against cal ventilation was numerically shorter (but mg/kg by IV infusion on day 1, fol- ECMO or for those without adequate
SARS-CoV and MERS-CoV; not statistically significant) in remdesivir lowed by maintenance doses of 2.5 improvement after a 5-day remdesivir
active in animal models of group; only a small percentage of pts mg/kg by IV infusion once daily from regimen; the panel states that some
SARS and MERS; prevented (0.4%) were on invasive mechanical ventila- day 2. Optimal duration of treatment experts extend the duration of
MERS in Rhesus macaques tion at time of enrollment. Remdesivir did not known. For pts requiring invasive remdesivir treatment up to 10 days in
when given before infec- not result in significant reduction in SARS- mechanical ventilation and/or such patients. 20
tion and provided benefits CoV-2 viral load in nasopharyngeal, oropha- ECMO, recommended total treat-
when given after animal ryngeal, and sputum samples. Remdesivir ment duration is 10 days. For those NIH panel states that data are insuffi-
already infected 1-8 was discontinued in 18 pts (12%) because not requiring invasive mechanical cient to recommend for or against use
of adverse effects. Note: Enrollment was ventilation and/or ECMO, recom- of remdesivir for the treatment of mild
Pharmacokinetic data terminated before the pre-specified num- mended total treatment duration is or moderate COVID-19. 20
available from evaluations ber of pts was attained (lack of available 5 days; if pt does not demonstrate
for Ebola
pts); trial was insufficiently powered to clinical improvement, treatment may Emergency use authorization (EUA) for
detect assumed differences in clinical out- be extended for up to 5 additional remdesivir: FDA issued an EUA on May
come. 21 days (i.e., up to a total treatment 1, 2020 that permits use of the drug for
duration of 10 days). 26 the treatment of COVID-19 only in hos-
Phase 3 randomized, open-label trial in pitalized adults and children with sus-
hospitalized pts with severe COVID-19 Phase 3 trial in adults and children pected or laboratory-confirmed COVID-
(NCT04292899; GS-US-540-5773; SIMPLE- ≥12 years of age with severe COVID- 19 who have severe disease (defined as
Severe) sponsored by the manufacturer 19 (NCT04292899; SIMPLE-Severe): oxygen saturation [SpO2] 94% or lower
(Gilead): Initial study protocol was designed 200 mg IV on day 1, then 100 mg IV on room air or requiring supplemental
to evaluate safety and antiviral activity of 5- daily on days 2-5 (arm 1) or 200 mg oxygen, mechanical ventilation, or
and 10-day regimens of remdesivir (200 mg IV on day 1, then 100 mg IV daily on ECMO) and requires that the drug be
IV on day 1, followed by 100 mg IV once days 2-10 (arm 2); 10 200 mg IV on administered by a healthcare provider
daily for total of 5 or 10 days) in conjunc- day 1, then 100 mg IV daily on days 2 in an inpatient hospital setting via IV
tion with standard of care in adults with -10 (extension arms that include pts infusion at dosages recommended in
severe COVID-19 not receiving mechanical who are or are not receiving me- the EUA. 25, 26 Distribution of remdesivir
ventilation at study entry; 10 protocol was chanical ventilation) 10 under this EUA is controlled by the US
subsequently modified to include pts 12 government for use consistent with the
years of age or older, add an extension Phase 3 trial in adults and children terms and conditions of the EUA. 25 The
phase, and include a cohort of pts receiving ≥12 years of age with moderate manufacturer (Gilead) donated
mechanical ventilation. 10, 23 Data for the COVID-19 (NCT04292730; SIMPLE- remdesivir for use under the EUA; distri-
initial 397 pts not requiring mechanical Moderate): 200 mg IV on day 1, bution to hospitals and other healthcare
ventilation at study entry (200 received a 5 then 100 mg IV daily on days 2-5 facilities is being directed by the HHS
-day regimen and 197 received a 10-day (arm 1) or 200 mg IV on day 1, then Office of the Assistant Secretary for
regimen) indicate similar clinical improve- 100 mg IV daily on days 2-10 (arm 2) Preparedness and Response (ASPR) in
11
ment with both treatment durations after collaboration with state health depart-
adjusting for baseline clinical status. Pt Phase 3 NIAID adaptive study in ments. To request remdesivir for use
demographics and clinical characteristics at adults (NCT04280705; ACTT-1): 200 under the EUA, healthcare providers
baseline generally were similar in both mg IV on day 1, then 100 mg IV daily should contact their state health de-
groups, although the 10-day group included for duration of hospitalization up to partments. 28 The EUA requires that
a higher percentage of pts in the most se- 10 days total 13 healthcare facilities and healthcare pro-
vere disease categories and a higher providers administering remdesivir comply
portion of men (who are known to have with certain mandatory record keeping
worse COVID-19 outcomes than women); and reporting requirements (including
median duration of symptoms before first adverse event reporting to FDA Med-
dose of remdesivir was similar in both Watch). 25, 26 Consult the EUA, 25 EUA
groups (8 or 9 days). At day 14, 129/200 pts fact sheet for healthcare providers, 26
(65%) in the 5-day group and 106/197 pts and EUA fact sheet for patients and
(54%) in the 10-day group achieved clinical parent/caregivers 27 for additional infor-
improvement (defined as an improvement mation.
of at least 2 points from baseline on a 7-
point ordinal scale). After adjusting for
baseline imbalances in disease severity,
data indicate that clinical status at day 14,
time to clinical improvement, recovery, and
death (from any cause) were similar in both
groups. Although eligibility criteria accord-
ing to the initial study protocol excluded
pts receiving invasive mechanical ventila-
tion, 4 pts in the 5-day group and 9 pts in
the 10-day group were receiving invasive
mechanical ventilation or ECMO (need
identified after initial screening and before
treatment initiation or pts were accepted

as protocol deviations). There also were
more pts in the 10-day group (30%) who
required high-flow oxygen support at base-
line compared with the 5-day group (24%).
Post-hoc analysis among pts receiving me-
chanical ventilation or ECMO at day 5 indi-
cate that, by day 14, 40% of such individu-
als who had received the 5-day regimen
had died compared with 17% of those who
had received the 10-day regimen. Treat-
ment with remdesivir beyond 5 days did
not appear to improve outcomes among
pts who were receiving noninvasive posi-
tive-pressure ventilation or high-flow oxy-
gen, low-flow oxygen, or breathing ambient
air. Note: Results for the initial 397 study
pts with severe COVID-19 not requiring
mechanical ventilation at study entry can-
not be extrapolated to critically ill pts re-
ceiving mechanical ventilation. 23
Phase 3 randomized, open-label trial in

hospitalized pts with moderate COVID-19
(NCT04292730; GS-US-540-5774; SIMPLE-
Moderate) sponsored by the manufactur-
er (Gilead): Initial protocol was designed to
evaluate safety and antiviral activity of 5-
and 10-day regimens of remdesivir (200 mg
IV on day 1, followed by 100 mg IV once
daily for total of 5 or 10 days) in conjunc-
tion with standard of care compared with
standard of care alone in adults with mod-
erate COVID-19 (i.e., hospitalized with
evidence of pulmonary infiltrates but with-
out reduced oxygen levels); 11 protocol was
subsequently modified to include pts 12
years of age or older and add an extension
phase to include additional pts. 11 Manu-
facturer announced preliminary data for
the initial group of pts who received a 5-
day regimen of remdesivir with standard of
care (n=191), 10-day regimen of the drug
with standard of care (n=194), or standard
of care alone (n=200). At day 11, data indi-
cate that 70, 65, or 61% of pts in the 5-day,
10-day, or standard of care alone group,
respectively, had clinical improvement
based on at least a 2-point improvement
from baseline on a 7-point ordinal scale.
When clinical improvement at day 11 was
based on at least a 1-point improvement,
data indicate a statistically significant im-

provement in clinical status in those treat-
ed with a 5-day regimen of remdesivir com-
pared with standard of care alone (76% of
pts in the 5-day group and 66% in the
standard of care alone group had clinical
improvement). Oxygen support of any kind
was required in 11% of pts treated with
standard of care alone compared with 6 or
7% of pts in the 5- or 10-day group, respec-
tively. Although the differences were not
statistically significant, at least a 1-point
worsening of clinical status was reported in
11% of pts treated with standard of care
alone compared with 3 or 6% of pts in the 5
- or 10-day group, respectively. There were
4 deaths reported in the standard of care
alone group compared with none in the 5-
day group and 2 in the 10-day group. 30
Note: Data regarding pt demographics and
clinical characteristics at study enrollment
(e.g., age, comorbidities, time to initiation
of treatment after symptom onset) and
information on any additional supportive
treatment received not provided to date.
Phase 3 adaptive, randomized, double-

blind, placebo-controlled trial
(NCT04280705; NIAID Adaptive COVID-19
Treatment Trial 1 [ACTT-1]) in hospitalized
adults with COVID-19: 1063 pts were ran-
domized 1:1 to receive remdesivir (200 mg
IV on day 1, then 100 mg IV once daily on
days 2-10 or until hospital discharge or
death) or placebo. 13, 22 All pts received
supportive care according to the standard
of care for the trial site hospital. Baseline
demographics and clinical characteristics
(e.g., age, disease severity, comorbidities at
study enrollment, time to initiation of
treatment after symptom onset) were simi-
lar in both groups. Overall, 88.7% of pts
had severe disease at study enrollment and
the median time from symptom onset to
randomization was 9 days (range: 6-13
days). Preliminary data analysis that includ-
ed 1059 pts (538 randomized to remdesivir
and 521 randomized to placebo) indicated
shorter median time to recovery in the
remdesivir group (11 days) vs the placebo
group (15 days) and suggested that
remdesivir treatment may have provided a
survival benefit (Kaplan-Meier estimates of

mortality by day 14 were 7.1% in the
remdesivir group vs 11.9% in the placebo
group). 22
Expanded access IND protocol

(NCT04323761): The manufacturer
(Gilead) established a protocol for emer-
gency access to remdesivir for the treat-
ment of severe acute COVID-19 in hospital-
ized adults and children 12 years of age or
older 17
Compassionate use access: The manufac-

turer (Gilead) has transitioned from individ-
ual compassionate use requests to expand-
ed access programs for emergency access
to the drug for the treatment of severe
COVID-19. The only individual compassion-
ate use requests for the drug still being
reviewed by the manufacturer are those
for pregnant women and children <18
years of age with confirmed COVID-19 and
severe manifestations of the disease. 15
(https://rdvcu.gilead.com/)
Compassionate use access (NCT04302766):

May be available for DoD personnel
through treatment IND protocol sponsored
by US Army Medical Research and Develop-
ment Command 12
Data from the manufacturer’s compas-

sionate use program: Preliminary data are
available for a cohort of 53 adults from
multiple sites in the US, Italy, Japan, and
other countries who were hospitalized with
severe COVID-19 and received treatment
with remdesivir; 40 pts received the full 10-
day regimen (200 mg IV on day 1, then 100
mg IV on days 2-10), 10 pts received 5-9
days and 3 pts received less than 5 days of
treatment with the drug. At baseline, 30
pts (57%) were receiving mechanical venti-
lation and 4 (18%) were receiving extracor-
poreal membrane oxygenation (ECMO).
Over a median follow-up of 18 days after
first dose, 36 pts (68%) showed clinical
improvement based on oxygen-support
status and 8 pts (15%) worsened. There
were 7 deaths (13%), including 6 pts receiv-
ing invasive ventilation. Adverse effects
(e.g., increased hepatic enzymes, diarrhea,
rash, renal impairment, hypotension) were
reported in 32 pts (60%); 12 pts (23%) had
serious adverse effects (e.g., multiple organ
dysfunction syndrome, septic shock, acute
kidney injury, hypotension); 4 pts (8%)
discontinued the drug because of adverse
effects. 16 Note: Data presented for this
small cohort of pts offers only limited infor-
mation regarding efficacy and safety of
remdesivir for treatment of COVID-19.
There was no control group and, although
supportive therapy could be provided at
the discretion of the clinician, it is unclear
whether pts at any of the various study
sites also received other therapeutic agents
being used for treatment of COVID-19. In
addition, data were not presented regard-
ing the effects of remdesivir on viral load.
Phase 3 adaptive, randomized, double-

blind trial to compare a regimen of
remdesivir alone vs a regimen of
remdesivir with baricitinib (NCT04401579;
ACTT2): This iteration of NIAID’s Adaptive
COVID-19 Treatment Trial (ACTT) is evalu-
ating possible benefits of using baricitinib
(a Janus kinase [JAK] inhibitor) in conjunc-
tion with remdesivir in hospitalized adults
with laboratory-confirmed SARS-CoV-2
infection and evidence of lung involvement
(abnormal chest x-rays, SpO2 of 94% or
lower on room air, or requiring supple-
mental oxygen, mechanical ventilation, or
ECMO). Pts will be randomized 1:1 to re-
ceive remdesivir (200 mg IV on day 1, then
100 mg IV once daily for the duration of
hospitalization up to 10 days total) with
either oral baricitinib (4 mg once daily for
the duration of hospitalization up to 14
days total) or placebo. 29, 31
Randomized, double-blind trial to com-

pare a regimen of remdesivir alone vs a
regimen of remdesivir with tocilizumab
(NCT04409262; REMDACTA): This trial will
evaluate possible benefits of using tocili-
zumab (an interleukin-6 [IL-6] inhibitor) in
conjunction with remdesivir in hospitalized
patients 12 years of age or older with se-
vere COVID-19 pneumonia. Pts will be ran-
domized to receive remdesivir (IV loading
dose on day 1, then once-daily IV mainte-

nance doses on days 2-10) with either tocil-
izumab (single IV infusion on day 1) or pla-
cebo. 32
Umifenovir 8:18.92 Broad-spectrum antiviral Retrospective cohort study in 50 adults Dosage recommended for treat- Not commercially available in the US
(Arbidol®) Antiviral with in vitro activity with COVID-19 in China suggests better ment of COVID-19 in China: Adults,
against various viruses, viral suppression with umifenovir vs LPV/ 200 mg orally 3 times daily for no Included in some guidelines for treat-
Updated including coronaviruses 4 RTV. All pts received conventional therapy, more than 10 days 5, 7 ment of COVID-19 7
5/8/20 including interferon α-2b. At 7 days after
Although data limited, in hospital admission, SARS-CoV-2 was unde- Dosage used or being investigated Efficacy for the treatment of COVID-19
vitro activity against SARS- tectable in 50% of pts treated with in COVID-19 clinical trials: 200 mg not established
CoV-1 4 and SARS-CoV-2 5 umifenovir vs 23.5% treated with LPV-RTV; orally 3 times daily for duration of 7-
reported at 14 days, viral load undetectable in all pts 10 days or longer 2, 3, 6, 8
treated with umifenovir vs 44.1% treated
Licensed in China, Russia, with LPV/RTV. Duration of positive SARS-
Ukraine, and possibly other CoV-2 RNA positive test was shorter with
countries for prophylaxis umifenovir vs LPV-RTV 8
and treatment of influenza
4
Retrospective cohort study in 33 adults
with COVID-19 in China suggests more fa-
vorable outcome with LPV/RTV plus
umifenovir vs LPV/RTV alone: Primary end
point was negative conversion in nasopha-
ryngeal samples and progression or im-
provement of pneumonia. At 7 days, SARS-
CoV-2 undetectable in nasopharyngeal
specimens in 12/16 pts (75%) treated with
LPV/RTV plus umifenovir vs 6/17 pts (35%)
treated with LPV/RTV alone; at 14 days,
undetectable in 15/16 pts (94%) treated
with both drugs vs 9/17 pts (53%) treated
with LPV/RTV alone. At 7 days, chest CT
scans were improving in 11/16 pts (69%)
treated with both drugs vs 5/17 pts (29%)
treated with LPV/RTV alone 1
Retrospective cohort study in 81 hospital-

ized, non-ICU adults with COVID-19 in Chi-
na found no difference in clearance of SARS
-CoV-2 virus between pts receiving
umifenovir vs those who did not. At 7 days,
SARS-CoV-2 undetectable in pharyngeal
specimens in 33/45 pts (73.3%) treated
with umifenovir vs 28/36 pts (77.8%) who
did not receive umifenovir. No difference in
median time from onset of symptoms to
negative SARS-CoV-2 test (18 vs 16 days) 9
Open-label, prospective, randomized,

multicenter study in 236 adults with
COVID-19 in China (ChiCTR200030254):
When favipiravir was compared with

umifenovir, clinical recovery rate was
greater in those treated with favipiravir
than in those treated with umifenovir. 6
(See Favipiravir in this Evidence Table.)
Randomized, single-center, partially blind-

ed trial in China (NCT0425885) evaluated
efficacy of umifenovir in conjunction with
standard care vs LPV/RTV in conjunction
with standard care vs standard care with-
out an antiviral in hospitalized adults with
mild/moderate COVID-19. 2, 10 Data for the
86 enrolled pts suggest no difference in
mean time for positive-to-negative conver-
sion of SARS-CoV-2 nucleic acid in respira-
tory specimens and no difference in clinical
outcomes between pts treated with
umifenovir or LPV/RTV compared with no
antiviral therapy 10
NCT04260594 (not yet recruiting): Random-

ized, open-label trial evaluating efficacy
and safety of umifenovir in conjunction
with standard of care in adults with COVID-
19 3
SUPPORTING AGENTS
Anakinra 92:36 Disease- Recombinant human inter- Currently no known published controlled Various dosage regimens are being Insufficient clinical data to recommend
modifying Anti leukin-1 (IL-1) receptor clinical trial evidence supporting efficacy or studied 3, 8 either for or against use in the treat-
Updated -rheumatic antagonist 1 safety of anakinra in treating COVID-19 7 ment of COVID-19 7
5/28/20 Drug Trial protocol in Italy (COVID-19 with
IL-1 levels are elevated in Encouraging preliminary results reported in hyperinflammation and respiratory Safety profile: Well established in
patients with COVID-19; China with another disease-modifying an- distress): 100 mg by IV infusion every adults with sepsis and has been studied
anakinra may potentially tirheumatic drug, tocilizumab 5, 6 6 hours (total of 400 mg daily) for 15 extensively in severely ill pediatric pa-
combat cytokine release days 3 tients with complications of rheumato-
syndrome (CRS) symptoms France: A small case series (9 patients) of logic conditions; pediatric data on use in
in severely ill COVID-19 open-label anakinra treatment in hospital- Some studies under way in Greece acute respiratory distress syndrome/
patients 2, 3, 4, 7 ized (non-ICU) adults with moderate to and Belgium are evaluating 100 mg sepsis are limited 7
severe COVID-19 pneumonia has been given subcutaneously once daily for
published with encouraging results 8 10 or 28 days, respectively, or until Pregnancy: Limited evidence to date:
hospital discharge 3 unintentional first trimester exposure
Italy: Phase 3 randomized, open-label, considered unlikely to be harmful 7
multicenter trial (NCT04324021) initiated In a French case series, anakinra was
by the manufacturer (Swedish Orphan given subcutaneously in a dosage of
Biovitrum) to evaluate efficacy and safety 100 mg every 12 hours on days 1-3,
of anakinra or emapalumab with standard then 100 mg once daily from day 4-
of care in reducing hyperinflammation and 10 8
respiratory distress in patients with COVID-
19 is recruiting 3 (Note: Anakinra is approved only for
subcutaneous administration in the
U.S.) 1, 7
Ascorbic acid 88:12 Vitamin Antioxidant and cofactor IV ascorbic acid: IV ascorbic acid: Current data not specific to COVID-
C for numerous physiologic Phase 3 randomized, blinded, placebo- Various dosages of IV ascorbic acid 19; additional study needed 6
Updated reactions; may support controlled trial (NCT03680274; LOVIT) eval- used in COVID-19 studies; 50 mg/kg
6/11/20 host defenses against in- uating effect of high-dose IV ascorbic acid IV every 6 hours for 4 days used in
fection and protect host on mortality and persistent organ dysfunc- NCT03680274 and NCT04401150 1
cells against infection- tion in septic ICU patients (including COVID-
induced 19 patients); other clinical trials of high- Various dosages of IV ascorbic acid
oxidative stress 3-5, 7 dose IV ascorbic acid for treatment of used in sepsis studies; 50 mg/kg eve-
COVID-19 registered, including: 1 ry 6 hours for 4 days used in CITRIS-
Presence of infection may NCT04264533 ALI study; 1.5 g every 6 hours until
decrease vitamin C concen- NCT04323514 shock resolution or for up to 10 days
trations 2-5 NCT04363216 used in VITAMINS study 4, 8-10
NCT04401150 (LOVIT-COVID)
NCT04395768 Oral ascorbic acid:
NCT04342728: Oral ascorbic acid
Oral ascorbic acid: dosage of 8 g daily, given in 2 or 3
Randomized, open-label study divided doses 1
(NCT04342728; COVIDAtoZ) initiated to
evaluate oral ascorbic acid (8 g daily), zinc, NCT04395768 (outpatients): Ascorbic
or both in combination in symptomatic acid 1 g orally 3 times daily for 7 days
outpatients receiving a positive COVID-19 following initial 200-mg/kg IV dose
test result; other clinical trials of outpatient
oral ascorbic acid treatment registered, Note: May interfere with laboratory
including NCT04395768 1 tests based on oxidation-reduction
Included at lower dosages as an active or reactions (e.g., blood and urine glu-
placebo-equivalent comparator (control) in cose testing, nitrite and bilirubin
other COVID-19 prevention or treatment concentrations, leukocyte counts).
studies 1 Manufacturer states to delay oxida-
tion-reduction reaction-based tests
Included as a component of some hy- until 24 hours after infusion, if possi-
droxychloroquine-based combination regi- ble 11
mens being studied for prevention or treat-
ment of COVID-19 1
Other infections:
Sepsis: Meta-analysis of several small stud-
ies suggested beneficial effects from IV
ascorbic acid; however, primary end points
not improved in CITRIS-ALI study
(NCT02106975) in patients with sepsis and
ARDS or in VITAMINS study (NCT03333278)
in patients with septic shock; additional
studies under way 4, 6, 8-10
Pneumonia: Limited study data available

regarding ascorbic acid (oral) in hospital-
ized patients with pneumonia 2, 3
Common cold: Effect of oral supplementa-

tion studied extensively; decreases dura-
tion of symptoms, may decrease incidence
of common cold in individuals under heavy
physical stress but not in overall population
2, 3
Azithromycin 8:12.12 Antibacterial with some in Adjunctive therapy in certain respiratory Adjunctive treatment in certain viral Current data insufficient to establish
Macrolides vitro activity against some viral infections: Although contradictory infections: 500 mg once daily has pros and cons of adjunctive use of
Updated viruses (e.g., influenza A results reported, some evidence of benefi- been used 13 azithromycin in management of COVID-
6/16/20 H1N1, Zika) 1, 3-5 cial immunomodulatory or anti- 19
inflammatory effects when used in pts with COVID-19: 500 mg on day 1, then
No data to date on in vitro some viral infections (e.g., influenza). 10, 12, 250 mg once daily on days 2-5 in Additional data needed from random-
13
activity against corona- However, in a retrospective cohort study conjunction with a 5-, 7-, or 10-day ized, controlled clinical trials before any
viruses, including SARS- in critically ill pts with laboratory-confirmed regimen of hydroxychloroquine has conclusions can be made regarding
CoV-2 MERS, there was no statistically significant been used or is being investigated 7, possible benefits of using a combined
18, 19, 23, 24, 29
difference in 90-day mortality rates or regimen of hydroxychloroquine and
Has immunomodulatory clearance of MERS-CoV RNA between those azithromycin in pts with COVID-19
and anti-inflammatory who received macrolide therapy and those
effects, including effects on who did not. 12 NIH COVID-19 Treatment Guidelines
proinflammatory cyto- Panel recommends against the use of a
kines; precise mechanisms Adjunctive therapy in certain respiratory combined regimen of hydroxychloro-
of such effects not fully conditions: Some evidence of beneficial quine and azithromycin for the treat-
elucidated 2, 6, 8, 9, 11-14, 17 immunomodulatory or anti-inflammatory ment of COVID-19, except in the context
Has been used as adjunc- effects when used in pts with certain res- of a clinical trial, because of the poten-
tive therapy to provide piratory conditions (e.g., ARDS). 8 In a ret- tial for toxicities. 21 (See Hydroxychloro-
antibacterial coverage and rospective cohort study in pts with moder- quine in this Evidence Table.)
potential immunomodula- ate or severe ARDS, a statistically signifi-
tory and anti-inflammatory cant improvement in 90-day survival was
effects in the treatment of reported in those who received adjunctive IDSA recommends that a combined
some viral respiratory tract azithromycin. 8 regimen of hydroxychloroquine (or chlo-
infections (e.g., influenza) roquine) and azithromycin be used for
10, 13
Clinical experience in pts with COVID-19: the treatment of COVID-19 only in the
Has been used for antibacterial coverage in context of a clinical trial. 22
Has been used as adjunc- hospitalized pts with COVID-19 15
tive therapy to provide Because azithromycin and 4- amino-
antibacterial coverage and Use in conjunction with hydroxychloro- quinolines (hydroxychloroquine, chloro-
potential immunomodula- quine in pts with COVID-19: Azithromycin quine) are independently associated
tory and anti-inflammatory (500 mg on day 1, then 250 mg daily on with QT prolongation, caution is advised
effects in the management days 2-5) has been used in addition to a 10- if considering use of azithromycin with
of certain respiratory con- day regimen of hydroxychloroquine (600 one of these drugs in pts with COVID-
ditions (e.g., bronchiecta- mg daily) in an open-label nonrandomized 19, especially in outpatients who may
sis, bronchiolitis, cystic study in France (6 pts), 7 open-label uncon- not receive close monitoring and in
fibrosis, COPD exacerba- trolled study in France (11 pts), 18 uncon- those at risk for QT prolongation or
tions, ARDS) 6, 8, 17 trolled observational study in France (80 receiving other drugs associated with
pts),19 and larger uncontrolled observation- arrhythmias. 20-22, 25-28
al study in France (1061 pts).23 Data pre-
sented to date are insufficient to evaluate NIH panel states that macrolides
possible clinical benefits of azithromycin in (including azithromycin) should be used
pts with COVID-19. (See Hydroxychloro- concomitantly with hydroxychloroquine
quine in this Evidence Table.) (or chloroquine) only if necessary. In
addition, because of the long half-lives
of both azithromycin (up to 72 hours)
Use in conjunction with hydroxychloro- and hydroxychloroquine (up to 40 days),
quine in hospitalized pts with COVID-19: caution is warranted even when the
Data from 2 retrospective studies that ana- drugs are used sequentially. The panel
lyzed outcome data for hospitalized pts in states that use of doxycycline (instead
New York treated with hydroxychloroquine of azithromycin) should be considered
with or without azithromycin indicate that for empiric therapy of atypical pneumo-
use of the 4-aminoquinoline antimalarial nia in COVID-19 pts receiving hy-
with or without azithromycin is not associ- droxychloroquine (or chloroquine). 21
ated with decreased in-hospital mortality.
30, 31
(See Hydroxychloroquine in this Evi- The benefits and risks of a combined
dence Table.) regimen of azithromycin and hy-
droxychloroquine (or chloroquine)
Randomized, double-blind, placebo- should be carefully assessed; if the regi-
controlled trial sponsored by NIAID is eval- men is used, diagnostic testing and
uating efficacy of hydroxychloroquine with monitoring are recommended to mini-
azithromycin for prevention of hospitaliza- mize risk of adverse effects, including
tion and death in symptomatic adult outpa- drug-induced cardiac effects. 20, 22, 25-28
tients with COVID-19 (A5395; (See Hydroxychloroquine in this Evi-
NCT04358068). 24, 29 (See Hydroxychloro- dence Table.)
quine in this Evidence Table.)
Multiple clinical trials to evaluate azithro-

mycin alone or azithromycin with hy-
droxychloroquine or chloroquine for treat-
ment of COVID-19 are registered at clini-
caltrials.gov (some listed below): 29
NCT04329832
NCT04332107
NCT04334382
NCT04335552
NCT04336332
NCT04341727
NCT04358081
NCT04370782
Baricitinib 92:36 Disease- Janus kinase (JAK) 1 and 2 Currently no known published controlled Therapeutic dosages of baricitinib (2 Minimal interaction with CYP enzymes
modifying Anti inhibitor; disrupts regula- clinical trial evidence supporting efficacy or or 4 mg orally once daily) are suffi- and drug transporters and low protein
(Olumiant®) -rheumatic tors of endocytosis (AP2- safety in patients with COVID-19 cient to inhibit AAK1 1, 2, 5 binding of baricitinib allow for com-
Drug associated protein kinase 1 In a small (12 patients) open-label study in bined use with antiviral agents and oth-
Updated [AAK1] and cyclin G- Italy (NCT04358614), use of baricitinib (4 Dosage information not yet available er drugs 4, 14
5/15/20 associated kinase [GAK]), mg orally once daily for 2 weeks) in combi- (see Trials or Clinical Experience)
which may help reduce nation with lopinavir/ritonavir was evaluat- NIH COVID-19 Treatment Guidelines
viral entry and inflamma- ed in patients with moderate COVID-19 Panel recommends against use of JAK
tion; also may interfere pneumonia.13, 14 Baricitinib was well toler- inhibitors for the treatment of COVID-
with intracellular virus ated with no serious adverse events report- 19 except in the context of a clinical
particle assembly 1, 2 ed.13 At week 1 and week 2, patients who trial; the panel states that at present
received baricitinib had significant improve- the broad immunosuppressive effect of
Inhibits JAK1 and JAK2- ment in respiratory function parameters JAK inhibitors outweighs the potential
mediated cytokine release; and none of the patients required ICU sup- for benefit 11
may combat cytokine report.13
lease syndrome (CRS) in
Baricitinib is included in the next iteration
severely ill patients 1, 2, 4, 5 of NIAID’s Adaptive COVID-19 Treatment
Trial (ACTT 2). 3, 12 Inclusion criteria: Labora-
Ability to inhibit a variety tory- confirmed COVID-19 infection and
of proinflammatory cyto- evidence of lung involvement, including
kines, including interferon, need for supplemental oxygen, abnormal
has been raised as a possi- chest X-ray, or need for mechanical ventila-
ble concern with the use of tion. 12 Patients randomized to receive
JAK inhibitors in the man- treatment with remdesivir with or without
agement of hyperinflam- baricitinib.12 Remdesivir to be administered
mation resulting from viral as one 200-mg IV dose on day 1 followed
infections such as COVID- by 100 mg IV daily for the duration of hos-
19 5 pitalization (up to 10-day treatment
course). Baricitinib to be administered as a
4-mg oral dose administered once daily for
the duration of hospitalization (up to 14-
day treatment course). 12
Adaptive phase 2/3 clinical trial: Open-
label study planned to evaluate safety and
efficacy of baricitinib in hospitalized pa-
tients with COVID-19 (NCT04340232) 6
Other planned clinical trials will evaluate
baricitinib in combination with or without
an antiviral agent for the treatment of
COVID-19 (NCT04346147, NCT04320277,
NCT04345289, NCT04321993) 7-10
Colchicine 92:16 Antigout Exerts broad anti- Minimal anecdotal experience and no clini- Dosage in NCT04322682: Colchicine Safety and efficacy for treatment of
Agents inflammatory and im- cal trial data reported to date in COVID-19 4 0.5 mg orally twice daily for 3 days, COVID-19 not established
Updated munomodulatory effects then 0.5 mg once daily for 27 days 1
6/3/20 through multiple mecha- Retrospective review of computerized The potential for toxic doses of colchi-
nisms, including inhibition healthcare database found no difference in Other studies are evaluating various cine to affect alveolar type II pneumo-
of NOD-like receptor pro- baseline use of colchicine (0.53 vs 0.48%) colchicine dosages and durations for cytes (which may inhibit surfactant re-
tein 3 (NLRP3) inflam- between patients with a positive RT-PCR treatment of COVID-19 2 lease and contribute to ARDS) and in-
masome assembly and result for SARS-CoV-2 (n = 1317) and those crease the risk of multiple-organ failure
disruption of cytoskeletal with a negative result (n = 13,203), sug- Consider possible need for colchicine and disseminated intravascular coagula-
functions through inhibi- gesting a lack of protective effect for colchi- dosage adjustment; 2 manufacturer- tion (DIC) has been raised as a possible
tion of microtubule cine against SARS-Cov-2 infection; indica- recommended dosages for labeled concern with the use of colchicine in
polymerization 2,3,5,6 tion for and duration of colchicine use were indications depend on patient's age, COVID-19 patients 14
unknown 15 renal and hepatic function, and con-
May combat the hyper- comitant use of interacting drugs,
inflammatory state of Phase 3, randomized, double-blind, place- including protease inhibitors (e.g.,
COVID-19 (e.g., cytokine bo-controlled study (NCT04322682; COL- lopinavir/ritonavir), other moderate
storm) by suppressing CORONA) initiated in adults with COVID-19 or potent CYP3A4 inhibitors, and P-
proinflammatory cytokines and at least one high-risk criterion to evalu- glycoprotein (P-gp) inhibitors 5
and chemokines 2 ate effect of colchicine on mortality, hospi-
talization rate, and need for mechanical Use of colchicine in patients with
NLRP3 inflammasone acti-
ventilation; study excludes enrollment of renal or hepatic impairment receiv-
vation results in release of
currently hospitalized patients; enrollment ing P-gp inhibitors or potent CYP3A4
interleukins, including IL-
target is approximately 6000 pts 1 inhibitors is contraindicated 5
1β 3,5,6,8,11
In experimental models of Other registered randomized, parallel-

acute respiratory distress group studies are evaluating the effects of
syndrome/acute lung inju- colchicine on various outcome measures
ry (ARDS/ALI), the NLRP3 (e.g., mortality, markers of myocardial
inflammasome had a major damage, clinical status, need for mechani-
role in the development of cal ventilation, duration of hospitalization)
lung injury 3,11 in patients with COVID-19: NCT04326790,
NCT04322565,
Potential to limit COVID-19 NCT04328480, NCT04350320,
-related myocardial dam- NCT04355143, NCT04392141,
age also has been hypothe- NCT04375202, NCT04360980,
sized 2,3 based on the NCT04367168, NCT04403243,
drug’s mechanisms of ac- NCT04363437 2,3
tion and promising results
of ongoing research on
colchicine in various cardi-
ac conditions 3,6-10
SARS-CoV-1 envelope (E)

protein, a viroporin in-
volved in replication and
virulence, activates the
NLRP3 inflammasome in
vitro in Vero E6 cells by
forming calcium-
permeable ion channels,
leading to increased IL-1β
production 2,12,13
Corticoster- 68:04 Potent anti-inflammatory Observational studies: Evidence suggests In general, low to moderate dosages Data on the use of corticosteroids in
oids (general) Adrenals and antifibrotic properties; that corticosteroid use in patients with of corticosteroids are recommended COVID-19 are limited. 3, 5, 7, 24, 25 The
use of corticosteroids may SARS, MERS, and influenza was associated in intubated patients with ARDS. 8 benefits and risks of corticosteroid ther-
Updated prevent an extended cyto- with no survival benefit and possible harm apy should be carefully weighed before
6/3/20 kine response and may (e.g., delayed viral clearance, avascular Regimens used in China were typical- use in patients with COVID-19. 1, 7
accelerate resolution of necrosis, psychosis, diabetes). 1, 25 ly methylprednisolone 40-80 mg IV
pulmonary and systemic daily for a course of 3-6 days. 8 Some NIH, CDC, WHO, IDSA, and other experts
inflammation in pneumo- Uncontrolled observational data from the experts suggest that equivalent dos- have issued guidelines for the use of
nia 3, 9 recent COVID-19 outbreak in China suggest ages of dexamethasone (i.e., 7-15 mg corticosteroids in patients with COVID-
a possible treatment benefit of daily, typically 10 mg daily) may have 19 based on the currently available
Evidence suggests that methylprednisolone in COVID-19 patients an advantage of producing less fluid information. Recommendations are
cytokine storm, a hyperin- with acute respiratory distress syndrome retention, since dexamethasone has made according to the severity of ill-
flammatory state resem- (ARDS). 6, 13 (See Methylprednisolone in this less mineralocorticoid activity. 8 This ness, indications, and underlying medi-
bling secondary hemopha- Evidence Table.) dosage of dexamethasone is con- cal conditions and should be considered
gocytic lymphohistiocytosis sistent with those used in the DEXA- on a case-by-case basis. 1, 2, 8, 12, 24, 25
(HLH), is a contributing Pending results of randomized controlled ARDS trial. 8, 17
factor in COVID-19- clinical studies specifically evaluating corti- General recommendations: WHO, CDC,
associated mortality. 8, 18 costeroids for COVID-19, indirect evidence Higher dosages have been suggested NIH, and IDSA generally recommend
Immunosuppression from from studies in patients with community- for cytokine storm. 8 (See Comments against the routine use of corticoster-
corticosteroids has been acquired pneumonia, ARDS, and other viral column.) oids for the treatment of COVID-19
proposed as a treatment infections has been used to inform treat- unless indicated for another reason
option for such hyperin- ment decisions for COVID-19 patients. 3, 5, 8, (e.g., asthma or COPD exacerbation,
flammation. 18 9, 12, 15-17, 25
refractory septic shock). 1, 2, 3, 8, 9, 24, 25
May improve dysregulated Systemic corticosteroid therapy has been Non-critical patients: Corticosteroids
immune response caused studied in several randomized controlled generally should not be used in the
by sepsis (possible compli- studies for the treatment of ARDS; overall treatment of early or mild disease since
cation of infection with evidence is low to moderate in quality and the drugs can inhibit immune response,
COVID-19) and increase BP most studies were performed prior to the reduce pathogen clearance, and in-
when low 4, 11 prelung protection strategy era. 5, 8, 9, 14, 17 crease viral shedding. 3, 8, 24
In a recent multicenter, unblinded, ran-
domized controlled study (DEXA-ARDS NIH recommends against the routine
trial), the effects of dexamethasone in con- use of systemic corticosteroids for the
junction with conventional care were eval- treatment of COVID-19 in hospitalized
uated in hospitalized patients with moder- patients unless they are in the intensive
ate-to-severe ARDS receiving lung- care unit. 24
protective mechanical ventilation. 17 Treat-
ment with IV dexamethasone at a dosage Critically ill patients: The Surviving
of 20 mg once daily on days 1-5, followed Sepsis Campaign COVID-19 subcom-
by 10 mg once daily on days 6-10 resulted mittee (a joint initiative of the Society of
in reduced duration of mechanical ventila- Critical Care Medicine and the European
tion and reduced overall mortality (i.e., Society of Intensive Care Medicine)
15% increase in 60-day survival) compared recommends against the routine use of
with conventional treatment alone. 17 systemic corticosteroids in mechanically
Based on results of this study, a clinical trial ventilated adults with COVID-19 and
(NCT04325061) has been initiated to respiratory failure (without ARDS). 12
specifically evaluate the use of dexame- However, these experts generally sup-
thasone in patients with ARDS due to port a weak recommendation to use
COVID-19. 21 low-dose, short-duration systemic corti-
costeroids in the sickest patients with
Other clinical trials have been initiated in COVID-19 and ARDS. 12
various countries to evaluate use of IV
corticosteroids (e.g., dexamethasone, hy- NIH also recommends against the rou-
drocortisone), oral corticosteroids (e.g., tine use of systemic corticosteroids for
prednisone), or inhaled corticosteroids the treatment of mechanically ventilat-
(e.g., budesonide, ciclesonide) for treated COVID-19 patients without ARDS.
ment of COVID-19 pneumonia or ARDS, However, the NIH panel states that
including the following trials registered at there is insufficient evidence for or
clinicaltrials.gov: 22 against the use of systemic corticoster-
NCT04327401 oids in mechanically ventilated patients
NCT04344288 with COVID-19 and ARDS. 24
NCT04344730
NCT04348305 IDSA suggests against using corticoster-
NCT04355637 oids in hospitalized patients with COVID
NCT04359511 -19 pneumonia; however, in those with
NCT04360876 ARDS due to COVID-19, systemic corti-
NCT04381364 costeroids may be used in the context
(For registered clinical trials evaluating use of a clinical trial. 25
of methylprednisolone, see Methylpredni-
solone in this Evidence Table.) Cytokine storm: There is no well-
established or evidence-based treat-
Randomized controlled studies evaluating ment for cytokine storm in patients with
use of corticosteroids (e.g., hydrocortisone, COVID-19. 8 However, some experts
dexamethasone, methylprednisolone, suggest that use of more potent immu-
prednisolone) in septic shock suggest a nosuppression with corticosteroids may
small, but uncertain mortality reduction. 3, 4 be beneficial in such patients. 8 These
experts suggest higher dosages of corti-
costeroids (e.g., IV methylprednisolone
60-125 mg every 6 hours for up to 3
days) followed by tapering of the dose
when inflammatory markers (e.g., C-
reactive protein levels) begin to de-
crease. 8 The decision to use cortico-
steroids in patients with early signs of
cytokine storm should be balanced with
the known adverse effects. 24
Septic shock: The effect of corticoster-

oids in COVID-19 patients with sepsis or
septic shock may be different than the
effects seen in those with ARDS. 12 The
Surviving Sepsis Campaign and NIH sug-
gest the use of low-dose corticosteroid
therapy (e.g., hydrocortisone 200 mg
daily as an IV infusion or intermittent
doses) over no corticosteroid therapy in
adults with COVID-19 and refractory
shock. 12, 24
Clinicians considering corticosteroids for
such patients with COVID-19 should
balance the potential small reduction in
mortality with potential effects of pro-
longed coronavirus shedding. 1 If corti-
costeroids are prescribed, monitor and
treat adverse effects including hypergly-
cemia, hypernatremia, and hypokale-
mia. 1, 4
Patients receiving corticosteroid thera-

py for chronic conditions: NIH states
that oral corticosteroids used for the
treatment of an underlying condition
prior to COVID-19 infection (e.g., prima-
ry or secondary adrenal insufficiency,
rheumatologic diseases) should not be
discontinued. Supplemental or stress
dosages of corticosteroids may be indi-
cated on an individual basis in patients
with such conditions. The guidelines
also recommend that inhaled cortico-
steroids used daily for the management
of asthma and COPD to control airway
inflammation should not be discontin-
ued in patients with COVID-19. 24
Rheumatology experts, including mem-

bers of the American College of Rheu-
matology COVID-19 Clinical Guidance
Task Force, state that abrupt discontinu-
ance of corticosteroid therapy in pa-
tients with rheumatologic diseases
should be avoided regardless of COVID-
19 exposure or infection status. These
experts also state that if indicated, corti-
costeroids should be used at the lowest
effective dosage to control manifesta-
tions, but also acknowledge that higher
dosages may be necessary in the con-
text of severe, vital organ-threatening
rheumatologic disease even following
COVID-19 exposure. 28-30
Endocrinology experts state that pa-

tients with primary or secondary adren-
al insufficiency who are receiving pro-
longed corticosteroid therapy should
follow usual steroid “sick day rules”
since these individuals may not be able
to mount a normal stress response in
the event of COVID-19 infection. 19, 26 If
such individuals develop symptoms such
as fever and a dry continuous cough,
they should immediately double their
daily oral corticosteroid dosage and
continue with this regimen until the
fever subsides. 19 These guidelines also
apply to patients who are receiving
prolonged therapy (> 3 months) with
corticosteroids for underlying inflamma-
tory conditions, including asthma, aller-
gy, and rheumatoid arthritis. 19 In such
patients whose condition worsens or in
those experiencing vomiting or diar-
rhea, treatment with parenteral cortico-
steroids may be necessary. 19, 26 Admin-
istration of physiologic stress doses of
corticosteroids (e.g., IV hydrocortisone
50-100 mg 3 times daily) and not phar-
macologic doses should be considered
in all cases to avoid potentially fatal
adrenal failure.19, 20 Additional study is
needed to determine the optimum cor-
ticosteroid stress dosage regimens in
patients with COVID-19. 26, 27 There is
some evidence suggesting that continu-
ous IV infusion of hydrocortisone
(following an initial IV bolus dose) may
provide more stable circulating cortisol
concentrations in patients with adrenal
insufficiency and reduce the potentially
harmful effects of peak and trough con-
centrations of cortisol on the immune
system. 26, 27
Pregnancy considerations: For preg-

nant women with COVID-19, NIH guide-
lines state that the antenatal use of
corticosteroids that cross the placenta
(i.e., betamethasone, dexamethasone)
is generally reserved for when admin-
istration is required for fetal benefit.
Other systemic corticosteroids do not
cross the placenta, and pregnancy is not
a reason to restrict their use if other-
wise indicated. ACOG recommends
against administration of antenatal
corticosteroids for fetal benefit in the
late preterm period (i.e., 34 weeks and
0 days through 36 weeks and 6 days) in
patients with suspected or confirmed
COVID-19 because the benefits of such
therapy in late preterm are less well
established. Treatment should be indi-
vidualized, weighing the neonatal bene-
fits of antenatal corticosteroid therapy
with the risks of potential harm to the
pregnant patient. 24
Epoprostenol 48:48 Selective pulmonary vaso- No studies evaluating use specifically in Various dosages of inhaled epo- The Surviving Sepsis Campaign states
(inhaled) Vasodilating dilator; may be useful in COVID-19 patients 10 prostenol have been used in ARDS that due to the lack of adequately pow-
Agent the adjunctive treatment studies 2, 9 ered randomized controlled studies, a
Updated of acute respiratory dis- Experience in patients with ARDS indicates recommendation cannot be made for or
5/28/20 tress syndrome (ARDS), a that inhaled epoprostenol can substantially Dosages up to 50 ng/kg per minute against the use of inhaled prostacyclins
potential complication of reduce mean pulmonary artery pressure have been used (titrated to re- in COVID-19 patients with severe ARDS
COVID-19 1-9 and improve oxygenation in such patients; sponse) in patients with ARDS. 1-4, 6, 9 10
however, data demonstrating clinical bene- To provide a clinically important

Inhaled epoprostenol has fit are lacking 3, 6-9 increase in PaO2 and reduction in The NIH COVID-19 Treatment Guide-
been suggested as an alter- pulmonary artery pressure, data lines Panel and the Surviving Sepsis
native to inhaled nitric from these studies suggest that the Campaign state that a trial of inhaled
oxide due to its similar most effective and safe dosage ap- pulmonary vasodilator as rescue thera-
efficacy, lower potential pears to be 20-30 ng/kg per minute py may be considered in mechanically
for systemic adverse in adults and 30 ng/kg per minute in ventilated adults with COVID-19, severe
effects, lower cost, and pediatric patients 9 ARDS, and hypoxemia despite optimized
ease of delivery 1, 2, 9 ventilation and other rescue strategies;
if no rapid improvement in oxygenation
is observed, the patient should be ta-
pered off treatment 10, 12
Interferons 8:18.20 Interferons (IFNs) modu- Only limited clinical trial data available to IFN beta: Various sub-Q dosages of Efficacy and safety of IFNs for treatment
Interferons late immune responses to date specifically evaluating efficacy of IFNs IFN beta-1a and IFN beta-1b are be- or prevention of COVID-19 not estab-
Updated some viral infections; 2, 7, 19 for treatment of COVID-19; for information ing evaluated for treatment of COVID lished
6/18/20 10:00 in vitro studies indicate on additional studies including IFN alfa or -19 10, 16
Antineoplastic only weak induction of IFN IFN beta as a component of combination Relative effectiveness of different IFNs
Agents following SARS-CoV-2 in- therapy (e.g., background regimen), see Open-label, randomized study in against SARS-CoV-2 not established 12
fection, and a possible role antiviral entries in this Evidence Table. hospitalized adults with COVID-19,
92:20 for IFNs in prophylaxis or mainly mild disease (NCT04276688): NIH COVID-19 Treatment Guidelines
Immunomod- early treatment of COVID- Clinical trials are currently evaluating IFN IFN beta-1b 8 million units was giv- Panel recommends against use of IFNs
ulatory Agents 19 has been suggested to beta-1a or IFN beta-1b, generally added to en sub-Q on alternate days for 1, 2, for treatment of COVID-19, except in
compensate for possibly other antivirals, for treatment of COVID-19, or 3 doses (when initiated on day 5- the context of a clinical trial, because no
insufficient endogenous including: 16 NCT04315948 (IFN beta-1a 6, 3-4, or 1-2, respectively, following benefit was observed with use of IFNs
IFN production 1, 3, 4, 7, 18 plus lopinavir/ritonavir [LPV/RTV] vs LPV/ symptom onset) in conjunction with for treatment of other coronavirus in-
RTV vs remdesivir vs hydroxychloroquine 14-day regimen of LPV/RTV and rib- fections (SARS, MERS), clinical trial re-
Type 1 IFNs (IFN alfa and [each regimen given with standard care] vs avirin 10, 16 sults for treatment of COVID-19 are
IFN beta) are active in standard care) lacking, and toxicity of IFNs outweighs
vitro against MERS-CoV in NCT04324463 (IFN beta-1b vs IFN beta-1b Open-label, randomized study in the potential for benefit 11
Vero and LLCMK2 cells and plus hydroxychloroquine [or chloroquine] hospitalized adults with COVID-19
in rhesus macaque model plus azithromycin vs usual care) (NCT04324463) is evaluating IFN Surviving Sepsis Campaign COVID-19
of MERS-CoV infection; NCT04343768 (IFN beta-1a plus hy- beta-1b 0.25 mg sub-Q on days 1, 3, subcommittee states that there is in-
type I IFNs also active in droxychloroquine plus LPV/RTV vs IFN beta 5, and 7, either alone or in conjunc- sufficient evidence to issue a recom-
vitro against SARS-CoV-1 in -1b plus hydroxychloroquine plus LPV/RTV tion with 7-day regimen of hy- mendation on use of interferons, alone
Vero, vs hydroxychloroquine plus LPV/RTV) 16 droxychloroquine (or chloroquine) or in combination with antivirals, in
fRhK-4, and human cell and 5-day regimen of azithromycin 16 critically ill adults with COVID-19 12
lines; 8 IFN beta is more Open-label, randomized study in Hong
active than IFN alfa in vitro Kong in hospitalized adults with COVID-19, Adaptive, open-label, randomized Interferon alfa via atomization inhala-
against SARS-CoV-1 and mainly mild disease (NCT04276688): Com- study in hospitalized adults with tion is included in Chinese guidelines as
MERS-CoV 2, 8, 12 bination regimen of LPV/RTV, ribavirin, and moderate or severe COVID-19 dis- a possible option for treatment of
sub-Q IFN beta-1b (IFN beta-1b was ease (NCT04315948) is evaluating COVID-19 13
IFN alfa and IFN beta are omitted to avoid proinflammatory effects IFN beta-1a 44 mcg sub-Q on days 1,
active in vitro against SARS when treatment was initiated 7-14 days 3, and 6 in conjunction with 14-day
-C0V-2 in Vero cells at after symptom onset) was associated with regimen of LPV/RTV 16
clinically relevant concen- shorter median time from treatment initia-
trations; 1 in vitro study tion to negative RT-PCR result in nasopha- IFN alfa: Chinese guidelines suggest
suggests SARS-CoV-2 is ryngeal swab (7 vs 12 days), earlier resolu- IFN alfa dosage of 5 million units (or
more sensitive than SARS- tion of symptoms (4 vs 8 days), and shorter equivalent) twice daily via atomiza-
CoV-1 to IFN alfa 1, 3 hospital stay (9 vs 14.5 days) compared tion inhalation for treatment of
with control (LPV/RTV). In the subset of COVID-19 13
However, lack of clinical patients initiating treatment 7 or more days
benefit observed with use after symptom onset (i.e., those not treat- Peginterferon lambda-1a:
of type 1 IFNs, generally in ed with IFN beta-1b), there was no signifi- For treatment of COVID-19 in adults
combination with ribavirin, cant difference in time to negative RT-PCR (NCT04354259, NCT04388709):
for treatment of SARS and result, time to resolution of symptoms, or Peginterferon lambda-1a 180 mcg
MERS 2, 8, 9, 11, 12 duration of hospital stay between the com- sub-Q; number of doses (1 dose or 2
bination regimen (LPV/RTV and ribavirin) doses given 1 week apart) depends
IV IFN beta-1a did not re- and control (LPV/RTV). IFN beta-1b (8 mil- on the protocol 5
duce ventilator depend- lion units on alternate days) was adminis-
ence or mortality in a pla- tered for 1, 2, or 3 doses when initiated on For postexposure prophylaxis of CoV-
cebo-controlled trial in day 5-6, 3-4, or 1-2, respectively, following 2 infection in adults (NCT04344600):
patients with acute respir- symptom onset (median of 2 IFN beta-1b Two 180-mcg sub-Q doses of pegin-
atory distress syndrome doses given); 52 of 86 patients (60%) ran- terferon lambda-1a given 1 week
(ARDS) 11, 17 domized to combination regimen received apart 5
all 3 drugs, and 41 patients received control
Type 3 IFNs (IFN lambda) LPV/RTV. 10
are thought to provide
important immunologic Open-label, randomized study in Iran in
defense against respiratory hospitalized adults with severe suspected
viral infections 3, 4, 6, 7, 19 or RT-PCR-confirmed COVID-19: IFN beta-
and 1a (12 million units sub-Q 3 times weekly
may have less potential for 2 weeks) plus standard care (7- to 10-
than type 1 IFNs to pro- day regimen of hydroxychloroquine plus
duce systemic inflammato- lopinavir/ritonavir or atazanavir/ritonavir)
ry response, including in- (n = 42) was compared with standard care
flammatory effects on (control; n = 39). Time to clinical response
respiratory tract; 4, 7, 19 IFN (primary outcome; defined as hospital dis-
lambda receptor is ex- charge or 2-score improvement in a 6-
pressed mainly on epitheli- category ordinal scale) did not differ signifi-
al (including respiratory cantly between the IFN beta-1a group and
epithelial) cells and neutro- the control group (9.7 vs 8.3 days); dura-
phils, and is distinct from tions of hospital stay, ICU stay, and me-
the ubiquitous type 1 IFN chanical ventilation also did not differ be-
receptor; 2, 4, 7, 19 despite tween the groups. Discharge rate on day 14
different receptors and (67% vs 44%) was higher and 28-day overall
expression patterns, type 1 mortality rate (19 vs 44%) was significantly
and type 3 IFNs activate lower with IFN beta-1a compared with
similar signaling cascades; control; early initiation of IFN beta-1a (<10
4, 7, 19
unknown whether days after symptom onset), but not late
limited receptor distribu- initiation of the drug (≥10 days after symp-
tion might also affect effi- tom onset), was associated with reduced
cacy 4 mortality. NOTE: Total of 92 patients were
randomized; results are based on the 42
IFN beta-1a-treated patients and 39 control
patients who completed the study. Per-
centage of patients with RT-PCR-confirmed
disease not reported to date. Patients were
recruited from general, intermediate, and
ICU wards; 45% of the IFN beta-1a-treated
patients and 59% of the control patients
were admitted to ICU; 36 and 44%, respec-
tively, required invasive mechanical ventila-
tion. Mean time from symptom onset to
treatment initiation was 11.7 days for the
IFN beta-1a group and 9.3 days for the
control group. 20
Aerosolized IFN alfa (not commercially

available in U.S.) has been used in China in
children and adults for treatment of COVID-
19, 13, 14, 15 but limited clinical data present-
ed to date. 11 In a retrospective study of 77
hospitalized adults with moderate COVID-
19 disease who received aerosolized IFN
alfa-2b (5 million units twice daily) (n = 7),
umifenovir (Arbidol®) (n = 24), or both
drugs (n = 46), time from symptom onset to
negative RT-PCR result in throat swab ap-
peared to be shorter in those receiving IFN
alfa-2b alone or in combination with
umifenovir compared with those receiving
umifenovir alone; this exploratory study
was small and nonrandomized, and treat-
ment groups were of unequal size and de-
mographically unbalanced in age, comor-
bidities, and time from symptom onset to
treatment. 15
Sub-Q peginterferon lambda-1a (not com-

mercially available in U.S.) is being evaluat-
ed for treatment (e.g., NCT04354259,
NCT04388709) and postexposure prophy-
laxis (e.g., NCT04344600) of SARS-CoV-2
infection 5
Methylpred- 68:04 Potent anti-inflammatory Retrospective, observational, single-center Dosage used in the retrospective Findings from observational studies
nisolone Adrenal and antifibrotic properties; study: In 201 patients with confirmed study (Wu et al) not provided. 6 suggest that for patients with COVID-19
(DEPO- use of corticosteroids may COVID-19 pneumonia who developed pneumonia who progress to ARDS,
Medrol®, prevent an extended cyto- ARDS, methylprednisolone appeared to Dosage used in the retrospective methylprednisolone treatment may be
SOLU- kine response and may reduce the risk of death. 6 Among patients study (Wang et al) was 1-2 mg/kg beneficial. However, results should be
Medrol®) accelerate resolution of with ARDS, of those who received daily IV for 5-7 days. 13 interpreted with caution because of
pulmonary and systemic methylprednisolone treatment, 23 of 50 potential bias (drug used in sickest pa-
Updated inflammation in pneumo- (46%) patients died, while of those who did Dosage used in the randomized, tients) and small sample size. Confirma-
5/21/20 nia 3, 9 not receive methylprednisolone, 21 of 34 controlled study (NCT04244591) was tion from randomized controlled studies
(61.8%) died. 6 40 mg IV every 12 hours for 5 days. 23 is needed. 6, 13
(See Corticosteroids in this (See Corticosteroids in this Evidence
Evidence Table.) Retrospective, observational, single-center Table for general recommendations on
study: In 46 patients with confirmed se- corticosteroid use in patients with
vere COVID-19 pneumonia that progressed COVID-19.)
to acute respiratory failure, use of
methylprednisolone was associated with
improvement in clinical symptoms (i.e.,
fever, hypoxia) and a shortened disease
course in patients who received the drug
compared with those who did not. 13
Death occurred in 3 patients during hospi-
talization; 2 of these patients received
methylprednisolone. 13
Open-label, multicenter, randomized con-

trolled study (NCT04244591) was recently
completed in China that compared use of
methylprednisolone in conjunction with
standard care in patients with confirmed
COVID-19 infection that progressed to
acute respiratory failure; results have not
yet been posted. 23
Multiple clinical trials have been initiated in

various countries to evaluate use of
methylprednisolone for treatment of
COVID-19 pneumonia or severe acute res-
piratory syndrome, including the following
trials registered at clinicaltrials.gov: 22
NCT03852537
NCT04263402
NCT04273321
NCT04323592
NCT04329650
NCT04343729
NCT04374071
A non-randomized pilot study registered at

clinicaltrials.gov (NCT04355247) has been
initiated to evaluate use of methylpredni-
solone for the prevention of COVID-19
cytokine storm and progression to respira-
tory failure. 22
Nitric oxide 48:48 Vaso- Selective pulmonary vaso- No published studies evaluating use specifi- In the Chen et al. study in severe The NIH COVID-19 Treatment Guide-
(inhaled) dilating dilator with bronchodilato- cally in COVID-19 patients 10 SARS patients, inhaled nitric oxide lines Panel and the Surviving Sepsis
Agent ry and vasodilatory effects therapy was given for ≥3 days (30 Campaign recommend against the rou-
Updated in addition to other sys- One case report described possible benefit ppm on day 1, followed tine use of inhaled nitric oxide in me-
5/28/20 temic effects mediated in a SARS-CoV-2-positive outpatient who by 20 and 10 ppm on days 2 and 3, chanically ventilated COVID-19 patients
through cGMP-dependent also had idiopathic pulmonary arterial hy- respectively, then weaned on day 4; with ARDS; however, a trial of inhaled
or independent mecha- pertension 13 therapy was resumed at 10 ppm if pulmonary vasodilator as rescue thera-
nisms; may be useful for deteriorating oxygenation occurred) py may be considered in mechanically
2
supportive treatment of Randomized controlled studies of inhaled ventilated adults with COVID-19, severe
acute respiratory distress nitric oxide in ARDS patients generally ARDS, and hypoxemia despite optimized
syndrome (ARDS), a poten- demonstrated modest improvements in Various dosing protocols using differ- ventilation and other rescue strategies;
tial complication of COVID- oxygenation, but no effect on mortality and ent methods of delivery are being if no rapid improvement in oxygenation
19 2, 3, 9, 11, 14 possible harm (e.g., renal impairment) 4, 5, 6, evaluated in ongoing studies in is observed, the patient should be ta-
9
COVID-19 patients 3 pered off treatment 10, 12
Also has been shown to
have antiviral effects. 1, 14 In Clinical trials evaluating inhaled nitric oxide
vitro evidence of direct for the treatment or prevention of COVID-
antiviral activity against 19 are planned or underway, including the
severe acute respiratory following trials: NCT04388683,
syndrome coronavirus NCT04383002, NCT04358588 (Expanded
(SARS-CoV-1) 1, 14 Access), NCT04397692, NCT04398290,
NCT04338828, NCT04305457,
In a small pilot study (Chen NCT04306393, NCT04312243 3, 7
et al.) conducted during
the SARS outbreak, treat-
ment with inhaled nitric
oxide was found to reverse
pulmonary hypertension,
improve severe hypoxia,
and shorten the duration
of ventilatory support in
critically-ill SARS patients 2,
3
Genetic similarity between

SARS-CoV and SARS-CoV-2
suggests potential benefit
in patients with COVID-19
1, 14
Ruxolitinib 10:00 Janus kinase (JAK) 1 and 2 Currently no known published clinical trial Various dosages are being evaluated NIH COVID-19 Treatment Guidelines
Antineoplastic inhibitor; 7 may potentially evidence supporting efficacy or safety in 3, 6, 10
Panel recommends against use of JAK
(Jakafi®) Agents combat cytokine release patients with COVID-19 inhibitors for the treatment of COVID-
syndrome (CRS) in severely Phase 3 study (NCT04362137): Rux- 19 except in the context of a clinical
Updated ill patients 4, 5 Phase 3 randomized, double-blind, place- olitinib 5 mg twice daily trial; the panel states that at present
6/3/20 bo-controlled clinical trial (NCT04362137; for 14 days with possible the broad immunosuppressive effect of
Ability to inhibit a variety RUXCOVID) is evaluating ruxolitinib plus extension to 28 days 10 JAK inhibitors outweighs the potential
of proinflammatory cyto- standard of care vs placebo plus standard for benefit 8
kines, including interferon, of care in patients ≥12 years of age with Phase 3 study (NCT04377620): Rux-
has been raised as a possi- COVID-19-associated cytokine storm olitinib 5 or 15 mg twice daily Severe reactions requiring drug discon-
ble concern with the use of (sponsored by Incyte in U.S. and Novartis (approximately every 12 hours) 12 tinuance observed in 2 COVID-19 pa-
JAK inhibitors in the outside of U.S.) 1, 10 tients following initiation of ruxolitinib:
purpuric lesions with thrombocytopenia
management of hyperin- Phase 3, randomized, double-blind, place- and deep-tissue infection in one pa-
flammation resulting from bo-controlled clinical trial (NCT04377620; tient, and progressive decrease in he-
viral infections such as RUXCOVID-DEVENT) is evaluating rux- moglobin and erythrodermic rash over
COVID-19 5, 7 olitinib plus standard of care vs placebo the whole body surface area in the sec-
plus standard of care in adults with COVID- ond patient; these cases differed in the
19-associated acute respiratory distress
timing of ruxolitinib initiation and the
syndrome (ARDS) who require mechanical
severity of COVID-19 illness 11
ventilation (sponsored by Incyte) 12
Expanded-access (managed-access, com-

passionate use) program (NCT04337359)
available for eligible adults and children ≥6
years of age with severe or very severe
COVID-19 illness; address inquiries to In-
cyte (855-463-3463 or me-
dinfo@incyte.com) 1, 2
Expanded-access program (NCT04355793)

available for emergency treatment of cyto-
kine storm from COVID-19 infection in
adults and pediatric patients ≥12 years of
age; address inquiries to Incyte (855-463-
3463 or medinfo@incyte.com) 9
Other clinical trials also registered, includ-

ing: 3
NCT04331665
NCT04338958
NCT04348071
NCT04348695
NCT04403243
Sarilumab 92:36 Disease- Recombinant humanized Currently no known published clinical trial Large US-based controlled study NIH COVID-19 Treatment Guidelines
(Kefzara®) modifying Anti monoclonal antibody spe- evidence supporting efficacy or safety in (NCT04315298): Dosage of 400 mg Panel states that there are insufficient
-rheumatic cific for the interleukin-6 treatment of patients with COVID-19 IV as a single dose or multiple doses clinical data to recommend either for
Updated Drug (IL-6) receptor; IL-6 is a (based on protocol criteria); the low- or against use of sarilumab in the treat-
6/18/20 proinflammatory cytokine. However, based on encouraging results in er-dose (200-mg) treatment arm was ment of COVID-19 7
Sarilumab may potentially China with a similar drug, tocilizumab, a discontinued following a preliminary
combat cytokine release large, U.S.-based, phase 2/3, randomized, analysis of study results 9, 10 (see No new safety findings observed with
syndrome (CRS) and pul- double-blind, placebo-controlled, adaptive- Trials or Clinical Experience) use in COVID-19 patients 9
monary symptoms in se- ly designed study (NCT04315298) evalu-
verely ill patients 1, 2, 5, 7 ating efficacy and safety of sarilumab in Note: IV formulation not commer-
patients hospitalized with severe COVID-19 cially available in the U.S., but is be-
is currently under way. 3, 4, 9, 10 Patients in ing studied in the above-mentioned
this study were randomized (2:2:1) to re- clinical trial. The sub-Q formulation
ceive sarilumab 400 mg, sarilumab 200 mg, is not FDA-labeled to treat cytokine
or placebo. Preliminary data were released release syndrome (CRS) in the U.S. 7
after an Independent Data Monitoring
Committee recommended discontinuing
the 200-mg arm and restricting future en-
rollment only to critically ill patients (i.e.,
those requiring mechanical ventilation,
high-flow oxygenation, or ICU treatment).
Of the first 457 patients enrolled, 28% had
severe illness, 49% had critical illness, and
23% had multisystem organ dysfunction.
Sarilumab rapidly lowered C-reactive pro-
tein (CRP) levels, meeting the primary end
point. Baseline IL-6 levels were elevated in
all treatment arms; higher levels were ob-
served in critical patients compared with
severe patients. At the time of data analy-
sis, of the 226 critical patients, 32% in the
sarilumab 400-mg group had died or were
on a ventilator, compared with 46% in the
200-mg group and 55% in the placebo
group. Comparing mortality alone, 23% of
those in the sarilumab 400-mg group died
compared with 36% in the 200-mg group
and 27% in the placebo group. In contrast
to the positive outcomes among critical
patients, negative trends for most out-
comes were observed in severe patients. 9
A second manufacturer-sponsored phase 3

clinical trial is under way in countries out-
side the U.S. (Italy, Spain, Germany, France,
Canada, Russia, Israel, and Japan). Approxi-
mately 400 patients hospitalized with
COVID-19 are expected to be enrolled;
initial results expected in the third quarter
of 2020. 9
Italian case series (Benucci et al.) describes

8 patients hospitalized with COVID-19
pneumonia at one hospital in Florence
treated with sarilumab (initial 400-mg IV
dose followed by 200-mg IV doses after 48
and 96 hours) in addition to standard ther-
apy (hydroxychloroquine, azithromycin,
darunavir, cobicistat, enoxaparin). Treat-
ment was started within 24 hours of hospi-
talization. Sarilumab was used in these
patients because of a lack of tocilizumab at
this institution. Seven of the patients
demonstrated an improvement in oxygena-
tion and lung echo score and were dis-
charged within 14 days; the remaining pa-
tient died in 13 days. 8
Multiple clinical trials to evaluate sari-

lumab for treatment of COVID-19 are reg-
istered at clinicaltrials.gov 10
For compassionate use access or investiga-
tor-sponsored clinical studies, contact the
manufacturer (Sanofi Genzyme) for fur-
ther information (1-800-633-1610) 6
Siltuximab 10:00 Recombinant chimeric Italy: Early (non-peer-reviewed) findings In the SISCO study in Italy, patients Efficacy and safety of siltuximab in the
Antineoplastic monoclonal antibody spe- from an observational case-control study of received an initial dose of siltuximab treatment of COVID-19 not established;
(Sylvant®) agents cific for the interleukin-6 the first 21 patients with COVID-19 and 11 mg/kg by IV infusion over 1 hour; additional study needed
(IL-6) receptor; may poten- pneumonia/acute respiratory distress syn- a second dose could be administered
Added tially combat cytokine re- drome (ARDS) who participated in a com- at the physician’s discretion (5 of the
5/13/20 lease syndrome (CRS) passionate use program (SISCO study; first 21 patients received a second
symptoms (e.g., fever, NCT04322188) in one hospital and were dose after 2-3 days) 4
organ failure, death) in followed for up to 7 days showed reduced
severely ill patients 1-5 and normalized C-reactive protein (CRP) Other clinical studies under way are
levels (a marker of systemic inflammation) evaluating a single siltuximab dose of
by day 5 in all 16 siltuximab-treated pa- 11 mg/kg by IV infusion 7, 8
tients with sufficient available data. An
interim analysis revealed that the condition
of 33% of the siltuximab-treated patients
improved and no clinically relevant change
in condition was reported in 43% of pa-
tients while 24% of patients worsened,
including one patient who died and anoth-
er with a cerebrovascular event. This co-
hort study with patients treated with
standard therapy is ongoing. 4, 6
Other clinical trials evaluating siltuximab in

the treatment of COVID-19 currently are
recruiting in Belgium (NCT04330638) 7 and
Spain (NCT04329650) 8
Sirolimus 92:44 Immu- mTOR complex 1 Clinical trials evaluating sirolimus for the Dosage being investigated in a ran- Although possible clinical application,
(Rapamune®) nosuppressive (mTORC1) is involved in treatment of COVID-19 are planned or un- domized, double-blind, placebo- current data not specific to COVID-19;
agent (mTOR the replication of various derway including the following trials: 4 controlled trial (NCT04341675): 6 mg additional study needed 5
Updated inhibitor) viruses, including corona- NCT04341675 orally on day 1 followed by 2 mg
5/28/20 virus 1, 2, 5 NCT04374903 daily for a maximum treatment dura-
In vitro studies demon- NCT04371640 tion of 14 days or until hospital dis-
strated inhibitory activity charge 4
against MERS-CoV infec-
tion 2
Limited experience in pa-
tients with H1N1 pneumo-
nia suggests possible bene-
fit; in one study, treatment
with sirolimus 2 mg daily in
conjunction with cortico-
steroids for 14 days was
associated with improved
patient outcomes (e.g.,
shortened duration of
mechanical ventilation,
improved hypoxia and
multiorgan function) 3
Tocilizumab 92:36 Disease- Recombinant humanized Case reports and observational studies IV infusion: China recommends an In China, tocilizumab can be used to
(Actemra®) modifying Anti monoclonal antibody spe- describing use of tocilizumab in patients initial dose of 4–8 mg/kg infused treat severely or critically ill COVID-19
-rheumatic cific for the interleukin-6 with COVID-19 reported from various areas over more than 60 minutes. If initial patients with extensive lung lesions and
Updated Drug (IL-6) receptor; may poten- of the world 1, 3, 10, 12 dose not effective, may administer high IL-6 levels 2
5/1/20 tially combat cytokine re- second dose (in same dosage as ini-
lease syndrome (CRS) In preliminary data from a non-peer- tial dose) after 12 hours. No more NIH COVID-19 Treatment Guidelines
symptoms in severely ill reviewed, single-arm, observational Chi- than 2 doses should be given; maxi- Panel states that there are insufficient
COVID-19 patients 1-3, 6, 10, 14 nese trial (Xu et al.) involving 21 patients mum single dose is 800 mg 2 clinical data to recommend either for
with severe or critical COVID-19 infection, US/Global randomized, placebo- or against use of tocilizumab in the
patients demonstrated rapid fever reduc- controlled trial (manufacturer spon- treatment of COVID-19 9
tion and a reduced need for supplemental sored; COVACTA): Will evaluate an
oxygen within several days after receiving initial IV infusion of 8 mg/kg (up to a The role of routine cytokine measure-
tocilizumab (initially given as a single 400- maximum dose of 800 mg); one addi- ments (e.g., IL-6, CRP) in determining
mg dose by IV infusion; this dose was re- tional dose may be given if symp- the severity of and treating COVID-19
peated within 12 hours in 3 patients be- toms worsen or show no improve- requires further study 14
cause of continued fever) 3 ment 8
In a retrospective, observational study in

China (Luo et al.) involving 15 patients
moderately to critically ill with COVID-19,
tocilizumab (80-600 mg per dose) was giv-
en, and was used in conjunction with
methylprednisolone in 8 of the patients.
About one-third of the patients received 2
or more doses of tocilizumab. Elevated C-
reactive protein (CRP) levels rapidly de-
creased in most patients following treat-
ment, and a gradual decrease in IL-6 levels
was noted in patients who stabilized fol-
lowing tocilizumab administration. Clinical
outcomes were equivocal. 10
A single-center, retrospective observational

study of 20 kidney transplant recipients in
Italy with COVID-19 hospitalized for pneu-
monia included 6 patients who received
tocilizumab. Half of the patients experi-
enced reduced oxygen requirements and 2
(33%) showed improved radiologic findings
following administration; 2 (33%) of the 6
tocilizumab-treated patients died. 12
Zhang et al. from China reported on a pa-

tient with COVID-19 and multiple myeloma
who appeared to be successfully treated
with tocilizumab 13
Currently, there are no well-controlled

published studies on the efficacy and safety
of tocilizumab for the treatment of COVID-
19; however, numerous clinical trials are
planned or under way globally 1, 5, 7, 8
China: Randomized, multicenter, con-
trolled clinical trial evaluating efficacy &
safety in 188 patients with COVID-19 under
way through 5/10/20. Results not yet avail-
able. Chinese Clinical Trial Registry link:
http://www.chictr.org.cn/
showprojen.aspx?proj=49409
US/Global randomized, placebo-controlled

trial: Manufacturer (Roche) conducting a
randomized, double-blind, placebo-
controlled phase 3 trial (COVACTA;
NCT04320615) in collaboration with the US
Health and Human Services’ Biomedical
Advanced Research and Development Au-
thority (BARDA); the study will evaluate
safety and efficacy of tocilizumab in combi-
nation with standard of care compared
with placebo. Expected to enroll about 330
patients globally, including in the U.S., be-
ginning in April 2020 7, 8
OTHER
ACE Inhibi- 24:32 Renin- Hypothetical harm: Human Data are lacking; no evidence of harm or American Heart Association (AHA), Amer-
tors, Angio- Angiotensin- pathogenic coronaviruses benefit with regards to COVID-19 infec- ican College of Cardiology (ACC), Heart
tensin II Re- Aldosterone bind to their target cells tion.1-3, 9 Failure Society of America (HFSA), Euro-
ceptor Block- System Inhib- through angiotensin- pean Society of Cardiology (ESC) recom-
ers (ARBs) itor converting enzyme 2 Large, observational study analyzed a mend to continue treatment with renin-
(ACE2).1, 4, 5 Expression of cohort of pts tested for COVID-19 to eval- angiotensin-aldosterone system (RAAS)
Updated ACE2 may be increased in uate the relationship between previous antagonists in those patients who are
6/18/20 patients treated with ACE treatment with 5 common classes of anti- currently prescribed such agents.2, 3
inhibitors or ARBs.1, 4, 8 In- hypertensive agents (including ACE inhibi-
creased expression of ACE2 tors, ARBs) and the likelihood of a posi- NIH COVID-19 Treatment Guidelines Pan-
may potentially facilitate tive or negative test result for COVID-19 el states patients who are receiving an
COVID-19 infections.1 as well as the likelihood of severe COVID- ACE inhibitor or ARB for cardiovascular
19 illness among pts who tested positive: disease (or other indications) should con-
Hypothetical benefit: ACE Study included data obtained from a large tinue receiving these drugs; recommends
inhibitors or ARBs may have health network in New York City for against use of ACE inhibitors or ARBs for
a protective effect against 12,594 pts who were tested for COVID-19 the treatment of COVID-19 except in the
lung damage or may have from Mar 1 to Apr 15, 2020. Among these context of a clinical trial. 9
paradoxical effect in terms pts, 4357 (34.6%) had a history of hyper-
of virus binding.1, 2, 6 tension. Of these patients, 2573 (59.1%) Patients with cardiovascular disease are
tested positive for COVID-19. Among the at an increased risk of serious COVID-19
2573 pts with hypertension and positive infections.1, 4
results for COVID-19, 634 pts (24.6%) had
severe disease (i.e., indicated by ICU ad- Abrupt withdrawal of RAAS inhibitors in
mission, mechanical ventilation, or death). high-risk patients (e.g., heart failure pa-
Results of COVID-19 testing were stratified tients, patients with prior myocardial
in propensity-score-matched patients with infarction) may lead to clinical instability
hypertension according to previous treat- and adverse health outcomes. 8
ment with selected antihypertensive
agents. Propensity-score matching was
based on age, sex, race, BMI, medical his-
tory, various comorbidities, and other
classes of medications. The authors stated
that no substantial increase was observed
in the likelihood of a positive test for
COVID-19 or in the risk of severe COVID-19
among patients who tested positive in
association with any single antihyperten-
sive class (including ACE inhibitors,
ARBs).13
Large, population-based case-control

study was conducted to evaluate the
association between the use of RAAS
blockers (including ACE inhibitors, ARBs)
and the risk of COVID-19: Study included
data obtained from a regional healthcare
database in the Lombardy region of Italy
for 6272 case pts with confirmed severe
COVID-19 acute respiratory syndrome
from Feb 21 to Mar 11, 2020 who were
matched to 30,759 controls based on sex,
age, and place of residence. Information
about use of selected drugs and clinical
profiles was obtained from regional
healthcare databases. Use of ACE inhibitors
or ARBs was more frequent in patients with
COVID-19 than among controls because of
their higher prevalence of cardiovascular
disease. Percentage of patients receiving
ACE inhibitors was 23.9% for case pts and
21.4% for controls. Percentage of patients
receiving ARBs was 22.2% and 19.2% for
case and control pts, respectively. The au-
thors concluded that there was no evi-
dence that treatment with ACE inhibitors or
ARBs significantly affected the risk of
COVID-19 or altered the course of infection
or resulted in more severe disease. 14
Large, multinational, retrospective study

analyzed outcome data for hospitalized
pts with confirmed COVID-19 to evaluate
the relationship between cardiovascular
disease and preexisting treatment with
ACE inhibitors or ARBs with COVID-19
(Mehra et al; now retracted): Original
publication included multinational data for
8910 pts hospitalized with COVID-19 be-
tween Dec 20, 2019 and Mar 15, 2020 that
were obtained from a global healthcare
data collaborative. The authors concluded
that those data confirmed previous obser-
vations suggesting that underlying cardio-
vascular disease is independently associat-
ed with an increased risk of death in hospi-
talized pts with COVID-19. They also stated
that they were not able to confirm previous
concerns regarding a potential harmful
association of ACE inhibitors or ARBs with
in-hospital mortality. 10 Note: This pub-
lished study has now been retracted by
the publisher at the request of the original
authors. Concerns were raised with re-
spect to the veracity of the data and anal-
yses that were the basis of the authors’
conclusions. 11,12
Clinical trial underway: Initiation of losartan

in adults with COVID-19 requiring hospitali-
zation; primary outcome measure:
sequential organ failure assessment (SOFA)
respiratory score. (NCT04312009) 7
Other clinical trials have been initiated in

various countries to evaluate the effect of
continuing or discontinuing treatment with
ACE inhibitors or ARBs on clinical outcomes
in patients with COVID-19, including the
following trials registered at clinicaltri-
als.gov: 7
NCT04329195
NCT04330300
NCT04331574
NCT04338009
NCT04351581
NCT04353596
NCT04357535
Anticoagu- 20:12.04 Anti- Patients with COVID-19, Limited data from a retrospective study in Additional study is needed to under-
lants coagulants particularly those with China showed reduced mortality in COVID- stand the anticoagulant needs of COVID
severe disease, may devel- 19 patients with severe sepsis-induced -19 patients. 9 , 11, 27-29 VTE risk should be
Updated op a hypercoagulable coagulopathy or markedly elevated D- assessed in all patients on an individual
6/11/20 state, which has been asso- dimer levels (>6 x ULN) who received basis. 4, 5, 10, 17, 18, 27, 28, 32
ciated with poor outcomes prophylactic anticoagulation (low molecu-
(e.g., progressive respirato- lar weight heparin [LMWH] or unfractionat- Several organizations have published
ry failure, acute respiratory ed heparin [UFH]).4, 19 interim guidance for the management
distress syndrome [ARDS], of COVID-19-associated coagulopathy. 4,
death). 1-6, 14, 16, 28, 29 Observational data derived from a large US 5, 9, 25, 27, 28, 30, 32
cohort of hospitalized patients with COVID-

Observed coagulation ab- 19 suggest possible benefit of therapeutic- The NIH COVID-19 Treatment Guide-
normalities include pro- dose anticoagulation; however, the study lines Panel recommends VTE prophylax-
thrombotic disseminated had important limitations (e.g., indications is according to the usual standard of
intravascular coagulation for anticoagulation initiation and details on care in all hospitalized adults with
(DIC), elevated D-dimer patient characteristics not reported). 28, 31 COVID-19 unless contraindicated. 28
levels, high fibrinogen lev-
els, and microvascular and Several clinical trials have been initiated or The International Society for Throm-
macrovascular thrombosis. currently underway to evaluate anticoagu- bosis and Haemostasis, American Col-
1-6, 9, 11, 13, 16, 26, 27
lant strategies in patients with COVID-19, lege of Cardiology, and American Socie-
including the following: NCT04373707, ty of Hematology recommend that all
High rates of VTE have NCT04372589, NCT04345848, hospitalized COVID-19 patients receive
been reported in critically NCT04412304, NCT04416048 12 prophylactic-dose LMWH unless contra-
ill patients with COVID-19. indicated (e.g., active bleeding, severe
7, 8, 11, 15, 18, 28, 36
thrombocytopenia, fibrinogen <0.5 g/L).
4, 5, 30
Pathogenesis of COVID-19-
related coagulopathy not WHO recommends pharmacologic
completely known, but prophylaxis with LMWH (preferred) or
may be related to an un- UFH (5000 units sub-Q twice daily) in
controlled immunothrom- adults and adolescents with COVID-19
botic response to viral who do not have contraindications. 25
infection.16, 17, 27-29, 32
LMWH or UFH may be preferred over
oral anticoagulants in critically ill
Anticoagulant therapy may hospitalized patients with COVID-19
reduce the risk of throm- because of their shorter half-lives, abil-
botic complications and ity to be administered parenterally, and
improve clinical outcomes. fewer drug-drug interactions.28 Patient-
2, 4, 5, 14, 25, 27
specific factors (e.g., renal function) and
practical concerns (e.g., need for fre-
quent monitoring, convenience of ad-
ministration, risk of medical staff expo-
sure) may influence choice of anticoagu-
lant. 14, 15, 20, 27, 32
Because of the severity of coagulopathy

in critically ill COVID-19 patients and
reports of high rates of VTE despite
routine prophylaxis, some clinicians
have used (or suggested the use of)
higher prophylactic doses or even thera-
peutic doses of anticoagulants to pre-
vent thromboembolic complications in
such patients; however, prospective
studies are needed to evaluate these
approaches. 8, 11, 14-17, 20-24, 26-28, 30, 31, 32, 34,
36
Pending additional data, use of higher
-intensity nonstandard VTE prophylaxis
or therapeutic-dose anticoagulation
should ideally be done in the context of
a clinical trial. 28, 30
Based on expert opinion, the Anticoagu-

lation Forum suggests increased doses
of VTE prophylaxis (e.g., enoxaparin 40
mg BID, enoxaparin 0.5 mg/kg BID, hep-
arin 7500 units sub-Q 3 times daily, or
low-intensity heparin infusion) for criti-
cally ill patients (e.g., in the ICU) with
confirmed or suspected COVID-19. 32
NIH and other experts state that the

current data are insufficient to recom-
mend for or against the use of thera-
peutic anticoagulation in COVID-19 pa-
tients in the absence of confirmed or
suspected thrombosis. 4, 28, 30 The effica-
cy of intermediate or full-dose thera-
peutic anticoagulation for critically ill
COVID-19 patients without documented
VTE is currently being evaluated. 4, 12
Patients who are already on anticoagu-
lant therapy for an existing condition
(e.g., VTE, atrial fibrillation) should con-
tinue to receive such treatment unless
significant bleeding occurs or other
contraindications are present. 4, 28
Extended VTE prophylaxis after hospital

discharge is not routinely recommended
in patients with COVID-19, but may be
considered based on the same protocols
and risk-benefit analysis as for patients
without COVID-19. 27, 28, 30, 32
Although a relationship between mark-

edly elevated D-dimer levels and mor-
tality has been shown, whether this can
be applied to predicting or managing
VTE risk is not known. 5, 6, 7, 30, 32, 33
Bleeding appears to be infrequent in

COVID-19 patients. 5, 30 However, stand-
ard risk factors for bleeding should be
considered and patients should be indi-
vidually assessed to balance risk of
thrombosis with risk of bleeding. 4, 32
COVID-19 Plasma obtained from Uncontrolled pilot study in China (Duan et Efficacy and safety of COVID-19 conva-
Convalescent patients who have recov- al): 10 adults with severe COVID-19 re- lescent plasma for the treatment of
Plasma ered from COVID-19 (i.e., ceived a single transfusion of COVID-19 COVID-19 not established. 11, 25
COVID-19 convalescent convalescent plasma (containing SARS-CoV-
Updated plasma) that contains anti- 2 neutralizing antibody titers of 1:640 or The NIH COVID-19 Treatment Guideline
6/18/20 bodies against SARS-CoV-2 greater) with standard care; all patients Panel states that there are insufficient
may provide short-term received antiviral therapy (e.g., umifenovir data to recommend for or against the
passive immunity to the [Arbidol®], ribavirin, oseltamivir, peramivir, use of convalescent plasma in patients
virus; theoretically, such interferon α) and 6 patients also received with COVID-19. 25
immunity may prevent or methylprednisolone. The median time from
contribute to recovery onset of symptoms to transfusion of conva- The Surviving Sepsis Campaign COVID-
from the infection, possibly lescent plasma was 16.5 days. COVID-19 19 subcommittee suggests that conva-
as the result of viral neu- symptoms (fever, cough, shortness of lescent plasma not be used routinely in
tralization and/or other breath, chest pain) improved in all patients critically ill adults with COVID-19 be-
mechanisms. 1-5, 24, 25 within 1-3 days after the transfusion and all cause efficacy and safety not estab-
patients showed radiologic improvement in lished and uncertainty surrounding opti-
Convalescent plasma ther- pulmonary lesions. Titers of neutralizing mal preparation of convalescent plas-
apy has been used in the antibody increased in 5 patients after the ma. 30
treatment of other viral transfusion, but remained the same in 4
diseases with various de- patients. Prior to the transfusion, RT-PCR Appropriate criteria for selection of
grees of success. 16, 20, 22, 24, tests for SARS-CoV-2 RNA were positive in 7 patients to receive investigational
25
patients and negative in 3 patients; after COVID-19 convalescent plasma, optimal
In patients with SARS-CoV- transfusion, SARS-CoV-2 RNA was unde- time during the course of the disease to
1 infection, use of conva- tectable in 3 patients on day 2, 3 patients receive such therapy, and appropriate
lescent plasma was report- on day 3, and 1 patient on day 6. 9 dosage (e.g., volume, number of doses)
ed to shorten the duration not determined. 1-5, 9 Theoretically, con-
of hospitalization and de- Uncontrolled case series in China (Shen et valescent plasma should be more effec-
crease mortality; 6-8, 14 SARS al): 5 critically ill adults with rapidly pro- tive if given during the early course of
patients who received gressing severe COVID-19 and acute respir- the disease.1, 2, 16, 17, 20, 24
convalescent plasma less atory distress syndrome (ARDS) requiring
than 14 days after onset of mechanical ventilation who had high viral Optimal timing of donor plasma collec-
symptoms had better out- loads despite antiviral treatment received 2 tion in relation to recovery from COVID-
comes than those who transfusions of COVID-19 convalescent 19, most appropriate methods of anti-
received such plasma later plasma (containing SARS-CoV-2 neutralizing body testing, and minimum titers of
in the course of the dis- antibody end point dilution titers of 80-480 SARS-CoV-2 antibody in convalescent
ease. 1, 2, 6-8 depending on the donor); patients contin- plasma that may be associated with
ued to receive antiviral treatments (e.g., clinical benefits in pts with COVID-19
LPV/RTV, favipiravir, umifenovir [Arbidol®], not determined. 1-5
darunavir, interferon α-1b) and
methylprednisolone. Patients received the Logistics of obtaining, processing, stor-
convalescent plasma transfusions 10-22 ing, and distributing COVID-19 convales-
days after hospital admission. Following the cent plasma evolving. 1-5, 11, 14, 15 FDA
transfusions, body temperature normalized does not collect COVID-19 convalescent
within 3 days in 4/5 patients, sequential plasma and does not provide such plas-
organ failure assessment (SOFA) scores ma; healthcare providers and acute care
improved in all patients (decreased from facilities obtain COVID-19 convalescent
initial scores of 2-10 to 1-4 on day 12), ti- plasma from FDA-registered establish-
ters of SARS-CoV-2 IgG, IgM, and neutraliz- ments. 11
ing antibody increased in all patients, and
viral loads decreased and became negative Potential risks associated with COVID-19
within 12 days. 10 convalescent plasma therapy (e.g., inad-
vertent transmission of other infectious
Retrospective observational study in China agents, allergic reactions, thrombotic
(Zeng et al): 6 critically ill adults with complications, transfusion-associated
COVID-19 were treated with convalescent circulatory overload, transfusion-related
plasma at a median of 21.5 days after first acute lung injury [TRALI], antibody-
detection of viral shedding. Although viral dependent enhancement of infection)
clearance was observed in all patients fol- and steps to mitigate such risks not fully
lowing transfusion, death occurred in 5 of 6 determined and require further evalua-
patients. 16 tion. 1-5, 9, 23, 24, 25
Uncontrolled descriptive study in China FDA issued a guidance for industry to

(Ye et al): 6 adults with COVID-19 received provide recommendations to
convalescent plasma at a relatively late healthcare providers and investigators
stage of the disease (most patients re- regarding administration and study of
ceived 2 or 3 plasma transfusions); various investigational COVID-19 convalescent
laboratory, radiologic, and clinical improve- plasma. This guidance document in-
ments were reported. 18 cludes recommendations regarding
pathways for access to COVID-19 conva-
Uncontrolled case series in US (Salazar et lescent plasma, patient eligibility to
al): 25 adults with severe and/or life- receive such plasma, collection of such
threatening COVID-19 disease received plasma (including donor eligibility and
convalescent plasma in addition to multiple qualifications), product labeling, and
other treatments (e.g., antivirals, anti- recordkeeping. 11
inflammatory agents). 26 The median time
from symptom onset to plasma transfusion There are no convalescent blood prod-
was 10 days and 24/25 patients received a ucts currently licensed by the FDA. 25
single transfusion. 26 Convalescent plasma COVID-19 convalescent plasma is regu-
was well tolerated and no transfusion- lated as an investigational product. 11
related adverse events were reported. At FDA states that there are 3 available
day 7 post-transfusion, 9 patients (36%) pathways for administering or studying
had clinical improvement (defined as at the use of such plasma:
least a 1-point improvement based on a 6-
point ordinal scale); by day 14 post- 1). Clinical Trials: Requests to study use
transfusion, 19 patients (76%) had clinical of COVID-19 convalescent plasma
improvement or were discharged. The con- should be submitted to FDA under the
tribution of convalescent plasma to clinical traditional investigational new drug
improvement in these patients is unclear (IND) regulatory pathway. 11
since there was no control group and pa- 2). Expanded Access IND: For patients
tients also received other treatments. 26 with serious or immediately life-
threatening COVID-19 who are not eligi-
Cochrane review: A systematic review of 8 ble or are unable to participate in ran-
published studies evaluating convalescent domized clinical trials, an expanded
plasma in adults with COVID-19 (total of 32 access IND can be used. A National Ex-
study participants) found very low confi- panded Access Treatment Protocol has
dence in the efficacy and safety of this been established to facilitate access
treatment approach based on the current through participation of acute care facil-
evidence. There was a high risk of bias ities under an IND that is already in
within and across the studies (all were un- place. 11 Information on a protocol that
controlled, nonrandomized, and included a is currently in place is available at
small number of participants) and great https://www.uscovidplasma.org. 12
variability in terms of dose and timing of 3). Single Patient Emergency IND
convalescent plasma administration, donor (eIND): Licensed physicians seeking to
and recipient characteristics, and outcomes administer COVID-19 convalescent plas-
evaluated. 27 ma to individual patients with serious or
life-threatening disease may request an
Open-label, randomized, controlled study eIND from the FDA. Consult the FDA
in China (Li et al): Results of this study in guidance document for specific infor-
103 adults with severe or life-threatening mation on applying for an eIND. 11
COVID-19 found no significant difference in
time to clinical improvement within 28 Donor eligibility: FDA guidance sug-
days, mortality, or time to hospital dis- gests that COVID-19 convalescent plas-
charge in patients treated with convales- ma be collected from individuals with
cent plasma (containing a high titer of anti- laboratory-confirmed evidence of
body to SARS-CoV-2) plus standard of care COVID-19 infection and complete reso-
compared with standard of care alone. 28 lution of symptoms for at least 14 days
Convalescent plasma therapy was well before donation (a negative result for
tolerated by the majority of patients; 2 COVID-19 by a diagnostic test is not
cases of transfusion-associated adverse necessary to qualify the donor). 11
events were reported. 28 There was a signal
of possible benefit in the subgroup of pa- Antibody titers in donor plasma: If
tients with severe COVID-19 disease. 28, 29 measurement of antibody titers is avail-
However, the study had several limitations able, FDA recommends a neutralizing
that preclude any definite conclusions, antibody titer of at least 1:160 (a titer of
including the possibility of being under- 1:80 may be considered acceptable if an
powered as the result of early termination alternative matched unit of plasma is
because of the lack of available patients. 28, not available). 11
29
In addition, most patients received con-
valescent plasma treatment at least 14 Patient eligibility: For healthcare pro-
days after symptom onset and it is unclear viders seeking an eIND for the treat-
whether earlier treatment would have ment of patients with severe or life-
resulted in greater benefit. 28, 29 threatening disease, consideration
should be given to following the patient
eligibility criteria used in the National
Although there is some evidence sug- Expanded Access Treatment Protocol
gesting possible benefits of convalescent https://www.uscovidplasma.org. 11 Ac-
plasma in patients with COVID-19, availa- cording to the protocol, severe disease
ble data to date are largely from case re- is defined as one or more of the follow-
ports or series; confirmation from addi- ing: shortness of breath, respiratory
tional randomized controlled studies is frequency 30/minute or greater, blood
required. 1, 20-23, 27-29 oxygen saturation 93% or lower, PaO2/
FiO2 ratio less than 300, lung infiltrates
Multiple clinical trials have been initiated greater than 50% within 24-48 hours,
globally to evaluate use of COVID-19 con- and life-threatening disease is defined
valescent plasma in various settings (e.g., as one or more of the following: respira-
postexposure prophylaxis, treatment of tory failure, septic shock, multiple organ
different stages of the disease). 19, 22 Some dysfunction or failure. 11
trials are listed below. For additional trials,
see clinicaltrials.gov:
NCT04374370 (Expanded Access)

NCT04343261 (US)
NCT04372368 (US)
NCT04343755 (US)
NCT04344535 (US)
NCT04364737 (US)
NCT04340050 (US)
NCT04344015 (US)
NCT04376034 (US)
NCT04359810 (US)
NCT04362176 (US)
NCT04411602 (US)
NCT04388527 (US)
NCT04397757 (US)
NCT04412486 (US)
NCT04392232 (US)
NCT04360486 (US ARMY)
NCT04347681
NCT04346446
NCT04345523
NCT04342182
NCT04352751
NCT04375098
NCT04357106
NCT04327349
NCT04292340
Famotidine 56:28.12 Computer-aided, structure- Currently no known published prospective Dosage in NCT04370262: Fa- Safety and efficacy for treatment of
Histamine H2 based, virtual screening of clinical trial evidence supporting efficacy or motidine is being given IV in 120-mg COVID-19 not established
Updated Antagonists libraries of compounds safety for treatment of COVID-19 doses (proposed total daily dosage
6/18/20 against SARS-CoV-2 proof 360 mg) for maximum of 14 days
teins suggested potential Randomized, double-blind, historical- or until hospital discharge, whichev-
for famotidine to interact controlled, comparative trial er comes first 5
with viral proteases in- (NCT04370262) initiated in New York in
volved in coronavirus repli- hospitalized adults with moderate to se- Proposed daily dosage in
cation 1-4 vere COVID-19; trial includes 2 active NCT04370262 is 9 times the usual
treatment groups (high-dose IV famotidine manufacturer-recommended IV
Anecdotal observations: with oral hydroxychloroquine, IV placebo adult dosage; 6 the study excludes
Observations based on with oral hydroxychloroquine) and a histor- patients with creatinine clearance
retrospective medical rec- ical control group receiving neither of these (Clcr) ≤50 mL/minute, including
ord review indicated that drugs (patients treated during early stages dialysis patients; 5 renally impaired
many Chinese COVID-19 of the COVID-19 pandemic in New York); patients may be at increased risk of
survivors had received targeted enrollment is 600 patients in each adverse CNS effects since drug half-
famotidine for chronic active treatment group; 2 interim analyses life is closely related to Clcr 6
heartburn; mortality rate planned 5
appeared to be lower in
hospitalized COVID-19 Retrospective cohort study of 10 outpa-
patients receiving fa- tients self-medicating with high-dose fa-
motidine than in patients motidine following onset of symptoms
not receiving the drug (14 consistent with COVID-19: No hospitaliza-
vs 27%); observations did tions reported; all patients reported symp-
not control for possible tomatic improvement within 1-2 days, with
confounding (e.g., socioec- continued improvement over 14-day peri-
onomic) factors 3 od. Patients were symptomatic for 2-26
days before initiating famotidine. Total of 7
Retrospective matched patients had PCR-confirmed COVID-19, 2
cohort study of COVID-19 had serologic confirmation of antibodies
patients hospitalized, but against SARS-CoV-2, and 1 had clinical diag-
not requiring intubation nosis only. Famotidine dosage of 80 mg 3
within the first 48 hrs, at a times daily was reported by 6 patients
single New York medical (range: 20-80 mg 3 times daily); median
center indicated that the reported duration of use was 11 days
risk for the composite out- (range: 5–21 days); high-dose famotidine
come of death or intuba- generally was well tolerated. Data were
tion was reduced (mainly collected by telephone interviews and
due to difference in mor- written questionnaires. Patients retrospec-
tality) in patients who re- tively provided symptom scores on a 4-
ceived famotidine within point ordinal scale. Potential exists for pla-
24 hours of hospital admis- cebo effect, recall bias, and enrollment
sion (n = 84) vs those who bias; symptomatic improvement also could
did not receive the drug (n reflect treatment-independent
= 1536); overall, 21% of convalescence 8
patients met the compo-
site outcome (8.8% were
intubated and 15% died);
the finding appeared to be
specific to the H2 antago-
nist and to COVID-19, as
the investigators reported
observing no protective
effect with proton-pump
inhibitors or in non-COVID-
19 patients. Home use of
famotidine was document-
ed on admission in 15% of
patients who received the
drug in hospital vs 1% of
those who did not; 28% of
all famotidine doses were
IV; 47% of doses were 20
mg, 35% were 40 mg, and
17% were 10 mg; the me-
dian duration of use was
5.8 days, and the total
median dose was 136 mg
(63-233 mg) 7
HMG-CoA 24:06 Antilipe- In addition to lipid- Data from randomized controlled trials are NIH COVID-19 Treatment Guidelines
Reductase mic Agents lowering effects, statins lacking on the use of statins in patients Panel states patients who are receiving
Inhibitors have anti-inflammatory with COVID-19. a statin for the treatment or prevention
(statins) and immunomodulatory of cardiovascular disease should contin-
effects, which may prevent Retrospective cohort study in 154 nursing ue statin therapy; 2 recommends against
Updated acute lung injury. 1 home residents in Belgium with clinically use of statins for the treatment of
6/18/20 suspected COVID-19 and/or positive PCR COVID-19 except in the context of a
Statins affect ACE2 as part test for SARS-CoV-2: Statin use was associ- clinical trial. 2
of their function in reduc- ated with absence of symptoms (i.e.,
ing endothelial dysfunc- asymptomatic infection) in this cohort; 45% Patients with cardiovascular disease are
tion. 2, 8 of the 31 patients receiving statin therapy at an increased risk of serious COVID-19
remained asymptomatic compared with infections. 3
22% of the 123 patients not receiving
statins 10 In patients with active COVID-19 who
may develop severe rhabdomyolysis, it
Preliminary findings have shown mixed may be advisable to withhold statin
results with other respiratory illnesses; therapy for a short period of time. 3
some observational studies suggest statin
therapy is associated with a reduction in Most statins are substrates for the
various cardiovascular outcomes and possi- CYP450 system; potential for drug inter-
bly mortality in patients hospitalized with actions. 7
influenza and/or pneumonia. 3-6
Clinicians should ensure that their high-
Clinical trials evaluating statin use in risk primary prevention (for ASCVD)
COVID-19: patients are on guideline-directed statin
Multiple trials registered at clinicaltrials.gov therapy. 3
(some listed below): 9
NCT04333407
NCT04380402
NCT04343001
NCT04348695
Immune 80:04 Commercially available SARS Experience: IGIV has been used in IGIV dosage of 0.3-0.5 g/kg daily for 3 Role of commercially available immune
Globulin Immune Glob- immune globulin (IGIV, the treatment of SARS. 4-7, 15 Benefits were -5 days has been used or is being globulin (IGIV, IVIG, γ-globulin) and in-
ulin IVIG, γ-globulin) is derived unclear because of patient comorbidities, investigated in patients with COVID- vestigational SARS-CoV-2 immune glob-
Updated from pooled plasma and differences in stage of illness, and effect of 19 8, 12 ulin in the treatment of COVID-19 un-
6/18/20 contains many antibodies other treatments; 5 IGIV may have contrib- clear. 16
normally present in adult uted to hypercoagulable state and throm-
human blood; used for botic complications in some patients. 6, 7 The NIH COVID-19 Treatment Guide-
replacement therapy in lines Panel recommends against the use
patients with primary hu- COVID-19 case reports in China (Cao et al): of commercially available IGIV (i.e., non-
moral immunodeficiency Treatment with IGIV at the early stage of SARS-CoV-2-specific IGIV) for the treat-
who are unable to produce clinical deterioration was reported to pro- ment of COVID-19 except in the context
sufficient IgG antibodies vide some clinical benefit in 3 adults with of a clinical trial and states that current
and also used to provide severe COVID-19; 2 patients also received IGIV preparations are not likely to con-
passive immunity to certain antivirals and 1 patient also received short- tain SARS-CoV-2 antibodies. 16 This does
viral infections in other term steroid treatment. Patients were afe- not preclude the use of IGIV when it is
individuals. 1 brile within 1-2 days and breathing difficul- otherwise indicated for the treatment
ties gradually improved within 3-5 days of of complications arising during the
Investigational SARS-CoV-2 IGIV administration. 8 course of COVID-19 disease. 16
immune globulin is a con-
centrated immune globulin COVID-19 clinical experience in China: IGIV NIH states that there are insufficient
preparation containing has been used as an adjunct in the treat- data to recommend for or against the
specific antibody derived ment of COVID-19 and has been mentioned use of investigational SARS-CoV-2 im-
from the plasma of individ- in Chinese guidelines as a possible treat- mune globulin for the treatment of
uals who have recovered ment option for severe and critically ill COVID-19. 16
from COVID-19.16 children with COVID-19. 9-11, 14
The Surviving Sepsis Campaign COVID-
Immune globulin prepara- Multicenter retrospective study in China: 19 subcommittee suggests that IGIV not
tions containing antibodies Among a cohort of 325 patients with severe be used routinely in critically ill adults
specific to SARS-CoV-2 may or critical COVID-19 disease, no difference with COVID-19 because efficacy data
theoretically help suppress in 28-day or 60-day mortality was observed not available, currently available IGIV
the virus and modulate the between patients who were treated with preparations may not contain antibod-
immune response to IGIV and those who were not treated with ies against SARS-CoV-2, and IGIV can be
COVID-19 infection. 2, 16 IGIV. However, patients who received IGIV associated with increased risk of severe
were older and more likely to have coro- adverse effects (e.g., anaphylaxis, asep-
Commercially available nary heart disease and critical status at tic meningitis, renal failure, thrombo-
preparations of immune study entry; patients also received numer- embolism, hemolytic reactions, transfu-
globulin (IGIV, IVIG, γ- ous other treatments which limit interpre- sion-related lung injury). 13
globulin) may contain anti- tation of these findings. 16, 19
bodies against some previ-
ously circulating corona- Retrospective study in China: 58 cases of
viruses. 2, 3, 13, 18 Antibodies severe or critical COVID-19 illness in ICU
that cross-react with SARS- patients were reviewed. 17 Patients re-
CoV-1, MERS-CoV, and ceived IGIV in addition to other treatments
SARS-CoV-2 antigens have (e.g., antiviral and anti-inflammatory
been detected in some agents). A statistically significant difference
currently available IGIV in 28-day mortality was observed between
products; 18 however, fur- patients who received IGIV within 48 hours
ther evaluation is neces- of admission compared with those who
sary to assess potential in received IGIV after 48 hours (23 vs 57%).
vivo activity of such anti- Treatment with IGIV within 48 hours also
SARS-CoV-2 antibodies was associated with reduced duration of
using functional tests such hospitalization and reduced ICU length of
as neutralization assays. 18
stay and need for mechanical ventilation.
17
Efficacy data not available from con-

trolled clinical studies to date.
Several clinical studies have been initiat-

ed to evaluate efficacy and safety of IGIV
or SARS-CoV-2 immune globulin in patients
with COVID-19, including the following
trials: 12
NCT04264858
NCT04350580
NCT04381858
NCT04261426
NCT04411667
Ivermectin 8:08 In vitro activity against Currently no known published data regard- No data to date to support use in the
Anthelmintic some human and animal ing efficacy or safety in the treatment of treatment of COVID-19
Updated viruses 1-6 COVID-19
5/15/20 Ivermectin plasma concentrations
In vitro evidence of activity attained with dosages recommended for
against SARS-CoV-2 in in- treatment of parasitic infections are
fected Vero-hSLAM cells substantially lower than concentrations
reported with high concen- associated with in vitro inhibition of
trations of the drug 1 SARS-CoV-2; 7, 9 pharmacokinetic model-
ing predicts that plasma concentrations
attained with dosages up to 10 times
higher than usual dosage also are sub-
stantially lower than concentrations
associated with in vitro inhibition of the
virus 9
FDA issued a warning concerning possi-

ble inappropriate use of ivermectin
products intended for animals as an
attempt to self-medicate for the treat-
ment of COVID-19 8
Nebulized Potential harm: Concern Nebulizer treatment used in clinical prac- American College of Allergy, Asthma &
drugs that use of nebulized drugs tice to treat influenza and other respirato- Immunology (ACAAI) recommends that
(e.g., albuterol) for the ry infections is thought to generate drop- nebulized albuterol should be adminis-
Added management of respirato- lets or aerosols. In one study, nebulized tered in a location that minimizes expo-
3/27/20 ry conditions in patients saline delivered droplets in the small- and sure to close contacts who do not have
with COVID-19 infection medium-size aerosol/droplet range. These COVID-19 infection. In the home, choose
may distribute the virus results may have infection control implica- a location where air is not recirculated
into the air and expose tions for airborne infections, including (e.g., porch, patio, or garage) or areas
close contacts.1, 2 severe acute respiratory syndrome and where surfaces can be cleaned easily or
pandemic influenza infection. 3 may not need cleaning. 1
In hospitals, clinicians typically use nebu-

lizers to deliver medications such as
albuterol, but are being encouraged to
switch to use of metered-dose inhalers
because of the risk of the virus becom-
ing airborne when treating patients
infected with COVID-19. 2
Niclosamide 8:08 Broad antiviral activity Currently no known published clinical trial Protocol in one ongoing trial Not commercially available in the US
Anthelmintic data regarding efficacy or safety in the (NCT04372082) for treatment of
Updated In vitro evidence of activity treatment of COVID-19 COVID-19 specifies a niclosamide No data to date support use in treat-
5/28/20 against SARS-CoV and MERS dosage of 2 g on day 1, then 500 mg ment of COVID-19
-CoV 1,2 In drug repurposing screens, was found to twice daily for 10 days 3
inhibit replication and antigen synthesis of
SARS-CoV; did not interfere with virion’s Protocol in one ongoing trial
attachment into cells 1, 2 (NCT04399356) for treatment of
mild to moderate COVID-19 specifies
Randomized, open-label, controlled trial in a dosage of 2 g once daily for 7 days
3
France (NCT04372082; HYdiLIC) to evaluate
niclosamide in adults with SARS-CoV-2
infection (asymptomatic or onset of symp-
toms less than 8 days previously) and
comorbidities 3
Randomized, double-blind placebo-

controlled trial in Boston, (NCT04399356)
to evaluate niclosamide in adults with mild
to moderate COVID-19 3
Nitazoxanide 8:30.92 In vitro activity against vari- Currently no known published clinical trial Dosages investigated for treatment Current data not specific to COVID-19;
Antiprotozoal ous viruses, including coro- data regarding efficacy or safety in the of influenza and influenza-like ill- additional study needed 1
Updated naviruses 4, 5 treatment of COVID-19 ness or being investigated for other
5/28/20 viral infections: Adults and adoles-
Structurally similar to niclos- Experience in treating influenza: In a ran- cents (≥12 years of age): 500 or 600
amide 3, 5 domized, placebo-controlled study in 624 mg orally twice daily for 5 days 6, 7, 8
otherwise healthy adult and adolescent
In vitro evidence of activity patients with acute uncomplicated influen- Protocol in one ongoing trial
against SARS-CoV-2 1 za, treatment with nitazoxanide reduced (NCT04348409) for treatment of
duration of symptoms by approximately 1 moderate COVID-19 specifies a nita-
In vitro activity against day 6 zoxanide dosage of 600 mg twice
MERS-CoV 4 daily for 7 days 8
Experience in treating influenza-like ill-
Suppresses production of ness: In two studies for the treatment of Protocol in two ongoing trials
proinflammatory cytokines influenza-like illness symptoms associated (NCT04343248, NCT04359680) eval-
in peripheral blood mono- with viral respiratory infection in 186 adults uating pre- and/or post-exposure
nuclear cells; suppresses IL- and pediatric pts, treatment with nitazoxa- prophylaxis of COVID-19 and other
6 in mice 4 nide reduced duration of symptoms (4 days viral respiratory illnesses specifies a
versus ≥7 days with placebo). 7 In another nitazoxanide dosage of 600 mg oral-
study in 260 adults and pediatric pts hospi- ly twice daily for 6 weeks 8
talized with influenza-like illness (≥50%
with pneumonia at presentation), treat- Results of a physiologically based
ment with nitazoxanide did not reduce the pharmacokinetic model predict that
duration of hospital stay (primary end nitazoxanide dosages of 1200 mg 4
point) or duration of symptoms 7 times daily, 1600 mg 3 times daily,
and 2900 mg twice daily in the fast-
ed state and 700 mg 4 times daily,
COVID-19: Randomized, double-blind, 900 mg 3 times daily, and 1400 mg
placebo-controlled proof-of-concept trial twice daily in the fed state are capa-
(NCT04348409) initiated to evaluate nita- ble of maintaining plasma and lung
zoxanide for treatment of moderate COVID tizoxanide (major metabolite of nita-
-19 8 zoxanide) exposures exceeding the
EC90 for SARS-CoV-2 9
Two randomized, double-blind, placebo-
controlled clinical trials have been initiat-
ed by the manufacturer (Romark) to evalu-
ate efficacy and safety for pre- or post-
exposure prophylaxis of COVID-19 and
other viral respiratory illnesses in
healthcare workers (NCT04359680) and
post-exposure prophylaxis of COVID-19 and
other viral respiratory illnesses in elderly
residents of long-term care facilities
(NCT04343248) 8
Multiple other clinical trials planned or

initiated to evaluate nitazoxanide in com-
bination with other drugs (chloroquine,
hydroxychloroquine, or ivermectin) or
alone for treatment of COVID-19 8
Nonsteroidal 28:08.04 Ibuprofen: Speculative link Ibuprofen: None; anecdotal 1 Ibuprofen: A letter published in The
Anti- Nonsteroidal between ibuprofen and Lancet Respir Med stated that increased
inflammatory Anti- increased ACE2 expression Indomethacin: In vitro studies and animal expression of ACE2 could facilitate in-
Agents inflammatory leading to worse outcomes models only; 6, 7 currently no published fection with COVID-19. The letter states
(NSAIAs) Agent in COVID-19 patients, and studies evaluating use specifically in COVID- that thiazolidinediones and ibuprofen
(NSAIA) should NOT be used in pa- 19 patients can increase ACE2; however, this ap-
Updated tients with COVID-19 1 pears to be based on animal studies. 1, 4
6/18/20
Indomethacin: In vitro anti- A statement attributed to WHO spokes-
viral activity in SARS-CoV-2 person Christian Lindmeier recommend-
pseudovirus-infected Vero ing paracetamol and avoiding ibuprofen
E6 cells; 7 also has in vitro as a self-medication was widely circulat-
activity against other coro- ed in the media; however, such a posi-
naviruses: SARS-CoV-1 (in tion could not be found on the WHO
Vero E6 and human pulmo- website or other official sources. WHO
nary epithelial [A549] cells) has stated "after a rapid review of the
and canine coronavirus; also literature, is not aware of published
has in vivo activity against clinical or population-based data on this
canine coronavirus in dogs 6, topic." WHO states that there is no
7
(interferes with viral RNA evidence of severe adverse events or
synthesis) 6, 8 effects on acute health care utilization,
long-term survival, or quality of life in
patients with COVID-19 as a result of
the use of NSAIAs. 9
There have been unsubstantiated re-

ports of younger, healthy patients who
took ibuprofen and suffered severe
outcomes with COVID-19. Official case
reports are lacking.
On 3/19/20, FDA issued a statement
that it is not aware of scientific evidence
connecting the use of NSAIAs, such as
ibuprofen, with worsening COVID-19
symptoms. FDA stated that it is investi-
gating this issue further and will com-
municate publicly when more infor-
mation is available. FDA also noted that
all prescription NSAIA labels warn that
by reducing inflammation, and possibly
fever, these drugs may diminish the
utility of diagnostic signs in detecting
infections. https://www.fda.gov/drugs/
drug-safety-and-availability/fda-advises-
patients-use-non-steroidal-anti-
inflammatory-drugs-nsaids-covid-19
Therefore, currently no compelling evi-

dence to support an association be-
tween ibuprofen and negative out-
comes in patients with COVID-19. How-
ever, some experts have recommended
preferentially using acetaminophen for
treatment of fever 2, 3, 4
NIH COVID-19 Treatment Guidelines

Panel states that patients who are re-
ceiving NSAIAs for other conditions
should continue receiving the drugs;
states antipyretic strategy (e.g., use of
acetaminophen or NSAIAs) should be no
different between patients with or with-
out COVID-19. 5
The Surviving Sepsis Campaign COVID-

19 guidelines state that until more evi-
dence is available, use of acetamino-
phen over no treatment for fever con-
trol is suggested (weak recommenda-
tion) 2
Indomethacin: Additional data needed

to determine whether in vitro activity
against SARS-CoV-2 corresponds with
clinical efficacy in the treatment of
COVID-19
Tissue Plas- 20:12.20 A consistent finding in Results of a small phase 1 study suggested Two dosage regimens of t-PA t-PA has been proposed as a salvage
minogen Thrombolytic patients with severe COVID possible benefit of plasminogen activators (alteplase) are being evaluated in the treatment for COVID-19 patients (e.g.,
Activator (t- agents -19 is a hypercoagulable in the treatment of ARDS.1-3 In this study, open-label systemic fibrinolytic ther- those with decompensating respiratory
PA; alteplase) state, which has been 20 patients with ARDS secondary to trauma apy trial (NCT04357730): 50 mg function who do not have access to
shown to contribute to and/or sepsis who failed to respond to (administered as a 10-mg IV bolus mechanical ventilation or extracorpore-
Updated poor outcomes (e.g., pro- standard ventilator therapy and were not followed by IV infusion of the real membrane oxygenation [ECMO]). 1 , 13,
14
6/3/20 gressive respiratory failure, expected to survive were treated with uro- maining 40 mg over a total time of 2
acute respiratory distress kinase or streptokinase; such therapy im- hours) and 100 mg (administered as Several institutions (Beth Israel Deacon-
syndrome [ARDS], death). 1- proved PaO2 and also appeared to improve a 10-mg IV bolus dose followed by IV ess, University of Colorado Anschultz
3, 5-9, 14, 16, 18, 19
survival. 1-3 administration of the remaining 90 Medical Campus, Denver Health) are
mg over a total time of 2 hours); a currently testing this approach under
Coagulation abnormalities In a case series of 5 COVID-19 patients who heparin infusion will be initiated the FDA compassionate use program. 2, 4
observed include pro- had severe hypoxemia, declining respirato- immediately following completion of Preliminary findings from the first few
12
thrombotic disseminated ry status, and increasing oxygen require- the alteplase infusion cases reported an initial, but transient
intravascular coagulation ments, administration of t-PA (alteplase) at improvement in PaO2/FiO2 (P/F) ratio. 9
(DIC), venous thromboem- an initial IV bolus dose of 25 mg over 2 Other dosage regimens have been
bolism, elevated D-dimer hours followed by a continuous IV infusion evaluated in patients with COVID-19, The NIH COVID-19 Treatment Guide-
levels, high fibrinogen lev- of 25 mg over the next 22 hours appeared including an initial t-PA (alteplase) lines Panel states that current data are
els, and microvascular and to improve oxygen requirements in all pa- dose of 25 mg administered IV over 2 insufficient to recommend for or against
macrovascular thrombosis. tients and prevent progression to mechani- hours, followed by an IV infusion of the use of thrombolytic agents in hospi-
1, 2, 5-10, 13, 14, 16
cal ventilation in 3 of the patients; howev- 25 mg of t-PA over the subsequent talized COVID-19 patients outside the
er, multiple confounding factors limit inter- 22 hours, with a dose not to exceed setting of a clinical trial; patients who
20
A consistent finding in pretation of these findings. 0.9 mg/kg; however, the optimum develop catheter thrombosis or other
patients with ARDS dose, route of administration, and indications for thrombolytic therapy
(regardless of the cause) is An open-label, randomized trial duration of treatment remain to be should be treated according to the usual
fibrin deposition and mi- (NCT04357730) is being conducted to eval- determined. 1, 9, 14, 20 standard of care in patients without
crothrombi formation in uate systemic fibrinolytic therapy with t-PA COVID-19. 17
the alveoli and pulmonary versus standard of care in mechanically
vasculature. 1, 11, 14 ventilated COVID-19 patients with severe The American Society of Hematology
Dysregulation of the 12 states that treatment of the underlying
respiratory failure
clotting system in ARDS is a pathology is paramount in COVID-19
result of both enhanced An open-label, nonrandomized pilot study patients with coagulopathies; sup-
activation of coagulation (NCT04356833) is being conducted to eval- portive care should be individualized
and suppression of fibrinol- uate an inhaled formulation of t-PA (via and standard risk factors for bleeding
ysis. 12, 19 nebulization) in patients with ARDS due to should be considered. 8
12
COVID-19; the inhaled formulation of t-
Thrombolytic therapy may PA is investigational at this time
15
restore microvascular pa-
tency and limit progression
of ARDS in patients with
COVID-19 1, 14, 19
a See US prescribing information for additional information on dosage and administration of drugs commercially available in the US for other labeled indications.
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Baloxavir:
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Colchicine:
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Corticosteroids, including methylprednisolone:

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Favipiravir
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HMG-CoA Reductase Inhibitors (statins)

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Immune Globulin:
1. AHFS drug information 2020. Snow EK, ed. Immune Globulin. Bethesda, MD. American Society of Health-System Pharmacists; 2020: 3433-53. (https://www.ahfscdi.com/drugs/382815)
2. Jawhara S. Could intravenous immunoglobulin collected from recovered coronavirus patients protect against COVID-19 and strengthen the immune system of new patients? Int J Mol Sci.
2020; 21. (http://dx.doi.org/10.3390/ijms21072272). PMID: 32218340 DOI: 10.3390/ijms21072272
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Interferons:
1. Mantlo E, Bukreyeva N, Maruyama J et al. Antiviral activities of type I interferons to SARS-CoV-2 infection. Antiviral Res. 2020 Apr 29; 179:104811. DOI: 10.1016/j.antiviral.2020.104811. PMID:
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2. Sallard E, Lescure FX, Yazdanpanah Y et al. Type 1 interferons as a potential treatment against COVID-19. Antiviral Res. 2020 Apr 7; 178:104791. DOI: 10.1016/j.antiviral.2020.104791. PMID:
32275914.
3. Lokugamage KG, Hage A, Schindewolf C et al. SARS-CoV-2 is sensitive to type I interferon pretreatment. Preprint (not peer reviewed). bioRxiv. 2020 Apr 9;2020.03.07.982264. DOI:
10.1101/2020.03.07.982264. PMID: 32511335.
4. Prokunina-Olsson L, Alphonse N, Dickenson RE et al. COVID-19 and emerging viral infections: the case for interferon lambda. J Exp Med. 2020; 217:e20200653. DOI: 10.1084/jem.20200653.
PMID: 32289152.
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6. Mordstein M, Neugebauer E, Ditt V et al. Lambda interferon renders epithelial cells of the respiratory and gastrointestinal tracts resistant to viral infections. J Virol. 2010; 84:5670-7. DOI:
10.1128/JVI.00272-10. PMID: 20335250.
7. O’Brien TR, Thomas DL, Jackson SS et al. Weak induction of interferon expression by SARS-CoV-2 supports clinical trials of interferon lambda to treat early COVID-19. Clin Infect Dis. 2020 Apr
17:ciaa453. DOI: 10.1093/cid/ciaa453. PMID: 32301957.
8. Stockman LJ, Bellamy R, Garner P et al. SARS: systematic review of treatment effects. PLoS Med. 2006; 3:e343. DOI: 10.1371/journal.pmed.0030343. PMID: 16968120.
9. Arabi YM, Shalhoub S, Mandourah Y et al. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: a multicenter observational study. Clin Infect Dis.
2020; 70:1837-1844. DOI: 10.1093/cid/ciz544. PMID: 31925415.
10. Hung IF, Lung KC, Tso EY et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, ran-
domised, phase 2 trial. Lancet. 2020; May 8: S0140-6736(20)31042-4. DOI: 10.1016/S0140-6736(20)31042-4. PMID: 32401715.
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14. Qiu H, Wu J, Hong L et al. Clinical and epidemiological features of 36 children with coronavirus disease 2019 (COVID-19) in Zhejiang, China: an observational cohort study. Lancet Infect Dis.
2020; Mar 25:S1473-3099(20)30198-5. DOI: 10.1016/S1473-3099(20)30198-5. PMID: 32220650.
15. Zhou Q, Chen V, Shannon CP et al. Interferon-α2b treatment for COVID-19. Preprint (not peer reviewed). Available at medRxiv website (https://www.medrxiv.org). Posted 2020 Apr 10. DOI:
10.1101/2020.04.06.20042580.
16. U.S. National Library of Medicine. ClinicalTrials website (https://www.clinicaltrials.gov/ct2/results?cond=COVID&term=interferon+beta&cntry=&state=&city=&dist=). Accessed 2020 May 18.
17. Ranieri VM, Pettilä V, Karvonen MK et al. Effect of intravenous interferon β-1a on death and days free from mechanical ventilation among patients with moderate to severe acute respiratory
distress syndrome: a randomized clinical trial. JAMA. 2020; 323:725-33. DOI: 10.1001/jama.2019.22525. PMID: 32065831.
18. Chu H, Chan JFW, Wang Y et al. Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis
of COVID-19. Clin Infect Dis. 2020 Apr 9:ciaa410. DOI: 10.1093/cid/ciaa410. PMID: 32270184.
19. Andreakos E, Salagianni M, Galani IE et al. Interferon-λs: front-line guardians of immunity and homeostasis in the respiratory tract. Front Immunol. 2017; 8:1232. DOI: 10.3389/
fimmu.2017.01232. PMID: 29033947.
20. Davoudi-Monfared E, Rahmani H, Khalili H et al. Efficacy and safety of interferon β-1a in treatment of severe COVID-19: A randomized clinical trial. Preprint (not peer reviewed). Available at
medRxiv website (https://www.medrxiv.org). Posted 2020 May 30. DOI: 10.1101/2020.05.28.20116467.
Ivermectin:
1. Caly L, Druce JD, Catton MG et al. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020. Preprint. (https://www.sciencedirect.com/science/
article/pii/S0166354220302011?via%3Dihub).
2. Mastrangelo E, Pezzullo M, De Burghgraeve T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimi-
crob Chemother. 2012; 67:1884-94. PMID: 22535622 DOI:10.1093/jac/dks147.
3. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 2020. PMID: 32134219 DOI:
10.1016/j.antiviral.2020.104760.
4. Varghese FS, Kaukinen P, Glasker S, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antiviral Res. 2016. 126:117-24. PMID:
26752081 DOI: 10.1016/j.antiviral.2015.12.012.
5. Azeem S, Ashraf M, Rasheed MA, et al. Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus. Pak J Pharm Sci. 2015; 28:597-602. PMID: 25730813.
6. Tay MY, Fraser JE, Chan WK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor ivermectin. Antiviral Res.
2013; 99:301-6. PMID: 23769930 DOI: 10.1016/j.antiviral.2013.06.002.
7. Momekov G, Momekova D. Ivermectin as a potential COVID-19 treatment from the pharmacokinetic point of view. 2020. Preprint. (https://doi.org/10.1101/2020.04.11.20061804). DOI:
10.1101/2020.04.11.20061804.
8. US Food and Drug Administration. FDA letter to stakeholders: do not use ivermectin intended for animals as treatment for COVID-19 in humans. April 10, 2020. From FDA website. (https://
www.fda.gov/animal-veterinary/product-safety-information/fda-letter-stakeholders-do-not-use-ivermectin-intended-animals-treatment-covid-19-humans).
9. Schmith VD, Zhou JJ, Lohmer LR. The approved dose of ivermectin alone is not the ideal dose for the treatment of COVID-19. Clin Pharmacol Ther. 2020; May 7. PMID: 32378737 DOI: 10.1002/
cpt.1889
Nebulized drugs:
1. American College of Allergy, Asthma & Immunology. COVID-19 and asthma: What you need to know moving forward. From ACAAI website. Accessed 2020 Mar 24. Available from https://
acaai.org/news/covid-19-and-asthma-what-you-need-know-moving-forward.
2. American College of Allergy, Asthma & Immunology. ACAII announces U.S. albuterol inhaler shortage: a message to asthma sufferers about a shortage of albuterol metered-dose inhalers.
From Allergic Living website. Accessed 2020 Mar 25. Available from https://www.allergicliving.com/2020/03/20/acaai-announces-u-s-albuterol-inhaler-shortage/.
3. Simonds AK, Hanak A, Chatwin M et al. Evaluation of droplet dispersion during non-invasive ventilation, oxygen therapy, nebuliser treatment and chest physiotherapy in clinical practice: im-
plications for management of pandemic influenza and other airborne infections. Health Technol Assess. 2010; 14(46):131-72. PMID: 20923611 DOI: 10.3310/hta14460-02.
Neuraminidase Inhibitors (e.g., oseltamivir):

1. Chen N, Zhou M, Dong X et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–513.
PMID: 32007143 DOI: 10.1016/S0140-6736(20)30211-7
2. Lu H. Drug treatment options for the 2019-new coronavirus (2019-nCoV). Biosci Trends. 2020;14:69–71. PMID: 31996494 DOI: 10.5582/bst.2020.01020
3. Singhal T. A Review of Coronavirus Disease-2019 (COVID-19). Indian J Pediatr. 2020. PMID: 32166607 DOI: 10.1007/s12098-020-03263-6
4. Tan EL, Ooi EE, Lin CY et al. Inhibition of SARS coronavirus infection in vitro with clinically approved antiviral drugs. Emerg Infect Dis. 2004;10:58–6. PMID: 15200845 DOI: 10.3201/
eid1004.030458
5. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 May 6. Available at https://clinicaltrials.gov.
Niclosamide:
1. Wu CJ, Jan JT, Chen CM et al. Inhibition of severe acute respiratory syndrome coronavirus replication by niclosamide. Antimicrob Agents Chemother. 2004; 48:2693–6. PMID: 32125140 DOI:
10.1021/acsinfectdis.0c00052
2. Xu J, Shi PY, Li H et al. Broad Spectrum Antiviral Agent Niclosamide and Its Therapeutic Potential. ACS Infect Dis. 2020. PMID: 15215127. DOI: 10.1128/AAC.48.7.2693-2696.2004
3. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 May 26. Available at http://www.clinicaltrials.gov.
Nitazoxanide:
1. Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30:269–271. PMID: 32020029 DOI:
10.1038/s41422-020-0282-0
2. Beigel JH, Nam HH, Adams PL et al. Advances in respiratory virus therapeutics - A meeting report from the 6th isirv antiviral group conference. Antiviral Res. 2019; 167:45–67. PMID:
30974127 DOI: 10.1016/j.antiviral.2019.04.006
3. Xu J, Shi PY, Li H et al. Broad spectrum antiviral agent niclosamide and its therapeutic potential. ACS Infect Dis. 2020. PMID: 15215127. DOI: 10.1128/AAC.48.7.2693-2696.2004
4. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health. 2016 May–Jun; 9:227–30. PMID: 27095301 DOI:
10.1016/j.jiph.2016.04.001
5. Rossignol JF. Nitazoxanide: a first-in-class broad-spectrum antiviral agent. Antiviral Res. 201; 110: 94–103. PMID: 25108173 DOI: 10.1016/j.antiviral.2014.07.014
6. Haffizulla J, Hartman A, Hoppers M et al. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3
trial. Lancet Infect Dis. 2014; 14:609–18. PMID:24852376 DOI: 10.1016/S1473-3099(14)70717-0
7. Gamiño-Arroyo AE, Guerrero ML, McCarthy S et al. Efficacy and safety of nitazoxanide in addition to standard of care for the treatment of severe acute respiratory illness. Clin Infect Dis.
2019; 69:1903–1911. PMID: 30753384 DOI: 10.1093/cid/ciz100
9. Rajoli R, Pertinez H, Arshad U et al. Dose predication for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. medRxiv. Posted May 6, 2020. Preprint (not peer reviewed).
DOI: 10.1101/2020.05.01.20087130
Nitric Oxide (inhaled):

1. Akerstrom S, Mousavi-Jazi M, Klingstom J et al. Nitric oxide inhibits the replication cycle of severe acute respiratory syndrome coronavirus. J Virol. 2005; 79(3):1966-9. PMID: 15650225
DOI:10.1128/JVI.79.3.1966-1969.2005
2. Chen L, Liu P, Gao H et al. Inhalation of nitric oxide in the treatment of severely acute respiratory syndrome: a rescue trial in Beijing. Clin Infect Dis. 2004; 39(10):1531-5. PMID:15546092 DOI:
10.1086/425357
4. Fuller BM, Mohr NM, Skrupky L et al. The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta-analysis. Chest. 2015; 147(6):1510-22. PMID: 25742022 DOI:
10.1378/chest.14-3161
5. Griffiths MJD, McAuley DF, Perkins GD et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Resp Res. 2019; 6:e000420. PMID 31258917 DOI: 10.1136/
bmjresp-2019-000420
6. Papazian L, Aubron C, Brochard L et al. Formal guidelines: management of acute respiratory distress syndrome. Ann Intensive Care. 2019; 9(1): 69. PMID: PMID: 31197492 DOI: 10.1186/
s13613-019-0540-9.
7. Biospace. Mallinckrodt Evaluates the Potential Role for Inhaled Nitric Oxide to Treat COVID-19 Associated Lung Complications, Engages with Scientific, Governmental and Regulatory Agen-
cies. From the Biospace website. Accessed 2020 Mar 24. https://www.biospace.com/article/releases/mallinckrodt-evaluates-the-potential-role-for-inhaled-nitric-oxide-to-treat-covid-19-
associated-lung-complications-engages-with-scientific-governmental-and-regulatory-agencies/.
8. FDA Grants Bellerophon Emergency Expanded Access for INOpulse® for the Treatment of COVID-19 Virus [press release]. Warren, NJ; Bellerophon Therapeutics, Inc: 2020 Mar 20. http://
investors.bellerophon.com/news-releases/news-release-details/fda-grants-bellerophon-emergency-expanded-access-inopulser. Accessed 2020 Mar 24.
9. Gebistorf F, Karam O, Wetterslev J et al. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016; Jun 27 (6): 1-98. PMID:
27347773 DOI: 10.1002/14651858.CD002787.pub3.10. Alhazzani W, Moller MH, Arabi YM et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Corona-
virus Disease 2019 (COVID-19). Crit Care Med. 2020. PMID: 32224769 DOI: 10.1097/CCM.0000000000004363
10. Alhazzani W, Moller MH, Arabi YM et al. Surviving Sepsis Campaign: Guidelines on the Management of Critically Ill Adults with Coronavirus Disease 2019 (COVID-19). Crit Care Med. 2020.
PMID: 32224769 DOI: 10.1097/CCM.0000000000004363
11. Kobayashi J, Murata I. Nitric oxide inhalation as an interventional rescue therapy for COVID-19-induced acute respiratory distress syndrome. Ann Intensive Care. 2020;10(1):61. Published
2020 May 20. PMID: 32436029 DOI:10.1186/s13613-020-00681-9
13. Zamanian RT, Pollack CV Jr, Gentile MA et al. Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive IPAH and COVID-19 Infection [published online ahead of print, 2020 May 5]. Am J
Respir Crit Care Med. 2020;10.1164/rccm.202004-0937LE. PMID: 32369396 DOI:10.1164/rccm.202004-0937LE
14. Ignarro LJ. Inhaled NO and COVID-19 [published online ahead of print, 2020 Apr 28]. Br J Pharmacol. 2020;10.1111/bph.15085. PMID: 32346862 DOI:10.1111/bph.15085
NSAIAs, including ibuprofen:

1. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020; 8:e21. PMID: 32171062 DOI: 10.1016/
S2213-2600(20)30116-8
2. Alhazzani W, Moller MH, Arabi YM, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med.
2020; 46:854-87. PubMed: 32222812 DOI: 10.1007/s00134-020-06022-5
3. Sodhi M, Etminan M, Safety of Ibuprofen in Patients with COVID-19; Causal or Confounded? CHEST. 2020 Mar 31 [Epub ahead of print]. PubMed: 32243944 DOI: https://doi.org/10.1016/
j.chest.2020.03.040
4. Gupta R, Misra. Contentious issues and evolving concepts in the clinical presentation and management of patients with COVID-19 infection with reference to use of therapeutic and other
drugs used in co-morbid diseases (hypertension, diabetes etc). Diabetes Metab Syndr. 2020; 14:251-254. PubMed: 32247213 DOI: 10.1016/j.dsx.2020.03.012
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6. Amici C, Di Caro A, Ciucci A, et al. Indomethacin has a potent antiviral activity against SARS coronavirus. Antivir Ther. 2006; 11:1021-30. PMID: 17302372
7. Xu T, Gao X, Wu Z, et al. Indomethacin has a potent antiviral activity against SARS CoV-2 in vitro and canine coronavirus in vivo. Preprint. (not peer reviewed). (DOI: https://
doi.org/10.1101/2020.04.01.017624)
8. Clark C. Indomethacin in Covid-19. From MedicalUpdateOnline website. Available at https://medicalupdateonline.com/2020/05/indomethacincovid19/. May 4, 2020. Accessed May 14, 2020.
9. World Health Organization. The use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with COVID-19: Scientific brief, 2020 April 19. Available at https://apps.who.int/iris/
handle/10665/331796. Accessed 2020 Jun 15.
Remdesivir:
1. Wang M, Cao R, Zhang L et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020; 30:269-271. (PubMed 32020029)
(DOI 10.1038/s41422-020-0282-0)
2. Agostini ML, Andres EL, Sims AC et al. Coronavirus Susceptibility to the Antiviral Remdesivir (GS-5734) Is Mediated by the Viral Polymerase and the Proofreading Exoribonuclease. mBio. 2018;
9. (PubMed 29511076) (DOI 10.1128/mBio.00221-18)
3. Brown AJ, Won JJ, Graham RL et al. Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase.
Antiviral Res. 2019; 169:104541. (PubMed 31233808) (DOI 10.1016/j.antiviral.2019.104541)
4. Sheahan TP, Sims AC, Graham RL et al. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med. 2017; 9. (PubMed 28659436) (DOI 10.1126/
scitranslmed.aal3653)
5. de Wit E, Feldmann F, Cronin J et al. Prophylactic and therapeutic (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci U S A. 2020; (PubMed
32054787) (DOI 10.1073/pnas.1922083117)
6. Gordon CJ, Tchesnokov EP, Feng JY et al. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. J Biol
Chem. 2020; (PubMed 32094225) (DOI 10.1074/jbc.AC120.013056)
7. Sheahan TP, Sims AC, Leist SR et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun. 2020; 11:222.
(PubMed 31924756) (DOI 10.1038/s41467-019-13940-6)
8. Ko WC, Rolain JM, Lee NY et al. Arguments in favor of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents. 2020; :105933. Editorial. (PubMed 32147516) (DOI 10.1016/
j.ijantimicag.2020.105933)
9. Martinez MA. Compounds with therapeutic potential against novel respiratory 2019 coronavirus. Antimicrob Agents Chemother. 2020; (PubMed 32152082) (DOI 10.1128/AAC.00399-20)
10. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with severe coronavirus disease (COVID-19). NCT04292899. (https://www.clinicaltrials.gov/ct2/show/
NCT04292899)
11. Study to evaluate the safety and antiviral activity of remdesivir (GS-5734) in participants with moderate coronavirus disease (COVID-19) compared to standard of care treatment.
NCT04292730. (https://www.clinicaltrials.gov/ct2/show/NCT04292730)
12. Expanded access remdesivir (RDV; GS-5734). (https://www.clinicaltrials.gov/ct2/show/NCT04302766)
13. Adaptive COVID-19 treatment trial (ACTT). NCT04280705. (https://clinicaltrials.gov/ct2/show/NCT04280705).
14. Lai CC, Liu YH, Wang CY et al. Asymptomatic carrier state, acute respiratory disease, and pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Facts and myths. J
Microbiol Immunol Infect. 2020; (PubMed 32173241) (DOI 10.1016/j.jmii.2020.02.012)
15. Gilead Sciences. Emergency access to remdesivir outside of clinical trials. From Gilead website. Accessed 2020 May 24. (https://www.gilead.com/purpose/advancing-global-health/covid-19/
emergency-access-to-remdesivir-outside-of-clinical-trials)
16. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med. 2020; 382:2327-2336. PMID: 32275812 DOI: 10.1056/NEJMoa2007016.
17. Expanded access treatment protocol: remdesivir (RDV; GS-5734) for the treatment of SARS-CoV2 (CoV) infection (COVID-19). Update posted May 13, 2020. NCT04323761. (https://
www.clinicaltrials.gov/ct2/show/NCT04323761?cond=NCT04323761).
18. Choy KT, Wong AYL, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antivir Res. 2020 Apr 3; 178 [Epub ahead of print].
(https://doi.org/10.1016/j.antiviral.2020.104786). PMID: 32251767 DOI: 10.1016/j.antiviral.2020.104786.
19. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Nature. 2020 Jun 9 [Epub ahead of print]. PMID: 32516797 DOI:
10.1038/s41586-020-2423-5..
20. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Updated 2020 Jun 11. From NIH website https://www.covid19treatmentguidelines.nih.gov/). Ac-
cessed 2020 Jun 12.
21. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomized, double-blind, placebo-controlled, multicentre trial. Lancet. 2020; 395: 1569-78. PMID: 32423584 DOI:
10.1016/S0140-6736(20)31022-9. (https://doi.org/10.1016/S0140-6736(20)31022-9)
22. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of COVID-19–preliminary report. N Engl J Med. 2020 May 22 [Epub ahead of print]. PMID: 32445440 DOI: 10.1056/
NEJMoa2007764
23. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 days in patients with severe covid-19. N Engl J Med. 2020 May 27. PMID: 32459919 DOI: 10.1056/NEJMoa2015301
24. Gordon CJ, Tshesnokov EP, Woolner E et al. Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with
high potency. J Biol Chem. 2020; 295:6785-6797. PMID: 32284326 DOI: 10.1074/jbc.RA120.013679
25. US Food and Drug Administration. Letter of authorization: Emergency use authorization for use of remdesivir for the treatment of hospitalized 2019 coronavirus disease (COVID-19) patients.
2020 May 1. From FDA website. (https://www.fda.gov/media/137564/download)
26. US Food and Drug Administration. Fact sheet for health care providers: Emergency use authorization (EUA) of remdesivir (GS-5734). Revised 2020 Jun. From FDA website. (https://
www.fda.gov/media/137566/download)
27. US Food and Drug Administration. Fact sheet for patients and parent/caregivers: Emergency use authorization (EUA) of remdesivir for coronavirus disease 2019 (COVID-19). From FDA web-
site. (https://www.fda.gov/media/137565/download)
28. US Department of Health and Human Services. HHS announces shipments of donated remdesivir for hospitalized patients with COVID-19. May 9, 2020. From HHS website. (https://
www.hhs.gov/about/news/2020/05/09/hhs-ships-first-doses-of-donated-remdesivir-for-hospitalized-patients-with-covid-19.html)
29. National Institutes of Health. NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins. 2020 May 8. From NIH website. (https://www.nih.gov/
news-events/news-releases/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib-covid-19-begins). Accessed 2020 May 11.
30. Gilead Sciences. Gilead announces results from phase 3 trial of remdesivir in patients with moderate COVID-19. Press release. 2020 Jun 1. Available at https://www.gilead.com/news-and-
press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19.
31. Adaptive COVID-19 treatment trial 2 (ACTT-II). NCT04401579. (https://www.clinicaltrials.gov/ct2/show/NCT04401579).
32. A study to evaluate the efficacy and safety of remdesivir plus tocilizumab compared with remdesivir plus placebo in hospitalized participants with severe COVID-19 pneumonia (REMDACTA).
NCT04409262. (https://www.clinicaltrials.gov/ct2/show/NCT04409262).
33. US Food and Drug Administration. Communication regarding remdesivir and newly discovered potential drug interactions that may reduce effectiveness of treatment. 2020 Jun 15. Available
at FDA website (https://www.fda.gov/safety/medical-product-safety-information/remdesivir-gilead-sciences-fda-warns-newly-discovered-potential-drug-interaction-may-reduce).
Ruxolitinib
1. Incyte announces plans to initiate a phase 3 clinical trial of ruxolitinib (Jakafi®) as a treatment for patients with COVID-19 associated cytokine storm. Press release. Incyte: 2020 Apr 2. (https://
investor.incyte.com/news-releases/news-release-details/incyte-announces-plans-initiate-phase-3-clinical-trial).
2. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 May 1. Available from https://clinicaltrials.gov/ct2/show/NCT04337359.
3. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 May 29. Available from https://clinicaltrials.gov/ct2/results?cond=COVID&term=ruxolitinib&cntry=&state=&city=&dist=.
4. Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020; 395:1033-4. PMID: 32192578. DOI: 10.1016/S0140-6736(20)
30628-0.
from China. Clin Immunol. 2020; 214: 108393. PMID: 32222466. DOI: 10.1016/j.clim.2020.108393.
6. Chinese Clinical Trial Registry. Accessed 2020 Apr 7. Available at http://www.chictr.org.cn/enindex.aspx.
7. Elli EM, Barate C, Mendicino F et al. Mechanisms underlying the anti-inflammatory and Immunosuppressive activity of ruxolitinib. Front Oncol. 2019; 9:1186. PMID: 31788449. DOI: 10.3389/
fonc.2019.01186.
11. Gaspari V, Zengarini C , Greco S et al. Side effects of ruxolitinib in patients with SARS-CoV-2 infection: two case reports. Int J Antimicrob Agents. 2020 May 22 [Preproof]. PMID: 32450201.
DOI: 10.1016/j.ijantimicag.2020.106023.
Sarilumab:
1. Genentech, Inc, South San Francisco, CA. Actemra use in Coronavirus Disease 2019 (COVID-19) standard reply letter. 2020 Mar 16.
2. National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). (Mandarin;
English translation.) 2020 Mar 3.
4. Sanofi and Regeneron begin global Kevzara® (sarilumab) clinical trial program in patients with severe COVID-19 [press release]. Cambridge, Mass and Tarrytown, NY; Sanofi: March 16, 2020.
http://www.news.sanofi.us/2020-03-16-Sanofi-and-Regeneron-begin-global-Kevzara-R-sarilumab-clinical-trial-program-in-patients-with-severe-COVID-19. Accessed 2020 Mar 19.
5. Sanofi and Regeneron Pharmaceuticals, Inc, Cambridge, MA and Tarrytown, NY. Sarilumab and COVID-19 standard reply letter. 2020 Mar 24.
6. Sanofi Genzyme, Cambridge, MA: Personal communication.
cessed 2020 Jun 16.
8. Benucci M, Giannasi G, Cecchini P et al. COVID-19 pneumonia treated with sarilumab: a clinical series of eight patients. J Med Virol. 2020 May 30 [Epub ahead of print]. PMID 32472703 DOI:
10.1002/jmv.26062
9. Regeneron and Sanofi provide update on U.S. Phase 2/3 adaptive-designed trial Kevzara® (sarilumab) in hospitalized COVID-19 patients [press release]. Tarrytown, NY and Paris; Regeneron
Pharmaceuticals, Inc. and Sanofi: April 27, 2020. Accessed 2020 Jun 11.
Siltuximab:
1. Janssen Biotech, Inc. Sylvant® (siltuximab) injection, for intravenous use prescribing information. Horsham, PA; 2018 May.
2. Ceribelli A, Motta F, De Santis M. Recommendations for coronavirus infection in rheumatic diseases treated with biologic therapy. J Autoimmun. 2020; 109:102442. PMID: 32253068. DOI:
10.1016/j.jaut.2020.102442.
from China. Clin Immunol. 2020; 214:108393. PMID: 32222466. DOI: 10.1016/j.clim.2020.108393.
4. Gritti G, Raimondi F, Ripamonti D et al. Use of siltuximab in patients with COVID-19 pneumonia requiring ventilator support. Preprint (not peer reviewed). (https://
doi.org/10.1101/2020.04.01.20048561).
5. Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 16: pii: S0140- 6736(20)30628-0 [Epub ahead of print]. PMID
32192578. DOI: 10.1016/S0140-6736(20)30628-0.
6. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 May 7. Available from: https://www.clinicaltrials.gov/ct2/show/NCT04322188.
Sirolimus:
1. Stohr S, Costa R, Sandmann L et al. Host cell mTORC1 is required for HCV RNA replication. Gut. 2016; 65(12):2017-28. PMID 26276683 DOI: 10.1136/gutjnl-2014-308971
2. Kindrachuk J, Ork B, Hart BJ et al. Antiviral potential of ERK/MAPK and PI3K/AKT/mTOR signaling modulation for middle east respiratory syndrome coronavirus infection as identified by tem-
poral kinome analysis. Antimicrob Agents Chemother. 2015; 59(2):1088-99. PMID 25487801 DOI: 10.1128/AAC.03659-14
3. Wang CH, Chung FT, Lin SM et al. Adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe H1N1 pneumonia
and acute respiratory failure. Crit Care Med. 2014; 42:313-321. PMID: 24105455 DOI: 10.1097/CCM.0b013e3182a2727d.
5. Zhou Y, Hou Y, Shen J et al. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery. 2020; 6 (14): 1-18.
6. Arabi YM, Fowler R, and Hayden FG. Critical care management of adults with community-acquired severe respiratory viral infection. Intensive Care Med. 2020; 46(2): 315-28. PMID: 32040667
DOI: 10.1007/s00134-020-05943-5.
Tissue Plasminogen Activator (t-PA; alteplase):

1. Moore HB, Barrett CD, Moore EE et al. Is there a role for tissue plasminogen activator (tPA) as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome
(ARDS)?. J Trauma Acute Care Surg. 2020. 88(6): 713-714. DOI: 10.1097/TA.0000000000002694
2. Massachusetts Institute of Technology. MIT news: a stopgap measure to treat respiratory distress. From the MIT website. Accessed 2020 Apr 8. Available from http://news.mit.edu/2020/
covid-19-treat-respiratory-patients-plasminogen-0324
3. Hardaway RM, Harke H, Tyroch AH et al. Treatment of severe acute respiratory distress syndrome: a final report on a phase I study. Am Surg. 2001; 67: 377-82. PMID: 1130800
4. Beth Israel Deaconess Medical Center. BIDMC launches clinical trial to assess common anti-clotting medication for treatment of COVID-19-related respiratory failure. From the BIDMC web-
site. Accessed 2020 Apr 8. Available from https://www.bidmc.org/about-bidmc/news/2020/04/covid-19-anti-clotting-medication
5. Deng Y, Liu W, Liu K et al. Clinical characteristics of fatal and recovered cases of coronavirus disease 2019 (COVID-19) in Wuhan, China: a retrospective study. Chin Med J (Engl). 2020. PMID:
32209890 DOI: 10.1097/CM9.0000000000000824
6. Li T, Lu H, Zhang W. Clinical observation and management of COVID-19 patients. Emerg Microbes Infect. 2020; 9: 687-690. PMID: 32208840 DOI: 10.1080/22221751.2020.1741327
7. Wu C, Chen X, Cai Y et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern
Med. 2020. PMID: 32167524 DOI: 10.1001/jamainternmed.2020.0994
8. American Society of Hematology. COVID-19 and coagulopathy: frequently asked questions. From the ASH website. Accessed 2020 Apr 9. Available from https://www.hematology.org/covid-
19/covid-19-and-coagulopathy
9. Wang J, Hajizadeh N, Moore EE et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series. J Thromb Haemost.
2020. PMID: 32267998 DOI: 10.1111/jth.14828
10. Tang N, Li D, Wang X et al. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020; 18: 844-847. PMID:
32073213 DOI: 10.1111/jth.14768
11. MacLaren R, Stringer KA. Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. Pharmacotherapy. 2007; 27: 860-73. PMID: 17542769 DOI:
10.1592/phco.27.6.860
12. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Apr 22. Available at https://clinicaltrials.gov
13. Choudhury R, Barrett CD, Moore HB et al. Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: a Markov
decision analysis. World J Emerg Surg. 2020; 15: 29. PMID: 32312290 DOI: 10.1186/s13017-020-00305-4
14. Barrett CD, Moore HB, Yaffe MB et al. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: a comment. J Thromb Haemost. 2020. PMID: 32302462 DOI:
10.1111/jth.14860
15. Dunn JS, Nayar R, Campos J et al. Feasibility of tissue plasminogen activator formulated for pulmonary delivery. Pharm Res. 2005; 22: 1700-7. PMID: 16180128 DOI: 10.1007/s11095-005-6335
-8
16. Ranucci M, Ballotta A, Di Dedda U et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost. 2020. PMID: 32302448 DOI: 10.1111/
jth.14854
17. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. From NIH website (https://www.covid19treatmentguidelines.nih.gov/). Accessed 2020 Jun 1.
18. US Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19). Updated May 20, 2020. From CDC web-
site. Accessed 2020 Jun 1. (https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html).
19. Whyte CS, Morrow GB, Mitchell JL et al. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost.
2020. PMID: 32329246 DOI:10.1111/jth.14872
20. Christie DB 3rd, Nemec HM, Scott AM et al. Early outcomes with utilization of tissue plasminogen activator in COVID-19 associated respiratory distress: a series of five cases. J Trauma Acute
Care Surg. 2020. PMID: 32427774 DOI:10.1097/TA.0000000000002787
Tocilizumab:
1. Genentech, Inc, South San Francisco, CA. Actemra use in Coronavirus Disease 2019 (COVID-19) standard reply letter. 2020 Apr 20.
2. National Health Commission and State Administration of Traditional Chinese Medicine. Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia (Trial Version 7). (Mandarin;
English translation.) 2020 Mar 3.
4. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Apr 1. Available from https://clinicaltrials.gov/ct2/show/study/NCT04317092. NLM identifier: NCT04317092.
6. Mehta P, McAuley DF, Brown M et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 16: pii: S0140- 6736(20)30628-0 [Epub ahead of print].
PMID 32192578 DOI: 10.1016/S0140-6736(20)30628-0.
7. F. Hoffmann-La Roche Ltd. Roche initiates Phase III clinical trial of Actemra/RoActemra in hospitalized patients with severe COVID-19 pneumonia [press release]. Basel, Switzerland; Roche;
March 19, 2020. https://www.roche.com/dam/jcr:f26cbbb1-999d-42d8-bbea-34f2cf25f4b9/en/19032020-mr-actemra-covid-19-trial-en.pdf. Accessed 2020 Apr 2.
8. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Apr 2. Available from https://clinicaltrials.gov/ct2/show/study/NCT04320615. NLM identifier: NCT04320615.
9. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. From NIH website (https://www.covid19treatmentguidelines.nih.gov/). Accessed 2020 Apr 22.
10. Luo P, Liu Y, Qiu L et al. Tocilizumab treatment in COVID-19: a single center experience. J Med Virol. 2020 Apr 6. [Epub ahead of print.]
PubMed: 32253759 DOI: 10.1002/jmv.25801. Available from https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25801.
11. World Health Organization. WHO R&D Blueprint. COVID-19. Informal consultation on the potential role of IL-6/IL-1 antagonists in the clinical management of COVID 19 infection. 2020 Mar
25. Available at https://www.who.int/blueprint/priority-diseases/key-action/Expert_group_IL6_IL1_call_25_mar2020.pdf. Accessed 2020 Apr 27.
12. Alberici F, Delbarba E, Manenti C et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2
pneumonia. Kidney Int. 2020 Apr 21. [Epub ahead of print.] Available at https://doi.org/10.1016/j.kint.2020.04.002.
13. Zhang X, Song K, Tong F et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020; 4:1307-10. PubMed 32243501 DOI: 10.1182/
bloodadvances.2020001907.
14. Liu B, Li M, Zhou et al. Can we use interleukin-6 (IL-6) blockade for coronavirus disease 2019 (COVID-19)-induced cytokine release syndrome (CRS)? J Autoimmun. 2020;102452. [Epub ahead
of print.] DOI: 10.1016/j.jaut.2020.102452. Available at https://doi.org/10.1016/j.kint.2020.04.002
Umifenovir:
1. Deng L, Li C, Zeng Q, et al. Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. J Infect. 2020. PubMed: 32171872 DOI: 10.1016/
j.jinf.2020.03.002
2. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Mar 31. Available from https://clinicaltrials.gov/ct2/show/study/NCT04252885. NLM identifier: NCT04252885.
3. U.S. National Library of Medicine. ClinicalTrials.gov. Accessed 2020 Apr 1. Available from https://clinicaltrials.gov/ct2/show/study/NCT04260594. NLM identifier: NCT04260594
4. Blaising J, Polyak SJ, Pecheur EI. Arbidol as a broad-spectrum antiviral: an update. Antiviral Res. 2014; 107:88-94. PubMed: 24769245 DOI: 10.1016/j.antiviral.2014.04.006
5. Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020; 14:58-60. PubMed: 32147628 DOI: 10.5582/ddt.2020.01012
6. Chen C, Huang J, Cheng Z, et al. Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv. Posted March 27, 2020. Preprint (not peer reviewed). DOI: https://
doi.org/10.1101/2020.03.17.20037432
7. National Health Commission (NHC) & State Administration of Traditional Chinese Medicine (Trial Version 7). Diagnosis and treatment protocol for novel coronavirus pneumonia. (http://busan.
china-consulate.org/chn/zt/4/P020200310548447287942.pdf)
8. Zhu Z, Lu Z, Xu T, et al. Arbidol monotherapy is superior to lopinavir/ritonavir in treating COVID-19. J Infect. 2020. [Epub ahead of print]. PubMed: 32283143 DOI: 10.1016/j.jinf.2020.03.060
9. Lian N, Xie H, Lin S, et al. Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: A retrospective study. Clin Microbiol Infect. 2020. [Epub
ahead of print]. Pubmed: 32344167 DOI: 10.1016/j.cmi.2020.04.026
10. Li Y, Xie Z, Lin W, et al. Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med J. 2020. Journal pre
-proof. DOI: 10.1016/j.medj.2020.04.001
The information contained in this evidence table is emerging and rapidly evolving because of ongoing research and is subject to the professional judgment and interpretation of the practi-
tioner due to the uniqueness of each medical facility’s approach to the care of patients with COVID-19 and the needs of individual patients. ASHP provides this evidence table to help practi-
tioners better understand current approaches related to treatment and care. ASHP has made reasonable efforts to ensure the accuracy and appropriateness of the information presented.
However, any reader of this information is advised ASHP is not responsible for the continued currency of the information, for any errors or omissions, and/or for any consequences arising
from the use of the information in the evidence table in any and all practice settings. Any reader of this document is cautioned that ASHP makes no representation, guarantee, or warranty,
express or implied, as to the accuracy and appropriateness of the information contained in this evidence table and will bear no responsibility or liability for the results or consequences of
its use.

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Assessment of Evidence for COVID-19-Related Treatments: Updated 6/18/2020

ANTIVIRAL AGENTS SUPPORTING AGENTS OTHER

Another randomized controlled trial regis-

Emergency use authorization (EUA) for

followed by 800 mg twice daily on

US: Randomized, open-label trial For the treatment of COVID-19, one

LPV/RTV with ribavirin and interferon β-

LPV/RTV retrospective cohort study in

LPV/RTV Clinical Experience (COVID-19):

LPV/RTV Clinical Experience (SARS and

LPV/RTV COVID-19 Clinical Trials: Multiple

Darunavir COVID-19 Clinical Trials:

Hydroxychloroquine with azithromycin

Hydroxychloroquine (with or without

supportive management were analyzed for

Two different retrospective studies ana-

Rosenberg et al analyzed data for 1438 pts

Geleris et al analyzed data for 1376 pts

Large, randomized, controlled, adaptive

Large, multinational, retrospective study

Hydroxychloroquine for postexposure

Efficacy measures: Initial studies evalu-

Hydroxychloroquine with azithromycin

daily on day 1, then 200 mg twice daily for

Multiple clinical trials to evaluate hy-

Multiple clinical trials to evaluate hy-

Neither oseltamivir nor zanamivir has

Clinicaltrials.gov trials for COVID-19 that

treatment initiation or pts were accepted

Phase 3 randomized, open-label trial in

data indicate a statistically significant im-

Phase 3 adaptive, randomized, double-

survival benefit (Kaplan-Meier estimates of

Expanded access IND protocol

Compassionate use access: The manufac-

Compassionate use access (NCT04302766):

Data from the manufacturer’s compas-

Phase 3 adaptive, randomized, double-

Randomized, double-blind trial to com-

dose on day 1, then once-daily IV mainte-

Retrospective cohort study in 81 hospital-

Open-label, prospective, randomized,

When favipiravir was compared with

Randomized, single-center, partially blind-

NCT04260594 (not yet recruiting): Random-

Pneumonia: Limited study data available

Common cold: Effect of oral supplementa-

Multiple clinical trials to evaluate azithro-

In experimental models of Other registered randomized, parallel-

SARS-CoV-1 envelope (E)

Septic shock: The effect of corticoster-

Patients receiving corticosteroid thera-

Rheumatology experts, including mem-

Endocrinology experts state that pa-

Pregnancy considerations: For preg-

however, data demonstrating clinical bene- To provide a clinically important

Aerosolized IFN alfa (not commercially

Sub-Q peginterferon lambda-1a (not com-

Open-label, multicenter, randomized con-