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International Journal of General Medicine Dovepress

open access to scientific and medical research

Open Access Full Text Article


C L I N I C A L T R I A L R E P O RT

Efficacy of a Nasal Spray Containing Iota-Carrageenan


in the Postexposure Prophylaxis of COVID-19 in
Hospital Personnel Dedicated to Patients Care with
COVID-19 Disease

Juan Manuel Figueroa, 1 Mónica Edith Background: Iota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae,
Lombardo,2,3 Ariel Dogliotti,4 Luis Pedro
Flynn,5 Robert Giugliano,6 Guido Simonelli,7
with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of
Ricardo Valentini,2 Agñel Ramos,8 Pablo common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture.
Romano,9 Marcelo Marcote,10 Alicia Research Question: Can a nasal spray with Iota-Carrageenan be useful in the prophylaxis
Michelini,11 Alejandro Salvado,12 Emilio
of COVID-19 in health care workers managing patients with COVID-19 disease?
Sykora,13 Cecilia Kniz,14 Marcelo
Kobelinsky,15 David Manuel Salzberg, 16 Study Design and Methods: This is a pilot pragmatic multicenter, randomized, double-
Diana Jerusalinsky,17 Osvaldo Uchitel18 blind, placebo-controlled study assessing the use of a nasal spray containing I-C in the
1
Sleep and Respiratory Research Center, Instituto de prophylaxis of COVID-19 in hospital personnel dedicated to care of COVID-19 patients.
Ciencia y Tecnología Cesar Milstein, Ciudad Autónoma
de Buenos Aires, Argentina; 2Clinical Research Unit, Clinically healthy physicians, nurses, kinesiologists and other health care providers mana­
Hospital Universitario CEMIC, Ciudad Autónoma de ging patients hospitalized for COVID-19 were assigned in a 1:1 ratio to receive four daily
Buenos Aires, Argentina; 3Scientific Direction,
Nobeltri S.R.L, Ciudad Autónoma de Buenos Aires, doses of I-C spray or placebo for 21 days. The primary end point was clinical COVID-19, as
Argentina; 4Department of Cardiology, Instituto
Cardiovascular de Rosario, Rosario, Santa Fe, confirmed by reverse transcriptase polymerase chain reaction testing, over a period of 21
Argentina; 5Department of Infectology, Sanatorio de
Niños de Rosario, Rosario, Santa Fe, Argentina; days. The trial is registered at ClinicalTrials.gov (NCT04521322).
6
Division of Cardiovascular Medicine, Brigham and
Women’s Hospital, and Department of Medicine,
Results: A total of 394 individuals were randomly assigned to receive I-C or placebo. Both
Harvard Medical School, Boston, MA, USA; treatment groups had similar baseline characteristics. The incidence of COVID-19 differs
7
Département de Médecine, Université de Montréal
and Centre d’études avancées en médecine du som­ significantly between subjects receiving the nasal spray with I-C (2 of 196 [1.0%]) and those
meil, Hôpital du Sacré-Coeur de Montréal, Montréal,
Quebec, Canada; 8Intensive Care Department, receiving placebo (10 of 198 [5.0%]). Relative risk reduction: 79.8% (95% CI 5.3 to 95.4;
Sanatorio Parque de Rosario, Rosario, Santa Fe,
Argentina; 9Otolaryngology Department, Clínica p=0.03). Absolute risk reduction: 4% (95% CI 0.6 to 7.4).
y Maternidad Santa Isabel, Ciudad Autónoma de Interpretation: In this pilot study a nasal spray with I-C showed significant efficacy in
Buenos Aires, Argentina; 10Medical Direction
Department, Hospital Interzonal de Agudos Pte. preventing COVID-19 in health care workers managing patients with COVID-19 disease.
Perón, Avellaneda, Buenos Aires, Argentina;
11
Pulmonology Department, Hospital Pediátrico Clinical Trials Registration: NCT04521322.
Avelino Castelán, Resistencia, Chaco, Argentina;
12
Pulmonology Department, Hospital Británico de Keywords: COVID-19, prophylaxis, nasal, spray, hospital workers
Buenos Aires, Ciudad Autónoma de Buenos Aires,
Argentina; 13Department of Medicine, Clínica Monte
Grande, Monte Grande, Buenos Aires, Argentina;
14
Pulmonology Department, Hospital 4 de Junio
Dr Ramón Carrillo, Chaco, Argentina; 15Medical
Direction, Clínica Modelo De Morón, Morón,
Provincia de Buenos Aires, Argentina; 16Department of
Introduction
Family Medicine, Hospital Gral. de Agudos Dr. Teodoro A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV
Alvarez, Ciudad Autónoma de Buenos Aires,
Argentina; 17Cell Biology and Neurosciences Institute -2), was first identified in December 2019 as the cause of a respiratory illness called
(IBCN), Buenos Aires University–CONICET, Ciudad
Autónoma de Buenos Aires, Argentina; 18Institute of Coronavirus disease 2019, or COVID-19. Current available evidence shows that
Physiology, Molecular Biology and Neurosciences,
Buenos Aires University-CONICET, Ciudad COVID-19 virus (SARS-CoV-2) is transmitted between people through close contact
Autónoma de Buenos Aires, Argentina
and inhalation of droplets. Being in close contact with infected individuals is there­
fore a risk factor to contract COVID-19. Unvaccinated health care providers, who are
Correspondence: Juan Manuel Figueroa
Instituto de Ciencia y Tecnología Cesar Milstein, in close contact with COVID-19 patients are therefore at an increased risk for
Ciudad Autónoma de Buenos Aires, Argentina
Email figuejuan@gmail.com COVID-19. This inevitably places unvaccinated health and other hospital workers

International Journal of General Medicine 2021:14 6277–6286 6277


Received: 8 July 2021 © 2021 Figueroa et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.
Accepted: 14 September 2021 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the
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Figueroa et al Dovepress

at a high risk of infection. COVID-19 vaccine develop­ sold as an over-the-counter (OTC) product in Europe, Asia
ments have shown high efficacy at preventing COVID- and Australia, as part of a variety of over-the-counter
19,1,2 and vaccination rate among healthcare workers in products addressing common cold and related diseases
high income countries has grown steadily since the first (https://www.carragelose.com/en/portfolio/launched-
quarter of 2020.3–6 Nevertheless, vaccine production chal­ products). In Argentina a nasal spray with carrageenan has
lenges, distribution delays and global vaccine access have been approved by regulatory authorities and has been
once again highlighted global inequality. Developed nations available for use for more than 7 years (ANMAT disposi­
are vaccinating their populations much faster than less tion 5158–2013). The same spray is sold in many Latin
developed countries. To date, less than 10% of the world American countries (Belice, Costa Rica, registro sanitario
population has received the complete schedule of any of the M-AR-17-00376, Ministerio de Salud de la República de
vaccines and another 10% has received only one dose of Costa Rica), Guatemala (registro sanitario PF-51028-2020,
any of those vaccines requiring two doses. The distribution Ministerio de Salud Pública y Asistencia Social de
of vaccines shows great inequality: for example, the USA Guatemala), Honduras (registro sanitario M-21389,
and the United Kingdom have vaccinated more than 50% of Secretaría de Estado en el Despacho de Salud del
their population, while in Argentina and Colombia less than Gobierno de la República de Honduras), Panamá (registro
10% of the population has been vaccinated. In furtherance, sanitario 106976, Ministerio de Salud de la República de
more than 60 countries have a vaccination rate below the Panamá), Paraguay (registro sanitario 03686–01-DM
world average. At least 17,000 health workers have died Ministerio de Salud Pública y Bienestar Social de la
from COVID-19 over the last year, according to an analysis República del Paraguay), República Dominicana (registro
by Amnesty International, Public Services (https://www. sanitario 2016–0815 Ministerio de Salud Pública
amnesty.org/en/latest/news/2021/03/covid19-health-worker- y Asistencia Social de República Dominicana) and
death-toll-rises-to-at-least-17000-as-organizations-call-for- Uruguay (registro sanitario 44540, Ministerio de Salud
rapid-vaccine-rollout/). The need to develop additional low- Pública de la República Oriental del Uruguay), informa­
cost interventions to mitigate the risk of contracting tion provided by the Head of International Regulatory
COVID-19 among unvaccinated healthcare providers is Affairs of Laboratorio Pablo Cassará S.R.L., manufacturer
crucial for the global South, where vaccination rate among of the nasal spray in Argentina.
healthcare providers remains low. The existence of other Since the primary site of infection and replication of
prophylactic intervention against this disease is yet most cold-causing viruses is the nasal mucosa, it has been
unknown. hypothesized that early and targeted treatment of the nasal
Iota-Carrageenan – a sulfated polysaccharide found in mucosa with Iota-Carrageenan might block viral entry and
some species of red seaweed (Chondrus crispus) – has locally interferes with the propagation of viral replication.
demonstrated antiviral activity against respiratory and Three randomized clinical trials (two in adults and one
other viruses in cell culture and in animal models.7–10 Iota- in children) that compared Iota-Carrageenan nasal spray
Carrageenan inhibits viruses due to its interaction with the with saline solution (placebo) revealed high efficacy,
surface of viral particles, thus preventing them from enter­ including significantly reduced cold symptoms,15 faster
ing cells and trapping the viral particles released from the reduction of symptoms intensity16 and significant reduc­
infected cells.10–13 In vitro and in vivo studies have tion of viral loads14–16 in the carrageenan group.
demonstrated the effectiveness of Iota-Carrageenan against Treatments were safe and well tolerated.15–17
several respiratory viruses such as Human Rhinovirus, Iota-Carrageenan has demonstrated antiviral activity
influenza A and common cold Coronavirus.10–17 against SARS-CoV-2 virus and SARS-CoV-2 Spike
Carrageenan has been extensively used in food, cosmetic Pseudotyped Lentivirus (SSPL) in cell lines and in primary
and pharmaceutical industries, and is on the FDA list of differentiated human airway epithelial cultures.18–20 In
generally recognized as safe (GRAS) products for con­ preprint results, dilutions of the nasal spray available in
sumption (21 CFR 172.620). Carrageenan is contained in Latin America were effective in inhibiting SARS-CoV-2
medical device nasal spray that have been approved in infection in monkey kidney cell line (Vero) and human
USA (FDA Medical Devices Databases Establishment respiratory cell line (Calu-3).21,22
Registration & Device Listing D 441354). It has been Given that the concentrations found to be active
approved as a medical device class IIa in Europe and is in vitro against SARS-CoV-2 may be easily achieved by

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the application of nasal sprays already sold in several with COVID-19. Participants were excluded if they (a)
countries18 and that at the onset of the disease the virus had worked in an area without patients with a recent
is localized mainly in the nasal cavity and the diagnosis of COVID no longer than 24 hours, (b) they
nasopharynx,23 we hypothesized that a nasal spray with were younger than 18 years (c) participated in any other
Iota-Carrageenan could potentially be used as postexpo­ clinical trial of an experimental treatment for COVID-19,
sure and during exposure prophylaxis, to prevent COVID- (d) did not have a cell phone for remote monitoring, (e)
19 in health workers managing patients with COVID-19. reported hypersensitivity or known allergy to any compo­
nent of the product, or (f) were pregnant or lactating.
Additionally, health workers under suspicion of COVID-
Methods
19, COVID-19 history or with COVID-19 antibodies
Study Design and Participants found in a previous routine screening were deemed ineli­
We conducted a pilot pragmatic randomized, placebo- gible to participate in this study.
controlled study to determine whether a nasal spray with
Iota-Carrageenan can prevent COVID-19 disease in health­ Randomisation and Masking
care workers managing COVID-19 patients. This study was Randomisation occurred at the coordinator center.
carried out when vaccination plans were not yet implemented A permuted-block randomisation sequence was carried
in Argentina. We randomly assigned participants in a 1:1 out using sized blocks of 8. A research pharmacist sequen­
ratio to receive either Iota-Carrageenan or placebo. Trial tially assigned participants to either of the groups. The
enrollment began on July 24, 2020. Health and other hospital assignments were concealed from investigators and parti­
workers managing hospitalized patients with a positive poly­ cipants (double blind).
merase-chain-reaction (PCR) assay for SARS-CoV-2, were
eligible. This trial was carried out in ten hospitals in Procedures
Argentina (Hospital Universitario CEMIC, Sanatorio The participants were recruited in person by the researcher
Parque de Rosario, Clínica y Maternidad Santa Isabel, in charge of the center. Inclusion and exclusion criteria
Hospital Interzonal de Agudos Pte. Perón, Hospital were reviewed for each one of them and they signed the
Pediátrico Avelino Castelán, Hospital Británico de Buenos informed consent.
Aires, Clínica Monte Grande, Hospital 4 de Junio Dr Ramón Participants were instructed to self-administer 1 puff
Carrillo, Clínica Modelo de Morón, Hospital Gral. de (0.10 mL = 0.17 mg of I-C) of trial medication to each
Agudos Dr. Teodoro Alvarez), in compliance with ICH- nostril 4 times per day. Trial medication was either Iota-
GCP and according to the Declaration of Helsinki. It was Carrageenan nasal spray approved for use in many Latin
approved by the institutional review board and the ethics American countries or placebo. Each individual received
committees of the participating centers (or a centralized com­ two vials. The inhaler bottles containing the active princi­
mittee as applicable) (Registrations: Comité de Ética del ple or placebo were identical and odorless. The formula­
Centro de Educación Médica e Investigaciones Clínicas- tions and placebos were prepared at Laboratorio Pablo
CEMIC 1322, Comité Hospitalario de Ética Hospital 4 de Cassará S.R.L. (Argentina) under aseptic conditions.
Junio 0035/20, Comité provincial de Bioética, Provincia de Carrageenan spray: Iota-Carrageenan 0.17%, Sodium
Santa Fé 963, Comité de Ética para Investigación Clínica Chloride 0.9%, pH 6.00–7.00, isotonic; in a High-
Fundación Dr. J. R. Villavicencio 24-07-2020, Comité de Density Polyethylene bottle, 10 mL content, with dosing
Bioética HIGA “Eva Perón” 57/20, Comité de Ética del pump (100 µL) and Preservative-Free System. Both the
Hospital Británico de Buenos Aires 1080, Comité active sprays and the placebos were provided free of
Hospitalario de Ética Hospital Dr Avelino Castelán charge by the manufacturer.
22072020, Comité de Ética del Hospital Gral. de Agudos The determination of posology is based on several
Dr. Teodoro Alvarez 2706). Participants provided written antecedents: the application of Iota-Carrageenan spray 3
consent prior to their participation. times a day has shown efficacy in clinical trials carried out
We included physicians, nurses, kinesiologists and on other respiratory viruses in which the active in vitro
other hospital workers with no history of COVID-19 dis­ concentrations are similar to the active concentrations
ease, who managed patients in a COVID-19 hot zone in against the SARS-CoV-2; on the other hand, it has been
the hospital, and were therefore daily exposed to patients shown that the Iota-Carrageenan spray applied to the nasal

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mucosa remains on it for about 4 hours.24 Application four hours have you experienced reduction or loss of taste?
times a day results in a reasonable balance between the Over the last 24 hours have you experienced reduction or
chance of efficacy and adherence to treatment. loss of smell?
Post-exposure prophylaxis (PEP) is a treatment that The responses were reviewed every night and should
can stop an infection after the individual has been in any participant report symptoms, they were informed to
close contact with the virus. Since the objective was to the investigator in charge at the center. The head of the
intervene during the incubation period (the mean, median center was also informed of all the individuals who had
and 95th percentile for incubation period of COVID-19 are not answered the daily questionnaire.
around 6, 5 and 13 days, respectively,25,26) most of the The investigator at the center evaluated whether the
research done or proposed on COVID-19 PEP followed up symptoms could be assigned to a cause other than COVID-
the participants within 14 days after trial enrollment.27–30 19 (for example, migraine in a patient with a history of such
We followed our participants an extra week, since by the condition who had previously reported to the researcher that
time the study was designed, the pandemic was just begin­ their headache was their usual manifestation).
ning in Argentina and it was yet unknown whether it Regarding those subjects who failed to answer the
would take any particular form of development. The dura­ form, they were asked to do so in the morning, and to
tion of this follow-up differs from that of studies on treat­ further report it to the investigator of the center.
ments for the disease, which begin after diagnosis and are Upon confirmation of suspicious symptoms of
longer (28 or more days), since they aim to evaluate the COVID-19, the participants were sent to undergo
last and more severe phases of the disease.31 a nasopharyngeal swab with a PCR test for SARS-CoV-2
Treatment was mandatory for 21 days. At days 14 and and were isolated on a preventive basis until the PCR
21 participants had a face-to-face control visit that result was available. Patients with positive PCR continued
included a review of the volume of liquid remaining in in isolation for management of their disease. PCR-negative
the container in use. The participants were excluded if the individuals returned to their workplace 48 hours after their
residual volume in the container exceeded 20% of the symptoms had disappeared. Participants with a negative
amount expected to be present if the doses had been duly PCR whose symptoms persisted for 48 hours after the first
applied until that day. PCR, must undergo a new PCR.
Participants continued to adhere to handwashing, use The symptom questionnaire should not be submitted only
of personal protective equipment, physical distancing and in the case of participant with a confirmed positive PCR.
general guidelines in compliance with regulations from
health authorities. Follow-up was measured at day 21. Statistical Analysis
We estimated that 200 participants should be enrolled in each
Outcomes group to give the trial approximately 80% power, at two-sided
The primary outcome was prespecified as symptomatic type I error rate of 5%, to show that COVID-19 would be 50%
illness confirmed by detection of SARS-CoV-2 by reverse lower in the active treatment group than in the placebo.
transcriptase–polymerase chain reaction (PCR) at a local The strength of association was expressed as a relative
testing facility (using a protocol-defined acceptable test). risk reduction and its 95% confidence intervals (95% CI).
On a daily basis, in the afternoon, participants received via Proportions were compared with the chi-square test or
text message in their phones, a Google Form survey with Fisher´s exact test, and the continuous quantitative vari­
a structured questionnaire including the symptoms that ables with the Student’s t-test. All analyses were con­
should be reported: Over the last 24 hours have you been ducted with Statistical Analysis Software SAS® version
in contact with a patient with a confirmed diagnosis of 9.4 (SAS Institute, Inc, Cary, North Carolina), according
COVID-19? Over the last 24 hours have you had tempera­ to the intention-to-treat principle, with two-sided type
ture higher than 37.5°C? Over the last 24 hours have you I error with an alpha of 0.05.
had cough? Over the last 24 hours have you had a sore
throat? Over the last 24 hours have you had muscle aches Results
not consistent with knocks or exercise? Over the last 24 From July 24 to December 20, 2020, a total of 400 hospi­
hours have you had a headache? Over the last 24 hours tal workers were enrolled and randomized at 10 hospitals
have you had diarrhea and/or vomiting? Over the last 24 in Argentina.

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Six participants were excluded from the final analysis The incidence of COVID-19 differs significantly
because they had symptoms suggestive of COVID-19 at between subjects receiving the nasal spray with Iota-
the time of randomisation. Of the remaining 394 partici­ Carrageenan (2 of 196 [1.0%]) and those receiving pla­
pants, 196 had been assigned to receive Iota-Carrageenan cebo (10 of 198 [5.0%]). Relative risk reduction: 79.8%
and 198 placebo. (95% CI 5.3 to 95.4; p=0.03). Absolute risk reduction: 4%
Thirteen individuals in the Iota-Carrageenan group and (95% CI 0.6 to 7.4). The 2 individuals in the I-C arm
14 in the placebo group withdrew their consent before day began with symptoms on days 2 and 4 after randomisation.
21 and did not provide information about their health In contrast, in the placebo arm 2 individuals were sympto­
status (6.8%) (Figure 1). All the remaining participants matic on days 4 and 8 and the rest developed symptoms 11
answered the daily surveys and complied with at least days after randomisation (Figure 2).
80% of the doses indicated for the study. In the Iota-Carrageenan group and placebo group,
The mean age of participants was 38.5±9 years, and 17.3% and 15.2%, respectively, reported at least one
75.1% were female (Table 1). adverse effect (p = 0.5) Table 2.
Forty-three participants underwent a PCR test due to the
presence of symptoms suggestive of COVID-19 (Table 2), 31 Discussion
were negative (7.6% in the Iota-Carrageenan group and 8.6% The results of this study suggest that the Iota-Carrageenan
in the placebo group; p= 0.8). nasal spray is safe and effective to prevent COVID-19
Overall, new COVID-19 (symptomatic with confirmed disease in hospital workers managing COVID-19 patients.
PCR) developed in 12 of 394 participants (3.04%) during In our study we identified a risk reduction around 80%.
the 21 days of follow-up (Table 2). The effect was obtained using the spray within the dosage

Figure 1 Study flowchart.

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Table 1 Baseline Characteristics of the Intention-to-Treat Population


I-C (n= 196) Placebo (n= 198) p value

Sex
Female 141 (71.9%) 155 (78.3%) 0.1
Male 55 (28.1%) 43 (21.7%)

Age, years 38.3 (10.1) 38.8 (9.2) 0.8

Ethnic origin
White and latino 196 (100%) 198 (100%) 1.0

Physicians 97 (49.5%) 95 (48.0%) 0.8

Nurses 50 (25.5%) 62 (31.3%) 0.2

Technicians 24 (12.2%) 26 (13.1%) 0.8

Others medical providers 22 (11.2%) 18 (9.1%) 0.5

Co-morbidities
No co-morbidities 157 (80.1%) 147 (74.2%) 0.2
Chronic pulmonary disease 6 (3.0%) 7 (3.5%) 1.0*
High blood pressure 9 (4.6%) 10 (5.1%) 0.8
Obesity 7 (3.6%) 13 (6.6%) 0.2
Severe obesity 0 (0%) 0 (0%)
Hypothyroidism 12 (6.1%) 9 (4.5%) 0.5
Smoking 1 (0.5%) 3 (1.5%) 0.6*
Type 2 diabetes mellitus 0 (0%) 1 (0.5%) 1.0*
Cancer 0 (0%) 0 (0%)
Chronic kidney disease 0 (0%) 0 (0%)
Down syndrome 0 (0%) 0 (0%)
Heart disease 0 (0%) 0 (0%)
Inmunocompro-mised state 0 (0%) 0 (0%)
Notes: Data are n (%), mean (SD). *Fisher´s exact test. Obesity (body mass index of 30 Kg/m or higher but <40 kg/m2).
2

Abbreviation: I-C, Iota carrageenan.

Table 2 Findings
Participants (n=394) I-C (n=196) Placebo (n=198) OR (95% CI) p value

Primary outcome 12 (3.0%) 2 (1.0%) 10 (5.0%) 0.19 (0.05 to 0.77) 0.03*

Death or hospitalization for any cause 0 (0%) 0 (0%) 0 (0%)

Symptomatic negative PCR 31/382 (8.1%) 15/197 (7.6%) 16/185 (8.6%) 0.87 (0.42 to 1.8) 0.7

Adverse effects
At least one adverse effect 64 (16.2%) 34 (17.3%) 30 (15.2%) 0.5
Headache 30 (7.6%) 17 (8.7%) 13 (6.6%) 0.4
Rhinorrhea 9 (2.3%) 3 (1.5%) 6 (3.0%) 0.5*
Suspended for intolerance 5 (1.2%) 2 (1.0%) 3 (1.5%) 1.0*
Note: *Fisher´s exact test.
Abbreviations: CI, confidence interval; I-C, Iota-carrageenan; OR, odds ratio; PCR, reverse-transcriptase–polymerase-chain-reaction testing.

that is approved for use by the health authority. A small placebo group. Adverse effects were mild, which is con­
number of individuals presented adverse effects, with no sistent with that described in other clinical trials15–17 and
difference between the group treated with I-C and the in short, medium, and long-term toxicity studies conducted

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Figure 2 Kaplan-Meier survival plot of COVID-19 disease in the trial participants.

in experimental animals.32 These results are particularly infection in Calu-3 cell line observing the same inhibitory
relevant since today the only prophylactic interventions effect as in Vero cells (submitted).
with demonstrated efficacy are vaccines yet accessible The devastating urgency of COVID-19 pandemic
worldwide. In fact, vaccination rates among healthcare requires a simple and pragmatic design trial able to pro­
workers remain particularly low, especially in the global vide, in this context, a quick and efficient answer.
south. Our study has some limitations. First, we included
There has been growing interest in the potential efficacy apparently healthy individuals without confirmation by
of drugs with demonstrated in vitro efficacy. During the PCR test. Given that early disease manifested more fre­
early days of COVID-19 pandemic, there was an increased quently in the arm with active treatment, we could assume
attention to the use of hydroxychloroquine, an agent that that some people may have been at the end of the incuba­
was active in vitro but failed to prevent COVID-19 when tion period of the disease at the time of their inclusion in
used as pre or postexposure prophylaxis.27,28 With at least this clinical trial. This would contribute to the notion of the
two registered clinical trials as of February 2021 (United prophylactic effect of the I-C spray. Second, those subjects
Kingdom, NCT04590365, and Austria, NCT04681001), who remained asymptomatic were not tested. PCR or ser­
Iota-Carrageenan is being proposed as a potential effica­ ologic testing for all the participants would have added to
cious prophylactic drug. The nasal spray with Iota- the scientific strength of this trial. However, it was not
Carrageenan has already shown clinical efficacy in diseases feasible, and an effect on asymptomatic infections cannot
of the upper airways produced by viruses against which be assessed. Our study has also a number of strengths. First,
Iota-Carrageenan had demonstrated efficacy in vitro. we chose healthcare and other hospital workers to partici­
Additionally, Iota-Carrageenan in vitro efficacy was shown pate in this research as a simple and easy-to-follow model.
in in vitro concentrations equal to and up to 100 times lower Second, the number of active principle and placebo admi­
than those estimated to be reached in the nasal cavity with nistered in each participating center were identical. Third,
the use of sprays available in different countries with stan­ enrollment took place during high community transmission
dard dosages. We have recently repeated the in vitro study in Argentina (140.48 cases per 100K inhabitants in July to
of the effect of carrageenan spray on SARS-COV-2 173.77 in December, and 1,429,814 total new positive cases

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during the study period * https://iecs.shinyapps.io/covid- Peña, Chaco, Argentina), Sofía Golé (Department of Family
argentina/). Therefore, our participants were also exposed Medicine, Hospital Gral. de Agudos Dr. Teodoro Alvarez,
outside the hospital. Finally, a small number of individuals Ciudad Autónoma de Buenos Aires, Argentina) and Lorena
were lost to follow up (6.8%). Itati Ibañez (Institute of Physical Chemistry of Materials,
Environment and Energy (INQUIMAE-CONICET, Buenos
Conclusions Aires University, Buenos Aires, Argentina).
Our results suggest that the nasal spray with I-C could give
significant protection for COVID-19 prophylaxis in health Funding
care workers managing patients with COVID-19 disease. The study did not receive any support for hospitals, staff or
This finding should be replicated in future clinical trials. patients involved. Publication and administrative costs were
supported by: Programa de articulación y fortalecimiento fed­
Data Sharing Statement eral de las capacidades en ciencia y tecnología COVID-19,
Data related to this manuscript can be made available from Proyecto CABA 20. Ministerio de Ciencia, Tecnología
the corresponding author upon reasonable request since e Innovación, Argentina. Laboratorio Pablo Cassará provided
the publication. the drug and placebo samples, free of charge.

Acknowledgments Disclosure
We thank all participants of the CARR-COV2 research Dr Juan Manuel Figueroa report grantfrom Programa de
team for their commitment and contributions to this study: articulación y fortalecimiento federal de las capacidades
M. Jimena Ortega and Cristina Soler Riera (Hospital en ciencia y tecnología COVID-19, Proyecto CABA 20.
Universitario CEMIC, Ciudad Autónoma de Buenos Aires, Ministerio de Ciencia, Tecnología e Innovación,
Argentina), Ana Cajelli (Department of Otolaryngology, Argentina; Freely provided drug and placebo samples
Clínica y Maternidad Santa Isabel, Ciudad Autónoma de from Laboratorio Pablo Cassará, during the conduct of
Buenos Aires, Argentina), Fernando Ross and Mirta the study; personal fees from Laboratorio Pablo Cassará,
Gutiérrez (Department of Medicine, Clínica y Maternidad outside the submitted work; Dr Mónica Lombardo report
Santa Isabel, Ciudad Autónoma de Buenos Aires, Argentina), personal fees from Laboratorio Pablo Cassará, outside the
Daniela Federico and Viviana Jalife (Department of Medicine, submitted work, is a Director of Scientific Affairs at
Hospital Interzonal de Agudos Pte. Perón, Avellaneda, Buenos Nobeltri S.R.L; Dr Robert Giugliano report personal fees
Aires, Argentina), Mariel Trinidad (Department of from Astra Zeneca, personal fees from CVS Caremark,
Pulmonology, Hospital Interzonal de Agudos Pte. Perón, personal fees from Pfizer, personal fees from Novartis,
Avellaneda, Buenos Aires, Argentina), Paula Bellagamba outside the submitted work; and Institutional research
(Department of Pediatrics, Hospital Interzonal de Agudos grant to the TIMI Study Group at Brigham and Women’s
Pte. Perón, Avellaneda, Buenos Aires, Argentina), Teresa Hospital for research he is not directly involved in from
Corallo and Daniel Lamberti (Department of Pulmonology, Abbott; Aralez; AstraZeneca; Bayer; Eisai;
Hospital Pediátrico Avelino Castelán, Resistencia, Chaco, GlaxoSmithKline; Intarcia; Janssen Research and
Argentina), Pablo Oyhamburu, Yael Gonzalez and Carmen Development; Medicines Company; MedImmune;
Rios (Department of Pulmonology, Hospital Británico de Novartis; Poxel; Pfizer; Quark Pharmaceuticals; Roche;
Buenos Aires, Ciudad Autónoma de Buenos Aires, Takeda; Zora Biosciences. The authors report no other
Argentina), Glenda Ernst (Scientific Committee, Hospital conflicts of interest in this work.
Británico de Buenos Aires, Ciudad Autónoma de Buenos
Aires, Argentina), Ricardo Reisin (Department of Neurology, References
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