Open access
Protocol
David J Leehey ,1,2 Kimberly Carlson,3 Domenic J Reda,3 Ian Craig,4
Christina Clise,5 Todd A Conner,5 Rajiv Agarwal,6 James S Kaufman,7
Robert J Anderson,8 Douglas Lammie,3 Jeffrey Huminik,5 Linda Polzin,1
Conor McBurney,1 Grant D Huang,9 Nicholas V Emanuele1
To cite: Leehey DJ, Carlson K,
Reda DJ, et al. Pentoxifylline
in diabetic kidney disease
(VA PTXRx): protocol for
a pragmatic randomised
controlled trial. BMJ Open
2021;11:053019. doi:10.1136/
bmjopen-2021-053019
►► Prepublication history and
additional online supplemental
material for this paper are
available online. To view these
files, please visit the journal
online. To view these files,
please visit the journal online
(http://dx.doi.org/10.1136/
bmjopen-2021-053019).
Received 03 May 2021
Accepted 16 June 2021
© Author(s) (or their
employer(s)) 2021. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ.
For numbered affiliations see
end of article.
Correspondence to
Dr David J Leehey;
david.leehey@va.gov
ABSTRACT
Introduction Diabetic kidney disease (DKD) is the most
frequent cause of end-stage renal disease (ESRD) in the
USA and worldwide. Recent experimental and clinical data
suggest that the non-specific phosphodiesterase inhibitor
pentoxifylline (PTX) may decrease progression of chronic
kidney disease. However, a large-scale randomised clinical
trial is needed to determine whether PTX can reduce ESRD
and death in DKD.
Methods and analysis Veterans Affairs (VA) PTXRx is a
pragmatic, randomised, placebo-controlled multicentre VA
Cooperative Study to test the hypothesis that PTX, when
added to usual care, leads to a reduction in the time to
ESRD or death in patients with type 2 diabetes with DKD
when compared with usual care plus placebo. The study
aims to enrol 2510 patients over a 4-year period with an
additional up to 5-year follow-up to generate a total of
646 primary events. The primary objective of this study
is to compare the time until ESRD or death (all-cause
mortality) between participants randomised to PTX or
placebo. Secondary endpoints will be: (1) health-related
quality of life, (2) time to doubling of serum creatinine, (3)
incidence of hospitalisations for congestive heart failure,
(4) incidence of a three-point major adverse cardiovascular
events composite (cardiovascular death, non-fatal
myocardial infarction, non-fatal stroke), (5) incidence of
peripheral vascular disease, (6) change in urinary albumin-
to-creatinine ratio from baseline to 6 months and (7) rate
of annual change in estimated glomerular filtration rate
(eGFR) during the study period.
Ethics and dissemination This study was approved by
the VA Central Institutional Review Board (cIRB/18-36)
and will be conducted in compliance with the Declaration
of Helsinki and the Guidelines for Good Clinical Practice.
The Hines Cooperative Studies Programme will finalise the
study results, which will be published in accordance with
the Consolidated Standards of Reporting Trials statement
in a peer-reviewed scientific journal.
Trial registration number NCT03625648.
INTRODUCTION
Diabetic kidney disease (DKD) is the most
frequent cause of chronic kidney disease
(CKD) and end-stage renal disease (ESRD)
in the USA.1 Patients with diabetes with
Strengths and limitations of this study
►► Large randomised, controlled, pragmatic, multi-
centre clinical trial to determine if pentoxifylline (PTX)
can prevent end-stage renal disease (ESRD) and/or
death in patients with diabetic kidney disease.
►► PTX is a readily available, safe and inexpensive
medication which might be effectively repurposed
to treat this condition.
►► Study medication is added to standard of care therapy in both the active intervention and placebo control groups. Standard of care is determined by the
treating physicians and not protocolised.
►► The primary outcome is time to ESRD or death (all-
cause mortality), hard endpoints that are clinically
significant to patients
►► As a Veterans Affairs study, most participants are
expected to be male, which could somewhat limit
generalisation of the findings to female patients.
ESRD on maintenance dialysis have markedly
impaired survival and quality of life (QoL).2
The non-specific phosphodiesterase inhibitor pentoxifylline (PTX) was approved
by the US Food and Drug Administration
(FDA) in 1984 for the treatment of peripheral vascular disease (PVD). PTX has been
shown in several animal models of kidney
disease to reduce proteinuria and preserve
renal function. These effects are associated
with a reduction in inflammation, oxidative
stress and fibrosis.3 There are clinical studies
supporting a role for PTX in DKD, but they
have enrolled a small number of subjects,
were of short duration, and used surrogate
endpoints such as reduction in proteinuria
and changes in eGFR, not hard endpoints
such as ESRD and death.4 In a recent clinical trial from Spain, PTX reduced loss of
eGFR and urinary albumin excretion (UAE)
in diabetic patients with stage 3–4 CKD and
UAE >30 mg/ 24 hours.5 There were no
serious safety concerns with PTX, only a 2-fold
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
1
BMJ Open: first published as 10.1136/bmjopen-2021-053019 on 16 August 2021. Downloaded from http://bmjopen.bmj.com/ on February 28, 2022 by guest. Protected by copyright.
Pentoxifylline in diabetic kidney
disease (VA PTXRx): protocol for a
pragmatic randomised controlled trial
Open access
Risk group
N
Mean SBP
(mm Hg)
1
2
3
46 442
51 342
21 672
139.4
138.3
140.7
Percent with
SBP ≥180 mm
Hg
Mean DBP
(mm Hg)
Percent with
DBP ≥110 mm
Hg
Mean HbA1c Percent with
(%)
HbA1c >10%
1.63%
1.07%
1.22%
73.1
73.2
75.6
0.16%
0.11%
0.14%
7.34
7.55
7.82
5.70%
6.83%
10.5%
Risk groups:
1=eGFR [15–30) (regardless of proteinuria).
2=eGFR [30–45) with UACR ≥30.
3=eGFR [45–60) with UACR ≥300.
Data are from calendar year 2015 and include SBP, DBP and HbA1c.
CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated haemoglobin;
SBP, systolic blood pressure; UACR, urinary albumin-to-creatinine ratio; VA, veterans affairs.
increased incidence of mild digestive symptoms noted.
These findings suggest that PTX could be an effective
and safe therapeutic option for treatment of DKD. Nevertheless, more definitive studies, with hard endpoints on
efficacy and safety, are needed.
STUDY DESIGN
Veterans Affairs (VA) PTXRx is a pragmatic, randomised,
controlled, parallel, multicentre clinical trial to test the
hypothesis that PTX, when added to usual care, leads to a
reduction in the incidence of ESRD or death in patients
with type 2 diabetes with DKD when compared with usual
care plus placebo. The study will recruit Veteran patients
from up to 40 VA hospitals throughout the USA with
an expected treatment duration of up to 9 years. This
study will use a pragmatic design, and other aspects of
patient care will not be protocolised. It was believed that
it was unnecessary to do so, as the VA has been acknowledged to meet or exceed national standards of care in
the care of diabetic patients.6–8 In a database analysis of
patients with diabetes with CKD, we looked at the three
high risk groups for ESRD which will be included in VA
PTXRx (see the Methods section). We found that control
of blood pressure and blood glucose in these patients
adhered to American Diabetes Association (ADA) guidelines (table 1). In addition, the study has been designed
with minimal clinic visits and laboratory testing to reduce
patient burden and study withdrawals. Other than randomisation to PTX or matched placebo in a 1:1 ratio,
patient care will be handled by uual providers according
to recommended standards of care. The study has been
approved by the VA Central Institutional Review Board
and is currently enrolling participants in the ramp-up
phase since November of 2019.
OUTCOMES
Primary outcome
The primary objective of this study is to compare the
time until ESRD or death (all-cause mortality) between
participants randomised to PTX or placebo. ESRD will be
2
defined as institution of chronic dialysis or renal transplantation. Chronic dialysis will be defined as any of the
following: (1) dialysis for >90 days, (2) dialysis for >30
days and <90 days, if the participant dies between 30 and
90 days, (3) dialysis for <30 days if the patient dies in <30
days, if it is determined by the adjudication committee
that the patient would not have recovered renal function.
This determination will be based primarily on the presence or absence of severe (eGFR <30) proteinuric DKD
prior to need for dialysis, since such patients are unlikely
to recover renal function.9
ESRD and death are the two most clinically relevant
endpoints in patients with CKD. However, the definition
of ESRD has not been consistent among clinical trials.10
We opted to use renal replacement therapy as the primary
renal outcome. In previous trials of renin-angiotensin-
aldosterone (RAAS) blockade and sodium glucose
cotransporter 2 (SGLT2) inhibition in DKD, composite
primary endpoints including hard (ESRD and death)
and surrogate (doubling of serum creatinine, changes
in eGFR) outcomes have been employed.11 12 However,
surrogate outcomes, as opposed to ESRD or death,
do not have the same degree of clinical importance to
patients. Nonetheless, we have recognised the necessity
of including only high-risk patients for ESRD and using a
prolonged (at least 5 years) follow-up period, longer than
in previous trials.
Secondary outcomes
Secondary outcomes that will be compared include (1)
health-related QoL (using the RAND Corporation Kidney
Disease Quality of Life-Short Form instrument), (2) time
to doubling of serum creatinine from baseline (corresponding to a decline in eGFR of ≥50%), (3) incidence
of hospitalisation for congestive heart failure (CHF),
(4) incidence of a three-point major adverse cardiovascular event (MACE) composite, including: cardiovascular
death, non-fatal myocardial infarction, non-fatal cerebrovascular event (stroke), (5) incidence of a PVD event (limb
revascularisation or non-
traumatic limb amputation),
(6) change in urine albumin to creatinine ratio (UACR)
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
BMJ Open: first published as 10.1136/bmjopen-2021-053019 on 16 August 2021. Downloaded from http://bmjopen.bmj.com/ on February 28, 2022 by guest. Protected by copyright.
Table 1 Care in patients with diabetes and CKD in VA during 2015
Open access
METHODS
Inclusion criteria will be the presence of both type 2
diabetes and CKD stage 3 or 4 (eGFR 15–60 mL/min/1.73
m2). Participants need to be in one of the following categories at the time of randomisation and on one or more
occasions 3 months or more prior to randomisation:
2
►► eGFR 15 to less than 30 mL/min/1.73 m .
2
►► eGFR 30 to less than 45 mL/min/1.73 m with UACR
>30 mg/g.
2
►► eGFR 45 to less than 60 mL/min/1.73 m with UACR
>300 mg/g.
Exclusion criteria are listed in box 1.
Why were the inclusion and exclusion criteria chosen?
The inclusion criteria are based on the Kidney Disease:
Improving Global Outcomes categorical meta-
analysis
(adjusted relative risk), commonly known as the ‘heat
map’,18 which gives relative risks of ESRD and mortality
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
Box 1
Exclusion criteria
1. Type 1 diabetes.
2. History of non-diabetic kidney disease.
3. Severe comorbid conditions expected to reduce life expectancy to
less than 1 year, as determined by LSI.
4. Active substance abuse, homelessness or other condition that is
likely to result in participant non-compliance as determined by the
LSI.
5. Previous organ or bone marrow transplant.
6. Pregnancy, breast feeding or female of childbearing potential unwilling to use a reliable form of contraception.
7. A recent (within 3 months) cerebral haemorrhage.
8. Current use of oral pentoxifylline.
9. Hypersensitivity to pentoxifylline or any of the components of the
formulation.
10. Current use of ketorolac (contraindicated with pentoxifylline).
11. Current use of riociguat (contraindicated with pentoxifylline).
12. Current use of dialysis.
13. Unable to provide informed consent.
14. Any condition that in the opinion of the LSI would make the potential participant non-compliant.
based on eGFR and UACR in patients with CKD. We are
including only patients in the highest risk zones of the
heat map for ESRD.
Why are we not requiring that patients take RAAS blockers or
SGLT2 inhibitors?
According to ADA guidelines, angiotensin converting
enzyme inhibitors (ACEIs) or ARBs are the preferred first-
line agent for blood pressure treatment among patients
with diabetes, hypertension, eGFR <60 mL/min/1.73
m2, and UACR ≥300 mg/g Cr because of their proven
benefits for prevention of ESRD and major cardiovascular events. In the setting of lower levels of albuminuria
(30–299 mg/g Cr), ACEI or ARB therapy reduces cardiovascular events but has not been demonstrated to prevent
progression to ESRD. In patients without albuminuria,
there are no clinical trials to determine whether ACEIs
or ARBs improve renal outcomes. Since our study will
include patients in all of the above categories, we cannot
expect that they will all be treated with RAAS blockers.
We have analysed data from the VA Corporate Data
Warehouse (CDW) on the use of ACEI/ARB in the VA
during calendar year 2015, and these data are displayed
in table 2. Our findings are in accord with data on utilisation with ACEI and ARB outside the VA.19–22 Although
we are not mandating the use of RAAS blockade, we
will stratify for utilisation and conduct a subgroup analyses examining the primary endpoint in those with and
without RAAS blockade at baseline.
SGLT2 inhibitors were not in common use at the time
of the design of this trial. Since, prescribing patterns have
increased due to expanding criteria for use. However,
these medications are generally avoided in patients with
severe CKD (eGFR <30), which will make up a large
portion of the patients in this trial.
3
BMJ Open: first published as 10.1136/bmjopen-2021-053019 on 16 August 2021. Downloaded from http://bmjopen.bmj.com/ on February 28, 2022 by guest. Protected by copyright.
from baseline to 6 months and (7) rate of annual change
in eGFR during the study period. Safety (serious adverse
events (SAEs), adverse events (AEs) possibly or probably
related to study drug, or discontinuation of study drug)
will also be a secondary outcome.
The QoL assessment was included since this is a patient-
centred trial and both severe CKD and ESRD have a
marked adverse effect on QoL.13 In addition, QoL is
underinvestigated and should be used more in trials.14
Time to doubling of serum creatinine will be a secondary
outcome as it is a surrogate for development of ESRD.
Hospitalisation for CHF is justified since CHF is the
most common adverse cardiovascular outcome in CKD.
A cardiovascular MACE composite is justified because of
the markedly increased risk of cardiovascular disease in
patients with renal disease and potential cardiovascular
benefits if PTX slows worsening of renal function. PVD was
included since PTX is FDA-approved for this condition.
Change in UACR from baseline is justified since studies
have shown that this is a predictor of renal outcomes.15
Rate of change in eGFR per year during the study period
is a reasonable predictor of the ultimate development of
ESRD.
Previous clinical trials in DKD have generally looked
at cardiovascular events as secondary outcomes because
the risk of cardiovascular events increases as renal
function worsens.16 17 Therefore, an intervention that
improves renal outcomes may also improve cardiovascular outcomes. Clinical trials of RAAS blockade in DKD
that have found benefits in terms of renal outcomes did
not necessarily show improvement in cardiovascular
outcomes,11 although SGLT2 inhibitors have been shown
to improve both renal and cardiovascular outcomes.12
Ultimately, we believed that inclusion of cardiovascular
endpoints in the primary outcome was not advisable,
considering contrary to RAAS blockers and SGLT2 inhibitors, we could find no evidence of a cardioprotective
effects of PTX in the literature.
Open access
Risk group
N
% Using ACEI or ARB
1
2
19 386
27 384
41.74
53.34
3
Total
13 949
60 719
64.36
50.83
Risk groups:
1=eGFR 15 to less than 30 (regardless of proteinuria)
2=eGFR 30 to less than 45 with UACR ≥30.
3=eGFR 45 to less than 60 with UACR ≥300.
Data are from calendar year 2015 for any use of ACEI or ARB.
ACEI, ACE inhibitors; ARB, angiotensin receptor blockers; eGFR,
estimated glomerular filtration rate; VA, Veterans Affairs.
Randomisation
Randomisation will be stratified according to study site,
use of RAAS blockers, and CKD risk category. The treatment allocation ratio, generated by the Hines VA Cooperative Studies Programme (CSP), for the two treatment
groups is 1:1 using permuted block scheme with random
block size. Eligible participants will be randomly assigned
in a double-blind fashion to PTX or placebo using a study-
specific web-
based randomisation system maintained
by the CSP Clinical Research Pharmacy Coordinating
Centre (CSPCRPCC).
Treatment regimens
Patients will receive PTX 400 mg extended release
(ER) tablets once per day or matching placebo starting
at randomisation. At the first follow-
up visit, approximately 5 weeks after randomisation, the PTX dose will be
increased to PTX 400 mg ER tablets two times per day
(a maximum daily dose of 800 mg) or matching placebo
as tolerated. Drug titration is implemented to minimise
possible gastrointestinal side effects of the medication. If
a participant develops intolerance while taking the study
medication at the max dose, 400 mg ER two times per
day dose, then the regimen may be reduced to 400 mg
ER once daily. If the intolerance dissipates and does not
reappear after 1 month, a rechallenge of the max dose,
400 mg ER two times per day, can be initiated. If the intolerance reappears, the participant can be maintained at
the reduced dose, 400 mg ER tablets once daily, for the
remainder of study participation.
If the intolerance continues at the 400 mg ER once
daily dosing, the study medication will be discontinued.
However, every effort should be made to minimise permanent discontinuation of study medication or withdrawal
of patients from the study. Temporary suspension or
permanent discontinuation of study medication may
occur under the following circumstances: (1) medication
intolerance, (2) pregnancy or breast feeding by participant, (3) decision of investigator or participant to discontinue study treatment for any reason. If the condition
leading to a suspension of study medication resolves and
deemed reasonable by the investigator and acceptable
4
by the participant, the participant should be restarted
on study medication at a previously well-tolerated dose.
Whenever study treatment is suspended or discontinued,
it will be documented on the Study Drug Prescription
Dosage Change form.
In clinical trials to date, daily doses of PTX from 400 to
1200 mg daily have been employed. PTX is metabolised
by the liver to both inactive and active metabolites. In
CKD patients, there is accumulation of an active metabolite of PTX (Metabolite V), but not the parent drug. In
the only study specifically looking at pharmacokinetics in
CKD patients, the authors recommended a dosage reduction from 600 mgtwo times per day to 400 mg two times
per day for patients with moderate renal impairment and
200–400 mg/day for severe renal impairment.23 These
doses are consistent with those listed in published dosage
guidelines24:
►► Creatinine clearance >50 mL/min: 400 mg every 8–12
hours.
►► Creatinine clearance 10–50 mL/min: 400 mg every
12–24 hours.
►► Creatinine clearance <10 mL min: 400 mg every 24
hours.
We are aware that the PREDIAN (Pentoxifylline for
Renoprotection in Diabetic Nephropathy) trial5 as well as
the study of Han et al,25 the largest trial to date, used a
daily dose of 1200 mg. However, since we will be studying
patients with moderate to severe CKD, we will not exceed
the 800 mg daily dose.
PTX has a very favourable safety profile, with gastrointestinal disturbances (eg, dyspepsia, nausea, vomiting)
being the most commonly reported adverse effect in
studies comparing PTX to placebo. The PTX package
insert lists ‘recent cerebral or retinal haemorrhage’ as a
contraindication to its use. While recent (within 90 days)
cerebral haemorrhage will be an exclusion criterion, we
were concerned that a retinal haemorrhage exclusion
would affect the generalisability of the study, as a substantial portion of diabetic patients with CKD have coexistent
retinal disease.
We spent considerable effort gathering information
about the association of PTX with retinal haemorrhage.
Neither the various manufacturers of PTX nor the FDA
were able to provide any data on which this contraindication was based. A search of the FDA’s Adverse Event
Reporting System database discovered only 11 cases of
retinal haemorrhage reported in the past 30 years. There
is no literature that indicates an increased risk of retinal
haemorrhage with PTX. One paper actually suggested
that PTX might reduce neovascularisation and promote
absorption of haemorrhage.26 FDA has approved our
Investigational New Drug (IND) application to omit the
exclusion of recent retinal haemorrhage. The study will
have a Data Monitoring Committee (DMC), which will be
able to determine if there is an increased risk of retinal
haemorrhage in patients receiving PTX.
In addition, it is possible that PTX may increase bleeding
event risk, especially in high-risk patients. Therefore, we
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
BMJ Open: first published as 10.1136/bmjopen-2021-053019 on 16 August 2021. Downloaded from http://bmjopen.bmj.com/ on February 28, 2022 by guest. Protected by copyright.
Table 2 Use of ACEI or ARB in VA during 2015
Open access
Study visits
The first visit (Baseline) will focus on inclusion and exclusion criteria and medication review (including dosages
of all anti-
diabetic and antihypertensive medications)
in addition to randomisation within up to 5 days if eligibility criteria is met. The first follow-up visit (5 weeks±1
week from randomisation) will be focused on adherence
and possible adverse effects from study medication and
titration to maximal dose as tolerated. Subsequent visits
will occur quarterly. They may be conducted either in
person or by phone, and will focus on capture of potential endpoints, SAEs (hospitalisations, life-
threatening
illnesses or a new or worsening clinical condition requiring
acute intervention) and study-related AEs. Health-related
QoL will be assessed on a yearly basis. An end-of-trial
visit will be conducted in person for all participants who
have not reached a primary endpoint. All study medications will be shipped directly to the study patients using a
well-established VA infrastructure (VA Consolidated Mail
Outpatient Pharmacy). Pill counts will not be employed,
though participants will be asked to return unused medication. There will be no prohibited care or intervention
during the trial other than the contraindicated medication listed in the exclusion criteria. It is expected that
patients will be enrolled for 4 years and followed for up
to 9 years (table 3).
STATISTICAL ANALYSIS
The key statistical assumption is that occurrence of the
primary endpoint occurs in 26.6% of the placebo group
and 21.6% of the PTX group at 6 years, and a relative risk
reduction of 19% for PTX compared with the placebo
group is considered a clinically important effect. The
study aims to randomise 2510 participants to either PTX
or placebo and will be performed at 40 VA research sites
over 4 years of recruitment. It is anticipated that this
sample size will generate a total of 646 primary events by
the end of the study.
Based on a meta-analysis demonstrating that each 30%
reduction in albuminuria translates to a 23.7% decrease
in the risk of ESRD,27 we sought to quantify the expected
reduction of ESRD by PTX. In small clinical trials using
PTX, the average reduction in albuminuria due to PTX
was 32.1%, which translates to a projected 25.4% decrease
in the risk of ESRD.5 25 28–31 As the proposed study will
be the first to examine the effect of PTX compared with
placebo on time to development of ESRD or death, it
is powered to detect a 19% relative reduction in the 6
years event rate for the PTX group, compared with the
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
placebo group. This effect size is commensurate with
observed reductions in event rates from other comparable renoprotective studies. For example, the RENAAL
trial demonstrated that treatment with losartan reduced
the risk of ESRD by 28% (p=0.0002), and it reduced the
risk of ESRD or death by 20% (p=0.01).11
The expected event rates for the control group were estimated using retrospective data from a cohort of Veterans
meeting study inclusion criteria obtained from the VA
CDW. Using ICD diagnoses codes and laboratory results, a
dataset was compiled of all Veterans matching the inclusion
criteria between 1 January 2008 and 31 December 2010 with
respect to type 2 DM and CKD risk group. A total of 78 718
potentially eligible Veterans were allocated to one of the
three risk groups (N=38 801 for risk group 1; N=28 838 for
risk group 2; N=11 079 for risk group 3). This cohort was
followed through 2016 to determine how many would have
experienced the primary outcome of either death or ESRD.
The observed event rates for a primary event based on the
amount of follow-up time are shown in table 4. After 6 years,
26.6% of Veterans in our retrospective cohort experienced a
primary outcome of either death or ESRD.
The primary analysis will compare Kaplan-Meier curves
using a two-sided log rank test to test the null hypothesis that
the distribution of time to ESRD or death is the same for the
two treatment groups. In addition, to support the primary
analysis, the proportional hazards assumptions will be assessed
and the hazard ratio (HR) will be estimated. Cox regression
will be used to assess the treatment effect as well as to adjust
for baseline participant characteristics and to examine treatment by characteristic interactions. A preplanned subgroup
analysis of the primary outcome will also be conducted to
compare time to first occurrence of primary event between
treatment groups with each of the randomisation strata.
Secondary outcome measures will be organised with a hierarchical structure with a gatekeeping procedure to control the
family wise-type I error due to multiple testing. The primary
analyses will be on an intention-to-treat basis. All participants
will be followed a minimum of 5 years and a maximum of 9
years. Average follow-up will be approximately to 6.7 years
per participant. One non-binding interim analysis has been
planned a-priori to examine both efficacy and futility and
will be conducted when 50% (323) of primary events have
occurred. If either of the thresholds is met for futility or efficacy, this will trigger a DMC discussion on whether to stop or
continuing to enrol participants. If neither of the thresholds
is met at the interim analysis, the study will continue.
Given the complexities of implementing a large-scale
trial, we built in a ramp-up phase starting at six sites
during the initial 12 months. The ramp-up phase intends
to assess and streamline the recruitment process, determine the most effective recruitment strategies, and identify best processes to be used by site coordinators at future
centres. We plan to recruit based on patient lists generated by the VA CDW as well as by local VA Informatics
departments in addition to traditional methods. Based on
CDW data, there are an adequate number of patients to
obtain the desired sample size.
5
BMJ Open: first published as 10.1136/bmjopen-2021-053019 on 16 August 2021. Downloaded from http://bmjopen.bmj.com/ on February 28, 2022 by guest. Protected by copyright.
will track use of anticoagulant and antiplatelet medications at each study visit and the DMC will closely monitor
study patients for bleeding events. Careful attention
will also be paid at each clinic visit to other medications
which are either contraindicated with PTX (ketorolac,
riociguat) or can interact with PTX (PTX can increase
plasma levels of theophylline).
Open access
Years
2–8
Year 9
Year 1
Procedure
Baseline
Week 5
Month 3 Month 6 Month 9 Month
12
(V1)
(V2)
(V3)
(V4)
(V5)
±1 week
±2 wks
±2 wks
±2 wks
Visit window
In-person visit
X
Consent form
X
Randomisation
X
+5 days
Medical history
X
KDQoL†
X
Month
96
Month
99
Month
102
Month
105
Month
108
(V6)
(V34)
(V35)
(V36)
(V37)
(V38)
EOT*
±2 wks
±2 wks
±2 wks
±2 wks
±2 wks
→
X
X
X
X
X
Study medication X
dispensed
centrally
X
X
X
X
X
X
X
X
X
Confirmation
call for study
medication
receipt
X‡
X‡
X‡
X‡
X‡
X‡
X‡
X‡
X‡
X§
X§
X‡
Study medication
titration
X
Blood pressure
X
Calcium,
Phosphorus,
Magnesium,
albumin, HbA1c
X
Creatinine/eGFR
X
X§
UACR
X
X¶
X§
X§
Adherence
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
Clinical events
review (endpoints
and safety)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
review
X
Urine pregnancy
test
X
*EOT visit will not be required if a living participant has experienced dialysis or renal transplantation or is on limited participation.
†KDQoL will be measured at baseline, every 12 months thereafter, and at the end of the trial (V1, V6, V10, V14, V18, V22, V26, V30, V34, V38).
‡Confirmation call will be done after medication was dispensed to confirm if patient has received study drug.
§Creatinine/eGFR will be collected every 6 months unless available in the chart within past 3 months (V1, V4, V6, V8, V10, V12, V14, V16, V18, V20,
V22, V24, V26, V28, V30, V32, V34, V36, V38).
¶If not available in the chart within past 14 days.
eGFR, estimated glomerular filtration rate; EOT, End of Trial; HbA1c, glycosylated haemoglobin; KDQoL, Kidney Disease Quality of Life; UACR,
urinary albumin-to-creatinine ratio.
QUALITY BY DESIGN CONSIDERATIONS
VA PTXRx has embedded quality by design principles
into the design, start-up and conduct of the trial. This
approach that has been widely adopted by pharmaceutical
sponsored trials. The goal is to improve the quality and
efficiency of the trial by prospectively identifying critical
to quality trial factors and developing a plan to periodically monitor these factors. During planning, a risk-based
monitoring approach was used to define performance
6
metrics for the trial. These efforts were taken to further
enhance the ability to have the trial provide evidence to
put findings into practice.32 33
ETHICAL CONSIDERATIONS
This study has been approved by the VA Central Institutional Review Board (cIRB/18-36) and will be conducted
under FDA IND oversight and in compliance with the
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
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Table 3 Study procedures
Open access
Amount of follow-up
time
% of participants experiencing
primary endpoint
% of participants
experiencing ESRD event
% of participants
experiencing death
2 years
3 years
9.4
14.4
7.4
11.0
2.0
3.4
4 years
18.9
13.9
5.0
5 years
22.8
16.1
6.7
6 years
7 years
26.6
29.7
18.1
19.9
8.5
9.9
ESRD, end-stage renal disease.
ethical principles of the Declaration of Helsinki, the
protocol, and the Guidelines for Good Clinical Practice.
Informed consent will be obtained from every participant by study personnel. Surrogate consent will not
be allowed. Personal information about potential and
enrolled participants will be collected, shared and maintained in a confidential fashion. Protocol modifications
will be disseminated to all study stakeholders as a new
protocol version as necessary.
Post-trial care and compensation for harm
If a participant is injured because of taking part in this
study, the VA will provide necessary medical treatment at
no cost unless the injury was due to non-compliance with
study procedures. Participants will continue their care in
the VA post-trial.
PATIENT AND PUBLIC INVOLVEMENT
Veterans were engaged as stakeholders through the
CSP Coordinating Centre’s (CSPCC) Human Rights
Committee (HRC). The HRC meets on an annual basis to
review study protocols, both during the design and active
phases of the study, to assess progress and provide recommendations regarding human rights issues for Veteran
participants. The HRC will also conduct a selected
number of site visits to interview study staff and participants regarding the process and personal experiences
in recruitment and continued participation to ensure
that participants’ rights and safety are being properly
protected.
ROLES AND RESPONSIBILITIES: COMMITTEES
The study is managed by the CSPCC located in Hines, IL
and the CSPCRPCC in the Albuquerque, NM. There is
an Executive Committee (EC), the Cooperative Studies
Scientific Evaluation Committee (CSSEC), a HRC and a
DMC (see 'Study monitoring and data access' section).
The data management team is composed of members of
the CSPCC. Blinded, physician members of the EC will
adjudicate whether a participant who dies while on dialysis for <30 days should be counted as having had a death
endpoint or an ESRD endpoint.
Leehey DJ, et al. BMJ Open 2021;11:053019. doi:10.1136/bmjopen-2021-053019
DATA COLLECTION PLAN AND DATA MANAGEMENT
The Hines CSPCC will be responsible for the management
and quality control of the study data. Data collection and
entry is the responsibility of the study coordinator at each
site, under the supervision of the local site investigator.
Case report forms and operations manual were developed jointly by the Chairs’ Office, the CSPCRPCC and
the Hines CSPCC. Data will be entered the into an electronic data capture system (DF/Net Research, V.2016.1).
Data management and quality staff at the Hines CSPCC
and the CSPCRPCC will further review submitted data
for completeness and consistency adding data queries
to items that fail these checks. The Hines CSPCC will
prepare summary reports for the Study Chair, the DMC
and other monitoring groups of the data to track study
progress and conduct final analyses of the study data.
Missing data
We will use VA data sources and federally maintained databases to make primary endpoint determinations for most
participants, in particular those lost to active follow-up. In
the event of missing data due to withdrawal, participants
will be censored at the date of withdrawal.
Data security
The analytical database will not contain information that
can directly identify the study participant. Only CSP-
approved individuals will have access to the personal
health information of study participants. Neither the
Study Chair nor Chair’s office will have access to personal
health information.
STUDY MONITORING AND DATA ACCESS
Data quality and completeness of data retrieval will be
closely monitored on an ongoing basis by the CSPCC.
The study biostatistician will present interim monitoring
reports (overall and by site) to the EC and DMC that
will include recruitment of participants, characteristics
of the population, completeness of data retrieval, and
data quality. All reportable study intervention-related AEs
and SAEs (intervention related or not related) will be
provided to the DMC on a schedule set by the DMC, but
no less than annually. The DMC will determine the need
7
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Table 4 Event rates by amount of follow-up time
Open access
ETHICS AND DISSEMINATION
This study was approved by the VA Central Institutional
Review Board (cIRB/18-36) (ID: 1382143) and will
be conducted in compliance with the Declaration of
Helsinki and the Guidelines for Good Clinical Practice.
The Hines CSP will finalise the study results, which will be
published in accordance with the Consolidated Standards
of Reporting Trials statement in a peer-reviewed scientific
journal.
The EC has the authority to establish one or more
publication committees, usually made up of selected site
investigators and members of the EC, for the purpose of
producing manuscripts for presentation and publication.
Any presentation or publication needs to be approved by
the EC. All publications will list all participating personnel
in the study (not necessarily as authors of the manuscript). The full study protocol and informed consent will
be made publicly available.
In this manuscript, we used the Standard Protocol
Items: Recommendations for Interventional Trials
reporting guidelines.34
Contributors DL, KC, DJR, TAC, CC, RA, JSK, RJA, GDH, and NVE designed the
study and prepared the manuscript. IC analysed data preparatory to research. DL,
JH, LP and CM provided managerial assistance. All authors read and approved the
final manuscript.
Funding This study is funded by the U.S. Veterans Affairs Cooperative Studies
Program [grant number NA].
Competing interests RA has the following general disclosures: Member data
safety monitoring committees: Astra Zeneca, Ironwood Pharmaceuticals, Chinook;
Member steering committees of randomised trials: Akebia, Bayer, Relypsa, Sanofi
and Genzyme US Companies; Member adjudication committees: Bayer, Boehringer
Ingelheim; Member scientific advisory board or consultant: Bayer, Relypsa, Reata,
Boehringer, Merck, Lexicon, Diamedica.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has
not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer-reviewed. Any opinions or recommendations discussed are solely those
of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
responsibility arising from any reliance placed on the content. Where the content
includes any translated material, BMJ does not warrant the accuracy and reliability
of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
and/or omissions arising from translation and adaptation or otherwise.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the use
is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
David J Leehey http://orcid.org/0000-0002-2078-9948
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Author affiliations
1
Edward Hines Junior VA Hospital, Hines, Illinois, USA
2
Loyola University Medical Center, Maywood, Illinois, USA
3
Cooperative Studies Program, Edward Hines Junior VA Hospital, Hines, Illinois, USA
4
Division of Strategic Innovation, Evaluation, and Communication, Center for Clinical
Standards and Quality, Baltimore, Maryland, USA
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VA Cooperative Studies Program, Clinical Research Pharmacy Coordinating Center,
Albuquerque, New Mexico, USA
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Veterans’ Affairs Medical Center, Indianapolis, Indiana, USA
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Research Service, New York Harbor Health Care System, New York, New York, USA
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Veterans' Affairs Medical Center, Omaha, Nebraska, USA
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Veterans Affairs Office of Research and Development, Washington, District of
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for unblinding to treatment assignment based on AE/SAE
data. The DMC will advise the CSP Director whether the
study should continue or be stopped for safety reasons.
The trial will also be audited by the VA Site Monitoring,
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will be a collaboration of onsite site visits conducted by
SMART Clinical Research Monitors; remote monitoring
performed by SMART and Coordinating Centre Quality
Assurance RNs; and centralised statistical monitoring
on at least an annual basis, a process independent from
the investigators and sponsor. The CSPCC will maintain
access to all data throughout the trial. Digital data underlying primary scientific publications from this study will
be held as part of a data sharing resource maintained by
the CSP. The data may be available through execution of
a data use agreement and only under certain conditions
consistent with the informed consent and CSP policy,
which prioritise protecting subjects’ privacy and confidentiality to the fullest extent possible.
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