A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients With Acute Respiratory Distress Syndrome Associated With COVID-19
Phase: PHASE3
Conditions: Covid19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

A Multicenter, Adaptive, 
Randomized, Blinded Controlled 
Trial of the Safety and Efficacy of 
Investigational Therapeutics for 
Hospitalized Patients with Acute 
Respiratory Distress Syndrome 
Associated with COVID-19 
Protocol Appendix H2: Remdesivir
 Version 1.0
 01 April 2021 
 NCT04843761

TESICO Appendix H2: Remdesivir v 1.0 (15MAR2021)  (corrections made 01 Apr 2021) 
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The content of this appendix is confidential and should only be viewed by persons covered by the 
relevant CDA between NIAID and the collaborating companies.   
This appendix provides detailed information pertaining to the study of remdesivir when studied alone 
and in combination with aviptadil. Although remdesivir is licensed for use in the United States and is 
standard of care for most hospitalized patients with COVID-19, the key registration trials1 included 
insufficient patients in this subgroup to provide strong evidence in favor of remdesivir for critically ill 
patients. Thus, randomization to remdesivir versus placebo is a key component of this trial.   
Remdesivir is not considered standard of care for this protocol: the protocol does not recommend 
routine initiation of remdesivir in this patient population. For patients who have already initiated 
remdesivir by the time of enrollment, this protocol makes no recommendation regarding whether to 
continue or discontinue remdesivir as part of background therapy. The core question being evaluated 
by this protocol is whether to start (or not to start) remdesivir among patients with ARDS from COVID-
19. 
Following a description of our rationale for studying remdesivir and description of the study agent, we 
state the objectives of the factorial study of aviptadil and remdesivir, describe the study design, and 
provide an overview of the planned analyses.  
If not stated otherwise in this appendix, the text in the TESICO master protocol provides the approach 
that will be taken to study these agents 
1. Introduction and rationale for studying remdesivir
Remdesivir is an adenosine nucleotide prodrug with antiviral activity against severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2). Specifically, remdesivir triphosphate acts as an analog of
adenosine triphosphate (ATP) and competes with the natural ATP substrate for incorporation into
RNA chains by the SARS-CoV-2 RNA-dependent RNA polymerase, which results in delayed chain
termination during replication of the viral RNA.
COVID-19 is caused by infection with SARS-CoV-2, which requires viral replication. While such 
replication initially occurs in the upper respiratory tract, a transition to the lower respiratory tract and 
other tissues marks disease progression, which may develop into COVID-19 pneumonia. In the most 
severe stage of the disease, COVID-19 presents as ARDS; at this stage of illness, both ongoing viral 
replication and dysfunctional immune activation contribute to morbidity and mortality.2 Importantly, 
RNA-emia is more prevalent in COVID-19 ARDS than in mild-to-moderate disease; in addition, levels 
of RNA in blood are prognostic among COVID-19 ARDS patients.3 These observations suggest the 
possibility that anti-viral therapies may be of use in patients with COVID-19 ARDS.
In the Adaptive COVID-19 Treatment Trial 1 (ACTT-1) trial, remdesivir administered once daily for up 
to 10 days reduced time to recovery in hospitalized patients with COVID-19.4 The rate ratio for 
recovery was largest in patients receive low flow rates of oxygen at baseline (ordinal category 5, rate 
ratio for recovery, 1.45; 95% CI, 1.18 to 1.79) and among patients without supplemental oxygen at 
baseline (ordinal category 4, rate ratio 1.29; 95% CI, 0.91 to 1.83). However, the clinical impact was 
uncertain for patients receiving baseline high flow oxygen or non-invasive ventilation (ordinal category 
6, rate ratio for recovery 1.09; 95% CI, 0.76 to 1.57) and those receiving invasive mechanical 
ventilation or ECMO (ordinal category 7, rate ratio for recovery 0.98; 95% CI, 0.70 to 1.36). These 
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subgroup comparisons were underpowered, though, and do not exclude clinically important benefit 
for patients with COVID-19 ARDS.  
 
In the large, open-label, pragmatic SOLIDARITY trial, no survival benefit was observed with use of 
remdesivir, although the study design did not allow direct assessment of the effect on time to 
recovery.5 In the subgroup of hospitalized patients without COVD-19 ARDS (no mechanical 
ventilation), the observed mortality favored remdesivir treatment (rate ratio for mortality 0.86; 95% CI 
0.67-1.11), consistent with that observed in the ACTT-1, whereas for patients with COVID-19 ARDS 
(mechanical ventilation required) in the SOLIDARITY trial, the opposite was present (rate ratio for 
mortality 1.20; 95% CI 0.80-1.80). Given the pragmatic nature of the trial, the lack of blinding, and the 
requirement for longer hospital stay among treated patients, how best to interpret the SOLIDARITY 
results is not clear. 
 
Despite the FDA approval for remdesivir, on the basis of the SOLIDARITY trial results, NIH treatment 
guidelines do not currently recommend remdesivir for patients receive invasive mechanical 
ventilation/ECMO and provides a weak recommendation (BIII) for remdesivir in combination with 
dexamethasone in patients receiving high flow oxygen or non-invasive ventilation.6 The lack of 
definitive evidence for remdesivir in patients with COVID-19 ARDS provides motivation for this 
substudy.  
 
1.1 Potential risk and benefits from remdesivir  
Anticipated risk is considered low, based on the known mechanism of action and extensive clinical 
experience with the drug. The most common adverse reactions observed more commonly with 
treatment with remdesivir than with placebo are nausea, increase in ALT, and increase in AST.  
 
The potential benefits of remdesivir include faster time to recovery, including earlier hospital 
discharge. There is no current evidence to suggest that remdesivir reduces mortality in hospitalized 
patients based on data from ACTT-1 and the WHO SOLIDARITY trial.5 
 
 
Remdesivir is currently FDA approved and licensed in the United States for the treatment of 
hospitalized patients with COVID-19. More detailed information about the known and expected 
benefits and risks and reasonably expected adverse events of remdesivir may be found in the 
Package Insert.5 The overall benefit-risk assessment of this study is considered favorable. 
 
1.2 Justification for dose chosen  
Remdesivir will be administered as a 200 mg IV loading dose, followed by a 100 mg once-daily IV 
maintenance dose while hospitalized up to a 10-day total course. This regimen is the dosing 
recommended by the FDA (https://www.gilead.com/-/media/files/pdfs/medicines/covid-
19/veklury/veklury_pi.pdf) and evaluated in prior trials. 
 
B2. Agent-specific exclusion criteria 
1) Prior receipt of any dose of remdesivir during the present illness 
2) GFR < 30 ml/min and not receiving dialysis 
3) ALT or AST > 10 times upper limit of normal 
4) Unwillingness to commit to avoid sex that may result in pregnancy for at least 7 days after 
completion of remdesivir vs. placebo 
 
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B3. Description of investigational agent 
3.1. Administration and duration 
The prepared diluted solution should be administered through a separated/dedicated intravenous line 
and should not be infused simultaneously with other antimicrobials or antibody preparations (e.g., 
monoclonal antibodies, convalescent plasma, hyperimmune globin). The compatibility of remdesivir 
injection with IV solutions and medications other than 0.9% sodium chloride is not known. Administer 
remdesivir via IV infusion over 30 minutes. Slower infusion rates of up to 120 minutes can be 
considered to potentially prevent signs and symptoms of infusion-related reaction. See the PIM and 
Pharmacy Procedures for additional details. 
 
The duration of study treatment will be 10 days. The initial loading dose is 200 mg, with all 
subsequent doses 100 mg. Treatment will be discontinued if the participant is discharged or 
transferred from the study hospital. In addition, the study treatment may be discontinued after at least 
5 days, per discretion of the treating clinician, if the participant is no longer requiring respiratory 
support (high flow oxygen, noninvasive ventilation or invasive mechanical ventilation). 
 
3.2. Formulation and preparation 
Remdesivir is a sterile drug product. Remdesivir for injection, 100 mg, is a preservative-free, white to 
off-white to yellow, lyophilized solid containing 100 mg of remdesivir that is to be reconstituted with 
sterile water for injection and diluted into 0.9% saline prior to administration by IV infusion. Once 
prepared for infusion, remdesivir is colorless. In addition to the active ingredient, remdesivir for 
injection, 100 mg, contains the following inactive ingredients: sulfobutylether-beta-cyclodextrin 
(SBECD), water for injection, hydrochloric acid, and sodium hydroxide. Hydrochloric acid and sodium 
hydroxide are used to adjust the formulation to a pH of 3.0 to 4.0. Remdesivir for injection is supplied 
as a sterile product in a single-use, 30-mL Type I clear glass vial. Each vial is sealed with a rubber 
stopper and an aluminum overseal with a red, plastic flip-off cap. 
 
The placebo to match remdesivir for injection, 100 mg, is 0.9% sodium chloride solution, 
commercially available and prepared locally in the research site pharmacy, as was true for the ACTT-
1 trial. 
 
3.3 Supply, distribution, and accountability 
Procedures for ordering and accepting drug, for maintaining inventory of remdesivir, and for breaking 
the blind in the event of a medical emergency will be described in the Pharmacy Procedures. 
 
3.4. Contraindicated medications 
1) Hydroxychloroquine or chloroquine for any indication 
 
3.5. Precautionary medications 
The clinical site should have necessary equipment and medications for the management of any 
infusion-related or anaphylactic reaction.  
. 
4. Clinical and laboratory evaluations 
 
4.1 Timing of Assessments 
All assessments are outlined in the relevant section of the master protocol.  
 
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4.2. Pharmacokinetic Assessments 
Relevant pharmacokinetics are outlined in the FDA-approved package insert for remdesivir (Veklury). 
After a 10-day course of remdesivir, it is anticipated that remdesivir will persist in the body for 5 days 
after completion of the course of therapy. No pharmacokinetic assessments will occur within this trial. 
 
5. Clinical management issues 
All participants should be monitored closely for infusion-related or anaphylactic reactions. eGFR and 
transaminases should be monitored during use as clinically appropriate, consistent with the Package 
Insert. Since remdesivir is approved in the United States, has been used extensively in clinical 
practice, and has a good safety protocol, specific additional monitoring for infusions is not required for 
this agent. 
 
5.1. Symptoms and Signs 
Hypersensitivity, including infusion-related and anaphylactic reactions, has been observed during and 
following administration of remdesivir, and hence it is required to monitor patients under medical 
supervision for hypersensitivity reactions during and following administration of remdesivir. This 
occurs as part of standard clinical practice. Symptoms may include hypotension, hypertension, 
tachycardia, bradycardia, hypoxia, fever, dyspnea, wheezing, angioedema, rash, nausea, 
diaphoresis, and shivering. Slower infusion rates (maximum infusion time ≤120 minutes) can 
potentially prevent these reactions if there are symptoms of infusion-related hypersensitivity reaction 
during the current or prior infusion. If a severe infusion-related hypersensitivity reaction occurs, 
remdesivir will be immediately discontinued and appropriate treatment initiated. 
 
Transaminase elevations have been observed in healthy volunteers and in patients with COVID-19 
who received remdesivir; frank hepatic failure has not been observed. Other minor side effects have 
been observed including constipation, nausea, vomiting, decreased appetite, and headache. 
 
5.2. Site Needs 
The clinical site should have necessary equipment, medications, adequately qualified and 
experienced staff with appropriate medical cover for the management of any infusion-related or 
anaphylactic reactions. 
 
5.3. Management of Infusion Reactions including Discontinuation 
Investigators will use their clinical judgement and standard of care to evaluate and manage all 
infusion reactions. Severe infusion-related hypersensitivity reaction should result in immediate 
discontinuation of remdesivir. Discontinuation should be considered if transaminases increase to 
>10x upper limit of normal or if transaminase elevation is accompanied by signs or symptoms of liver 
inflammation. If the complete infusion is not administered, all follow-up procedures and reporting 
outlined in the master protocol should be adhered to as indicated. 
 
5.4. Factorial design features 
 
5.4.1 Rationale for Studying Remdesivir and Aviptadil in a Factorial Study   
Remdesivir and aviptadil have complementary mechanisms (pure anti-viral versus immune-modulator 
and pneumocyte stabilization combined with modest anti-viral effects) and no evidence to suggest an 
important drug-drug interaction. Notably, remdesivir has been commonly coadministered with 
aviptadil in the Expanded Access Program (EAP) and Phase 2 clinical experience with aviptadil. In 
neither experience was an important safety concern related to coadministration identified. Based on 
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this, we do not anticipate an interaction between aviptadil and remdesivir (i.e., the effect of aviptadil 
compared to placebo will be similar for those randomized to remdesivir and placebo for remdesivir).  
 
If this assumption about the absence of an interaction is valid, there are substantial efficiencies 
gained by combining the study of remdesivir and aviptadil in a single 2x2 factorial study where 
possible. 
 
Certain key assumptions and principles guide the approach to factorial study. 
 
5.4.2 Severability of factors. Some patients will be eligible for aviptadil but not for remdesivir and vice 
versa. This may include patients with low GFR being ineligible for remdesivir as well as patients who 
have already received remdesivir. To accommodate such patients, randomization will be carried out 
in four distinct strata (see Figure 1). Considering the percentage of patients who enroll in each 
stratum, we estimated that approximately 800 patients will be randomized in order to achieve 
640 participants for each of the two primary comparisons. 
  
5.4.3 Primary objectives of the factorial study 
 
• 
Primary objective 1. To determine whether aviptadil is superior to placebo when given with 
standard of care for the primary outcome of recovery based on a 6-category ordinal outcome 
evaluated at 90 days after randomization. 
• 
Primary objective 2. To determine whether remdesivir is superior to placebo when given with 
standard of care for the primary outcome of recovery based on a 6-category ordinal outcome 
evaluated at 90 days after randomization. 
 
5.4.4 Randomization 
 
As described in the master protocol, randomization will be stratified by study site pharmacy and 
receipt of mechanical ventilation at enrollment.  Randomization will be further stratified by the strata 
shown in Figure 1. 
 
Within each stratum, as indicated in the master protocol, mass-weighted urn randomization will be 
used to prepare randomization schedules. For the 2x2 factorial, patients will be equally allocated to 
four possible combinations of aviptadil, remdesivir, that the matching placebos for these drugs: 1) 
aviptadil +  remdesivir placebo; 2) aviptadil placebo + remdesivir; 3) aviptadil + remdesivir; and 4) 
aviptadil placebo + remdesivir placebo.  For strata 2 through 4 in Figure 1, treatment will also be 
equally allocated to either aviptadil or placebo (strata 2 and 4) or to remdesivir or placebo (stratum 3). 
  
5.4.5 Analysis principles 
 
For each primary objective the two treatments will be compared using a proportional odds model for 
the primary analysis. This analysis will pool results over the four strata shown in Figure 1 and by 
receipt of mechanical ventilation.  Analyses will also be stratified by geographic region instead of site 
pharmacy to minimize the number strata. The effect of aviptadil and remdesivir, each compared to 
placebo will be estimated from a single proportional odds model. For example, just considering the 
strata in Figure 1, the comparison of aviptadil with placebo will be pooled over those assigned 
remdesivir and those given placebo for remdesivir in stratum 1, over those randomized in stratum 2, 
and over those randomized in stratum 4. The effect of remdesivir will be similarly estimated pooling 
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results over those assigned aviptadil and those assigned placebo for aviptadil in stratum 1, and over 
those randomized in stratum 3. 
 
An interaction test will be carried out for those randomized in stratum 1.  In addition, an interaction 
test will be carried for aviptadil versus placebo for 4 subgroups defined by randomization to 
remdesivir or placebo in the factorial (2 subgroups in stratum 1), contraindications to remdesivir 
(stratum 2), and current or previous use of remdesivir (stratum 4). Similar subgroup analyses will be 
performed for 3 groups for remdesivir versus placebo, e.g., randomization to aviptadil or placebo 
(2 subgroups in stratum 1) and randomization to remdesivir or placebo only due to contraindication to 
aviptadil (stratum 3). 
 
Analyses of secondary endpoints and of subgroups will follow the general plan described in the 
master protocol. 
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Figure 1. Schematic of approach to factorialization of aviptadil and remdesivir   
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6. Specific safety-monitoring activities 
 
Because remdesivir is already approved for the treatment of hospitalized patients with COVID-19 and 
has been administered to very large numbers of patients without significant safety concerns, 
remdesivir safety monitoring is simpler than for an investigational agent with limited human safety 
data. Specifically, no additional infusion monitoring beyond standard clinical monitoring will be 
required during remdesivir infusions. All other safety monitoring will occur as directed by the master 
protocol. 
 
No additional components will be added to the safety outcome outlined in the master protocol. 
 
The safety monitoring table (Table 1) from the master protocol has been reproduced here with the 
appropriate modifications relevant to remdesivir. Specifically, the requirement for additional infusion 
monitoring has been removed.  
 
Table 1  Overview of Safety Data Collection Specific to Remdesivir 
 
 Day 0–7 
Day 14 
Day 28 
Day 90 
All grade 3 and 4 clinical AEs (new or 
increased in severity to Grade 3/4) 
X 
Xa 
Xa 
 
Protocol-specified exempt serious 
eventsb 
Collected through Day 90 
SAEs that are not PSESEs 
Collected through Day 90 
Unanticipated problems 
Collected through End of Subject Participation 
(Day 180) 
Hospital admissions and deaths 
Collected through End of Subject Participation 
(Day 180) 
Any SAE relatedc to study intervention 
Collected through End of Subject Participation 
(Day 180) 
 
aParticipants will be asked about all new relevant adverse events which have occurred 
since the last data collection, up to that time point. On these visits, AEs of Grade 1 or 2 
that are present on the day of the visit will also be collected. 
bThese are collected on designated forms and consist of events most likely occurring due 
to the underlying disease. Hence they are study endpoints and will be reviewed by the 
DSMB regularly, but will be “exempt” from additional collection and reporting as adverse 
events for safety. See section 10.2.3 of the master protocol for further details 
cRelatedness determined as per protocol rules in section 10. 
 
 
 
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7. References 
 
1. 
Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the Treatment of Covid-19 - Preliminary 
Report. Reply. N Engl J Med 2020;383:994. 
2. 
Desai N, Neyaz A, Szabolcs A, et al. Temporal and spatial heterogeneity of host response to 
SARS-CoV-2 pulmonary infection. Nature Communications 2020;11:6319. 
3. 
Fajnzylber J, Regan J, Coxen K, et al. SARS-CoV-2 viral load is associated with increased 
disease severity and mortality. Nat Commun 2020;11:5493. 
4. 
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 - Final 
Report. New England journal of medicine 2020;383:1813-26. 
5. 
WHO Solidarity Trial Consortium. Repurposed antiviral drugs for COVID-19—interim WHO 
SOLIDARITY trial results. New England Journal of Medicine 2020. 
6. 
NIH COVID-19 Guidelines Committee. Therapeutic Management of Patients with COVID-19.  
https://wwwcovid19treatmentguidelinesnihgov/therapeutic-management/2020. 
 
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