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 (Trial H1: Aviptadil)
Phase: PHASE3
Conditions: Covid19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Master Protocol
To be used with agent-specific appendices
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 
 Version 3.0
 08 March 2022 
 NCT06729606
(Master protocol: NCT04843761)

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 
Short Title: Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) 
INSIGHT Protocol Number: 015 / ACTIV-3b 
NCT04843761, EudraCT 2021-001650-56 
Version: 3.0, 08 March 2022 
Funded by the USG COVID-19 Therapeutics Response through National Heart, Lung, and Blood 
Institute (NHLBI) and National Institute for Allergy and Infectious Disease (NIAID), National Institutes 
of Health (NIH), 
sponsored by NIAID, 
and carried out by a collaboration of  
International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) 
Prevention and Early Treatment of Acute Lung Injury (PETAL) Network 
Cardiothoracic Surgical Trials Network (CTSN) 
Department of Veterans Affairs, USA 
INSIGHT consists of the University of Minnesota (INSIGHT Statistical and Data Management 
Center (SDMC) in collaboration with six International Coordinating Centers (ICCs) 
-Centre of Excellence for Health, Immunity and Infection (CHIP), Rigshospitalet, University of
Copenhagen - Copenhagen, Denmark
-Medical Research Council (MRC) Clinical Trials Unit at University College London (UCL) -
London, United Kingdom
-The Kirby Institute, University of New South Wales - Sydney, Australia
-The Institute for Clinical Research at the Veterans Affairs Medical Center - Washington, D.C.,
United States of America (US)
-Department of Veterans Affairs, USA
-Division of Clinical Research, NIAID, USA
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Table of Contents 
 
1 
Protocol Summary............................................................................................................. 5 
2 
Introduction....................................................................................................................... 7 
2.1 
Study rationale ......................................................................................................... 7 
2.2 
Background ............................................................................................................. 7 
2.2.1 
SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19)...................................7 
2.2.2 
Natural history of COVID-19 ........................................................................................7 
2.2.3 
Hospitalization of people with COVID-19 ......................................................................8 
2.2.4 
Viral kinetics of SARS-CoV-2 infection .........................................................................9 
2.2.5 
COVID-19 ARDS, attributes and treatments .................................................................9 
2.2.6 
Current treatment strategies for COVID-19................................................................. 10 
2.3 
Investigational Agents............................................................................................. 10 
3 
Risk/Benefit Assessment ................................................................................................. 11 
3.1 
Known Potential Risks ............................................................................................ 11 
3.1.1 
Risks of Drawing Blood and IV Catheterization ........................................................... 11 
3.1.2 
Risks due to Study Treatments .................................................................................. 11 
3.1.3 
Risks to Privacy........................................................................................................ 11 
3.2 
Known Potential Benefits ........................................................................................ 12 
4 
Outcomes ....................................................................................................................... 12 
4.1 
Primary and Secondary Outcomes to Evaluate Efficacy and Safety ........................... 12 
4.1.1 
Rationale for primary outcome................................................................................... 13 
4.1.2 
Secondary outcomes ................................................................................................ 14 
4.1.3 
Rationale for secondary outcomes ............................................................................. 16 
5 
Objectives ...................................................................................................................... 16 
5.1 
Primary Objective ................................................................................................... 16 
5.2 
Secondary Objectives ............................................................................................. 17 
6 
Study Design .................................................................................................................. 17 
6.1 
Randomization and Stratification ............................................................................. 18 
6.2 
Blinding ................................................................................................................. 19 
6.3 
Sample size assumptions ....................................................................................... 19 
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6.4 
Schedule of Assessments ....................................................................................... 21 
6.5 
Approach to Intercurrent Therapies and Clinical Trial Co-enrollment .......................... 21 
7 
Study Population ............................................................................................................. 22 
7.1 
Inclusion Criteria .................................................................................................... 22 
7.2 
Exclusion Criteria ................................................................................................... 23 
7.3 
Costs to Participants ............................................................................................... 23 
8 
Study Product ................................................................................................................. 24 
9 
Study Assessments and Procedures ................................................................................ 24 
9.1 
Screening/Baseline and Follow-up Assessments ...................................................... 24 
9.1.1 
Screening/Baseline Assessments .............................................................................. 24 
9.1.2 
Follow-up Assessments ............................................................................................ 25 
9.1.3 
Stored Samples and Future Research ....................................................................... 26 
10 Safety Assessment ......................................................................................................... 27 
10.1 
Definitions .............................................................................................................. 30 
10.1.1 
Adverse Event (AE) ............................................................................................... 30 
10.1.2 
Criteria for Seriousness ......................................................................................... 30 
10.1.3 
Unanticipated Problems ......................................................................................... 30 
10.1.4 
Severity ................................................................................................................ 30 
10.1.5 
Causality............................................................................................................... 32 
10.1.6 
Expectedness ....................................................................................................... 33 
10.2 
Schedule for Reporting of Specific Events ................................................................ 33 
10.2.1 
Infusion-related reactions ....................................................................................... 33 
10.2.2 
Grade 3 and 4 clinical adverse events on days of study drug administration, and Days 
0–7, 14, and 28 .................................................................................................................... 33 
10.2.3 
Protocol-specified exempt serious events (PSESEs)................................................ 34 
10.2.4 
Reportable SAEs ................................................................................................... 35 
10.2.5 
Unanticipated Problems (UPs) ............................................................................... 36 
10.2.6 
Deaths .................................................................................................................. 36 
10.2.7 
Pregnancy ............................................................................................................ 36 
10.3 
Medical Monitor ...................................................................................................... 36 
10.4 
Halting Enrollment for Safety Reasons ..................................................................... 36 
11 Statistical Analyses and Monitoring Guidelines.................................................................. 37 
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11.1 
Analysis of the Primary Efficacy Endpoint................................................................. 37 
11.2 
Analyses of Secondary Efficacy Endpoints, Safety Outcomes, and Subgroups ........... 37 
11.3 
Data Monitoring Guidelines for an Independent DSMB.............................................. 39 
11.3.1 
Monitoring Guidelines for Interim Analyses.............................................................. 39 
12 Protection of Human Subjects and Other Ethical Considerations ........................................ 40 
12.1 
Participating Clinical Sites and Local Review of Protocol and Informed Consent ......... 40 
12.2 
Ethical Conduct of the Study ................................................................................... 41 
12.3 
Informed Consent of Study Participants ................................................................... 41 
12.4 
Confidentiality of Study Participants ......................................................................... 41 
12.5 
Regulatory Oversight .............................................................................................. 41 
 
 
 
List of Tables 
Table 1 Categories of the primary endpoint .................................................................................. 13 
Table 2 Estimated Distribution of Endpoint Categories Used for Power Calculation ......................... 21 
Table 3 Overview of Safety Data Collection .................................................................................. 29 
Table 4 Generic AE Grading Scale .............................................................................................. 31 
Table 5. Hypotension AE Grading ................................................................................................ 32 
 
 
 
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1 
Protocol Summary  
DESIGN 
TESICO (Therapeutics for Severely Ill Inpatients with COVID-19) is a master 
protocol to evaluate the safety and efficacy of investigational agents aimed at 
improving outcomes for patients with acute respiratory failure related to COVID-
19. The focus in this master protocol, a sister protocol to the TICO master 
protocol, is on patients with critical respiratory failure (i.e., those receiving high-
flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation or 
ECMO to treat acute hypoxemic respiratory failure caused by SARS-CoV-2 
pneumonia). 
Trials within this protocol will be adaptive, randomized, blinded and initially 
placebo-controlled. Participants will receive standard of care (SOC) treatment as 
part of this protocol. If an investigational agent shows superiority over placebo, 
SOC for the study of future investigational agents may be modified accordingly.  
The international trials within this protocol will be conducted in up to several 
hundred clinical sites. Participating sites are affiliated with networks funded by 
the United States National Institutes of Health (NIH) and the US Department of 
Veterans Affairs. 
The protocol is for a phase III randomized, blinded, controlled platform trial that 
allows investigational agents to be added and dropped during the course of the 
study for efficient testing of new agents against control within the same trial 
infrastructure. When more than one agent is being tested concurrently, 
participants may be randomly allocated across agents (as well as between the 
agent and its placebo) so the same control group can be shared, when feasible. 
In some situations, a factorial design may be used to study multiple agents. 
The primary endpoint is a 6-category ordinal outcome that assesses the recovery 
status of the patient at Day 90. The categories of the ordinal outcome, from best 
to worst, start with 3 categories of “recovery” defined by the number of days alive 
at home and not on new supplemental oxygen, followed by 3 categories for “not 
recovered” defined as a) discharged but not to home or at home but still requiring 
continued new supplemental oxygen, b) hospitalized or receiving hospice care, 
and c) death at day 90. The definition of home will be operationalized as the level 
of residence or facility where the participant was residing prior to hospital 
admission leading to enrollment in this protocol.  
DURATION 
Participants will be followed for 90 days following randomization for the primary 
endpoint and most secondary endpoints. Selected secondary endpoints will be 
measured at 180 days. 
SAMPLE SIZE 
This Phase III trial is planned to provide 80% power to detect an odds ratio of 1.5 
for improvement in recovery status at Day 90 for an investigational agent versus 
placebo with use of the ordinal outcome. The planned sample size is 640 
participants (320 per group) for each investigational agent / placebo. Sample size 
may be re-estimated before enrollment is complete based on an assessment of 
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whether the pooled proportions of the outcome are still consistent with adequate 
power for the hypothesized difference measured by the odds ratio.  
POPULATION 
All participants enrolled will include inpatient adults (≥18 years) who have 
documented SARS-CoV-2 infection within 14 days of enrollment and are 
receiving high-flow nasal cannula, non-invasive ventilation, invasive mechanical 
ventilation, or ECMO at enrollment, in whom the current respiratory failure is 
thought to be due to SARS-CoV-2 infection and in whom respiratory support was 
initiated within 4 days prior to randomization.   
STRATIFICATION Randomization will be stratified by study site pharmacy and by receipt of invasive 
mechanical ventilation or ECMO at enrollment.  Other agent-specific stratification 
factors may be considered. 
REGIMEN 
Investigational agents suitable for testing in the inpatient setting will be prioritized 
based on in vitro data, preclinical data, phase I pharmacokinetic and safety data, 
and clinical data from completed and ongoing trials. In some cases, a vanguard 
cohort/initial pilot phase may be incorporated into the trial. 
MONITORING 
An independent DSMB will review interim safety and efficacy data at least 
monthly. Pre-specified guidelines will be established to recommend early 
stopping of the trial for evidence of harm or substantial efficacy. The DSMB may 
recommend discontinuation of an investigational agent if the risks are judged to 
outweigh the benefits.  
                                 
 
 
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2 
Introduction 
2.1 Study rationale 
COVID-19 is a respiratory disease caused by a novel coronavirus (SARS-CoV-2). While most 
cases are mild or asymptomatic, progressive disease can result in hospitalization, requirement 
for mechanical ventilation, and substantial morbidity and mortality.1 While the most common 
mode of disease progression is progressive respiratory failure following the development of 
pneumonia, other severe complications including thrombosis and ischemia are increasingly 
recognized.2,3 Patients with respiratory failure, which in COVID-19 is likely best termed Acute 
Respiratory Distress Syndrome (ARDS), have extremely high morbidity and mortality. Novel 
treatments for these patients are an urgent clinical and public health need. (We use the term 
ARDS interchangeably with acute respiratory failure in this master protocol.) 
Several clinical trials utilizing novel drugs and repurposing older agents have been 
implemented to investigate the treatment of adults hospitalized with severe or critical COVID-
19 (see section 2.2.6). Standard-of-care is hence rapidly evolving (see Appendix I for current 
recommendations).   
2.2 Background 
2.2.1 
SARS-CoV-2 Infection and Coronavirus Disease 19 (COVID-19) 
In December 2019, the Wuhan Municipal Health Committee identified an outbreak of viral 
pneumonia cases of unknown cause. A novel coronavirus was rapidly identified by sequencing 
and named SARS-CoV-2, and the illness caused by infection with SARS-CoV-2 has been 
named COVID-19.4 While SARS-CoV-2 mostly causes a mild respiratory illness, some 
individuals, particularly those who are elderly5,6 and have comorbidities,7 may progress to 
severe disease requiring hospitalization, mechanical ventilation in intensive care units, and 
death. As of 5 October 2020, less than seven months following the declaration of a pandemic 
on 11 March 2020 by the World Health Organization (WHO), there have been more than 35 
million cases diagnosed and more than 1 million deaths worldwide.1 Over 300,000 cases 
continue to be reported daily.5  
2.2.2 
Natural history of COVID-19 
SARS-CoV-2 has a median incubation period of 4 days (interquartile range [IQR] 2-7 days)8 
and the mean serial interval defined as the time duration between a primary case-patient 
(infector) having symptom onset and a secondary case-patient (infectee) having symptom 
onset for COVID-19 was calculated as 3.96 (95% confidence interval [CI] 3.53–4.39) days.9 
COVID-19 illness is predominantly a respiratory disease typified by upper respiratory 
symptoms in mild cases and pneumonia and ARDS in advanced disease. Initial symptoms 
typically involve the upper respiratory tract with cough, sore throat and malaise. Fever is 
present in approximately 44-98% of cases. Notably, persons with COVID-19 often 
experience loss of smell and taste.10  
 
Complications of COVID-19 illness include cytopenias (lymphopenia, thrombocytopenia and 
anemia), and acute cardiac events (elevated troponin, changes on electrocardiogram), 
vasopressor-dependent shock, acute kidney injury and dialysis-dependent renal failure, liver 
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impairment, and neurological events including acute cerebrovascular events, impaired 
consciousness, muscle injury and thrombotic events.  
In most patients (approximately 80%) symptoms resolve without the need for intervention 
within five to seven days of symptom onset up to a maximum of 14 days. However, 
approximately 20% of patients show signs of clinical disease progression, most notably 
pneumonia, around day 3 to 8 following symptom onset. Other manifestations of disease 
progression include thrombotic episodes including stroke and myocardial infarction (MI). This 
resembles the documented 6-8 fold excess risk of thrombosis when patients are infected with 
influenza virus.11  
A proportion of those who progress then further deteriorate, including with the development 
of ARDS around 1-5 days after onset of respiratory symptoms.6,12-14  Acute kidney injury 
necessitating dialysis and failure of other organs may also occur at this severe stage of 
disease. 
Of the nearly 1,099 persons described in the Wuhan cohort, 16% had severe disease at 
presentation; 67 persons (6%) reached a composite primary endpoint of intensive care 
admission, mechanical ventilation or death.9,15 As described below, outcomes for those 
requiring mechanical ventilation and with other manifestations of end-organ failure are poor, 
and treatments for such patients are critically needed. 
 
In this protocol, we aim to enroll patients hospitalized for medical management of COVID-
19, with acute respiratory failure, defined as the use of high-flow nasal cannula, non-
invasive ventilation, invasive mechanical ventilation or ECMO (extracorporeal membrane 
oxygenation). 
 
2.2.3 
Hospitalization of people with COVID-19 
Countries and jurisdictions differ in the clinical management of COVID-19 patients. Early in the 
epidemic, faced with small numbers of infected persons, some resource-rich countries such as 
Singapore elected to admit all persons with COVID-19 regardless of symptom severity to 
facilitate strict isolation. Admission for reasons of public health or quarantine, rather than 
medical management, continues to be a requirement in some countries, notably in Asia.  
Elsewhere, it is more common for those with mild illness to be advised to self-isolate at home, 
while only those severely unwell are admitted for medical management.  
Mortality rates for those who develop end-organ failure requiring intensive support, including 
those admitted to ICU, differ widely. Among 1,591 ICU patients from Lombardy, the region in 
Italy hardest hit by COVID-19, 88% required mechanical ventilation and 11% noninvasive 
ventilation.14 The ICU mortality rate was 26%. Of 1,043 patients with available data, 709 (68%) 
had at least 1 comorbidity, 509 (49%) had hypertension, and 21% had cardiovascular disease. 
Younger patients (≤63 years) compared to older patients, had lower ICU mortality and higher 
rates of discharge from ICU. The median length of stay in the ICU was 9 days, though 58% 
remained in ICU at time of report.16 In the United Kingdom, of the 4,078 COVID-19 patients 
admitted into critical care with reported outcomes, 50.7% died in ICU; those requiring 
advanced respiratory support and renal support had worse outcomes.15 More recent mortality 
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estimates among patients with COVID-19-associated ARDS range from 30–45%. These 
mortality estimates underline the importance of testing and implementing new effective 
treatments for these critically ill patients. 
 
2.2.4 
Viral kinetics of SARS-CoV-2 infection 
Viral kinetic studies have demonstrated extensive SARS-CoV-2 viral replication in the pharynx 
just before and early after symptom onset.17 Viral ribonucleic acid (RNA) shedding from the 
pharynx gradually wanes as symptoms resolve, but viral RNA is still detectable weeks after 
symptom resolution.18-20 Median duration of viral shedding was 20 days in survivors (longest 
37 days), but SARS-CoV-2 was detectable until death in non-survivors.7 Whether this is viable 
virus with the potential for continued transmission remains uncertain. RNAemia has been 
reported especially in more severe disease but is relatively rare among outpatients.21-23 Viral 
detection in sputum is higher and outlasts pharyngeal swabs in those with pneumonia.24  
Persons with asymptomatic disease clear their virus faster than symptomatic individuals.25 
The contribution of ongoing viral replication to disease progression in the most severe stage of 
COVID-19 (i.e., on ventilator or ECMO) is unclear, but one study reported that SARS-CoV2 
viral loads were higher on admission and throughout the hospital course in patients who died,26 
a finding that matches well with evidence for impaired type-1 interferon responses with more 
severe COVID-19 illness.27 SARS-CoV-2 viral RNA is also present in blood in large numbers of 
critically ill patients, with higher viral loads in blood among non-survivors than among 
survivors.23 Distribution of virus in the body of severely ill patients is heterogeneous in both 
space and time, and even patients who die of COVID-19 ARDS may have high viral load in 
lung, especially in the first two weeks.28 
2.2.5 
COVID-19 ARDS, attributes and treatments 
Notwithstanding the observed high viral loads, and progression of viral shedding from the 
upper to lower respiratory tract in those with progressive disease, the humoral immune 
response to SARS-CoV-2 appears variable and may be impaired.29 
SARS-CoV-2 infection may also induce significant changes in elements of the cellular immune 
response. As the disease process progresses, the peripheral lymphocyte count typically 
declines. The depletion of peripheral lymphocytes likely reflects translocation to the pulmonary 
tissue. The extent that this influx is exclusively helpful to the host, or possibly may contribute 
adversely to disease severity is currently unclear. In severe cases this decline in CD4+ and 
CD8+ lymphocytes is also associated with an increase in activated CD4+ and CD8+ subsets, 
increases in key proinflammatory cytokines including interleukin 6 (IL-6), and increases in 
natural killer (NK) cells.30,31 Trials assessing the use of various immunomodulatory agents with 
the aim of dampening this migration and systemic inflammation are underway, and may help to 
clarify this question.32,33 
In addition, cohorts of patients with ARDS before COVID-19 (a physiology that is likely highly 
relevant to patients with COVID-19-associated ARDS) identify risks of ventilator-associated 
injury, immune depletion and associated risk of secondary infection, encephalopathy and 
delirium, dysfunctional repair mechanisms, oxidative stress, NETosis, surfactant dysfunction, 
impairment in GM-CSF and macrophage function, mitochondropathy, dysregulated 
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microvascular thrombosis and shunting, myocardial suppression, and multiple other insults, 
which together contribute to the high morbidity and mortality in ARDS. One recent study 
provided detailed information on COVID-19 ARDS34 and a recent review considers features of 
classical ARDS and selected issues related to COVID-19 ARDS.35 
Phenotypic variability of ARDS is also well described in multiple cohorts, especially with sorting 
into inflammatory and pauci-inflammatory phenotypes.36 While COVID-19 has a single 
underlying cause (SARS-CoV-2 infection), phenotypic variability has also been observed in 
COVID-19.34,35,37 The relevance of such subtypes to possibly heterogenous treatment effects 
is as yet unknown. 
Standard supportive care for ARDS from COVID-19 including lung protective ventilation, prone 
positioning and fluid conservative care is still the most important approach to reducing mortality 
and morbidity when COVID-19 patients develop ARDS.35,38 The addition of dexamethasone for 
treatment of patients who are mechanically ventilated was effective in reducing mortality in the 
large pragmatic UK RECOVERY trial,39 although several outstanding issues relate to 
glucocorticoids for severe COVID-19.40 
2.2.6 
Current treatment strategies for COVID-19 
Hundreds of clinical trials have been completed or are underway to study the safety and 
efficacy of treatments for COVID-19. Treatments being studied include direct anti-viral 
treatments, including repurposed drugs found in vitro to have activity against SARS-CoV-2; 
immune modulators especially in patients with advanced disease; drugs to reduce 
inflammation, including corticosteroids, and modifiers of other pathophysiological pathways 
implicated in disease progression, including potentially anticoagulants and anti-platelet agents.  
As results of randomized trials for these and other treatments become available and treatment 
guidelines are updated, standard of care (SOC) for hospitalized patients with COVID-19 will 
change. This may influence the background treatment recommended (or required) by this 
protocol and/or second line or supportive care treatments recommended by the protocol.  To 
accommodate this fast-moving field Appendix I (which outlines the SOC to be recommended in 
addition to investigational agent or matched placebo) will be regularly updated. 
Of note, whereas evidence supports use of the interventions outlined in Appendix I, the most 
optimal approach to applying these interventions remains uncertain, and is the subject of 
ongoing comparative effectiveness trials.     
2.3 Investigational Agents 
Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) has formed an 
overarching “trial oversight committee (TOC)” for both ACTIV-2 (a parallel study assessing 
COVID-19 therapeutics in outpatients) and ACTIV-3 (the TICO master protocol and this 
paired TESICO master protocol). The TOC (and the agent selection committee) will select 
agents for study in the three protocols. Members of the protocol team (non-voting) and NIH 
are members of this committee. This committee reviews data for investigational agents and 
considers a number of factors relevant to the likely efficacy and safety of candidates for 
inclusion in the relevant protocols.  
 
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It is possible that several agents from different sources will be combined at some point in 
the conduct of this master protocol – but not initially. It is also possible that one agent will be 
identified as effective and then incorporated as SOC (providing there is good safety data 
and adequate supply of the agent). 
 
Information on dosing, administration, supply and distribution, matching placebo, and any 
special considerations as far as inclusion/exclusion criteria and safety monitoring for each 
investigational agent studied as part of this protocol is outlined in an appendix (see Appendix 
H), including known benefits and risk, justification for dosing, and administration. The appendix 
will also include whether any aspects of study procedures outlined in this master protocol will 
need to be deviated from. The informed consent will describe any risks associated with the 
investigational agents. 
In some cases, especially where additional data about safety and feasibility are desired, a 
vanguard cohort/pilot phase may be incorporated into a trial of a given investigational agent. 
Details of such vanguard cohorts—including design features, additional safety monitoring, and 
sample size—will be specified in the agent-specific appendix. 
3 
Risk/Benefit Assessment 
3.1 Known Potential Risks 
Potential risks of participating in this trial are those associated with the product, and these are 
described in an agent-specific appendix and in the sample informed consent. Other risks 
include having blood drawn, intravenous (IV) catheterization, and breach of confidentiality.  
Given the significant disease-related risks faced by this target population, there is felt to be a 
favorable risk/benefit profile, and significant risk acceptability.   
3.1.1 
Risks of Drawing Blood and IV Catheterization 
Drawing blood may cause transient discomfort and, rarely, fainting. Fainting is usually transient 
and managed by having the participant lie down and elevate his/her legs. Bruising at the blood 
collection sites may occur but can be prevented or lessened by applying pressure to the blood 
draw site for a few minutes after the blood is taken. IV catheterization may cause insertion site 
pain, phlebitis, hematoma formation, and infusate extravasation; less frequent but significant 
complications include bloodstream and local infections. The use of aseptic (sterile) technique 
will make infection at the site of blood draw or at catheterization less likely. 
3.1.2 
Risks due to Study Treatments 
Infusions of investigational agents likely to be used in this protocol are generally well-tolerated, 
except in rare cases of existing allergy to the products infused. However, each agent may have 
associated risks, which will be specified in the relevant agent-specific appendix.  
3.1.3 
Risks to Privacy 
Participants will be asked to provide personal health information (PHI). All attempts will be 
made to keep this PHI confidential within the limits of the law. However, there is a chance that 
unauthorized persons will see the participant’s PHI. All source records including electronic data 
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will be stored in secured systems in accordance with institutional policies and government 
regulations.  
All study data that leave the site (including any electronic transmission of data) will be 
identified only by a coded number that is linked to a participant through a code key maintained 
at the clinical site. Names or readily identifying information will not be released. Electronic files 
will be password protected. 
Only people who are involved in the conduct, oversight, monitoring, or auditing of this trial will 
be allowed access to the PHI that is collected. Any publication from this trial will not use 
information that will identify study participants. Organizations that may inspect and/or copy 
research records maintained at the participating site for quality assurance and data analysis 
include groups such as the study monitor, other authorized representatives of the institutional 
review board (IRB), NIH, and applicable regulatory agencies (e.g. FDA).  
3.2 Known Potential Benefits 
While the trial is conducted to test the hypothesis that each investigational agent will improve 
participant status on an ordinal recovery outcome assessed at 90 days, the agents studied may 
or may not achieve these outcomes in any individual who participates in this trial. However, there 
is an anticipated benefit to society from a patient’s participation in this trial, due to insights that 
will be gained about the investigational agent(s) under study as well as the natural history of the 
disease. While there may not be benefits for an individual, there will be benefits to society if a 
safe, efficacious therapeutic agent can be identified during this global COVID-19 outbreak. 
4 
Outcomes 
This section describes the key outcome measures used in this phase III protocol. The 
complete approach to measurement and evaluation of trial endpoints will be specified in the 
statistical analysis plan before unblinding. 
4.1 Primary and Secondary Outcomes to Evaluate Efficacy and Safety 
The primary endpoint is an ordinal outcome that assesses participant recovery status at Day 
90. The primary ordinal endpoint is referred to as recovery. The outcome includes 6 
categories, consisting of 3 ranked categories of the number of days alive, at home, and not 
receiving new supplemental oxygen at Day 90 (77 or more consecutive days, 49–76 days, or 
1–48 days) as well as an additional 3 categories for patients who are not recovered at Day 90: 
(1) discharged from the hospital but either not yet home, or home but receiving new 
supplemental oxygen, (2) still hospitalized or receiving hospice care, or (3) dead.  
Consistent with the TICO protocol (NCT04501978), home is defined as the level of residence 
or facility where the participant was residing prior to onset of COVID-19 leading to the hospital 
admission that led to enrollment in this protocol. Residence or facility groupings to define home 
are: 1) Independent/community dwelling with or without help, including house, apartment, 
undomiciled/homeless, shelter, or hotel; 2) Residential care facility (e.g., assisted living 
facility, group home, other non-medical institutional setting); 3) Other healthcare facility (e.g., 
skilled nursing facility, acute rehab facility); and 4) Long-term acute care hospital (hospital 
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aimed at providing intensive, longer term acute care services, often for more than 28 days). 
Lower (less intensive) level of residence or facility will also be considered as home. By 
definition, “home” cannot be a “short-term acute care” facility. Participants previously residing 
in a “long-term acute care” hospital recover when they return to the same or lower level of 
care.  
Since some patients will be receiving supplemental oxygen before their COVID-19 illness, we 
define new supplemental oxygen as any supplemental oxygen in participants who were not 
receiving supplemental oxygen before their COVID-19 illness or an increase in supplemental 
oxygen above pre-COVID-19 baseline among patients who were receiving supplemental 
oxygen before their COVID-19. 
The “last-off” method for assessing recovery will be used, as has been customary in the use of 
similar ordinal endpoints in ARDS trials for decades. According to the “last-off” method, periods 
of recovery that are followed by hospital re-admission, change from home to a higher level of 
care, or receipt of new supplemental oxygen will not be counted toward the number of days of 
recovery. In other words, only days between the last time the patient entered a recovered state 
(returned home, free of new supplemental oxygen), and Day 90 are counted as days of 
recovery. The categories of the primary endpoint are displayed in Table 1. 
Table 1 Categories of the primary endpoint 
Category 
Status at 90 days 
1 (Best) 
At home and off oxygen. 
No. of consecutive days at Day 90 
 
≥ 77 
2 
49-76 
3 
1-48 
4 
Not hospitalized AND either at home on 
oxygen OR not at home  
5 
Hospitalized for medical care OR in 
hospice care 
6 (Worst) 
Dead 
 
Participants residing in a facility solely for public health or quarantine purposes will be 
considered as residing in the lowest level of required residence had these public health 
measures not been instated. If such patients are receiving new supplemental oxygen, they will 
not be classified as recovered. 
4.1.1 
Rationale for primary outcome 
The primary ordinal endpoint, recovery, was selected given the high mortality in COVID-19 
ARDS and the expectation that agents may have effects on both mortality and time to recovery 
among survivors. The common use of new supplemental oxygen after discharge (as high as 
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40% of discharged patients among ARDS patients in prior cohorts) and frequent 
rehospitalizations also motivated the structure of this endpoint.  
The primary outcome is intended to identify relevant efficacy among investigational agents 
using an endpoint that is patient-centered, clinically relevant, and appropriately efficient.  
Whereas mortality may be the most important ultimate outcome, the sample size to detect a 
plausible treatment effect for such an outcome would be much larger than outlined in this 
protocol. It was determined that use of a mortality-only endpoint would unduly increase the 
amount of time and resources necessary to make a determination of efficacy and was thus not 
feasible in current pandemic circumstances. Importantly, mortality was not considered to be 
the only relevant measure of efficacy in COVID-19—among survivors, the duration of recovery 
at Day 90, which also reflects length of hospitalization, is also an important benchmark. This 
position is consistent with decades of work in ARDS trials. Notably, while data specific to 
COVID-19 have not yet been generated, in general ARDS populations, a longer time to 
recovery has been associated with worse long-term outcomes, making recovery evaluated at 
Day 90 an important patient-centered endpoint.41-44 
The primary outcome is assessed at 90 days of follow-up, which is longer than for other trials 
of investigational agents for COVID-19, which have typically been 28 days. The longer follow-
up will allow better ascertainment of recovery from the longer-term consequences of the 
underlying disease, and hence the efficacy of the investigational agent. This is likely to be 
particularly true for the TESICO target population, who are critically ill. Based on data from 
COVID-19 observational cohorts and ARDS trials before the pandemic, it is also projected that 
excess mortality will be observed between Day 28 and Day 90. A single category of death at 
Day 90 is used for the worst category of the primary endpoint instead of time to death given 
the 90 day follow-up period. Time to death is a secondary endpoint. 
4.1.2 
Secondary outcomes 
In addition to the primary endpoint, several secondary efficacy endpoints will be assessed. 
These endpoints will be assessed for all participants enrolled.  
1. All-cause mortality through Day 90, dichotomous as well as time to death  
 
2. (a) Composite endpoint that considers the number of days at home off new supplemental 
oxygen and the time to death as well as the other categories of the primary ordinal 
outcome;  
(b) a dichotomous composite endpoint of alive, at home, and off new supplemental oxygen 
at Day 90;  
(c) a three-category ordinal endpoint, measured at Day 90, with the following categories: 
recovered (alive, at home, and off new supplemental oxygen), alive and not recovered, and 
dead. 
 
3. Time from randomization to recovery defined as alive, at home, and off oxygen (treating 
death as a competing risk). 
 
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4. Days alive outside of a short-term acute care hospital up to Day 90 (among survivors), 
using the “last off” method 
 
5. Clinical organ failure or serious infections defined by development of any one or more of 
the following clinical events through Day 28 (see PIM for criteria for what constitutes each 
of these conditions; such conditions that existed at baseline are not counted):  
 
a. Worsening respiratory dysfunction 
1. Increase in the level of respiratory support from high-flow nasal cannula or 
non-invasive mechanical ventilation at baseline to mechanical ventilation or 
ECMO, or from invasive mechanical ventilation at baseline to ECMO. 
 
b. Cardiac and vascular dysfunction: 
1. Myocardial infarction 
2. Myocarditis or pericarditis  
3. Congestive heart failure: new onset NYHA class III or IV, or worsening to class 
III or IV 
4. Hypotension treated with vasopressor therapy 
5. Atrial or ventricular tachyarrhythmias  
 
c. Renal dysfunction: 
1. New requirement for renal replacement therapy  
 
d. Hepatic dysfunction: 
1. Hepatic decompensation 
 
e. Neurological dysfunction 
1. Acute delirium 
2. Cerebrovascular event (stroke, cerebrovascular accident [CVA]) 
3. Transient ischemic events (i.e., CVA symptomatology resolving <24 hrs) 
4. Encephalitis, meningitis or myelitis 
 
f. Haematological dysfunction: 
1. Disseminated intravascular coagulation 
2. New arterial or venous thromboembolic events, including pulmonary embolism 
and deep vein thrombosis 
3. Major bleeding events (>2 units of blood within 24 hours, bleeding at a critical 
site (intracranial, intraspinal, intraocular, pericardial, intraarticular, 
intramuscular with compartment syndrome, or retroperitoneal), or fatal 
bleeding). 
 
g. Serious infection: 
1. Intercurrent, at least probable, documented serious disease caused by an 
infection other than SARS-CoV2, requiring antimicrobial administration and 
care within an acute-care hospital.  
 
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6. A composite of death, clinical organ failure or serious infections (see above) through Day 
90.  
 
7. Outcomes assessed in other treatment trials of COVID-19 for hospitalized participants in 
order to facilitate meta analyses and facilitate generation of norms, including an ordinal 
scale measuring the degree of oxygen support through Day 14, time to discharge from the 
initial hospitalization, and binary outcomes defined by worsening based on the worst 3 
categories of the primary ordinal recovery outcome at day 90. 
 
8. A composite of cardiovascular events (outcomes listed above in items 5b1, 5e2 and 5e3) 
and thromboembolic events (item 5f2) through Day 28 and Day 90.  
 
9. Safety and tolerability as measured by 
a. A composite safety outcome of grade 3 and 4 clinical adverse events, SAEs, 
PSESEs (see 10.2.3), or death through Day 5 (primary safety endpoint) and through 
Day 28 (secondary safety endpoint) 
b. Infusion-related reactions of any severity  
c. Percentage of participants for whom the infusion was interrupted or stopped prior to 
completion for any reason and separately for an adverse event 
d. A composite of hospital readmissions or death through 90 days. 
 
4.1.3 
Rationale for secondary outcomes 
The main secondary outcomes for the TESICO trial are constituents of the primary outcome 
(mortality, time to death, number of days home off oxygen) or closely related to them (days 
alive outside of the hospital). In addition, given the evolving information about the effects of 
COVID-19 outside of the lungs, measuring organ failure is important to understand the full 
range of COVID-19. Given that secondary infections are common among ARDS patients, 
including those with ARDS from COVID-19, measuring and monitoring secondary infections is 
also important to understanding the full scope of the effect of a COVID-19 therapeutic agent. In 
addition, the importance of understanding COVID-19 epidemiology (and supporting potential 
meta-analyses) across the range of therapeutic trials mandates collection of outcomes relevant 
to the calculation of endpoints from other trials. The rationale for the safety outcomes collected 
is presented in Section 10. If a specific secondary outcome is to be added for a given 
investigational agent, that additional outcome will be specified in the corresponding Appendix 
H. 
5 
Objectives 
5.1 Primary Objective 
The primary objective of this protocol is to determine whether investigational agents are safe 
and superior to control (initially and primarily placebo) when given with SOC for the primary 
endpoint of recovery (based on a 6-category ordinal outcome) evaluated at 90 days after 
randomization.  
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SOC may be modified (updated based on data from this or other trials) during the course of 
evaluating different investigational agents with this master protocol. SOC may also be studied 
in this master protocol along with investigational agents if data from trials indicate that efficacy 
is uncertain for this target population of patients with COVID-19 ARDS. 
5.2 Secondary Objectives 
Four key secondary objectives are to compare each investigational agent with control for: 
1. Time to death through Day 90  
2. A composite endpoint that considers the number of days at home off new supplemental 
oxygen and the time to death as well as the other categories of the primary ordinal 
outcome,  
3. Time to recovery defined as alive, at home, and off new supplemental oxygen,  
4. A three-category ordinal outcome, measured at Day 90, with the following categories: 
recovered (alive, at home, and off new supplemental oxygen), alive and not recovered, 
and dead.  
 
Other secondary objectives are to compare each investigational agent with control for the 
secondary outcomes listed in section 4. 
In addition, the primary ordinal endpoint of recovery will be evaluated for subgroups defined by 
the following characteristics measured at enrollment: 
• Receipt of invasive mechanical ventilation or ECMO 
• Age 
• Biological sex 
• Race/ethnicity 
• Type of residence/facility (home)  
• Body mass index (BMI) 
• History of chronic conditions (cardiovascular disease, diabetes, asthma, chronic 
obstructive pulmonary disease, hypertension, chronic kidney disease, hepatic 
impairment, or cancer) 
• Geographic location 
• Duration of symptoms prior to enrollment 
• Concomitant treatments (including other randomized treatments) at enrollment 
• SARS-CoV-2 vaccination status at baseline 
• Disease progression risk score (defined using pooled treatment groups with the 
following baseline predictors of the primary outcome (recovery evaluated at 90 days): 
age, biological sex, duration of symptoms, receipt of invasive mechanical ventilation or 
ECMO vs. neither, and presence of chronic health conditions. 
6 
Study Design  
TESICO (Therapeutics for Severely Ill Inpatients with COVID-19) is a master protocol to 
evaluate the safety and efficacy of multiple investigational agents for COVID-19 ARDS. Master 
protocols can be a more efficient approach to the evaluation of multiple experimental 
interventions for a single disease such as COVID-19 in a continuous manner.  
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The trial described in this master protocol is a phase III randomized, blinded, controlled 
platform trial that allows investigational agents to be added and dropped during the study for 
efficient testing of new agents against placebo within the same trial infrastructure. When more 
than one agent is being tested concurrently, participants will be randomized across agents, as 
well as to agent/control. This general approach will allow rapid testing of multiple agents as the 
pooling of controls across agents requires fewer patients to be randomized to the matched 
control arm of each agent.  However, this will only occur when feasible and when multiple 
agents are available to be tested at the same time.  If an investigational agent shows 
superiority over placebo + SOC as initially defined, SOC for future investigational treatment 
evaluations will be modified accordingly.  
In some cases, more than one dose of an investigational agent will be studied. For such 
agents, specific details of the dose selection will be outlined in the relevant Appendix H.  
6.1 Randomization and Stratification 
Patients will be equally allocated to each investigational agent + SOC or to placebo + SOC. 
For example, for a study of a single investigational agent, participants will be randomized in a 
1:1 ratio to the investigational agent + SOC or to placebo + SOC. If a participant is eligible for 
two investigational agents, the allocation will be 1:1:1 to investigational agent A + SOC, agent 
B + SOC, or placebo + SOC.  Because the two investigational agents (A and B) may require 
different placebos (for example, when infusion volumes or route of administration differ), the 
1:1:1 allocation ratio will be achieved through a two-step randomization procedure: in step 1, 
the participant is randomized 2:1 to “active” versus “placebo”; in step 2, the participant is 
randomized 1:1 to A versus B.  With k agents, this can be viewed as an initial k:1 allocation to 
“active” versus “placebo”, followed by a second, even allocation to one of the available agents 
(for example, if a participant was allocated to “placebo” in step 1, then the step 2 allocation will 
be 1:1 to “agent-specific placebo for A” versus “agent-specific placebo for B”).  Sites will be 
informed of the specific investigational agent/placebo (e.g., A or B) to which the participant was 
randomized (see section 6.2) but not whether the patient is receiving active agent versus 
placebo. For the analysis, the concurrent agent-specific placebo groups will be pooled, 
resulting in a 1:1 allocation ratio for comparing each investigational agent versus the (pooled) 
placebo group. 
If investigational agents are added or dropped, the allocation ratio to active versus placebo will 
be appropriately modified, and overall sample size will be recalculated as appropriate.  
Randomization will be stratified by study site pharmacy (several clinical sites may share one 
study site pharmacy) and receipt of invasive mechanical ventilation or ECMO (vs. neither) at 
entry. Within each randomization stratum, mass-weighted urn randomization45 will be used to 
generate the active and placebo assignments. This will ensure throughout the trial placebo 
allocation near the intended ratio while also ensuring near equal numbers of active and 
matched placebo assignments to each agent.   
If more than one investigational agent is being compared with placebo and they have different 
contraindications, consideration will be given to allowing participants to enter with 
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randomization to each agent versus placebo separately as well as randomization to both 
agents. If the number of participants expected to have a contraindication is small, they will be 
excluded from the trial rather than establishing a separate randomization mechanism. 
Comparisons will be of each investigational treatment against its control arm. The control arm 
consists of all participants who were “at risk” for being randomized to the investigational agent 
but were randomized to a control group instead. This concept is relevant when the 
randomization includes investigational agents with different eligibility criteria or introduction into 
the platform trial at different time points. Formal randomization includes a matched placebo 
group for each agent, and the placebo groups will be pooled across agents, but only 
participants who (1) were eligible for the investigational agent under consideration, and (2) 
were randomized contemporaneously and at participating sites will be included in the control 
group for a given agent. 
The default randomization allocation to agent (or its placebo) for which a participant is eligible 
is as outlined above. However, in some circumstances this allocation ratio may be changed by 
the (blinded) protocol leadership based on an overall assessment of how the master protocol 
framework is able to produce relevant and novel findings most effectively. In addition, some 
agents may undergo factorial randomization with other agents. Such details will be specified in 
the relevant agent-specific appendix. 
6.2 Blinding 
Investigational agents or placebo (as necessary) will be prepared by a pharmacist who is not 
blinded to the treatment assignment. All other study staff, including those at sites, and those in 
roles spanning multiple sites or spanning the protocol as a whole, will be blinded unless 
otherwise specified herein.  
For investigational agents infused, blinding of the participant and clinical staff may be achieved 
by placing a colored sleeve over the infusion bags used for investigational agents and 
placebos. Placebo will consist of an isotonic crystalloid, referred to as an isotonic saline 
solution.  
When more than one investigational agent is available for randomization, the clinical staff will 
be informed to which investigational agent/placebo the participant was randomly assigned for 
infusion, but they will remain blinded to whether the random assignment was to the active 
investigational agent or matching placebo.  
If the blind is broken, whether by accident, or for safety reasons, this will be recorded, and the 
protocol chair will be notified of the event. In that situation, every attempt will be made to 
minimize the number of people unblinded. Specific unblinding procedures and instructions are 
found in the PIM. 
6.3 Sample size assumptions 
All sample size calculations are aimed at pairwise comparisons between a given 
investigational agent and its control arm.  The following assumptions were made in estimating 
the required sample size for this phase III trial. 
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a. The primary analysis will be intention to treat. 
b. A proportional odds model will be used to compare recovery at Day 90 for the 
investigational agent and placebo.   
c. Patients will be assigned the worst category that applies at Day 90. 
d. The “last-off” method (for return to home and liberation from new supplemental oxygen) 
is used to calculate days of recovery among those who are recovered on Day 90. 
e. Approximately 80% of patients will enter the trial on high-flow nasal oxygen, while 
approximately 20% will enter with non-invasive or invasive mechanical ventilation or 
ECMO. Control-group event rates for these patients are based on findings from ACTT-
1, the Intermountain Prospective COVID Registry (IPOC), ISARIC, and other data 
sources. This includes estimates of the percentage of patients in each category of 
respiratory support (i.e., high flow nasal oxygen, non-invasive ventilation, invasive 
mechanical ventilation or ECMO) at baseline.46 
f. Most patients will be discharged in the first month after randomization; based on ACTT-
1 and PETAL Network data, we estimate 25% will be discharged to their home and stay 
home for 14 days by day 28 following randomization; half of these patients will be 
discharged to their home on oxygen; and most will receive oxygen for 3-4 weeks. Thus, 
the category 1 percentage is approximately 12% considering re-initiation of home 
oxygen and re-hospitalization. 
g. Categories 2 and 3 are wider and also consider home oxygen re-initiation and re-
hospitalization. 
h. Three categories of time at home off oxygen were considered because an intervention 
that shortened time on new supplemental oxygen and also decreased mortality was 
considered clinically relevant. 
i. Based on data from PETAL Network and Intermountain Healthcare, 33% of participants 
will die by Day 90.  A single category is used for death at Day 90 instead of time of 
death given the target population and planned follow-up. 
j. At Day 90 < 10% of patients will be in the hospital; and about 10% will be on oxygen or 
not at home. 
k. With type 1 error of 0.05 (2-sided) and 80% power to detect the OR of 1.5, sample size 
is 602. This is increased to 640 (320 in each group) to allow for a small percentage of 
patients who withdraw consent or are lost to follow-up before Day 90. 
 
 
The estimated control and treatment arm distribution of endpoint categories used to calculate 
sample size and power is displayed in Table 2. 
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Table 2 Estimated Distribution of Endpoint Categories Used for Power Calculation 
Category 
Status at 90 days 
Investigational 
Agent (%) 
Control (%) 
1 
At home and off oxygen. 
No. consecutive days at Day 90 
 
≥ 77 
 
 
 
 
17.0 
 
 
 
 
12.0 
2 
49-76 
27.7 
23.0 
3 
1-48 
17.2 
17.0 
4 
Not hospitalized AND either at 
home on oxygen OR not at home 
9.1 
10.0 
5 
Hospitalized for medical care OR 
in hospice care 
4.3 
5.0 
6 
Dead 
24.7 
33.0 
 
Total 
100.0 
100.0 
 
Sample size may be re-estimated before enrollment is complete to determine whether the 
pooled proportions are still consistent with 80% power to detect an OR 1.5.  
6.4 Schedule of Assessments 
Participants will be randomized and start therapy on Day 0. The primary endpoint and most 
secondary endpoints will be measured through Day 90. After Day 90 results are completed, 
data will be unblinded to allow expeditious reporting of primary results. In addition, all 
participants randomized will be followed through 180 days following randomization for 
collection of study data (Appendix B and section 9.1 for details).  
6.5 Approach to Intercurrent Therapies and Clinical Trial Co-enrollment 
In general, the study will take a pragmatic approach to the use of intercurrent, concomitant 
medications. Sponsor and/or protocol leadership may, based upon convincing new evidence, 
act in the interest of participant protection, and in avoidance of confounding, to 
exclude/disallow use of any specific concomitant therapy found to be reasonably 
contraindicated for a well-defined portion of the study population (see Appendix I). Such a 
determination may be made, communicated, and implemented by a Protocol Clarification 
Memo until it is reasonable to amend the protocol for other reasons.   
Coenrollment in other trials will only be allowed where a coenrolling trial has been approved by 
trial leadership for coenrollment.  
The planned analyses are by intention to treat (or modified intention to treat as noted). All 
participants will be compared throughout follow-up, irrespective of use of concomitant 
treatments or co-enrollment in other trials. Concomitant treatments will be recorded at 
baseline, daily through Day 7, and on Days 14 (which will reference Days 8–14), and 28. 
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7 
Study Population 
Pragmatic classifications of COVID-19 severity, largely based on an early WHO scale or 
variants, have been widely adopted in clinical trials. These scales generally specify the degree 
of respiratory impairment as determined by the location of care and the degree of organ 
support.47 The target population of TESICO are patients with SARS-CoV-2 pulmonary 
involvement severe enough to cause acute hypoxemic respiratory failure that is treated with 
high flow nasal oxygen or mechanical ventilation (whether invasive or noninvasive). The 
TESICO target population is thus a subset of “critical COVID-19,” as it is focused on 
hypoxemic respiratory failure due to COVID-19 pneumonia as the critical organ failure. The 
TESICO target population is also a subset of COVID-19 respiratory failure, since it is restricted 
to those with hypoxemia who are receiving advanced respiratory support. Based on 
unpublished data from a national and a regional cohort of hospitalized patients with COVID-19 
pneumonia suggesting that >90–95% of patients in this target population would meet the Berlin 
consensus statement48 oxygenation and radiographic criteria for ARDS, we at times use the 
term ARDS interchangeably with COVID-19-associated critical respiratory failure to describe 
our target population in this protocol. We anticipate that the members of the target population 
so defined will benefit from the investigational agents, as the vast majority will have bilateral 
pulmonary infiltrates from lung inflammation and injury due to life-threatening SARS-CoV-2 
infection. (To facilitate inferences about generalizability and subsequent meta-analyses, we will 
record and report chest radiograph results and SF ratios to allow alignment with the Berlin 
definition and newly proposed modifications49 at the conclusion of the trial.) 
In the context of this understanding of COVID-19-associated critical respiratory failure, COVID-
19 participants with ARDS will be enrolled at clinical trial sites globally. The estimated time 
from screening (Day -1 or Day 0) to end of study for an individual participant is 90 days for the 
primary endpoint and 6 months for some secondary endpoints. 
Patient eligibility must be confirmed by study personnel named on the delegation log. 
Protocol inclusion and exclusion criteria are intentionally straightforward and are NOT subject 
to exception for even minor deviations, e.g., by Study Medical Officers or by the Sponsor 
Medical Monitor. 
7.1 Inclusion Criteria 
1. Age ≥ 18 years; 
 
2. Informed consent by the patient or the patient’s legally-authorized representative (LAR)*; 
 
3. Requiring admission for inpatient hospital acute medical care for clinical manifestations of 
COVID-19, per the responsible investigator, and NOT for purely public health or quarantine 
purposes. 
 
4. Current respiratory failure (i.e., receipt of high-flow nasal cannula, non-invasive ventilation, 
invasive mechanical ventilation, or ECMO used to treat acute hypoxemic respiratory 
failure). 
 
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5. SARS-CoV-2 infection, documented by a nucleic acid test (NAT) or equivalent testing with 
most recent test within 14 days prior to randomization. (For non-NAT tests, only those 
deemed to have equivalent specificity to NAT by the protocol team will be allowed.  A 
central list of allowed non-NAT tests will be maintained.) 
 
6. Respiratory failure is believed to be due to SARS-CoV-2 pneumonia. 
 
*Continuing consent  
Participants for whom consent was initially obtained from a LAR, but who subsequently regain 
decision-making capacity while in hospital will be approached for consent for continuing 
participation, including continuance of data acquisition. 
 
7.2 Exclusion Criteria  
1. Known allergy to investigational agent or vehicle 
2. More than 4 days since initiation of support for respiratory failure (i.e., receipt of high-flow 
nasal cannula, non-invasive ventilation, invasive mechanical ventilation or ECMO used to 
treat acute hypoxemic respiratory failure). 
3. Chronic/home mechanical ventilation (invasive or non-invasive) for chronic lung or 
neuromuscular disease (non-invasive ventilation used solely for sleep-disordered breathing 
is not an exclusion). 
4. Moribund patient (i.e., not expected to survive 24 hours) 
5. Active use of “comfort care” or other hospice-equivalent standard of care 
6. Expected inability to participate in study procedures;  
7. In the opinion of the responsible investigator, any condition for which, participation would 
not be in the best interest of the participant or that could limit protocol-specified 
assessments; 
8. Previous enrollment in TESICO 
 
Exclusions that may be specifically appropriate for an investigational agent studied are 
referenced in the relevant appendix (H) for the investigational agent. The contraindications for 
use of components of SOC are outlined in Appendix I and in the PIM.  
 
7.3 Costs to Participants 
There is no cost to participants for the research tests, procedures/evaluations and study 
product while taking part in this trial. Procedures and treatment for clinical care including costs 
associated with hospital stay may be billed to the participant, participant’s insurance or third 
party. 
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8 
Study Product 
Investigational agents and SOC treatment to be used are described in Appendices H and I, 
respectively. 
9 
Study Assessments and Procedures 
9.1 Screening/Baseline and Follow-up Assessments 
Data collection at each visit is outlined below and summarized in Appendix B. Day 0 refers to 
the day on which randomization occurs and on which the investigational agent/placebo is first 
administered.  Screening and randomization can be done in the same session.  The term 
“baseline” refers to data that are collected prior to randomization. 
9.1.1 
Screening/Baseline Assessments 
After obtaining informed consent, the following assessments are performed within 24 hours 
prior to randomization to confirm eligibility and to collect baseline data: 
• Documentation of laboratory diagnosis of SARS-CoV-2 infection in the appropriate 
timeframe 
 
• A focused medical history, including the following information:  
 Demographics including age, gender, and type residence or facility prior to 
current illness (i.e. “home”) 
 Day of onset of COVID-19 signs and symptoms 
 History of chronic and current medical conditions, including targeted conditions 
for outcome analysis  
 Targeted concomitant medications and SARS-CoV-2 vaccine receipt or trial 
participation 
 
• A focused physical examination including vital signs (at least heart rate, systolic and 
diastolic blood pressure, respiratory rate, temperature, and oxygen saturation), height and 
weight, baseline degree of oxygen supplementation/respiratory support 
 
• Blood draw for local laboratory evaluations: 
 White blood cell count 
 Hemoglobin 
 Platelets 
 Lymphocyte and neutrophil counts 
 Ferritin 
 C-reactive protein  
 Basic metabolic panel 
 Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) 
 Total bilirubin 
 INR 
 D-DIMER 
 
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• Plasma and serum specimens for future related research (four 1.0 mL aliquots of serum and 
four 1.0 mL aliquots of plasma). Two 9 mL tubes, one SST and one EDTA, of blood (18 mL 
total) will be drawn in order obtain 8 aliquots. This includes antibody status and viral antigen, 
among other assays. 
• A mid-turbinate nasal swab for SARS-CoV-2 
• Among those who provide consent for host genetics, whole blood will be collected and 
stored for RNA (one 2.5mL PAXgene tube) and DNA (one 9mL EDTA tube to produce six 1-
mL aliquots) extraction 
• Contact details (phone, e-mail or other types of contact) for the participant and at least two 
close relatives/friends, to ensure reliable data collection during follow-up in the trial.   
• Urine or serum pregnancy test in women of childbearing potential who do not already have 
evidence of pregnancy 
In some cases, it may not be possible to draw blood for local laboratory assessments and 
storage prior to the time of randomization.  In these cases, the blood draw can be performed 
after the time of randomization but before the infusion of the blinded investigational 
agent/placebo. 
The overall eligibility of the patient for the study will be assessed once all screening information 
is available. The screening process can be suspended prior to completion of the assessment 
at any time if exclusions are identified by the study team. 
Participants who qualify will be randomized within 24 hours of consent and given the infusion 
of the blinded investigational agent/placebo. Immediately prior to randomization, receipt of 
high-flow nasal cannula, non-invasive ventilation, invasive mechanical ventilation, or ECMO by 
the participant should be verified. 
On days of study drug administration, before and during study drug administration, the 
following data will be collected, and reported on appropriate case report forms as applicable: 
• Adverse events of any grade severity present prior to the infusion (Day 0 only) 
• Start and stop times of the infusion of the investigational agent/placebo 
• Doses of study drug 
• Infusion-related reactions to the investigational agent/placebo 
• New adverse events of any grade severity during and up to 2 hours after the infusion 
• On Days 0, 1, and 2, a blood draw for local laboratory evaluations 
 
The details of monitoring during and immediately after the infusion will be specified in the 
agent-specific appendices. Participants who experience AEs during or immediately after the 
infusion should be followed closely until the resolution of the AE.   
9.1.2 
Follow-up Assessments 
Participants will be followed through 180 days following randomization for collection of study 
data (Appendix B). Relevant clinical data will be collected on Days 0–7, 14, 28, 42, 60, 75, 90, 
and 180. These data will include discharge status, and interim changes in medical history 
(targeted to components of primary and secondary endpoints). Concomitant medications will 
be collected on Days 0-7, Day 14 (retrospectively for Days 8-14), and on Day 28, clinical (i.e., 
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not limited to a laboratory abnormality) incident AEs of grade 3 and 4 severity through Day 28, 
and hospitalization readmissions and deaths through 180 days. 
Components necessary to determine the ordinal WHO/NIH ordinal outcome and the TICO 
Pulmonary endpoint will be collected to allow the computation of the ordinal outcome for every 
day through Day 14 and on Day 28. On Days 14 and 28 AEs of any grade severity will also be 
collected. 
At Day 3 and Day 5 for all participants still hospitalized, plasma and serum specimens for 
central testing for SARS-CoV-2 antibody determination, viral antigen, and storage (four 1.0 mL 
aliquots of serum and four 1.0 mL aliquots of plasma) will be obtained for future related 
research. Two 9 mL tubes, SST and EDTA, of blood (18 mL total) will be drawn in order obtain 
the 8 aliquots.   
At Day 3, among those participants who provided consent for host genetics, a whole blood 
specimen for RNA extraction will be collected (sufficient for one 2.5 mL PAXgene tube). 
At the time of discharge, the residence/place of living to which the participant was discharged 
and whether it was the type of residence (i.e. “home”) occupied at the time of onset of COVID-
19 symptoms will be ascertained.  All changes in this status (e.g., re-admission to another 
hospital or an intermediate care facility) will be collected at approximately 2-week intervals, 
starting with the day 14 visit, to determine the time of return “home” and time of liberation from 
new supplemental oxygen (as well as readmissions or resumption of new supplemental 
oxygen). Entry into hospice care will also be collected. 
For visits on Days 7, 14, 42, 60, 75, 90, and 180, contact with the participant for study data 
collection may be performed by telephone. However, other information will be gathered, as 
outlined in Appendix B. At Day 90 and Day 180, the EQ-5D-5L will be administered by 
telephone, with additional patient-reported outcomes (MRC Dyspnea, PROMIS fatigue, 
CONNECTS Recovery) also collected by telephone at Day 90 and Day 180. Safety data 
collection and reporting are described further in Section 10.  
9.1.3 
Stored Samples and Future Research 
The plasma, mid-turbinate, and serum specimens collected as outlined above will be stored at 
a central specimen repository in the US.  In addition to the specified testing to be done per 
protocol (collected at baseline and Day 3 for all hospitalized participants and collected at Day 5 
among participants still in the ICU on Day 5), the specimens will be available for later use in 
research concerning COVID-19, SARS-CoV-2, and the impact of the study treatment. The 
whole blood specimens for RNA and DNA extraction from those participants who provided 
consent for host genetics will also be stored at the same central specimen repository in the 
US. Proposed research utilizing these specimens will be reviewed and approved by the study 
scientific steering committee and overseen by an ethics committee as appropriate. Results of 
research tests on individual specimens will not be provided to participants or their clinicians. 
Aggregate research results will be made available. 
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10 Safety Assessment 
The safety monitoring and assessment within this trial reflects attributes of the anticipated 
investigational agents and the target population.  
First, investigational agents studied in this protocol are commonly expected to have short half-
lives and low probability of triggering a pathologic process or demonstrating a toxicity that 
would not manifest during, or shortly after treatment. As a consequence, the mainstay of safety 
monitoring will be broad safety monitoring through Day 90 plus collection and reporting of 
serious and/or high-grade events thought to be at least possibly related to the investigational 
agent for the duration of participation. If agents with longer half-lives or a likelihood of 
demonstrating effects that may potentially manifest with substantial delay are included, a 
longer duration of broad safety monitoring will be employed for those agents. Details of such 
additional safety monitoring will be specified in the corresponding agent-specific Appendix H . 
Second, patients with ARDS may each be reasonably anticipated to experience multiple 
serious adverse events regardless of any study procedures. Therefore, certain reasonably 
anticipated serious adverse events will be collected as study outcomes (these are termed 
protocol-specified exempt serious events (PSESEs); see Section 10.2.3), and will be 
monitored by the DSMB rather than reporting these as adverse events per se.  
Safety events and PSESEs will be monitored to ensure real-time participant protection through 
frequent unblinded DSMB review. The DSMB will review unblinded safety reports on an at 
least monthly basis.  
The safety evaluation of the study intervention includes several components, all of which will 
be regularly reviewed by the independent DSMB. For this protocol, the term “study 
intervention” refers to the investigational agent or placebo, and to any study provided SOC 
treatment(s).  
Infusion-related reactions are only collected for the blinded investigational agent/placebo. All 
other AEs are collected for the study intervention (either the blinded investigational 
agent/placebo or any study provided SOC treatment). 
Events will be reported to regulators and IRBs/ethics committees as appropriate/required. 
Adverse events, infusion reactions and unanticipated problems will be regularly reviewed by 
the DSMB.  
The following information will be collected on electronic case report forms, and will be regularly 
reviewed by the DSMB, to evaluate and help ensure safety: 
• Infusion-related reactions during and within 2 hours post-infusion of the investigational 
agent/placebo. 
• Clinical adverse events of grade 3 and 4 through study day 28 (isolated laboratory 
abnormalities that are not associated with signs or symptoms are not collected). 
• Protocol-specified exempt serious events (see section 10.2.3) through Day 90. 
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• Serious adverse events, including laboratory-only serious events, through Day 90, if 
they are not being collected as clinical organ failure or serious infections (Item 5 of 
4.1.2) or protocol-specified exempt serious events. 
• Serious adverse events through Day 180 if they are related to study intervention 
• Unanticipated Problems through Day 180 
• Deaths through Day 180. 
• Hospital readmissions through Day 180. 
 
An overview of safety data collected during the study is given in Table 3. 
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Table 3 Overview of Safety Data Collection 
 
During and at 
least 2 hrs after 
infusion (all days 
on which 
infusion occurs) 
 Day 0–7 
Day 14 
Day 28 
Day 90 
Infusion-related reactions 
and symptoms of any 
gradea 
X 
 
 
 
 
All grade 3 and 4 clinical 
AEs (new or increased in 
severity to Grade 3/4) 
X 
X 
Xb 
Xb 
 
Protocol-specified exempt 
serious events (PSESEs)c 
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 relatedd to study 
intervention 
Collected through End of Subject Participation (Day 180) 
 
aThis includes reporting of AEs of any grade present on day 0, before the first infusion. 
This allows assessment of whether a given AE is new after infusion. 
bParticipants will be asked about all new relevant adverse events of Grade 3 or 4 which 
have occurred since the last data collection, up to that time point. On these visits, AEs of 
any grade that are present on the day of the visit will also be collected. 
cThese are explained and defined in section 10.2.3. 
dRelatedness determined as per protocol rules in section 10. 
 
Definitions and methods of reporting each type of event are given below. 
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10.1 Definitions 
10.1.1 Adverse Event (AE) 
An AE is any untoward or unfavorable medical occurrence in a study participant, including any 
abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with their participation in research, whether or not considered related to 
the research. If a diagnosis is clinically evident (or subsequently determined), the diagnosis, 
rather than the individual signs and symptoms or lab abnormalities, will be recorded as the AE.  
In Appendix H details are outlined for each investigational agent under study of the following: 
specific AEs observed to be possibly associated with the agent in question, and how to monitor 
for, clinically handle and report such AEs, should they arise.  
10.1.2 Criteria for Seriousness 
Events are serious if they lead to one of the following outcomes:  
• 
Death 
• 
Life-threatening (i.e., an immediate threat to life)  
• 
Hospitalization or prolongation of hospitalization 
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions  
• 
Congenital abnormalities/birth defects  
• 
Other important medical events that may jeopardize the participant and/or may require 
intervention to prevent one of the outcomes listed above 
10.1.3 Unanticipated Problems 
An Unanticipated Problem (UP) is any incident, experience or outcome that is: 
1. Unexpected in terms of nature, severity, or frequency in relation to: 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents; and 
b. the characteristics of the population being studied; and 
2. Possibly, probably, or definitely related to participation in the research; and 
3. Places study participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized per the 
Investigator’s Brochure(s) (IBs).  
Furthermore, a UP could be an expected event that occurs at a greater frequency than would 
be expected based on current knowledge of the disease and treatment under study. The 
DSMB providing oversight to the study may make such an assessment based on an aggregate 
analysis of events. 
10.1.4 Severity 
The investigator will evaluate all AEs with respect to both seriousness (results in outcomes as 
above) and severity (intensity or grade).  AEs will be graded for severity according to the 
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DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (also known as 
the DAIDS AE Grading Table; see Appendix D for the URL). 
For specific events that are not included in the DAIDS AE Grading Table, the generic scale in 
Table 4 is to be used. Given the unique nature of the target population for this trial, 
hypotension will be graded according to the scale in Table 5 rather than the default DAIDS AE 
Grading Table. 
 
Table 4 Generic AE Grading Scale 
 
Grade 1 
Events causing no or minimal interference with usual social and 
functional activities, and NOT raising a concern, and NOT requiring a 
medical intervention/ therapy. 
Grade 2 
Events causing greater than minimal interference with usual social and 
functional activities; some assistance may be needed; no or minimal 
medical intervention/therapy required. 
Grade 3 
Events causing inability to perform usual social and functional 
activities; some assistance usually required; medical 
intervention/therapy required. 
Grade 4 
Events causing inability to perform basic self-care functions; medical or 
operative intervention indicated to prevent permanent impairment, 
persistent disability, or death 
Grade 5 
Events resulting in death 
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Table 5. Hypotension AE Grading 
AE GRADING 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4  
LIFE-
THREATENING 
SERIOUSNESS 
GUIDANCE* 
No 
No 
No (usually) 
Yes 
Hypotension 
criteia that apply 
to all 
assessments 
No 
intervention or 
complication 
meeting 
criteria for 
higher grade. 
IVF ≥500 mL OR 
low-dose 
vasopressor (e.g. 
<0.1 NE [or 
equivalent]) 
Moderate-dose 
vasopressor (e.g. ≥0.1 
NE [or equivalent]) OR  
≥2 vasopressors OR  
multiple interventions 
Life-threatening or 
clinically significant 
complications OR 
persistent clinically 
significant 
deterioration. 
Additional 
hypotension 
criteria for 
aviptadil/placebo 
infusion days 
No infusion 
change for 
hypotension 
Decrease infusion 
rate for 
hypotension OR 
pause infusion 
with resumption 
for hypotension 
Study drug discontinued 
for day for hypotension 
OR study drug not given 
for day for hypotension 
OR study drug 
discontinued 
permanently for 
hypotension 
No additional 
criteria 
* Guidance provides suggested seriousness alignment with AE grade but does not overrule investigator 
judgment. In particular, the presence of critical illness influences the threshold for considering a given 
hypotension AE ‘life-threatening’ or an ‘important medical event.’ Evaluation of other factors, including 
the intensity of intervention required and the event’s impact on the patient, are required to determine 
event seriousness. 
 
10.1.5 Causality 
Causality refers to the likelihood that the event is related to the study intervention.  It will be 
assessed for SAEs and UPs.  This assessment will be made for both the blinded 
investigational agent/placebo and any study-supplied SOC treatment using the following 
guidelines: 
• 
Reasonable possibility:  There is a clear temporal relationship between the study 
intervention and the event onset, and the event is known to occur with the study 
intervention or there is a reasonable possibility that the study intervention caused the 
event.   
NOTE: Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the event. 
• 
No reasonable possibility:  There is no evidence suggesting that the study intervention 
caused the event, there is no temporal relationship between the study intervention and 
event onset, or a more reasonable/likely alternate etiology has been established. 
The causality assessment is based on available information at the time of the assessment of 
the event.  The investigator may revise these assessments as additional information becomes 
available. 
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10.1.6 Expectedness 
Expectedness will be assessed for SAEs using the Reference Safety Information section of the 
IB(s) for the investigational agent(s) and any study-provided background therapy. Additional 
details of expectedness for a given agent will be specified in the relevant agent-specific 
appendix. 
The expectedness assessment is based on available information at the time of the assessment 
of the event.  The investigators and the sponsor may revise these assessments as additional 
information becomes available. 
10.2 Schedule for Reporting of Specific Events 
This section describes the schedule for reporting different types of safety outcomes on eCRFs 
as part of the protocol data collection plan.  It is recognized that in the care of study 
participants, more information may be collected and recorded in the participant’s medical 
record.  The information collected in the medical record serves as source documentation of 
events (e.g., signs, symptoms, diagnoses) considered for reporting on eCRFs as part of 
protocol data collection.  
10.2.1 Infusion-related reactions 
Certain infusion-related signs/symptoms will be collected as protocol-specified exempt serious 
events (see section 10.2.3) and will not be separately reported as adverse events.  
 
Adverse events that are  
(a) not protocol-specified exempt serious events, AND 
(b) are of grade 3 or 4 (whether new or as an increase in grade), AND 
(c) occur during or within 2 hours post infusion  
will be reported as adverse events on an eCRF. 
 
10.2.2 Grade 3 and 4 clinical adverse events on days of study drug administration, and 
Days 0–7, 14, and 28 
From Day 0 through Day 28, adverse clinical events reaching Grade 3 or 4 severity level will 
be reported on an eCRF. For a clinical adverse event that was present at baseline, only those 
which newly reach Grade 3 or 4 will be reported. 
 
Beginning 2 hours post-infusion of the investigational agent or matched placebo, on Days 0–7, 
clinical AEs of Grade 3 or 4 that are new or that have increased in grade compared to their 
pre-infusion level will be reported on eCRFs.  
 
Adverse clinical events reaching Grade 3 or 4 severity level that occur between Days 7 and 28 
will be reported on an eCRF at the Day 14, and Day 28 visits. The date the event reached the 
indicated grade will be collected to permit time-to-event analyses. These reportable AEs 
should be assessed for SAE/UP reporting on the SAE eCRF or for protocol-specified exempt 
serious events reporting on the eCRF documenting the hospital course. 
 
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On Days 14 and 28, AEs of any grade that are present on the day of the visit will also be 
collected. 
 
10.2.3 Protocol-specified exempt serious events (PSESEs) 
Consistent with FDA guidance on protocol-specified serious adverse events, the TESICO trial 
will systematically collect certain adverse events that are expected to occur commonly in the 
target population even in the absence of study interventions. These events, termed protocol-
specified exempt serious events (PSESEs), are in general exempted from the usual expedited 
reporting requirements for SAEs. This approach is taken to avoid creating a ‘noisy’ safety 
oversight environment, obscuring genuine safety signals, and imposing potentially 
unmanageable burdens on clinical/study staff, particularly in a pandemic critical care setting. 
Even as they are exempted from expedited reporting requirements, PSESEs will be reviewed 
regularly (unblinded, by treatment arm) by the DSMB to maintain the integrity of safety 
monitoring for the trial.  
PSESEs will NOT be reported as SAEs, even if they meet one or more of the criteria for 
seriousness, unless considered related to study intervention (blinded investigational 
agent/ placebo or study-supplied SOC treatment) (see section 10.2.4). These events may 
occur during the initial hospitalization, lead to a re-admission, or occur in a later hospitalization 
during follow-up.  
 
The following are protocol-specified exempt serious events.   
• 
Death 
• 
Stroke 
• 
Meningitis 
• 
Encephalitis 
• 
Myelitis 
• 
Myocardial infarction 
• 
Myocarditis 
• 
Pericarditis 
• 
New onset of worsening of CHF (NYHA class 3 or 4) 
• 
Arterial or deep vein thromboembolic events 
• 
Renal dysfunction treated with renal replacement therapy 
• 
Hepatic decompensation 
• 
Neurologic dysfunction, including acute delirium and transient ischemic events 
• 
Disseminated intravascular coagulation 
• 
Major bleeding events 
• 
Serious infections 
• 
Worsening respiratory failure 
• 
Hypotension treated with vasopressor therapy 
• 
Atrial or ventricular arrhythmias 
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Consistent with this approach, sites will evaluate a potential adverse event to determine 
whether it is a PSESE: 
 
• If the event is not a PSESE, it will be reported as an adverse event as outlined in section 10 
of the protocol.  
• If the event is a PSESE, it will be evaluated for relatedness.  
o If the PSESE is related to study interventions (either investigational agent or study-
supplied SOC therapy), then the event will also be reported as an SAE. Thus, the event 
will be reported on both eCRFs, the SAE eCRF and the PSESE eCRF.   
o If, however, the event is a PSESE and is not related to study interventions, then the 
event will be recorded on the PSESE eCRF as a study endpoint and not as an SAE.  
 
As noted earlier in this section, PSESEs are included in the unblinded safety reports reviewed 
by the DSMB to allow early detection of important imbalances in the distribution of these 
events between arms in the trial. 
 
10.2.4 Reportable SAEs 
Reportable SAEs for this study are: 
• Clinical SAEs which are not exempt from expedited reporting per the protocol-specified 
exempt serious event list and associated rules (10.2.3); and 
• Any SAE related to the study intervention  
Deaths, life-threatening events, and other SAEs considered potentially related to the blinded 
investigational agent/placebo or study-supplied SOC treatment, that occur from the time of 
infusion of the study intervention through the Day 180 visit must be recorded by sites on the 
SAE eCRF within 24 hours of site awareness. 
Suspected unexpected serious adverse reactions (SUSARs) are reportable SAEs that are 
assessed as related to a study intervention and are unexpected per the Reference Safety 
Information of the IB for that intervention.  SUSARs are reported from the INSIGHT Safety 
Office to applicable regulators in an expedited fashion.  SUSARs that result in death or are 
immediately life-threatening are reported to regulators within 7 calendar days of receipt.  All 
other SUSARs are reported to regulators within 15 calendar days. The INSIGHT Safety Office 
will generate a Safety Report for each SUSAR for distribution to investigators and other 
parties.  Investigators are responsible for submitting Safety Reports to their overseeing IRB/EC 
per requirements. 
SAEs that are not PSESEs and that are not related to the study intervention must be reported 
on the SAE eCRF within 3 days of site awareness. Such SAEs will be recorded through day 
90. 
 
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SAEs are followed until the outcome of the SAE is known. If the outcome of an SAE is still 
unknown at the time of the final follow-up visit, the outcome will be entered in the database as 
“unknown.” 
10.2.5 Unanticipated Problems (UPs) 
UPs must be reported via the appropriate eCRF to the INSIGHT Safety Office no later than 7 
calendar days after site awareness of the event. Investigators are responsible for submitting 
UPs that are received from the sponsor to their overseeing IRB/EC.  Investigators must also 
comply with all reporting requirements of their overseeing IRB/EC. 
10.2.6 Deaths 
All deaths are reported on the eCRF for deaths. Deaths considered related to the study 
intervention (blinded investigational agent/placebo or study-supplied SOC) must also be 
reported as an SAE.   
10.2.7 Pregnancy 
The investigator will collect pregnancy information on any female participants who are or 
become pregnant while participating in this study. (Where the agent-specific appendix 
excludes pregnant women, this applies to participants who become pregnant.) 
The participant will be followed to determine the outcome of the pregnancy.  
Male participants with partners who become pregnant 
If an investigator learns that a male participant’s partner becomes pregnant while the male 
participant is in this study, the investigator is asked to attempt to obtain information on the 
pregnancy, including its outcome.  Information obtained on the status of the mother and child 
will be forwarded to the sponsor. Whether such monitoring will be required is outlined in the 
agent-specific appendix. 
10.3 Medical Monitor 
A Medical Monitor appointed by the sponsor will be responsible for reviewing all SAEs, making 
an independent assessment of causality and expectedness, preparing sponsor safety reports, 
and communicating as needed with the DSMB and the Investigational New Drug (IND) holder 
through the study safety office or other mechanism mutually agreed to and documented.  
10.4 Halting Enrollment for Safety Reasons 
The sponsor medical monitor or the DSMB may request that enrollment be halted for safety 
reasons (e.g., unacceptably high rate of infusion-related reactions or other unanticipated AEs).  
If the study is temporarily halted or stopped for safety reasons, IRBs/ethics committees will be 
informed. The IND holder and sponsor, in collaboration with the protocol chair and the DSMB, 
will determine if it is safe to resume the study. The sponsor will notify the Site Investigators of 
this decision. The conditions for resumption of the study will be defined in this notification. The 
Site Investigators will notify their local IRBs/ethics committees of the decision to resume the 
study. 
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11 Statistical Analyses and Monitoring Guidelines 
This section describes the analysis for primary and secondary outcomes stated in section 4. A 
more detailed statistical analysis plan (SAP) will be developed as a separate document.  The 
SAP for each investigational agent may be updated by the blinded statisticians prior to 
unblinding for a specific treatment comparison.   
All analyses will be intent to treat with comparisons to concurrent controls as described in 
section 6.3. It is anticipated that all study site pharmacies serving active sites will be 
randomizing all agents under study at any given time, but if this is not the case, comparisons 
will be restricted to the set of controls enrolled at study site pharmacies where the drug was 
available for randomization. Specifically, the control group for an investigational agent will 
consist of those participants who could have been randomized to the agent, but were 
randomized to a control group instead (i.e., randomized to the matched control group of one of 
the agents included in the randomization). Agents will be compared to controls, but not to each 
other, unless explicitly specified in the analysis plan. 
All analyses will utilize 2-sided tests with a 5% significance level unless otherwise noted.   
11.1 Analysis of the Primary Efficacy Endpoint 
The primary ordinal outcome—recovery—assessed at Day 90 includes 6 ordered categories, 
best to worst, that assess 4 clinical states. The categories correspond to (1) the number of 
consecutive days at home off oxygen (3 categories); (2) receiving oxygen at home or living in a 
location other than home; (3) hospitalized for medical care or in hospice care; and (4) death. 
The percentage of patients in each category (6 total) will be compared at Day 90. The primary 
analysis will use a proportional odds model  to estimate a summary odds ratio (OR) for being 
in a better category in the investigational agent group compared with placebo; an OR > 1.0 will 
reflect a more favorable outcome for patients randomized to the investigational agent vs. 
placebo.   
The proportional odds regression model will include a treatment indicator, and an indicator for 
receipt of mechanical ventilation or ECMO (vs. neither) at enrollment.  
A test for the proportional odds assumption will be carried out.  Even if the proportional odds 
assumption is violated, the overall summary OR will be the basis for inference in the primary 
analysis, given the robustness of proportional odds regression to violation of the proportionality 
assumption. In order to further characterize the summary OR and any deviations from 
proportional odds, separate ORs will be estimated for different dichotomized definitions of 
improvement formulated from the components of the ordinal outcome (e.g., alive versus dead, 
alive and out of the hospital versus hospitalized or dead, etc.)  
 
11.2 Analyses of Secondary Efficacy Endpoints, Safety Outcomes, and Subgroups 
Four key secondary objectives are to compare investigational agent with placebo for the 
following endpoints  
1. Time to death through Day 90.  
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2. A composite endpoint that considers the number of days at home off new 
supplemental oxygen and the time to death as well as the other categories of the primary 
ordinal recovery outcome.  
3. Time to recovery defined as alive, at home, and off new supplemental oxygen.  
4. A three-category ordinal outcome, measured at Day 90, with the following categories: 
recovered (alive, at home, and off new supplemental oxygen), alive and not recovered, 
and dead. 
Time to death will be summarized using a log-rank test, stratified by receipt of invasive 
mechanical ventilation or ECMO vs. neither at randomization.  The hazard ratio (investigational 
agent vs control) will be estimated using a stratified Cox proportional hazards model, and the 
proportion of participants who died by fixed time points (for example, Day 28 or Day 90) will be 
estimated using Kaplan-Meier estimates.  
The composite outcome will be summarized with a win ratio statistic that ranks patients by time 
to death (instead of just survival status at Day 90), hospitalization at Day 90, home on oxygen 
or not at home, and duration of time (in days instead of weekly intervals) at home off new 
supplemental oxygen. Matching on mechanical ventilation (or ECMO) and a disease 
progression risk score at entry will be used to estimate the win ratio statistic.  
The cumulative incidence functions for recovery (at home and off new supplemental oxygen) 
taking into account death as a competing risk will be estimated using the Aalen-Johansen 
method and compared using Gray’s test. The recovery rate ratio will be estimated using a 
Fine-Gray regression model. The comparisons between treatment groups will be stratified by 
receipt of invasive mechanical ventilation or ECMO vs. neither at randomization.  Recovery is 
defined using the last-off method, as described in section 4. 
If there is evidence of benefit for an investigational agent versus placebo for the primary 
ordinal outcome, the comparison of the investigational agent with placebo for these three 
outcomes will help to inform the interpretation of the treatment effect. 
The primary safety outcome is a composite of grade 3 or 4 events, SAEs, PSESEs (see 
10.2.3), or death through Day 5, and tests for differences between treatment arms will be 
conducted with a Cochran Mantel Haenszel test stratified by receipt of invasive mechanical 
ventilation or ECMO at study entry, comparing the proportion of participants who had 
experienced any of these events by Day 5. Treatment differences for each of the components 
of this composite outcome will also be summarized. This composite safety outcome will also 
be assessed at Day 28. Time to event analysis will also be used to summarize this composite 
safety outcome. Proportions of participants who experienced any of these events will be 
compared using stratified Mantel Haenszel tests and logistic regression. SAEs and grade 3/4 
events will be classified by system organ class according to MedDRA.  
Safety analyses also include infusion reactions collected during or within 2 hours after the 
infusion of the investigational agent or placebo. Proportions of participants who experienced 
infusion reactions or prematurely terminated infusions will be summarized by study arm, and 
Mantel Haenszel tests will be used to test for differences across arms. 
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Several other secondary efficacy outcomes will also be investigated. The models will include 
an indicator for treatment group, and stratify by receipt of invasive mechanical ventilation or 
ECMO at study entry as appropriate. Time from study entry to discharge from the hospital 
admission during which randomization took place will be analyzed using the same methods as 
described above for time to recovery. Readmissions will be summarized using methods for 
recurrent events (i.e. those who are readmitted will reenter the risk set).  
Clinical organ failure is a composite of many different organ-specific events, listed in section 
4.1.2, item 5.  This outcome will be summarized as part of both safety and efficacy analyses. 
The incidence of organ failure, serious infection or death through Day 28 will be compared 
between arms using the log-rank test and Cox proportional hazards models.  In addition, 
specific components (e.g., cardiac and vascular dysfunction, or the composite of 
cardiovascular outcomes, thromboembolic events described in section 4.1.2, item 10, and 
worsening respiratory failure) will be analyzed using time-to-event analyses under competing 
risks, as described above for the primary analysis. Proportions of participants who experienced 
organ failure, serious infection or death will be summarized and compared between treatment 
arms at fixed time points using stratified Mantel Haenszel tests, overall and for specific organ 
dysfunctions. 
The impact of study arm on the primary efficacy (recovery) and safety outcomes (primary 
composite safety endpoint, composite of grade 3 or 4 events, SAEs, PSESEs, and death 
through Day 5 and through Day 28, composite of SAEs, PSESEs, and death, and composite of 
hospital readmissions and death through Month 6) along with mortality will be assessed for 
subgroups defined by baseline characteristics, including demographics, baseline classification 
of “home”, duration of symptoms at enrollment, clinical history and presentation, and tests for 
homogeneity of the treatment effect across subgroups will be carried out. Additionally, 
subgroup analyses will be conducted for subgroups formed by a disease progression risk 
score at baseline. The construction of this risk score is described in section 5.2. Subgroup 
analyses will be interpreted with caution due to limited power and uncontrolled type I error. 
11.3 Data Monitoring Guidelines for an Independent DSMB 
An independent DSMB will review interim data on a regular basis and use pre-specified 
guidelines to identify agents with evidence of harm based on a difference in all-cause mortality. 
The DSMB will also monitor other adverse events and safety signals. 
As a guideline, we do not recommend early termination for benefit based on the primary 
endpoint, which is most reliably estimated at Day 90. In addition, given the relatively short 
follow-up period of 90 days for this target population, full follow-up for the primary and all 
secondary endpoints is considered important to evaluate the investigational agents to be 
studied. An exception to this guideline is if the DSMB believe there is clear and substantial 
evidence of a mortality benefit for an investigational agent 
11.3.1 Monitoring Guidelines for Interim Analyses 
Multiple distinctive features of potential therapies for COVID-19-associated ARDS contribute to 
the monitoring guidelines for interim analyses within the master protocol. (If a specific 
investigational agent requires an alternative approach to interim monitoring, those details will 
be specified in the relevant agent-specific appendix.) 
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First, in many cases, potential agents may be relevant not only to COVID-19-associated ARDS 
but to other forms of ARDS. As such, even if an agent did not achieve its efficacy endpoint, 
enrollment to the planned sample size is expected to provide important insights relevant to 
future investigations in ARDS. These insights may especially pertain to potential effects among 
subgroups of patients or less common safety events of interest. 
Second, the primary endpoint of this trial requires 90 days of follow-up since the final 
classification of a patient’s recovery requires knowledge of their status on Day 90. While this 
duration of follow-up for the primary endpoint is essential for a patient-centered result at the 
conclusion of the trial, in the context of the anticipated rapid enrolment of the trial, this endpoint 
is infeasible to use for stopping boundaries for either efficacy or futility on the basis of 
conditional power. 
Third, enrollment should stop early for any agent that shows clear evidence for increased 
mortality. A stopping boundary for harm is thus indicated. 
Fourth, while it is important to avoid premature stopping for a potentially non-reproducible 
efficacy signal for the primary endpoint, clear and substantial improvement in mortality may 
appropriately lead to a DSMB recommendation to stop early for efficacy. 
On the basis of these and related factors, the monitoring guidelines for this master protocol will 
focus on a stopping boundary for harm, a stopping boundary for efficacy based on mortality, 
and ongoing close monitoring of safety by the DSMB, based on the totality of evidence. 
As a guideline to the DSMB for assessment of harm, a Haybittle-Peto boundary using a 2.5 
standard deviation (SD) for the first 100 participants enrolled and 2.0 SD afterwards. Harm will 
be assessed using all-cause mortality, specifically using a hazard ratio from a proportional 
hazard model for the time to death associated with the investigational agent. As an additional 
guideline to the DSMB for assessment of efficacy, a Haybittle-Peto boundary using a 3.0 SD 
threshold will be used after 100 patients have been enrolled and followed for at least 5 days. 
Efficacy will be assessed using all-cause mortality, specifically using a hazard ratio from a 
proportional hazard model for the time to death associated with the investigational agent. 
12 Protection of Human Subjects and Other Ethical Considerations 
12.1  Participating Clinical Sites and Local Review of Protocol and Informed Consent 
This study will be conducted by major medical centers participating in INSIGHT and partnering 
networks, including especially NHLBI networks. It is anticipated that potential participants will 
be recruited by the site investigators (and/or their delegates, as appropriate) and/or that 
positive SARS-CoV-2 laboratory testing will be used to enquire about potential enrollment. 
Information about this study will be disseminated to health care workers at enrolling sites. 
Prior to the initiation of the study at each clinical research site, the protocol, informed consent 
form and any participant information materials will be submitted to and approved by a 
central/national IRB/EC and/or the site’s local IRB/EC as required. Likewise, any future 
amendments to the study protocol will be submitted and approved by the same IRB(s) or 
EC(s). After IRB/EC approval, sites must register for this study before screening potential 
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participants, and must register for any protocol amendments. Protocol registration procedures 
are described in the PIM. 
12.2 Ethical Conduct of the Study 
The study will be conducted according to the Declaration of Helsinki in its current version; 
the requirements of Good Clinical Practice (GCP) as defined in Guidelines, EU Clinical 
Trials Regulation (EU 536/2014)/EU Clinical Trials Directive (2001/20/EC), and EU GCP 
Directive (2005/28/EC); International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) Guidelines; Human Subject Protection and Data 
Protection Acts; the US Office for Human Research Protections (OHRP); or with the local 
law and regulation, whichever affords greater protection of human subjects. 
12.3 Informed Consent of Study Participants 
Informed consent must be obtained (see sample in Appendix A) prior to conducting any 
study-related procedures. Many of the patients approached for participation in this research 
protocol will often have limitations of decision-making abilities due to their critical illness. 
Hence, some patients will not be able to provide informed consent. For patients who are 
incapacitated, informed consent may be obtained from a legally-authorized representative 
(LAR). Because the investigational agents are intended to treat critical illness and the 
impairment of decisional capacity is intrinsic to the critical illness, the use of LARs for 
consent is appropriate for this trial. The use of consent from LARs will follow applicable 
legislation (e.g., in the United States, 45 CFR 46.116 and 45 CFR 46 102 (i)). Capacity will 
be assessed according to local standards and policies.  Local standards and policies will 
also determine who is legally authorized to consent for an individual who is incapacitated. 
Should the individual regain capacity during the study, their direct reconsent should be 
obtained at the earliest feasible opportunity. 
Electronic consent may be used when a validated and secure electronic system is in place 
to do so, if in compliance with national legislation and approved by the responsible IRB/EC. 
Other methods of obtaining documentation of consent may be used when site staff are 
unable to be in direct contact with a potential participant or a legally-authorized 
representative due to infection-control restrictions.  No matter how the participant’s consent 
is obtained and documented, it is expected that consent will be preceded by research staff 
providing an explanation of the research and an opportunity for the participant (or their LAR) 
to have questions answered.  Sites should follow all available local or national guidance on 
suitable methods for obtaining documentation of participant (or their LAR) consent. 
12.4 Confidentiality of Study Participants 
The confidentiality of all study participants will be protected in accordance with GCP 
guidelines and national regulations.  
12.5 Regulatory Oversight 
Sites in the US will conduct this trial under the terms of the IND and will adhere to FDA 
regulations found in 21 CFR 312, Subpart D. Sites in countries other than the US will not 
conduct the trial under the IND. As stated in Section 12.2 above, all sites will conduct the 
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trial in accordance with the requirements of GCP as codified in their local law and 
regulation, under the oversight of their institution and competent regulatory authority. 
As part of fulfilling GCP and FDA requirements for adequate trial monitoring, multiple 
modalities will be employed. The objectives of trial monitoring are to ensure that participant 
rights and safety are protected, to assure the integrity and accuracy of key trial data, and to 
verify that the study has been conducted in accord with GCP standards and applicable 
regulations.   
A specific risk-based protocol monitoring plan will be developed.  The plan will include 
strategies for central monitoring of accumulating data and will take into account site-level 
quality control procedures.  On-site monitoring visits for targeted source document 
verification and review of regulatory and study pharmacy files will be conducted when 
possible, but these tasks will most likely need to be handled remotely during the pandemic.  
The monitoring plan will outline the frequency of this aspect of monitoring based on such 
factors as study enrollment, data collection status and regulatory obligations. 
 
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PID: _______________________ 
Appendix A  
Sample Informed Consent form  
 
Short Title: Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) 
Sponsored by: The University of Minnesota (UMN)/National Institute of Allergy and 
Infectious Diseases (NIAID) 
Funded by:  The National Heart, Lung, and Blood Institute (NHLBI) and National 
Institute of Allergy and Infectious Diseases (NIAID), US National 
Institutes of Health (NIH) 
Full Title of the Study:  A Multicenter, Adaptive, Randomized Blinded 
Controlled Trial of the Safety and Efficacy of Investigational Therapeutics 
for Severely Ill Patients with COVID-19 
CONSENT FOR PARTICIPATING IN AN NIH-FUNDED RESEARCH STUDY  
SITE INVESTIGATOR: ________________________________ PHONE: __________  
  
 
 
 
 
 
 
 
 
 
 
 
 
US Office for Human Research Protections (OHRP) Requirements to be read by the 
sites: 
 
PLEASE NOTE THAT THIS SAMPLE LANGUAGE DOES NOT PREEMPT OR REPLACE LOCAL 
IRB/EC REVIEW AND APPROVAL.  INVESTIGATORS ARE REQUIRED TO PROVIDE THE LOCAL 
IRB/EC WITH A COPY OF THIS SAMPLE LANGUAGE ALONG WITH THE LANGUAGE INTENDED 
FOR LOCAL USE.  LOCAL IRBs/ECs ARE REQUIRED TO WEIGH THE UNIQUE RISKS, 
CONSTRAINTS, AND POPULATION CONSIDERATIONS AS A CONDITION OF ANY APPROVAL.  
ANY DELETION OR SUBSTANTIVE CHANGE OF INFORMATION CONCERNING RISKS OR 
ALTERNATIVE TREATMENT MUST BE JUSTIFIED BY THE INVESTIGATOR, APPROVED BY THE 
LOCAL IRB/EC, AND NOTED IN THE IRB/EC MINUTES.  JUSTIFICATION AND IRB/EC APPROVAL 
OF SUCH CHANGES MUST BE FORWARDED TO THE INTERNATIONAL COORDINATING 
CENTER OR COLLABORATING NETWORK.  SPONSOR-APPROVED CHANGES IN THE 
PROTOCOL MUST BE APPROVED BY THE LOCAL IRB/EC BEFORE USE UNLESS INTENDED 
FOR THE ELIMINATION OF APPARENT IMMEDIATE HAZARD.  NEW INFORMATION SHALL BE 
SHARED WITH EXISTING SUBJECTS AT NEXT ENCOUNTER, WITH ALL NEW SUBJECTS PRIOR 
TO INVOLVEMENT, OR AS THE LOCAL IRB/EC MAY OTHERWISE ADDITIONALLY REQUIRE. 
ALL SITE INSTRUCTION THAT IS INCLUDED IN A TEXT BOX SHOULD BE 
REMOVED FROM THE SITE’S INFORMED CONSENT FOR PARTICIPANTS 
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PID: _______________________ 
Key information: 
We are asking you to join a research study about COVID-19.  It is your choice whether 
or not you want to join.  This form gives you information about the study that will help 
you make your choice.  You can discuss this information with your doctor or family or 
anyone else you would like before you make your choice.  Your choice will not affect the 
care you are getting for COVID-19. 
What is the research question we are trying to answer? 
We are studying two treatments for COVID-19. We are asking you to join the study 
because you are in the hospital with COVID-19 and have significant trouble with your 
breathing.   
First, we are studying an experimental medicine, aviptadil (also called VIP), supplied by 
NeuroRx.  We are trying to find out if giving this experimental medicine can help sick 
people in the hospital with COVID-19 have fewer bad effects from the disease, and if it 
may possibly help them get better and go home faster.  We are also trying to see if it is 
safe. 
This experimental medicine is a man-made version of a naturally occurring hormone in 
the body. It may decrease COVID-19 virus levels, inflammation, and blood clotting, and 
help protect the lung against injury. We think this experimental medicine may possibly 
help patients with COVID-19, and we think it will be safe, but we are not sure and so we 
are doing this study.   
Second, we are studying a drug called remdesivir (also called Veklury) supplied by 
Gilead. Remdesivir is approved in the United States and many other countries for the 
treatment for COVID-19 in people who are in the hospital. We are trying to find out if 
remdesivir helps patients with your level of COVID-19 illness get better and go home 
faster. Remdesivir may decrease COVID-19 virus levels and lung injury. Currently we 
do not know if remdesivir will help people with your level of COVID-19 illness which is 
why we are doing this study. 
What do you have to do if you decide to be in the study? 
The study staff at your hospital will check to see if there is any reason you should not be 
in the study.  They will check your medical history.  They will look at tests commonly 
done for your condition.  They will also check to see if you are able to get both of the 
drugs we are studying or just one of the drugs.  For example, if you are pregnant you 
will not be able to receive the aviptadil or matching placebo (inactive salt solution) but 
you will be able to receive the remdesivir or matching placebo.   
If you agree to be in the study, and you are able to get both treatments, we will assign 
you to one of four study groups.  This will be done by random chance -- like flipping a 
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coin.  You will have an equal chance of getting either the active drug or placebo (salt 
solution) for each drug.  
You will be assigned to one of the following 4 groups: 
 
Your doctor will NOT decide and will not know which of these four options you will get.  
The study staff will also not know which option you will get.   
If you agree to be in the study, and you are ONLY able to get Aviptadil we will assign 
you to one of two study groups.  This will be done by random chance -- like flipping a 
coin.  You have an equal chance of being in each group. 
 
 
If you agree to be in the study, and you are ONLY able to get remdesivir we will assign 
you to one of two study groups.  This will be done by random chance -- like flipping a 
coin.  You have an equal chance of being in each group. 
 
 
Aviptadil: You will receive the Aviptadil study product (either the experimental medicine 
or the matching placebo) for three consecutive days starting on the day you join the 
study (study Day 0).  You will get it by an intravenous (IV) drip through a tube in your 
vein.  This is called an infusion.  The infusion will take about 12 hours on each day that 
it is given.   
Aviptadil is the only thing you may be given that is experimental.  It is NOT approved for 
use in people with COVID-19 by the United States Food and Drug Administration (FDA) 
or any other regulatory body in the world.  It is approved in some countries outside the 
US for another condition but is given in a different way. Its use in the United States is 
strictly limited to research. 
Remdesivir: You will receive the remdesivir study product (either the active medicine or 
matching placebo) once per day for up to 10 days. You will also get this by an IV drip 
through a tube in your vein, which will generally take 1-2 hours. Remdesivir is approved 
Aviptadil  
+  
Remdesivir 
Aviptadil  
+  
Placebo for 
remdesivir 
Remdesivir  
+  
Placebo for 
aviptadil 
Placebo for 
remdesivir 
+  
Placebo for 
aviptadil 
OR 
OR 
OR 
Aviptadil  
OR 
Placebo for aviptadil 
Remdesivir  
OR 
Placebo for remdesivir 
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in the United States for the treatment of COVID-19 in people who are in the hospital.  
It’s not known whether it works in people with more severe COVID-19. 
Other treatments: As part of the study you may also get a drug called a steroid for up 
to 10 days while you are in the hospital, as care for your COVID-19, unless your doctor 
thinks the steroid would not be safe for you to take.  Steroids have been shown in prior 
studies to help people survive COVID-19.  Steroids are available for other diseases in 
the United States, so your doctor will be using it “off-label,” which means that while 
there is not formal FDA approval for this use, your doctors think it is reasonable. It is 
likely that you would receive steroid medicine even if you were not in the study. 
Any other medications or treatments you will be given will be what you would usually 
receive in this hospital for your condition. There may be some additional procedures or 
testing done for study purposes.  We will describe these below. 
You will be in the study for 180 days.  We will check on your health every day while you 
are in the hospital, and regularly after you leave the hospital.  
We will swab your nose to see how much of the virus that causes COVID-19 is present. 
We will take blood samples from you to better understand the body’s response to the 
infection.  Some of the blood may be used in future studies. 
To be in the remdesivir/placebo part of the study, you will need to agree to not have sex 
that could make you or a partner pregnant for seven days after you finish the remdesivir 
or placebo infusion.  This may involve not having sex at all (abstinence), or you may use 
effective contraception (hormonal contraception or barrier methods with spermicide) to 
avoid pregnancy.  Methods like rhythm, sympto-thermal or withdrawal are not effective 
for the purpose of the study.  You can ask the study team about this if you have 
questions or concerns. 
If you are pregnant, you cannot be in the aviptadil/placebo part of the study. You can 
still be in the remdesivir/placebo part of the study. 
If you become pregnant during the study, please let your study team know as soon as 
possible.  We will ask to follow you until your pregnancy is over, to see if there were any 
problems that may have been caused by any of the study treatments. 
 
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We will need to do the following things with you, and gather detailed information at 
these times: 
 
Study  
Timepoint 
 
            
What will happen & what we will check 
Up to 1 day 
before you get 
study product 
• Informed consent (this document) 
• Check to see how you are feeling 
• Your medical history 
• Whether you are taking certain medicines 
• A swab of your nose for virus detection 
• Blood tests to check your health (9 mL, about ½ tablespoon) 
• Blood for future research (18 mL, about 1 tablespoon) 
• Collection of urine or blood for a pregnancy test 
• Contact information like telephone numbers and addresses for you 
and at least two close relatives or friends 
Day 0, Day 1, 
Day 2 
• Infusion of study product (the experimental medicine or else placebo) 
if able to get this drug 
• Infusion of remdesivir study product (active drug or placebo) if able to 
get this drug (you may get this treatment for up to 10 days) 
• Blood tests to check your health (9 mL, about ½ tablespoon), unless 
your treatment team has already performed those tests 
Day 3, Day 5 
• How you are feeling 
• Blood for future research (18 mL, about a tablespoon)  
• If you’re not in the hospital, we will not draw your blood and the visit 
may take place by phone 
Day 2, Day 4, 
Day 5, Day 7, 
Day 14, Day 
42, Day 60, 
Day 75 
• How you are feeling (Days 2, 4, 7, 14, 60) 
• Update on return to home (Days 14, 42, 60, 75) 
• On Days 0-7 and 14, also whether you have taken certain medicines 
These “visits” may take place by phone. 
Day 28, Day 
90, and Day 
180 
• How you are feeling 
• On Day 28, also whether you have taken certain medicines 
• On day 90 and 180 only: we will ask you additional questions about 
your health 
  These “visits” will take place by phone. 
 
We may need to get some information from your medical record.  
• By signing this consent, you agree to let us get information for this study from 
your medical record.   
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• By signing this consent, you are giving us permission to contact other hospitals 
or medical facilities if you are admitted there during the time you are in the study. 
We will contact them to be sure we know how you are doing.   
• We will ask you to give us information about other people we can contact if we 
are not able to reach you after you leave the hospital, so we can find out how you 
are doing. 
 
 
We will send the information we collect to the University of Minnesota (UMN) in the US 
where it will be stored and analyzed.  In this information, only a code number, your year 
of birth, and a 3-letter code that the study staff chooses identifies you.   
The study staff here at this site are responsible for keeping your identifying information 
safe from anyone who should not see it.   
We will send the blood samples to a laboratory in the US for storage.  We will keep 
them for as long as we have the funding and space to do so, which we expect to be 
many years.  There is more information below about how we will use these samples.   
Why would you want to be in the study? 
If you get study drug, it is possible it may help you get better, or that you may get home 
faster, but we do not know that.   
It is important to remember that some people in this study will get inactive 
placebo and will not get study drug. 
By being in this study, you will help doctors learn more about how to treat COVID-19 in 
people in the hospital.  Because so many people are getting hospitalized with COVID-
19, this could help others.  There may be a large health impact if a treatment proves to 
be safe and is shown to be effective. 
Why would you NOT want to be in the study? 
Since only some people in this study will get study drug, you may not receive it.  Even if 
you do get study drug, it may not be useful, or it may have harmful side effects, so being 
in the study would not be of any direct help to you.   
What are the risks or side effects of the study treatments? 
All treatments have risks and may cause side effects.  These may happen to you from 
the study treatment.  
You may have an allergic reaction, including hives, trouble breathing, or other allergic 
responses. Allergic reactions like these are likely to be rare, but may be severe or 
life-threatening. 
 
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You will be monitored very closely while you are being given the infusion of the study 
product (aviptadil or placebo) and for at least 2 hours after the infusion is finished.  
We will give you prompt medical care if needed to treat any side effects from the 
infusion. 
 
There are discomforts and risks associated with blood draws. You will have these things 
done while you are in the hospital even if you are not in the study.  These discomforts 
and risks are no different from what you would experience if they were performed as 
part of your regular hospital care for COVID-19. 
 
What are the risks or side effects of Aviptadil? 
One effect of aviptadil is that it relaxes smooth muscle such as in your lungs, blood 
vessels, and intestines.  Relaxing this type of muscle opens up your airways so it is 
easier to breathe and get oxygen into your body.   
 
The most common side effect of aviptadil infusion is decreased blood pressure. In early 
studies of very ill patients with lung injury, about 1 in 5 people (20%) had lower blood 
pressure during the infusion of aviptadil.  The decrease was usually small and went 
away within 10 minutes of stopping the infusion. 
 
Facial flushing is common with aviptadil and is not dangerous. It is caused by relaxation 
of the blood vessels in the skin and goes away when the infusion is stopped. 
 
Increases in heart rate are common and usually not dangerous. The increase in heart 
rate is mostly due to blood vessel relaxation. 
 
Some people getting aviptadil have had mild to moderate diarrhea. The diarrhea goes 
away when the infusion is stopped. 
 
What are the risks or side effects of Remdesivir? 
The most common side effects of remdesivir included abnormal liver function test 
results, abnormal blood clotting test results, constipation, diarrhea, nausea, vomiting, 
decreased appetite, and headache. The abnormal liver function tests lasted longer than 
a few days in some people but went back to normal within a few weeks or less. 
Remdesivir might affect the way that other medications are processed by your body.  
They might stay in your body longer, or shorter, at higher or lower levels.  At the time 
this document was written, one person in another study had an increase in the level of a 
medication in their blood that was considered by study doctors to be at least possibly 
related to having taken remdesivir.  There did not appear to be any harm from this 
temporary change.  You can ask the study team more about this if you are concerned. 
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Some people may have some side effects after the infusion of remdesivir.  Other people 
may have no side effects. 
What are the risks and benefits of taking steroids? 
Steroids may cause your sodium (salt) and glucose (sugar) levels to rise in your 
blood. You may feel anxious while taking steroids.  You may be given steroids to 
treat your COVID-19 even if you do not join this study.   
 
What if you are pregnant or breastfeeding? 
If you are pregnant or breastfeeding, you can still join this study, although you cannot 
participate in the aviptadil portion of the study.  However, we do not have any 
information about how either aviptadil or remdesivir may affect your baby.  The risks to 
a pregnant woman or an unborn baby might be serious.  Please take this into account 
as you make your decision about whether to join this study. 
Additional information: 
Here is some additional information about the study that may help you make your 
choice about whether you want to be in the study. 
The NIH, an agency of the US Federal government, is paying for this study.   
We are required to comply with all rules and regulations for human research as well as 
the laws of each country where the study is taking place.   
This study is taking place in several countries.  We expect to enroll about 800 people 
around the world. 
You do not have to join this research study if you do not want to.  If you choose to join 
the study, you can stop at any time.  If you choose not to join or to stop, the medical 
care you are getting now will not change. 
If we get any new information that might change whether you want to join or stay in the 
study, we will tell you right away. 
If you do not want to be in this study, you will still get the usual care to treat COVID-19.  
However, you cannot get Aviptadil because it is experimental. 
 
What are the costs to you? 
We will give you the study treatment at no cost.  We will pay for all clinic visits, lab work, 
and other tests that are part of this study. 
 THE NEXT PARAGRAPH IS FOR UNITED STATES SITES ONLY.  SITES IN 
OTHER COUNTRIES SHOULD DELETE THE NEXT PARAGRAPH. 
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You, your insurance company, or some other third-party payer must pay for all other 
medicines and hospital costs. 
 
 
 
Will you be paid to be in the study? 
We will compensate you for your time and inconvenience participating in the study.  
[Specific details to be completed by site.] 
What if you are hurt as part of this study? 
If you are hurt because of being in this study, [insert the name of the hospital/clinic] will 
treat your injury right away.  You or your insurance will have to pay for this treatment.  
The study cannot pay you or pay for any care for study-related injuries or for your 
illness. 
 
 
 
[The following section, up to “What happens to the blood samples?” is for US sites only.] 
A Declaration under the Public Readiness and Emergency Preparedness (PREP) Act 
was issued by the Secretary of the United States Department of Health and Human 
Services on March 10, 2020.  This Declaration limits the legal rights of a subject 
participating in clinical studies utilizing COVID-19 countermeasures.  Because this study 
is covered by the Prep Act Declaration, covered persons, such as the manufacturers, 
study sponsor, researchers, healthcare providers and others have liability immunity (that 
is, they cannot be sued by you or your family under the laws of the United States). 
If you believe that you may have been harmed as a result of this research study, certain 
claims for serious injury or death caused by the countermeasure may be eligible for 
compensation through the Countermeasures Injury Compensation Program. This is a 
program set up by the United States Government.  
Information about this program can be found at 
https://www.hrsa.gov/cicp/about/index.html or by calling 1-855-266-2427. If you are 
SITES OUTSIDE THE UNITED STATES:  Please replace the paragraph 
above with language appropriate for your location 
If the above is not true for your site, i.e., if trial insurance covers such 
cost, please replace the above with appropriate language. 
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eligible for this program, you must file a claim within one year of the administration or 
use of the covered countermeasure. 
What happens to the blood samples? 
We will send the blood samples to a central laboratory in the United States.  You and 
your doctor will not get the results of any tests done on these samples.  We will not sell 
your samples and they will not be used for research aimed at making money 
(commercial research).  The laboratory where the samples are stored will not have any 
information that could identify you. 
The blood samples will measure how many COVID-19 antibodies are in your blood.  
This will tell us how your immune system responded to your COVID-19. The blood 
samples will also measure the amount of virus in your blood and other results related to 
your COVID infection. 
Any blood samples that are left over after these tests will be stored at the central 
laboratory for as long as we are able to keep them.  We hope to use these in the future 
to answer other questions about COVID-19, the virus that causes it, and how people 
respond to treatment.  You and your doctor will not get any results from these tests.   
You can withdraw your consent for us to keep these specimens at any time.  Let your 
study team know if you do not want the study to keep your specimens anymore, and 
every effort will be made to destroy all of your specimens that are still at the central 
laboratory. 
How do we protect your privacy? 
We will take every reasonable step to keep your health information private and to keep 
anyone from misusing it. 
Your information (data) and samples will not be identified by name, or in any other way, 
in anything published about this study.   
We will do everything we can to keep your personal information private, but we cannot 
guarantee that nobody will get it.  We may have to release your personal information if 
required by law. 
These people may see your medical and research information: 
• the [insert the name of the hospital/clinic] ethics committee (institutional 
review board [IRB]); 
• the sponsor, the group paying for the research (US NIH), other study research 
staff and study monitors 
• US and other participating countries’ health regulatory agencies, including the US 
FDA. 
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They are committed to protecting your privacy. 
As the research staff at [inset the name of the hospital/clinic], we are required to make 
sure that people not involved with this study cannot see your research and medical 
information.  We will keep your research files in a safe place and will handle your 
personal information very carefully.  
Your study data are sent electronically to the UMN in the US through a secure system.  
By signing this consent, you agree to having your data sent to UMN.  No information 
that could directly identify you is sent to UMN.  This is called “pseudonymized data.”  
Access to the data at UMN is limited through security measures, and no data breach or 
unauthorized access has ever occurred in this system.  After the study is over, the data 
will be stored securely for the period required by law. 
Your study data will be shared with the US National Institutes of Health (which is paying 
for this study), and with regulators that oversee the study, including the US FDA, as 
required by law.  Your study data will also be shared with the drug company that 
provides the study medicine to help them develop the drug.   
UMN may share your data and specimens with other people who study COVID-19.  
UMN will remove any information that could possibly be used to identify you before 
sharing.  This is called “anonymizing the data.”  We will not ask you for additional 
consent for this sharing. UMN will only share data and specimens for research projects 
that are approved by the group that is conducting this study.  
This study has a Certificate of Confidentiality from the US Federal Government.  This 
means that UMN cannot share any data it has about you with national, state, or local 
civil, criminal, administrative, legislative, or other authorities unless you specifically allow 
us to share it.   
A description of this clinical trial will be available at http://www.ClinicalTrials.gov, and on 
the EudraCT website (https://eudract.ema.europa.eu/). These websites will not include 
your name or any other direct identifiers such as your contact information.  These 
websites will include a summary of the results of this research once the study has been 
completed.  You can search either website at any time. 
[Note for US sites: The following brief HIPAA authorization is provided.  Your site-
specific consent should be modified to reflect the HIPAA authorization language 
requirements at your site.] 
To do this research, we will collect and use your personal data, as described above and 
in any HIPAA Authorization Form we have given you.  Please tell us whether you agree 
to have us collect and use your personal data by placing your initials in front of your 
selection. 
____Yes, I agree to the collection and processing of my personal data. 
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____No, I do not agree to the collection and processing of my personal data. 
It is your choice whether you allow us to collect and use your data.  However, you will 
not be able to be in this study if we cannot collect and use your data. 
[The following section (up to “What are your rights regarding your data?”) is for US sites 
only.] 
There are a lot of studies trying to find out more about COVID-19 and how people do 
after they have had COVID-19.  Sometimes other researchers studying COVID-19 may 
ask if we know of people who might be interested in being in a study.   If you think you 
might be interested in future studies, you can let us know now.  We are asking you for 
permission to share your contact information (name, email, phone number, mailing 
address) with other researchers outside the study team who ask us to help them. We 
would only share your contact information with researchers who have appropriate ethics 
approval for their study. We will never share your contact information with researchers 
doing studies aimed at making money (“commercial research”). Even if you let us give 
other researchers your contact information, you do not have to be in any future studies.  
You always have the choice to say “no” if someone contacts you for a future study.  If 
you tell us now that we can share your contact information but later you change your 
mind, let us know.  If you change your mind, we will no longer share your contact 
information with other COVID-19 researchers.   
Please put your initials by your choice: 
____Yes, you can share my contact information with other qualified researchers. 
____No, do not share my contact information with other qualified researchers. 
It is your choice whether to let us share your contact information with other researchers 
studying COVID-19. You can still be in this study even if you do not want us to share 
your contact information. 
[The following section (up to “What if you have problems or questions?”) is for only for 
countries subject to the GDPR or similar legislation requiring this information.  It 
should only be included in consents for sites subject to such legislation.  It will vary from 
place to place whether it must be in this consent document, a separate consent 
document, or an information sheet that does not require signature.  The amount of 
information provided may be reduced to meet the requirements of a particular country 
(e.g., not all countries/ECs require an enumeration of all of a data subject’s rights).] 
What are your rights regarding your data? 
The UMN is a public research university, and this study is funded primarily by a grant 
from the US Federal government.  UMN and the study funding source require the 
sponsor (UMN) to follow regulations and policies that are meant to protect your privacy.  
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UMN is also required to comply with the General Data Protection Regulation (GDPR), 
because it processes data obtained from people in Europe.   
 
There is no specific independent supervisory authority overseeing the processing of 
data in the US.  Any complaint you might have about the use of your data would be 
made to your national data protection authority. 
 
The GDPR gives you additional rights which we would like to inform you about below. 
 
Right to Information: You have the right to know what data about you is being 
processed. You can also get a free copy of this data provided. 
Right to Correction: You have the right to correct any information about you which is 
incorrect or had become incorrect. 
Right to Erasure/Anonymization: The sponsor is required under both EU and US law 
to retain data from research studies like this one for many years.  However, you have 
the right to request that your personal data be completely anonymized. This is done by 
destroying the information at your study center that links your identity to the 
pseudonymized data held by the sponsor.  This means that no one would ever be able 
to link the data held by the sponsor to you personally.  
 
Right to Restriction of processing: Under certain conditions, you have the right to 
demand processing restrictions, i.e. the data may then only be stored, not processed. 
You must apply for this. Please contact your study physician or the data protection 
officer of the study center if you want to do so.  This right may be limited if the restriction 
would affect the reliability of the study results. 
 
Right to Data portability: You have the right to receive the personal data that you have 
provided to the study center. This will allow you to request that this information be 
transmitted either to you or, where technically possible, to another agency designated 
by you. 
 
Right to Contradiction: You have the right to object at any time to any specific 
decision or action taken to process your personal data.  This right is limited for data that 
have already been processed and may be limited if your objection would affect the 
reliability of the study results. 
 
Right to Withdrawal of this consent: You may withdraw your consent at any time with 
effect for future data collection. This withdrawal may be in an informal or verbal 
communication to your investigator.  If you withdraw your consent this will not affect the 
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lawfulness of the data processing that has been or will be done with data collected until 
you withdraw consent.  Data already collected will be anonymized. 
 
If you would like to use one of these rights, please first contact the person responsible 
for the data collection at your study center: 
Person responsible for data collection at the study center: 
Name: 
 
Address:  
Phone: 
 
Email 
 
 
For concerns about data processing and compliance with data protection requirements 
you can also contact the data protection officer responsible for the study center: 
Data protection officer responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
In addition, you have the right to lodge a complaint with the competent authority if you 
believe that the processing of personal data concerning you is contrary to the GDPR: 
Data protection authority responsible for the study center: 
Name: 
 
Address: 
 
Phone: 
 
Email 
 
 
What if you have problems or questions? 
If you ever have questions about this study, or about the storage or use of your data or 
samples, or if you are hurt by being in the study, contact: 
• [name of the investigator or other study staff] 
• [telephone number of the above] 
 
If you have questions about your rights as a research participant, you can call: 
• [name or title of person on the ethics committee (IRB) or other organization 
appropriate for the site] 
• [telephone number of the above]  
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SIGNATURE PAGE FOR CONSENT TO PARTICIPATE IN THE TESICO STUDY  
I have read the consent or have had it explained to me. I believe that I understand the 
information.  By signing and dating this consent, I am stating that I want to join this 
study.  I understand that I do not waive any of my legal rights as a study participant by 
signing this consent.  I understand that I will receive a copy of the signed and dated 
consent. 
If you agree to be in this study, please sign below. 
 
________________________________________  
Date: _______________ 
Signature of participant 
 
________________________________________ 
Printed name of participant 
 
_____________________________________   
Date: _______________ 
Signature of investigator/designee 
 
_____________________________________ 
Printed name of investigator/designee 
 
FOR ADULTS NOT CAPABLE of GIVING CONSENT  
 
________________________________________ 
 Date: _______________ 
Signature of Legally Authorized Representative (LAR)  
 
_____________________________________ 
Printed name of LAR 
 
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____________________________________ 
Relationship of LAR to Participant 
(Indicate why the LAR is authorized to act as a surrogate health care decision-maker 
under state or applicable local law) 
 
Witness to Consent Interview 
On the date given next to my signature, I witnessed the consent interview for the research 
study named above in this document. I attest that the information in this consent form was 
explained to the subject, and the subject indicated that his/her questions and concerns 
were adequately addressed. 
_______________________________________ 
Date: _______________ 
Signature of witness 
 
________________________________________ 
Printed name of witness 
 
NOTE: This consent form, with the original signatures, MUST be retained on file 
by the Investigator of Record. A copy of the signed and dated consent must be 
given to the participant. A copy should be placed in the participant’s medical 
record, if applicable.  
If no-touch / electronic consent is used, the participant must be provided with a 
copy of the consent in a manner appropriate to the method used to obtain it.  A 
record of the act of consent must also be appropriately retained in the 
participant’s medical record. 
 
 
 
 
 
 
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Additional Consent for Genetic Testing on Stored Specimens  
WHY IS GENETIC TESTING BEING DONE? The study team would like your 
permission to collect a small amount of your blood and store them for researchers who 
will do genetic testing (testing on your genes) and other related tests in the future. 
These tests will help us understand how the genetic makeup of people affects the 
COVID-19 virus and how it makes people sick.   
Any future research done on the blood collected for this study will be related to the 
COVID-19 virus for which you are being studied in this trial. 
WHAT WILL HAPPEN DURING GENETIC TESTING?   
If you agree to take part in this study, three blood specimens will be collected 
along with other blood being drawn for the study, approximately 15 mL (about 1 
tablespoon) in total. The blood will be taken with other laboratory test samples 
so you will not get an extra needle stick.  
HOW WILL YOUR BLOOD BE USED? Your blood will be used to learn more about the 
health problems that may be caused by COVID-19.  This may include tests to better 
understand why some people have more severe complications (get sicker) than others 
and why medicines to prevent or treat these infections might work better in some people 
than in others. 
Researchers involved with this blood collection project do not know yet exactly which 
tests will be done. 
You and your study doctor or nurse will not get any results from the tests done on your 
blood collected for this genomics study.  These tests will only be used for research and 
may not apply to your medical care. 
Your blood sample collected for this study will: 
• Become the property of INSIGHT.   
• Not be sold or used to make commercial products.   
• Not be tested for any specific research study unless the plan for using your blood 
is approved - based on scientific and ethical considerations - by the INSIGHT 
Scientific Steering Committee, the U.S. National Institutes of Health (NIH), and a 
special committee (an Institutional Review Board or Ethics Committee) at the 
researcher’s institution. 
 
HOW WILL YOUR PRIVACY AND THE CONFIDENTIALITY OF YOUR 
INFORMATION BE PROTECTED? 
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Every reasonable step will be taken to protect your privacy and the confidentiality of 
your health information and to prevent misuse of this information, and to make sure your 
blood sample is handled with care at the storage facility. For example, your research 
records will be identified only by a code.  Your blood sample and results of any genetic 
testing will be identified by a second code.  Only a few statisticians (persons who 
analyze the study results) associated with the INSIGHT studies will have access to both 
codes in order to analyze the test results.  These statisticians will not have access to 
any information that can identify you. 
 
Researchers will write reports, including information they learn from future tests on your 
blood.  These reports will be shared with participating research sites.  These findings 
will also be submitted for publication in scientific or medical journals.  When the results 
of the research are published or discussed in conferences, no information will be 
included that would reveal your identity. 
However your records may be seen by: 
• Institutional Review Boards (IRBs) or Ethic Committees (ECs) who review the 
study to make sure it is ethically acceptable  
• Agencies of the U.S. government that fund or oversee this research, for example, 
the U.S. National Institutes of Health (NIH) or the U.S. Office for Human 
Research Protections (OHRP) 
• Research staff and study monitors, and their designees.   
 
Staff at [insert the name of the site] will handle your personal information very 
carefully.  They are required to make sure that people not involved with this study do not 
have access to your research and medical records. 
 
[For U.S. Sites Only] 
In addition to these efforts to keep your information confidential, the INSIGHT Genomics 
study is covered by a Certificate of Confidentiality from the U.S. Department of Health 
and Human Services.  This certificate means that researchers cannot be forced to give 
information collected as part of this study to people who are not involved with the study, 
for example, the court system.  However, this certificate has limited protection rights.  
You should know that it does not stop the doctor in charge of this study from taking 
appropriate steps to prevent serious harm to yourself or others. Federal and state laws 
also help protect research participants and others who have genetic testing done.  
[For International Sites Only]  
Efforts will be made to keep your personal information confidential, but we cannot 
guarantee complete confidentiality.  Your personal information may be released if 
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required by law.  Any publication of this study will not use your name or identify you 
personally.  
 
HOW LONG WILL YOUR BLOOD BE KEPT? 
Your blood specimen will be stored as long as funding is available for storage and 
testing. 
[Alternative to Previous Paragraph for non-US Sites Only] 
Your blood specimen will be stored safely and securely at a special facility called a 
specimen repository.  The repository may be located in the United States.  This facility 
follows strict procedures so that only approved researchers can use the stored 
specimen for future testing.  The employees at this facility who will store and track your 
blood specimen will not have information that identifies you by name. 
 
Risks: There are few risks involved with your participation in this study.  Having your 
blood drawn may result in a little pain and slight bruising where the needle goes into 
your skin.  You may also feel lightheaded, bleed, develop a small blood clot where the 
needle goes into your skin, or faint.  Very rarely, your skin may get infected.  Another 
small but unlikely risk is the possibility of others finding out about your participation in 
this study. 
Benefits: You will not receive any direct benefit from your samples. Information 
obtained from the tests may provide useful information, to help other patients, about the 
causes, risks, and prevention of the COVID-19 virus.  
WHAT IF YOU DON’T WANT YOUR BLOOD FOR GENETIC TESTING STORED ANY 
LONGER? If you sign the consent that your blood can be stored for research to be 
done at a later date you can change your mind at any time.  If you change your mind, 
you must write a letter to [insert the name of the principal investigator] at the [insert 
the name and address of the site] to let them know that you do not want your blood 
specimen collected for this study used for future research.  A sample letter will be given 
to you as a guide to help you express your request in writing. 
When [insert the name of the principal investigator] receives your letter, the 
research staff will contact you to come to the clinic to verify your decision by signing and 
dating this original informed consent form.  A second copy of this consent will be given 
to you as proof that we received your request.  If we do not hear from you within 30 
days after getting your letter to withdraw from this study, we will send your request to 
the storage facility. 
If you decide to withdraw consent for this study, your blood sample, including any parts 
separated from the sample, will not be used.  Every effort will be made to destroy your 
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PID: _______________________ 
blood sample and any parts separated from it.  If some testing has already been done 
on your blood sample, the results from this testing will remain as part of this research.  
The research staff at the [insert the name of the site] will notify you of the date your 
blood specimen and any of its parts were destroyed. 
Costs or compensation of study: There will be no costs to you or compensation. 
Consent: Please mark the box for yes or no and sign your name, indicating you have 
freely given your answers and consent: 
 
 
  
 
 
 
____________________________________      ________________ 
Signature (subject or surrogate)                                 Date   
 
_________________________________________ 
Subject or Surrogate Printed Name  
 
____________________________________      ________________ 
Signature of Person Obtaining Consent    
Date 
 
_________________________________________ 
Printed Name and Title of Person  
 
Yes ☐ 
No ☐ 
My blood samples may be stored and used for future genetic research 
in COVID-19 or other serious illness: 
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Appendix B  
Schedule of Assessments 
 
Screen 
or Day 
0 
Day 
0 
Study Day 
Day 
−1/01 
0 
1 
2 
3 
4 
5 
6 
7 
14 28 42 60 75 90 180 
Acceptable deviation 
from day 
0 
0 
0 
0 
0 
0 
0 
0 
+1 +2 +3 +3 +5 +5 
+ 
10 
± 
14 
ELIGIBILITY & 
BASELINE DATA 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline medical and 
social history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline concomitant 
medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Symptom-directed  
physical exam by the 
clinical team (includes 
vital signs) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nasal swab for virus 
detection and review 
SARS-CoV-2 test 
results 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline study labs 
(CBC with differential, 
ferritin, CRP, BMP, 
INR, D-DIMER, AST, 
ALT, bilirubin)2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research sample 
storage (includes DNA 
and RNA at baseline 
among patients who 
consent to genetics) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
or other documentation 
of pregnancy status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
INTERVENTION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Screen 
or Day 
0 
Day 
0 
Study Day 
Day 
−1/01 
0 
1 
2 
3 
4 
5 
6 
7 
14 28 42 60 75 90 180 
Acceptable deviation 
from day 
0 
0 
0 
0 
0 
0 
0 
0 
+1 +2 +3 +3 +5 +5 
+ 
10 
± 
14 
Study Drug/Placebo 
Administration3 
 
X 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
Assess infusion 
completion and 
adverse reactions3 
 
X 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
STUDY 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-randomization 
concomitant 
medications 
 
X 
X X 
X 
X 
X 
X 
X 
X4 
X 
 
 
 
 
 
On-study labs (BMP, 
CBC with differential, 
INR, D-DIMER, AST, 
ALT, bilirubin)2,5 
 
X 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical labs (BMP, 
CBC with differential, 
INR, D-DIMER, AST, 
ALT, bilirubin)5,6 
 
 
 
 
X7 
 
X8 
 
 
 
 
 
 
 
 
 
Research sample 
storage  (includes RNA 
at day 3 among 
patients who consent 
to genetics)4,5 
 
X7 
 
X8 
 
 
 
 
 
 
 
 
 
Vital signs5 
X 
X 
X X 
 
 
X 
 
 
X 
 
 
 
 
 
 
Hospitalization status 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Changes in 
residence/facility 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Interim medical history 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X9,
10 
X9, 
10 
Oxygen support (for 
WHO/NIH/TICO 
ordinal outcome) 
X 
X 
X X 
X 
X 
X 
X 
X 
X4 
 
 
 
 
 
 
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Screen 
or Day 
0 
Day 
0 
Study Day 
Day 
−1/01 
0 
1 
2 
3 
4 
5 
6 
7 
14 28 42 60 75 90 180 
Acceptable deviation 
from day 
0 
0 
0 
0 
0 
0 
0 
0 
+1 +2 +3 +3 +5 +5 
+ 
10 
± 
14 
Clinical AEs of grade 3 
and 4 severity 
 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Clinical AEs of any 
grade on day indicated 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
SAEs and PSESEs 
 
Report through 90 days 
 
 
SAEs related to study 
interventions 
 
Report as they occur 
Unanticipated 
problems 
 
Report as they occur 
Deaths and 
readmissions 
 
Report as they occur 
Hospitalization 
Summary 
 
Report upon hospital discharge 
1 Screening must be performed within 24 hours of randomization. 
2 These laboratory evaluations will only be performed as study procedures if they are 
unavailable clinically on that study day  
3 Duration of study drug administration may vary by investigational agent; the sample 
provided here is for 3 successive days. Where the duration of study drug 
administration varies from this schedule, the duration will be specified in the relevant 
agent-specific Appendix H . 
4 The Day 14 visit will record values for Days 8–14. 
5 These will be not be collected after hospital discharge. 
6 These laboratory assessments will only include clinically available results 
7 It is acceptable to perform the Day 3 draw on Day 4. 
8 It is acceptable to perform the Day 5 draw on Day 5±1, but the Day 3 and Day 5 draws 
cannot both be performed on Day 4. 
9 Includes telephone administration of the Euro-QOL-5D-5L instrument. 
10 Includes telephone administration of Patient-Reported Outcomes (MRC Dyspnea, 
PROMIS fatigue, CONNECTS Recovery) 
 
  
 
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Appendix C  
 TESICO / ACTIV-3b protocol team 
 
To oversee the implementation of this master protocol, a protocol team will be formed 
and include: 
• Protocol co-chair(s) 
• NIAID, Division of Clinical Research representatives 
• NHLBI Program Officers 
• INSIGHT University of Minnesota representatives 
• INSIGHT International Coordinating Center representatives 
• Representatives from collaborating trials networks, including PETAL, CTSN, and 
VA 
• Representatives from collaborating laboratory representatives 
• Representatives from collaborating manufacturers of investigational agents 
• Representatives from site investigators 
• Study biostatisticians  
• Community representative(s) 
A core team consisting of the co-chair(s), ICC leaders, NIH representatives, study 
statisticians, representatives from collaborating trials networks, and other 
representatives and the INSIGHT PI will also regularly convene to review study 
progress and address study conduct and administrative issues that arise. 
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Appendix D  
REFERENCES ON THE INSIGHT WEBSITE 
 
The INSIGHT website (www.insight-trials.org) will maintain updated links to the 
following documents referenced in the INSIGHT 014 protocol and to other information 
pertinent to the study: 
• DAIDS toxicity table: (https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables) 
 
• INSIGHT Publications and Presentations Policy 
(http://insight.ccbr.umn.edu/resources/P&P_policy.pdf) 
 
• Centers for Disease Control and Prevention (CDC) and European Centre for 
Disease Prevention and Control (ECDC) guidance on how to handle infection 
control measures (https://www.cdc.gov/sars/guidance/i-infection/healthcare.html 
and https://www.ecdc.europa.eu/en/publications-data/infection-prevention-and-
control-and-preparedness-covid-19-healthcare-settings). 
 
• Treatment guidelines, incl from NIH and WHO 
(https://www.covid19treatmentguidelines.nih.gov/, 
https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-
guidance/patient-management, https://www.idsociety.org/practice-
guideline/covid-19-guideline-treatment-and-management/, 
https://www.hematology.org/covid-19/covid-19-and-vte-anticoagulation and 
https://www.ersnet.org/covid-19-guidelines-and-recommendations-directory)  
 
 
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Appendix E  
LIST OF ACRONYMS 
 
ACTIV  
Accelerating COVID-19 Therapeutic Interventions and Vaccines  
ACTT 
Adaptive COVID-19 Treatment Trial 
AE 
adverse event 
ARDS 
acute respiratory distress syndrome 
CDC 
Centers for Disease Control and Prevention (US) 
CHF 
Congestive heart failure 
CI 
confidence interval 
COVID-19 
Coronavirus-Induced Disease 2019  
CTSN 
Cardiothoracic Surgical Trials Network  
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board  
EC 
ethics committee 
ECMO 
extracorporeal membrane oxygenation 
EU 
European Union 
FDA 
Food and Drug Administration (US) 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
HR 
hazard ratio 
ICC 
International Coordinating Center 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ICU 
intensive care unit 
IEC 
Institutional Ethics Committee 
INSIGHT 
International Network for Strategic Initiatives in Global HIV Trials 
IQR 
interquartile range 
IRB 
Institutional Review Board 
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IV 
intravenous 
LAR 
Legal Authorized Representative 
MI 
Myocardial infarction 
mL 
milliliter 
NAT 
Nucleic acid test (to identify genomic material; some uses amplification) 
NHLBI 
National Heart, Lung, and Blood Institute, NIH (US) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH (US) 
NIH 
National Institutes of Health (US) 
NIHSS 
National Institutes of Health Stroke Scale/Score 
nMAb 
Neutralizing Monoclonal Antibodies 
OHRP 
Office for Human Research Protections (US) 
OR 
odds ratio 
PCR 
polymerase chain reaction 
PETAL 
Prevention and Early Treatment of Acute Lung Injury Network 
PHI 
personal health information  
PIM 
Protocol Instruction Manual 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SARS-CoV-1 severe acute respiratory syndrome coronavirus 1 
SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 
SOC 
standard of care 
SUSAR 
suspected unexpected serious adverse reaction 
TOC 
trial oversight committee  
UMN 
University of Minnesota 
UP 
Unanticipated problem 
US 
United States of America 
VA 
Veterans Administration 
WHO 
World Health Organization 
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Appendix F  
This Is Intentionally Blank 
 
 
 
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Appendix G  
This Is Intentionally Blank 
 
 
 
 
 
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Appendix H  
Investigational Agent. 
 
This appendix will include the following information for each investigational agent studied. The 
rationale for studying the agent and the description and administration of the agent. Also, as 
appropriate, specific AEs observed to be possibly associated with the agent in question, and 
how to monitor for, clinically handle and report such AEs, should they arise. Changes in 
endpoint, SOC, inclusion and/or exclusion criteria, sample size estimation and approach to 
interim analyses and data analyses will also be included if appropriate for the investigation of 
the agent in question relative to what is stated in the master protocol. Finally, the text will also 
clarify whether the manufacturer of the investigational agent plans to pursue licensure in the 
countries where the trial will occur, should the investigational agent be demonstrated in the trial 
to have overall benefit. 
   Introduction/Rationale for studying the agent 
o Potential risks and benefits of agent 
o Motivation for agent selection with consideration of results from trials of other agents  
• Agent-specific eligibility criteria 
• Description of investigational agent 
o Administration and duration 
o Formulation and preparation 
o Supply, distribution, and accountability 
o Contraindicated medications 
o Precautionary medications 
• Clinical and laboratory evaluations in addition to master protocol 
o Timing 
o Special instructions 
• Clinical management issues 
o Infusion-related reactions 
o Hypersensitivity 
• Pregnancy and breast-feeding considerations 
• Criteria for discontinuation of infusion 
• References 
 
 
 
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Appendix I 
Standard of Care 
I1. Overview 
Currently, the only licensed treatment for COVID-19 is remdesivir, but the registration trials 
for remdesivir were too small to demonstrate efficacy in patients with critical illness from 
COVID-19. Considering the number of randomized trials being conducted to study 
treatments for COVID-19, it is likely that other effective treatments will be identified during 
performance of this master protocol. 
When treatments for COVID-19 are demonstrated to have safety and efficacy, those 
treatments should be considered in designing new studies.  Depending on the scientific 
question, an experimental treatment will be coupled with or compared to a known effective 
treatment.  When such known effective treatments are incorporated into both arms, they are 
called “background therapy” or standard of care (SOC).  In this case, the scientific question 
addressed is whether a new treatment added to an already effective treatment is superior to 
the established effective treatment alone.  
SOC may include general supportive care appropriate to the participant’s clinical status, 
and specific therapeutic agents, and measures to reduce risk of SARS-CoV-2 transmission 
to the participant and health care givers. 
As stated in section 5.1, the objective of this protocol is to evaluate investigational agents - 
aimed at treating patients with critical illness from SARS-CoV-2 infection - for safety and 
efficacy compared to placebo control, when all eligible participants receive background 
therapy that is considered effective.  Consistent with precedent, we refer to background 
therapy as standard of care (SOC).  All participants will receive an investigational agent + 
SOC vs. placebo + SOC. 
Below, principles for defining SOC are provided, and recommendations and guidance on 
SOC are given. Whether an individual SOC treatment is provided by the trial or not is based 
on multiple factors, including clinical and scientific considerations. In some cases, the 
decision to administer an SOC treatment is left entirely to the research participant’s primary 
medical team. 
I2. Guiding principles for inclusion of measures as part of SOC  
The SOC will be regularly updated based on review of the scientific literature and updated 
authoritative treatment guidelines on this topic. The standard for including one or more 
measures as SOC, includes a careful review of the existing literature and current 
guidelines (see Appendix D). As for therapeutic agents, those having been shown to be 
clinically effective in properly powered Phase III or Phase IV trials (i.e., high quality/level 1 
evidence) and with a reasonable safety profile will be considered by the protocol team for 
inclusion, if recommended by at least one major treatment guideline. This evaluation may 
also lead to a statement that one or more agents are either not recommended or should 
not be used as part of SOC. As knowledge will likely continue to accumulate rapidly, the 
protocol leadership team may occasionally decide to include or exclude an intervention as 
part of SOC before it is recommended in at least one major treatment guideline. In such 
cases, the relevant literature that lead to the determination will be cited.  
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The use of a given SOC intervention may apply to all or to a subgroup of the participants in 
the master protocol based on available evidence – the subgroup may be defined based on 
severity of disease, a clinical or laboratory defined feature, or a clinically or laboratory 
defined contraindication for using the SOC treatment. An SOC agent may be mandated for 
participants (required for protocol entry); mandated where not contraindicated (participants 
may enter if that SOC is unsuitable, and not receive that SOC); or recommended subject to 
clinical discretion. SOC may be protocol-supplied where mandated.  
The master protocol acknowledges that there may be local variation in the clinical 
availability of one or more agents chosen to be part of mandated protocol-supplied SOC 
from site to site. While acknowledging risks of inadvertent coercion, the importance of the 
scientific question (how candidate agents perform against the background of the current 
SOC treatments) is a crucial, high-priority question. There is no possible way to answer the 
question of efficacy against the background of an already proven effective agent without 
providing the agent – if not readily available - within the trial.  
I3. Current SOC in the master protocol: 
I3.1 Remdesivir 
Although remdesivir is licensed for use in the United States and is SOC for most 
hospitalized patients with COVID-19, the key registration trials50 included insufficient 
patients in this subgroup to provide strong evidence in favor of remdesivir for critically ill 
patients. It is anticipated that this master protocol may include a placebo-controlled 
investigation of remdesivir, possibly in a factorial design, in this patient population. Thus 
remdesivir is not considered SOC presently for this protocol: the protocol does not 
recommend routine initiation of remdesivir in this patient population (except potentially as 
an investigational agent). 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. (For patients enrolling in a remdesivir 
randomization, see the remdesivir appendix for further guidance on receipt of remdesivir 
prior to randomization.) 
I3.2 Dexamethasone and Other Corticosteroids 
Based on the findings of the RECOVERY trial,39 a meta-analysis of glucocorticoid trials,51 
and in line with NIH treatment guideline (Appendix D), it is recommended to consider 
initiation of corticosteroid therapy in participants with COVID-19 who have respiratory 
failure—the target population of this master protocol. Corticosteroids may increase the 
probability of reactivating latent infections including herpes viruses and tuberculosis, 
hyperglycemia, hypernatremia, secondary infections, and may delay clearance of SARS-
CoV-2, but the balance of evidence favors glucocorticoid therapy. Treatment with a 
corticosteroid is recommended for a total of 10 days, using doses outlined in this table.  
Corticosteroid name 
Daily dose 
Dexamethasone  
6 mg PO or IV 
Prednisone 
~40 mg PO 
Methylprednisolone 
~32 mg IV 
Hydrocortisone 
~160 mg IV 
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I3.3 Other Supportive Care 
All participants will be given supportive care for most complications of severe COVID-19 
including: pneumonia, hypoxemic respiratory failure/ARDS, sepsis and septic shock, 
cardiomyopathy and arrhythmia, acute kidney injury, and complications from prolonged 
hospitalization, including secondary bacterial infections, thromboembolism, gastrointestinal 
bleeding, and critical illness polyneuropathy/myopathy. Links to details of such care can be 
found in Appendix D.  Supportive care components of SOC include lung-protective 
ventilation for patients who require invasive mechanical ventilation52 (high quality 
evidence) and prone positioning for mechanically ventilated patients with more than 
moderate ARDS (high quality evidence53,54), treatment with anti-bacterial agents for 
patients believed to have bacterial infection (high quality evidence), guidelines-compliant 
management of sepsis when it is present (moderate quality evidence).55 Use or non-use 
of extra-corporeal life support (ECLS) is not mandated as part of SOC; nor is any specific 
approach to renal replacement therapy.  
Consideration should be given to the use of pharmacological thromboprophylaxis 
(thrombosis prevention) in line with local clinical guidelines for hospitalized patients as 
appropriate for an individual participant, in addition to approaches to maintain mobility and 
minimize other thrombotic risks. Standard approaches to thromboprophylaxis supported by 
high quality evidence include the use of low molecular weight heparin (for example, 
enoxaparin 0.5 m/kg daily), which is the preferred agent in some COVID-19 treatment 
guidelines. However other standard approaches in accordance with local and institutional 
guidelines and the medical circumstances of an individual participant may also be 
considered, including the use of low (prophylactic) dose unfractionated heparin (high quality 
evidence). Specialist advice should be sought for participants with pre-existing 
prothrombotic states, or who are pregnant.  
I3.4 Cautions and Contraindications 
It is not recommended to use chloroquine as SOC due to excess harm and no 
demonstrable benefit. Neither hydroxychloroquine nor chloroquine have documented 
clinical benefit, and hence are not recommended for use as SOC. Similarly, it is not 
recommended to use lopinavir/ritonavir as SOC, since there are studies suggesting no 
clinical benefit.56,57 These recommendations are consistent with current guidelines by the 
Infectious Disease Society of America, as included in Appendix D.  
I3.5 SARS-CoV-2 Infection Control 
Minimum standards of protection to reduce the risk of SARS-CoV-2 transmission from trial 
participants to research personnel, participants in other trials, or patients treated in the 
same facility can be found in links displayed in Appendix D. 
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Ref  1 
Appendix J  
References 
1.
Johns Hopkins University of Medicine. Johns Hopkins Coronavirus Resource Center.
Johns Hopkins University of Medicine. (https://coronavirus.jhu.edu/).
2.
Guo T, Fan Y, Chen M, et al. Cardiovascular Implications of Fatal Outcomes of Patients
With Coronavirus Disease 2019 (COVID-19). JAMA Cardiology 2020;5(7):811-818. DOI:
10.1001/jamacardio.2020.1017.
3.
Klok FA, Kruip M, van der Meer NJM, et al. Incidence of thrombotic complications in
critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-147. DOI:
10.1016/j.thromres.2020.04.013.
4.
World Health Organization. Timeline: WHO's COVID-19 response.
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/interactive-timeline).
5.
Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients
with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England)
2020;395(10229):1054-1062. (In eng). DOI: 10.1016/s0140-6736(20)30566-3.
6.
Ji D, Zhang D, Xu J, et al. Prediction for Progression Risk in Patients With COVID-19
Pneumonia: The CALL Score. Clinical infectious diseases : an official publication of the
Infectious Diseases Society of America 2020;71(6):1393-1399. (In eng). DOI:
10.1093/cid/ciaa414.
7.
CDC COVID-19 Response Team. Preliminary Estimates of the Prevalence of Selected
Underlying Health Conditions Among Patients with Coronavirus Disease 2019 - United
States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep 2020;69(13):382-
386. (In eng). DOI: 10.15585/mmwr.mm6913e2.
8.
Guan WJ, Zhong NS. Clinical Characteristics of Covid-19 in China. Reply. New England
journal of medicine 2020;382(19):1861-1862. (In eng). DOI: 10.1056/NEJMc2005203.
9.
Du Z, Xu X, Wu Y, Wang L, Cowling BJ, Meyers LA. Serial Interval of COVID-19 among
Publicly Reported Confirmed Cases. Emerg Infect Dis 2020;26(6):1341-1343. (In eng).
DOI: 10.3201/eid2606.200357.
10.
Menni C, Valdes AM, Freidin MB, et al. Real-time tracking of self-reported symptoms to
predict potential COVID-19. Nature medicine 2020;26(7):1037-1040. DOI:
10.1038/s41591-020-0916-2.
11.
Kwong JC, Schwartz KL, Campitelli MA, et al. Acute Myocardial Infarction after
Laboratory-Confirmed Influenza Infection. New England journal of medicine
2018;378(4):345-353. (In eng). DOI: 10.1056/NEJMoa1702090.
12.
Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with
SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective,
observational study. The Lancet Respiratory medicine 2020;8(5):475-481. (In eng). DOI:
10.1016/s2213-2600(20)30079-5.
13.
Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With
2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. J Am Med Assoc
2020;323(11):1061-1069. (In eng). DOI: 10.1001/jama.2020.1585.
14.
Grasselli G, Zangrillo A, Zanella A, et al. Baseline Characteristics and Outcomes of 1591
Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy.
JAMA: Journal of the American Medical Association 2020;323(16):1574-1581. DOI:
10.1001/jama.2020.5394.
15.
Intensive Care National Audit & Research Centre (ICNARC). ICNARC report on COVID-
19 in critical care: England, Wales and Northern Ireland. London: Intensive Care National
CONFIDENTIAL
Aviptadil
Page 76 of 79
Protocol ACTIV-3b, v3.0, 08Mar2022
OCRPRO/DCR/NIAID/NIH
IND154701 SN0022

Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) Master Protocol 
Version 3.0, 08 March 2022  
Ref  2 
Audit & Research Centre (ICNARC), Dec 11 2020. (https://www.icnarc.org/Our-
Audit/Audits/Cmp/Reports). 
16.
Choodari-Oskooei B, Parmar MK, Royston P, Bowden J. Impact of lack-of-benefit
stopping rules on treatment effect estimates of two-arm multi-stage (TAMS) trials with
time to event outcome. Trials 2013;14:23. (In eng). DOI: 10.1186/1745-6215-14-23.
17.
He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of
COVID-19. Nature medicine 2020;26(5):672-675. (In eng). DOI: 10.1038/s41591-020-
0869-5.
18.
Proschan MA, Lan KK, Wittes G, Turk J. Section 3.2.  Statistical Monitoring of Clinical
Trials: A Unified Approach. New York: Springer-Verlag; 2006.
19.
To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior
oropharyngeal saliva samples and serum antibody responses during infection by SARS-
CoV-2: an observational cohort study. The Lancet Infectious diseases 2020;20(5):565-
574. (In eng). DOI: 10.1016/s1473-3099(20)30196-1.
20.
Yu F, Yan L, Wang N, et al. Quantitative Detection and Viral Load Analysis of SARS-
CoV-2 in Infected Patients. Clinical infectious diseases : an official publication of the
Infectious Diseases Society of America 2020;71(15):793-798. (In eng). DOI:
10.1093/cid/ciaa345.
21.
O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for
phase 1 clinical trials in cancer. Biometrics 1990;46(1):33-48. (In eng).
22.
Chen W, Lan Y, Yuan X, et al. Detectable 2019-nCoV viral RNA in blood is a strong
indicator for the further clinical severity. Emerging microbes & infections 2020;9(1):469-
473. (In eng). DOI: 10.1080/22221751.2020.1732837.
23.
Bermejo-Martin JF, González-Rivera M, Almansa R, et al. Viral RNA load in plasma is
associated with critical illness and a dysregulated host response in COVID-19. Critical
Care 2020;24(1):691. DOI: 10.1186/s13054-020-03398-0.
24.
Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized
patients with COVID-2019. Nature 2020;581(7809):465-469. (In eng). DOI:
10.1038/s41586-020-2196-x.
25.
Chau NVV, Thanh Lam V, Thanh Dung N, et al. The natural history and transmission
potential of asymptomatic SARS-CoV-2 infection. Clinical infectious diseases : an official
publication of the Infectious Diseases Society of America 2020;71(10):2679–2687. DOI:
10.1093/cid/ciaa711.
26.
Hue S, Beldi-Ferchiou A, Bendib I, et al. Uncontrolled Innate and Impaired Adaptive
Immune Responses in Patients with COVID-19 Acute Respiratory Distress Syndrome.
Am J Respir Crit Care Med 2020;202(11):1509-1519. (In eng). DOI:
10.1164/rccm.202005-1885OC.
27.
Matthay MA, Leligdowicz A, Liu KD. Biological Mechanisms of COVID-19 Acute
Respiratory Distress Syndrome. Am J Respir Crit Care Med 2020;202(11):1489-1491. (In
eng). DOI: 10.1164/rccm.202009-3629ED.
28.
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(1):6319.
DOI: 10.1038/s41467-020-20139-7.
29.
Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory
responses in severe COVID-19 patients. Science (New York, NY) 2020;369(6504):718-
724. (In eng). DOI: 10.1126/science.abc6027.
30.
Qin C, Zhou L, Hu Z, et al. Dysregulation of Immune Response in Patients With
Coronavirus 2019 (COVID-19) in Wuhan, China. Clinical infectious diseases : an official
CONFIDENTIAL
Aviptadil
Page 77 of 79
Protocol ACTIV-3b, v3.0, 08Mar2022
OCRPRO/DCR/NIAID/NIH
IND154701 SN0022

Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) Master Protocol 
Version 3.0, 08 March 2022  
Ref  3 
publication of the Infectious Diseases Society of America 2020;71(15):762-768. DOI: 
10.1093/cid/ciaa248. 
31.
Wang F, Hou H, Luo Y, et al. The laboratory tests and host immunity of COVID-19
patients with different severity of illness. JCI Insight 2020;5(10). DOI:
10.1172/jci.insight.137799.
32.
Salama C, Han J, Yau L, et al. Tocilizumab in Patients Hospitalized with Covid-19
Pneumonia. N Engl J Med 2020 (In eng). DOI: 10.1056/NEJMoa2030340.
33.
Kalil AC, Patterson TF, Mehta AK, et al. Baricitinib plus Remdesivir for Hospitalized
Adults with Covid-19. New England Journal of Medicine 2020.
34.
Grasselli G, Tonetti T, Protti A, et al. Pathophysiology of COVID-19-associated acute
respiratory distress syndrome: a multicentre prospective observational study. The lancet
Respiratory medicine 2020;8(12):1201-1208.
35.
Matthay MA, Arabi YM, Siegel ER, et al. Phenotypes and personalized medicine in the
acute respiratory distress syndrome. Intensive care medicine 2020;46(12):2136-2152. (In
eng). DOI: 10.1007/s00134-020-06296-9.
36.
Calfee CS, Delucchi KL, Sinha P, et al. Acute respiratory distress syndrome
subphenotypes and differential response to simvastatin: secondary analysis of a
randomised controlled trial. The Lancet Respiratory Medicine 2018;6(9):691-698.
37.
Leisman DE, Ronner L, Pinotti R, et al. Cytokine elevation in severe and critical COVID-
19: a rapid systematic review, meta-analysis, and comparison with other inflammatory
syndromes. The Lancet Respiratory Medicine 2020.
38.
Rice TW, Janz DR. In Defense of Evidence-based Medicine for the Treatment of COVID-
19 Acute Respiratory Distress Syndrome. Ann Am Thorac Soc 2020;17(7):787-789. (In
eng). DOI: 10.1513/AnnalsATS.202004-325IP.
39.
Horby P, Lim WS, Emberson JR, et al. Dexamethasone in Hospitalized Patients with
Covid-19 - Preliminary Report. N Engl J Med 2020 (In eng). DOI:
10.1056/NEJMoa2021436.
40.
Matthay MA, Wick KD. Corticosteroids, COVID-19 pneumonia, and acute respiratory
distress syndrome. The Journal of clinical investigation 2020;130(12).
41.
Unroe M, Kahn JM, Carson SS, et al. One-year trajectories of care and resource
utilization for recipients of prolonged mechanical ventilation: a cohort study. Ann Intern
Med 2010;153(3):167-75. (In eng). DOI: 10.7326/0003-4819-153-3-201008030-00007.
42.
Combes A, Costa MA, Trouillet JL, et al. Morbidity, mortality, and quality-of-life outcomes
of patients requiring >or=14 days of mechanical ventilation. Critical care medicine
2003;31(5):1373-81. (In eng). DOI: 10.1097/01.Ccm.0000065188.87029.C3.
43.
Herridge MS, Chu LM, Matte A, et al. The RECOVER Program: Disability Risk Groups
and 1-Year Outcome after 7 or More Days of Mechanical Ventilation. Am J Respir Crit
Care Med 2016;194(7):831-844. (In eng). DOI: 10.1164/rccm.201512-2343OC.
44.
Hill AD, Fowler RA, Burns KE, Rose L, Pinto RL, Scales DC. Long-Term Outcomes and
Health Care Utilization after Prolonged Mechanical Ventilation. Ann Am Thorac Soc
2017;14(3):355-362. (In eng). DOI: 10.1513/AnnalsATS.201610-792OC.
45.
Zhao W. Mass weighted urn design--A new randomization algorithm for unequal
allocations. Contemporary Clinical Trials 2015;43:209-16. DOI:
10.1016/j.cct.2015.06.008.
46.
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the Treatment of Covid-19 -
Final Report. New England journal of medicine 2020;383(19):1813-1826. DOI:
10.1056/NEJMoa2007764.
CONFIDENTIAL
Aviptadil
Page 78 of 79
Protocol ACTIV-3b, v3.0, 08Mar2022
OCRPRO/DCR/NIAID/NIH
IND154701 SN0022

Therapeutics for Severely Ill Inpatients with COVID-19 (TESICO) Master Protocol 
Version 3.0, 08 March 2022  
Ref  4 
47.
Marshall JC, Murthy S, Diaz J, et al. A minimal common outcome measure set for
COVID-19 clinical research. The Lancet Infectious Diseases 2020.
48.
ARDS Definition Task Force, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress
syndrome: the Berlin Definition. JAMA 2012;307(23):2526-33. DOI:
10.1001/jama.2012.5669.
49.
Matthay MA, Thompson BT, Ware LB. Expanding the Berlin Definition of ARDS to Include
Patients Treated with High Flow Nasal Oxygen. Lancet Respir Med 2021;In press.
50.
Beigel JH, Tomashek KM, Dodd LE. Remdesivir for the Treatment of Covid-19 -
Preliminary Report. Reply. N Engl J Med 2020;383(10):994. DOI:
10.1056/NEJMc2022236.
51.
The WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group.
Association Between Administration of Systemic Corticosteroids and Mortality Among
Critically Ill Patients With COVID-19: A Meta-analysis. JAMA 2020;324(13):1330-1341.
DOI: 10.1001/jama.2020.17023.
52.
Brower RG, Matthay MA, Morris A, Schoenfeld D, Thompson BT, Wheeler A. Ventilation
with lower tidal volumes as compared with traditional tidal volumes for acute lung injury
and the acute respiratory distress syndrome. New England journal of medicine
2000;342(18):1301-8. (In eng). DOI: 10.1056/nejm200005043421801.
53.
Fan E, Del Sorbo L, Goligher EC, et al. An Official American Thoracic Society/European
Society of Intensive Care Medicine/Society of Critical Care Medicine Clinical Practice
Guideline: Mechanical Ventilation in Adult Patients with Acute Respiratory Distress
Syndrome. Am J Respir Crit Care Med 2017;195(9):1253-1263. (In eng). DOI:
10.1164/rccm.201703-0548ST.
54.
Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory
distress syndrome. N Engl J Med 2013;368(23):2159-68. (In eng). DOI:
10.1056/NEJMoa1214103.
55.
Society of Critial Care Medicine (SCCM). Adult Patients: SCC Adult Guidelines.
(https://sccm.org/SurvivingSepsisCampaign/Guidelines/Adult-Patients).
56.
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with
Severe Covid-19. N Engl J Med 2020;382(19):1787-1799. (In eng). DOI:
10.1056/NEJMoa2001282.
57.
RECOVERY Collaborators. Lopinavir-ritonavir in patients admitted to hospital with
COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet
2020;396(10259):1345-52. (In eng). DOI: 10.1016/s0140-6736(20)32013-4.
CONFIDENTIAL
Aviptadil
Page 79 of 79
Protocol ACTIV-3b, v3.0, 08Mar2022
OCRPRO/DCR/NIAID/NIH
IND154701 SN0022