RECOVER-VITAL: A Platform Protocol for Evaluation of Interventions for Viral Persistence, Viral Reactivation, and Immune Dysregulation in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)
Phase: PHASE2
Conditions: Long COVID, Long Covid19
Sponsor: Kanecia Obie Zimmerman

 
 
RECOVER-VITAL: A Platform Protocol for Evaluation of 
Interventions for Viral Persistence, Viral Reactivation, 
and Immune Dysregulation in Post-Acute Sequelae of 
SARS-CoV-2 Infection (PASC)  
 
National Clinical Trial (NCT) Identified Number: NCT05595369 
Co-Principal Investigator/IND Sponsor: Kanecia Zimmerman, MD, PhD, MPH 
   Co-Principal Investigator: Richard Whitley, MD 
 
Funded by: National Institutes of Health  
Version Number:  v3.0 
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Table of Contents 
List of Tables ...................................................................................................................................................... iv 
List of Figures .................................................................................................................................................... iv 
STATEMENT OF COMPLIANCE ......................................................................................................................... 1 
1.1 
Synopsis ........................................................................................................................................... 1 
1.2 
Schema for Phase 2 Study Designs .............................................................................................. 3 
1.3 
Key Roles ......................................................................................................................................... 5 
2 
INTRODUCTION ....................................................................................................................................... 5 
2.1 
Study Rationale ............................................................................................................................... 5 
2.2 
Background ...................................................................................................................................... 5 
2.3 
Risk/Benefit Assessment ................................................................................................................ 7 
2.3.1 
Known Potential Risks ................................................................................................. 7 
2.3.2 
Known Potential Benefits............................................................................................. 7 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 7 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 8 
4 
STUDY DESIGN ...................................................................................................................................... 10 
4.1 
Overall Design ............................................................................................................................... 10 
4.2 
Scientific Rationale for Study Design .......................................................................................... 10 
4.3 
Justification for Dose ..................................................................................................................... 11 
4.4 
End of Study Definition ................................................................................................................. 11 
5 
STUDY POPULATION ............................................................................................................................ 11 
5.1 
Inclusion Criteria ............................................................................................................................ 11 
5.2 
Exclusion Criteria .......................................................................................................................... 12 
5.3 
Special Considerations for Participant Enrollment ..................................................................... 13 
5.4 
Screen Failures ............................................................................................................................. 13 
5.5 
Study Definition of Enrollment ...................................................................................................... 13 
5.6 
Strategies for Recruitment and Retention ................................................................................... 14 
6 
STUDY INTERVENTION ........................................................................................................................ 14 
6.1 
Study Intervention(s) Administration ........................................................................................... 14 
6.1.1 
Study Intervention Description .................................................................................. 14 
6.1.2 
Dosing and Administration ........................................................................................ 14 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................. 14 
6.2.1 
Acquisition and Accountability .................................................................................. 14 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 15 
6.2.3 
Product Storage and Stability ................................................................................... 15 
6.2.4 
Preparation ................................................................................................................. 15 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................ 15 
6.3.1 
Unblinding ................................................................................................................... 15 
6.4 
Study Intervention Adherence ...................................................................................................... 16 
6.5 
Concomitant Therapy.................................................................................................................... 16 
6.5.1 
Symptomatic Therapy ................................................................................................ 16 
6.5.2 
Rescue Medicine ........................................................................................................ 16 
7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL ......................................................................... 17 
7.1 
Participant Discontinuation From Study Drug ............................................................................ 17 
7.2 
Participant Withdrawal from the Study ........................................................................................ 17 
7.3 
Lost to Follow-Up .......................................................................................................................... 17 
7.4 
Study Halting Rules....................................................................................................................... 18 

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STUDY ASSESSMENTS AND PROCEDURES FOR PHASE 2 STUDY DESIGNS ....................... 19 
8.1 
Schedule of Procedures ............................................................................................................... 19 
8.2 
Screening (Day -14 to 0) .............................................................................................................. 20 
8.3 
Baseline (Day -2 to 0) ................................................................................................................... 20 
8.4 
Drug Dosing Midpoint Clinic Visit................................................................................................. 21 
8.5 
End of Dosing Clinic Visit (Day End of Dosing + 3 days) .......................................................... 22 
8.6 
Follow-Up [End of Dosing (+3 Days) to Day 179] ...................................................................... 22 
8.7 
End of Study Visit (Day 183 ± 7 days) ........................................................................................ 23 
8.8 
Optional Blood Collection/Nasal Swab Visits ............................................................................. 23 
8.9 
Clinical Laboratory Assessments................................................................................................. 24 
8.10 
Study Assessments....................................................................................................................... 24 
8.10.1 
Biospecimen Collection ............................................................................................. 24 
8.10.2 
PROMIS-29+2 (PROPr) ............................................................................................ 25 
8.10.3 
Cluster Targeted COVID-19 Symptom Questions (CTCSQ) ................................. 25 
8.10.4 
Symptom Cluster Assessment .................................................................................. 26 
8.10.5 
PASC Symptom Questionnaire................................................................................. 29 
9 
SAFETY ASSESSMENTS AND REPORTING ..................................................................................... 29 
9.1 
Adverse Events and Serious Adverse Events ............................................................................ 29 
9.1.1 
Definition of Adverse Events (AE) and Serious Adverse Events (SAE) ............... 29 
9.1.2 
Collection Period for AE and SAE Information ........................................................ 30 
9.1.3 
Time Period and Frequency for Event Assessment and Follow-Up...................... 31 
9.1.4 
Reporting and Monitoring of SAEs ........................................................................... 31 
9.1.5 
Events of Special Interest .......................................................................................... 32 
9.1.6 
Reporting of Pregnancy ............................................................................................. 32 
10 
STATISTICAL CONSIDERATIONS FOR PHASE 2 DESIGN ............................................................ 32 
10.1 
Statistical Hypotheses .................................................................................................................. 32 
10.2 
Primary Estimand .......................................................................................................................... 33 
10.3 
Sample Size Determination .......................................................................................................... 33 
10.4 
Populations for Analyses .............................................................................................................. 35 
10.5 
Statistical Analyses ....................................................................................................................... 35 
10.5.1 
Primary Efficacy Analysis .......................................................................................... 36 
10.5.2 
Analysis of Secondary Endpoints ............................................................................. 37 
10.5.3 
Analysis of Safety Endpoints..................................................................................... 37 
10.5.4 
Analysis of Exploratory Endpoints ............................................................................ 38 
10.5.5 
Exploratory Longitudinal Analyses ........................................................................... 38 
10.5.6 
Exploratory Bayesian Analyses ................................................................................ 38 
10.5.7 
Analysis of Treatment Effect Heterogeneity ............................................................ 39 
10.5.8 
Missing Data ............................................................................................................... 39 
10.5.9 
Planned Interim Analysis ........................................................................................... 39 
11 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 40 
11.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 40 
11.1.1 
Informed Consent Process ........................................................................................ 40 
11.1.2 
Study Discontinuation and Closure .......................................................................... 41 
11.1.3 
Confidentiality and Privacy ........................................................................................ 41 
11.1.4 
Key Roles and Study Governance ........................................................................... 41 
11.1.5 
Data and Safety Monitoring Board ........................................................................... 42 
11.1.6 
Clinical Monitoring ...................................................................................................... 42 

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11.1.7 
Quality Assurance and Quality Control .................................................................... 42 
11.1.8 
Data Handling and Record Keeping ......................................................................... 43 
11.1.9 
Protocol Deviations .................................................................................................... 43 
11.1.10 
Publication and Data Sharing Policy ........................................................................ 43 
11.1.11 
Conflict of Interest Policy ........................................................................................... 44 
11.2 
Abbreviations ................................................................................................................................. 44 
11.3 
Protocol Amendment History ....................................................................................................... 45 
12 
REFERENCES ........................................................................................................................................ 47 
13 
APPENDIX A (PAXLOVID PHASE 2) ................................................................................................... 50 
13.1 
Risk Assessment ........................................................................................................................... 50 
13.2 
Additional Appendix-level Exploratory Objective(s) ................................................................... 50 
13.3 
Additional Appendix-level Exclusion Criteria .............................................................................. 51 
13.4 
Additional Appendix-level Study Assessments .......................................................................... 51 
13.5 
PAXLOVID Information ................................................................................................................. 52 
13.5.1 
Precautions ................................................................................................................. 52 
13.5.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 53 
13.5.3 
Drug Dispensing, Storage, and Stability .................................................................. 53 
13.5.4 
Dosing and Administration ........................................................................................ 53 
13.5.5 
Rationale for Selection of Dose ................................................................................ 54 
13.6 
Control Information ........................................................................................................................ 55 
13.6.1 
Formulation, Appearance, Packaging, and Labeling .............................................. 56 
13.6.2 
Control Dispensing, Storage, and Stability .............................................................. 56 
13.6.3 
Dosing and Administration ........................................................................................ 56 
13.7 
Events of Special Interest ............................................................................................................. 57 
13.8 
Appendix Halting Rules ................................................................................................................ 58 
 
List of Tables 
Table 1. Summary of study objectives, endpoints, and outcome measures. ................................... 8 
Table 2. Schedule of study procedures............................................................................................... 19 
Table 3. CTCSQ items #1-13 and associated symptom cluster(s) ................................................. 25 
Table 4. Symptom cluster assessments schedule ............................................................................ 26 
Table 5. Minimum treatment effects for 80% or 90% power ............................................................ 34 
  
List of Figures 
Figure 1. Study schema for phase 2 study designs ............................................................................ 3 
Figure 2. Concise study schema ............................................................................................................ 4 
Figure 3. Symptom cluster assignment flow. ........................................................................................ 4 
Figure 4. Multiple testing flowchart ...................................................................................................... 36 
Figure 5. Effect of PAXLOVID (PF-07321332) on lung viral titers following oral administration in 
BALB/c mice infected with SARS-COV-2-MA10......................................................... 56 

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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonization Good Clinical 
Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the central Institutional Review Board (IRB) for review and approval. Approval of both the 
protocol and the consent form(s) must be obtained before any participant is enrolled. Any amendment 
to the protocol will require review and approval by the IRB before the changes are implemented to the 
study. In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1.1 
SYNOPSIS  
Title: 
RECOVER-VITAL: A Platform Protocol for Evaluation of Interventions for 
Viral Persistence, Viral Reactivation, and Immune Dysregulation in Post-
Acute Sequelae of SARS-CoV-2 Infection (PASC) 
Study Description: 
This study is a platform protocol designed to be flexible so that it is 
suitable for a wide range of settings within health care systems and 
community settings where it can be integrated into COVID-19 programs 
and subsequent treatment plans. 
 
This protocol describes a prospective, multi-center, multi-arm, double-
blind, randomized, controlled, platform trial, with different interventions 
organized as appendices to the protocol. Each appendix evaluates 
potential mechanisms of action, efficacy, and safety of antivirals and other 
therapeutics in individuals with PASC, according to the platform protocol 
objectives. The hypothesis is that persistent viral infection and/or 
overactive/chronic immune response and inflammation are underlying 
contributors to PASC and that antiviral and other applicable therapies may 
result in viral clearance or decreased inflammation and improvement in 
PASC symptoms. 
Objectives: 
 
Primary: Evaluate the effect of intervention(s) versus control on symptom-
specific patient-reported outcome measures within each PASC symptom 
cluster at Day 90 
Secondary: 
1. Evaluate the effect of intervention(s) versus control on 
performance-based outcomes within each PASC symptom cluster 

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2. Characterize the safety and tolerability of intervention(s) in PASC  
Exploratory: 
1. Investigate mechanisms of potential intervention (s) efficacy   
2. Compare the effect of intervention(s) on symptom burden and 
health related quality of life (HRQOL) versus control 
3. Evaluate the durability of intervention(s) response 
4. Evaluate intervention(s) effect on healthcare utilization 
5. Describe the effect of intervention(s) versus control across 
exploratory performance-based outcomes and patient reported 
outcomes (PROs) within each PASC symptom cluster 
6. Determine biomarkers associated with PASC symptom clusters and 
intervention-associated recovery 
Study Population: 
Each study intervention appendix will require approximately 900 evaluable 
adult participants who experience at least one of three predominant 
symptom clusters: cognitive dysfunction, autonomic dysfunction, or 
exercise intolerance. Overall enrollment for the platform protocol will 
depend on the number of screen failures, the number of study 
intervention appendices that are added, the ability to pool their control 
groups for analysis, and adjustments to sample size based on study data. 
 
An estimated sample size of approximately 900 evaluable participants per 
study intervention appendix is expected to be sufficient to provide 
adequate proof-of-concept that will enable optimal design and facilitate 
rapid transition to phase 3 trials for interventions that demonstrate 
preliminary evidence of benefit.  
 
The goal is to have a diverse population, including underserved 
communities and racial/ethnic populations frequently underrepresented 
in clinical research.  
Phase: 
Appendices including phase 2 and phase 3 studies 
Description of 
Sites/Facilities Enrolling 
Participants: 
Participants may be recruited from acute COVID-19 trials and existing 
RECOVER initiatives including, but not limited to, the longitudinal cohort, 
as well as research sites and communities. Approximately 100 sites in the 
US will participate. 
Description of Study 
Intervention: 
Each study intervention appendix describes a different study drug/drug 
combination/duration and control. The following arms will be included in 
each study appendix: 
• 
Study Drug Arm: study drug(s) of interest (intervention(s), see 
appendices) 
• 
Control Arm: control 
Participant Duration: 
The duration of dosing will depend on the intervention. Participants will be 
in the study for approximately 6 months from the time of initiating study 
drug administration until their end of study visit.  
 
 

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1.2 
SCHEMA FOR PHASE 2 STUDY DESIGNS 
 
 
Figure 1. Study schema for phase 2 study designs 
Underline in Figure 1 indicates an in-person visit; *Day 90 primary outcome assessment 
Participants can be 
included in multiple 
symptom clusters 

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Figure 2. Concise study schema 
Underline in Figure 2 indicates and in-person visit where study outcomes and other procedures will be 
assessed. 
 
 
 
 
Figure 3. Symptom cluster assignment flow.  
Participants who report having at least two moderate symptoms from the same symptom cluster or one 
severe symptom from the Cluster Targeted COVID-19 Symptom Questions (CTCSQ) will be screened for 
symptom clusters based on which symptoms are reported as moderate or severe. Arrows from 
symptom boxes to cluster boxes indicate which symptom clusters should be assessed based on the 
moderate or severe symptoms. Arrows from cluster boxes to assignment designation indicate the 
required scoring of the PRO in order to be assigned to the cluster. Participants may be screened for and 
assigned to multiple symptom clusters. 
 
 

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1.3 
KEY ROLES 
 
Platform Protocol Co-Chair/IND Sponsor:  
Kanecia Zimmerman, MD, PhD 
Appendix A Principal Investigator: 
Lindsey Baden, MD 
Platform Protocol Co-Chair: Richard Whitley, MD 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Post-acute sequelae of SARS-CoV-2 infection (PASC), also known as Long COVID, is a chronic condition 
present in up to 80% of SARS-CoV-2-infected, hospitalized patients and 40 to 70% of non-hospitalized 
patients with COVID-19.1-4 Symptoms of PASC can be debilitating. The personal and global impact of 
these long-term symptoms from SARS-CoV-2 infection can be devastating, and the number of Long 
COVID patients is escalating. With the increasing number of people infected with SARS-CoV-2, an urgent 
and unmet clinical need exists to better understand the pathophysiology of PASC and to develop 
targeted therapeutics to resolve the disease more rapidly and restore patients’ health. This study aims 
to investigate various interventions including antivirals, immunomodulatory agents, and other 
therapeutics or combinations thereof, and evaluate their use in treating PASC, including 1) mechanisms 
of potential efficacy, 2) safety and tolerability, 3) optimal outcomes and endpoints, and 4) preliminary 
efficacy. If successful, this trial will rapidly provide the foundational evidence for future phase 3 studies 
to further establish intervention efficacy in the PASC population.  
2.2 
BACKGROUND  
In 2019, a novel coronavirus-disease (COVID-19) emerged in Wuhan, China. A month later the Chinese 
Center for Disease Control and Prevention identified a new beta-coronavirus (SARS coronavirus 2, or 
SARS-CoV-2) as the etiological agent.5 The clinical manifestations of COVID-19 range from asymptomatic 
infection or mild, transient symptoms to severe viral pneumonia with respiratory failure.  
COVID-19 has led to the death of more than 6 million people worldwide; however, this disease has 
affected even more lives through often-debilitating symptoms lingering long after acute SARS-CoV-2 
infection. Post-acute sequelae of SARS-CoV-2 infection, also known as PASC, is a chronic condition that 
affects nearly every organ system, with more than 200 individual symptoms, ranging from new-onset 
anxiety, depression, and cognitive difficulties to shortness of breath, dizziness, and arrhythmias.6 
Moreover, PASC can occur regardless of severity of acute COVID-19 disease, and it impacts across 
socioeconomic, racial and ethnic, and age strata. These prolonged symptoms open the door for 
substantial short- and long-term individual and societal costs, including healthcare costs and inability to 
work. Prolonged symptoms have kept individuals out of work, which has exacerbated poverty in the 
underserved, historically minoritized populations and worsened a decades-long mental health crisis. 
Considering these costs, identification of safe and effective methods to treat and prevent the 
occurrence of PASC represents an urgent, unmet public health need.  
To address this need, the NIH has launched the RECOVER initiative across the nation (RECOVER: 
Researching COVID to Enhance Recovery) to better understand the disease. The RECOVER Initiative 
brings together patients, caregivers, clinicians, community leaders, and scientists from across the nation 
to understand, prevent, and treat PASC. The RECOVER Consortium represents and supports researchers 

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who are leading studies on PASC at more than 200 sites around the country. These studies have a 
diverse group of participants, including adults, pregnant people, and children. Data from the RECOVER 
initiative, as well as existing literature, have highlighted three predominant symptom clusters, including 
exercise intolerance with post-exertional malaise (PEM), cognitive dysfunction, and autonomic 
dysfunction, which are frequently reported and of substantial importance to patients. In addition, data 
have revealed substantial heterogeneity in symptomology and presentation, even among those within a 
specific symptom cluster, and in many cases the lack of concordance between objective findings and 
reported symptoms.6,7  
Emerging research is also beginning to identify risk factors for PASC. Women are disproportionately 
impacted by PASC relative to men at an approximately 3:1 ratio, with this sex difference appearing to 
fade in older individuals 60 to 70 years of age.8-10 Longitudinal, multi-omic profiling of COVID patients 
has revealed several anticipating risk factors for PASC at the time of diagnosis, including type 2 diabetes, 
SARS-CoV-2 RNAemia, Epstein-Barr Virus viremia, and autoantibodies.11 
Three etiologies have emerged as leading candidates for instigating the manifestations of PASC: 
disordered anticoagulation, immune dysregulation, and viral persistence/reactivation.12,13 In particular, 
prior investigators have demonstrated in preliminary data that SARS-CoV-2 can persist throughout the 
body for up to 230 days after acute infection14, and that viral RNA has been identified within the gut 
mucosa and plasma of the majority of patients with PASC, but not within those without PASC.15 Direct 
targeting of viral persistence, coagulation, and immune dysregulation with therapeutic agents warrants 
further investigation.  
Preliminary data suggest that antiviral treatment of those with lingering symptoms of COVID-19 beyond 
four weeks after acute infection can result in symptom improvement. In a cohort study of 29 adults with 
lingering symptoms ranging from fatigue to inappropriate tachycardia, and many with severely reduced 
functional status (48%) on a patient reported scale, 18 patients received antiviral therapy 
(lopinavir/ritonavir and hydroxychloroquine). A statistically significant improvement in functional status, 
defined as at least a one-point improvement on the functional scale, was observed at some point over a 
6-week period among those receiving treatment compared to those who did not. Half of the patients 
who received antiviral therapy had SARS-CoV-2 RNA detected at treatment initiation via RT-PCR in 
plasma; no SARS-CoV-2 was detected in the plasma of these 9 patients during the 1st week following 
treatment.16 While these data are promising, the heterogeneity and novelty of PASC, discordance 
between reported symptoms and objective findings,6,7,17 and lack of validated measures and endpoints 
specific to this disease process highlight the importance of studying antiviral and other therapies’ effects 
in the context of well-controlled clinical trials to ensure that optimal and appropriate therapies are 
made rapidly available for patients. The proposed clinical trials will evaluate potential mechanisms 
underpinning PASC and PASC improvement and test the utility of endpoints and outcome measures that 
have been well-established in other disease processes in the PASC population. In addition, collection of 
key biospecimens can assist in the development of biomarkers associated with PASC symptom clusters 
and response to therapy allowing a better understanding of pathogenesis and potentially targeted 
interventions. Phase 3 appendix trials will be sized to build on learnings from phase 2 trials to more 
definitively define drug efficacy for interventions that show promise in preliminary evaluations.  
 
 
 
 
 
 

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2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
 
Potential risks of this study include those associated with the specific study drug (refer to appendices for 
details), blood draws, nasal swabs, performance measures, and loss of confidentiality.  
 
Risks associated with blood draws include momentary discomfort and/or bruising. Infection, excess 
bleeding, clotting, or fainting are also possible, although unlikely. 
 
Risks associated with nasal swabs include mild irritation, insignificant local pain, and minor bleeding. 
 
Risks associated with the incremental and endurance shuttle walk tests (ISWT/ESWT) include tiredness, 
shortness of breath, or palpitations during or after the test. The active stand test and full autonomic 
testing may cause some participants to faint or feel lightheaded or weak. The cardiopulmonary exercise 
test may result in fatigue, shortness of breath, possible bronchospasm, cardiac arrhythmia, and/or 
syncope.  
 
There is also a risk of loss of confidentiality. However, coding all participant data with a unique 
identification number will minimize risk to loss of participant confidentiality.  
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Participants may benefit from the potential clearance of the viral infection or reduction in inflammation 
and improvement in PASC symptoms.  
 
Society in general and future patients infected with SARS-CoV-2 may benefit from the study’s results, 
which aim to provide a better understanding of the benefit/risk of antiviral or anti-inflammatory 
treatment for PASC and alleviation of PASC symptoms.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Potential benefits may outweigh potential risks. Post-acute sequelae of SARS-CoV-2 infection (PASC) is a 
significant health issue and can have consequences that impact quality of life. These consequences are 
extremely important for the individual and also impact the society at large. 
 
 
 

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3 
OBJECTIVES AND ENDPOINTS 
 
The objectives, outcome measures, and endpoints for the study are listed in Table 1, below. Further details 
on outcome measures and endpoints are provided in Section 10 and the Statistical Analysis Plan (SAP).  
Table 1. Summary of study objectives, endpoints, and outcome measures.  
OBJECTIVES 
OUTCOME MEASURES 
ENDPOINTS  
Primary 
Evaluate the effect of 
intervention(s) versus control 
on symptom-specific patient-
reported outcome measures 
within each PASC symptom 
cluster at Day 90 
Cognitive dysfunction 
symptom cluster: PROMIS – 
cognitive 8a 
Autonomic dysfunction 
symptom cluster: Orthostatic 
Hypotension Questionnaire 
(OHQ) 
Exercise intolerance symptom 
cluster: Modified DePaul 
Symptom Questionnaire-Post 
Exertional Malaise (DSQ-PEM)  
Primary endpoint: 
Meeting pre-specified change 
from baseline to Day 90 on 
cluster-specific PRO outcome 
(yes/no) 
 
Exploratory endpoint:  
PRO outcome at Day 90 
 
See Section 10.5.1 
 
Secondary 
Evaluate the effect of 
intervention(s) versus control 
on performance-based 
outcomes within each PASC 
symptom cluster 
Cognitive dysfunction 
symptom cluster: 
neurocognitive battery  
Autonomic dysfunction 
symptom cluster: active stand 
test 
Exercise intolerance symptom 
cluster: endurance shuttle walk 
test (ESWT)  
 
Primary endpoint:  
Meeting pre-specified change 
from baseline to Day 90 on 
cluster-specific performance 
outcome (yes/no) 
 
Exploratory endpoint:  
Performance outcome at Day 90  
 
See Section 10.5.2 
Characterize the safety and 
tolerability of intervention(s) in 
PASC 
• Serious adverse events 
(SAEs) 
• Events of Special Interest 
(ESIs)  
• Adverse events (AEs) 
• Adherence in intervention 
versus control  
• Occurrence of individual SAEs  
• Occurrence of any one or 
more SAE  
• Occurrence of AEs and SAEs 
leading to discontinuation 
• Occurrence and duration of 
ESIs 
• Number of missed doses 
(adherence) 
 
See Section 10.5.3 
Exploratory  
Investigate mechanisms of 
potential intervention(s) 
efficacy 
• Antigenemia (plasma spike 
protein antigen and other 
markers of viral persistence 
and reactivation) 
Change from baseline through 
end of study / final follow-up of 
the following: 

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OBJECTIVES 
OUTCOME MEASURES 
ENDPOINTS  
• Viral RNA in nasal swabs 
• Blood inflammatory markers  
• Coagulation markers  
• Endogenous and exogenous 
metabolites 
• Viral clearance, persistence, 
and recurrence 
• Immune dysfunction 
• Coagulation  
• Biologic system functioning 
 
See Section 10.5.4 
Evaluate intervention(s) effect 
on healthcare utilization 
Healthcare utilization, including 
medical visits and 
hospitalizations 
• Cumulative medical visits in 
intervention vs control 
• Cumulative hospitalizations in 
intervention vs control 
 
See Section 10.5.4 
Describe the effect and 
durability of intervention(s) 
versus control across 
performance-based outcomes 
and patient reported outcomes 
(PROs) within each PASC 
symptom cluster 
All symptom clusters:  
• PASC Symptom 
Questionnaire 
• PROMIS-29+2 
• Global impression of change 
Cognitive dysfunction 
symptom cluster:  
• PROMIS - cognitive 8a 
• ECOG 2 
Autonomic dysfunction 
symptom cluster:  
• COMPASS 31  
• OHQ  
• Full autonomic testing 
(select sites) 
Exercise intolerance symptom 
cluster: 
• DSQ-PEM 
• Cardiopulmonary exercise 
test (select sites) 
Outcome at Day 90 and End of 
Study  
 
See Section 10.5.4 
Determine biomarkers 
associated with PASC symptom 
clusters and intervention-
associated recovery 
Outcome measures may 
include: 
• Active viral replication 
• Cytokine levels 
• Immune profiling (B and T 
cell) 
• Sanctuary site assessment 
• Infecting SARS-CoV-2 
variant, impact SARS-CoV-2 
immune state at time of 
infection 
Change in biomarker levels 
correlated with clinical outcomes 
by PASC symptom cluster 
 
See Section 10.5.4 
 
 

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4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
This multi-center, multi-arm, master platform clinical trial protocol describes the overall design for 
prospective, double-blind, randomized, controlled trials that are described in appendices evaluating 
treatment of PASC in adults previously infected with SARS-CoV-2. Each appendix describes a sub-study 
that will evaluate interventions for PASC. The interventions may include different dosing durations or 
drug combinations for phase 2 or 3 investigation. Phase 2 appendices are designed to understand 
mechanisms of potential efficacy, safety and tolerability, and preliminary efficacy. Phase 3 appendices 
build upon the knowledge gained in phase 2 to more definitively evaluate the efficacy of interventions 
that show promise in Phase 2 trials. To decrease sample size, control participants may be pooled across 
appendices when appropriate. Rules for pooling data will be specified for each sub-study.  
 
Within each sub-study, participants will be eligible to participate in assessments for up to three 
symptom clusters: cognitive dysfunction, autonomic dysfunction, exercise intolerance with PEM. 
Multiple symptom clusters are noted by up to 60% of individuals (unpublished data). Study intervention 
appendices may be added or removed according to adaptive design and/or emerging evidence; refer to 
the protocol appendices for further information on each intervention.  
 
All participants will undergo blood draws to assess presence of virus and other biomarkers and report 
overall global health status and symptomatology as well as undergo organ-specific assessments, 
including PROs of functional status and objective assessments. Follow-up will be a combination of face-
to-face visits when necessary to obtain objective clinical assessments and phone calls to be mindful of 
the participant burden.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
Each intervention under this platform protocol will follow a double-blind, randomized trial design to 
compare one or more dose levels of the study intervention to control. Antiviral agents and other 
therapeutics of interest will be used. Additional interventions can be studied as new agents are available 
or as the understanding of the viral sanctuary sites and/or immune/inflammatory response is improved 
and favorable drug properties are discovered. Both phase 2 and phase 3 appendices will be incorporated 
into this platform to enable a more seamless transition from phase 2 to phase 3 trials for promising 
interventions by allowing phase 3 trials to take advantage of the phase 2 infrastructure for trial 
implementation. In some cases, incorporation of phase 2 and phase 3 appendices within a single 
protocol will also enable shared utilization of data across appendices.   
 
Phase 2 and 3 trials conducted under this platform master protocol will share major design elements 
such as inclusion criteria, dose levels, follow-up schedule, and study outcomes. Because phase 3 designs 
are expected to be refined based on phase 2 experience, some implementation differences may occur, 
for example:  
• 
Inclusion criteria. One or more symptom clusters may be dropped from phase 3 if phase 2 data 
suggest a lack of efficacy, insufficient volumes of eligible patients, or other factors that might 
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subgroups if exploratory phase 2 data reveal participant factors that strongly predict presence 
or absence of treatment benefit.  
• 
Dose levels. In general, each phase 3 study is expected to focus on a single intervention dose 
level. Phase 2 exploratory analyses will inform the selection of an optimal dose for phase 3 
evaluation.  
• 
Follow-up schedule. The duration and frequency of patient follow-up may be modified in light 
of phase 2 data. Factors to be considered include participant burden, patterns of missing data 
and drop out, fluctuations in symptoms over time, and uncertainty regarding the durability of a 
hypothesized treatment benefit.  
• 
Study outcomes. An outcome designated as secondary in the current protocol may be elevated 
to primary in phase 3 if phase 2 data suggest that it outperforms a current primary outcome as a 
meaningful and sensitive measure of treatment benefit.  
 
4.3 
JUSTIFICATION FOR DOSE 
 
The dose and duration of the intervention(s) will be based on the specific agent. Refer to the appendices 
for details.  
 
4.4 
END OF STUDY DEFINITION 
 
The End of Study will occur when all participants have completed their End of Study Visit.  
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. ≥ 18 years of age at the time of enrollment 
2. Previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan 
American Health Organization18ɸ 
ɸ Suspected and probable cases will only be allowed if they occurred before May 1, 2021, and will 
be limited to 10% of the study population. Otherwise, confirmed cases are required. Refer to the 
MOP for details.  
Suspected case of SARS-CoV-2 infection - Three options, A through C: 
A. A person who meets the clinical OR epidemiological criteria. Clinical criteria: Acute onset 
of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the 
following signs or symptoms: fever, cough, general, weakness/fatigue, headache, 
myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia. Epidemiological 
criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or 
B. Acute respiratory infection with history of fever or measured fever of ≥ 38°C; and cough; 
with onset within the last 10 days; and who requires hospitalization); or 
C. With no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive 
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Probable case of SARS-CoV-2 infection: 
A. A patient who meets clinical criteria above AND is a contact of a probable or confirmed 
case or is linked to a COVID-19 cluster. 
Confirmed case of SARS-CoV-2 infection - Two options, A through B: 
A. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR 
epidemiological criteria; or 
B. Meeting clinical criteria AND/OR epidemiological criteria (See suspect case A). With a 
positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test. 
3. At least two moderate symptoms from the same Symptom Cluster or one severe cluster-
associated symptom identified via the Cluster Targeted COVID-19 Symptom Questions (CTCSQ), 
see Section 8.10.3, with participant identifying new symptoms since COVID-19 illness and having 
persisted for at least 12 weeks19 
4. Meeting PRO Symptom Cluster criteria for at least one Symptom Cluster (See Section 8.10.4) 
5. Willing and able to provide informed consent, complete the surveys, clinical assessments, and 
return for all of the necessary follow-up visits 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study. 
Refer to appendices for additional appendix-level criteria: 
1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent 
2. Known severe anemia, defined as < 8 g/dL20 
3. Meeting the following symptom cluster exclusion for all eligible clusters#:  
a. Cognitive dysfunction: known stroke that resulted in cognitive impairment within 3 
months of enrollment 
b. Autonomic dysfunction: atrial fibrillation or significant cardiac arrhythmia, more than 
moderate alcohol consumptionɣ, pre-existing sustained severe hypertension (BP> 
180/110 mmHg in the sitting position) 
c. Exercise intolerance:  
i. any of the following within 4 weeks of consent - an acute myocardial 
infarction or unstable angina, uncontrolled arrhythmias causing symptoms or 
hemodynamic compromise, acute myocarditis or pericarditis, uncontrolled 
acutely decompensated heart failure (acute pulmonary edema), acute 
pulmonary embolism, suspected dissecting aneurysm, severe hypoxemia at 
rest, any acute or chronic disorder that may affect exercise performance  
ii. if they are aggravated by exercise (e.g., infection, thyrotoxicosis, unable to 
cooperate) 
#Participants who are eligible for > 1 cluster must meet all inclusion and no exclusion criteria for 
an individual symptom cluster. If not, they will be excluded from that individual symptom cluster.  
ɣ Defined as greater than 2 drinks a day for men and 1 drink a day for women. A drink is 
equivalent to 12 ounces of beer (5% alcohol content), 8 ounces of malt liquor (7% alcohol 
content), 5 ounces of wine (12% alcohol content), 1.5 ounces or a “shot” of 80-proof (40% alcohol 
content) distilled spirits or liquor (e.g., gin, rum, vodka, whiskey). 21 
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5. Any non-marijuana illicit drug use within 30 days of informed consent 
6. Current or recent use (within the last 14 days) of study intervention*  
7. Known allergy/sensitivity or any hypersensitivity to components of the study intervention (s) or 
control* 
8. Known contraindication(s) to study intervention(s),  
9. Inability to discontinue symptomatic medications for the identified time periods (See Section 
6.5.1)  
10. Moderate or severe immunocompromised patients, such as those described in the NIH COVID-19 
Treatment Guidelines (https://www.covid19treatmentguidelines.nih.gov/special-
populations/immunocompromised/) 
11. Enrolled into another study intervention appendix in this platform protocol$  
$Participants may re-enroll in the trial for a different study intervention appendix if they have 
completed an appropriate washout period and efficacy has been determined for the appendix in 
which they were previously enrolled. 
12. Any condition that would make the participant, in the opinion of the investigator, unsuitable for 
the study 
 
*If only one study intervention appendix is open at the time of enrollment. If multiple study intervention 
appendices are open, a participant may be excluded from any study intervention appendix based on 
contraindications listed in the study intervention appendix, current use of study intervention, or known 
allergy/sensitivity/hypersensitivity and still remain eligible for the remaining study intervention appendices. 
 
5.3 
SPECIAL CONSIDERATIONS FOR PARTICIPANT ENROLLMENT  
 
Participants will not be enrolled into a symptom cluster cohort for which they also meet symptom 
cluster specific exclusion criteria. Assessments for a symptom cluster will be performed among 
participants who meet the symptom cluster-specific eligibility criteria. Participants may meet eligibility 
criteria for more than one symptom cluster. In phase 2 appendices, they will undergo screening and post 
randomization assessments for all of the symptom clusters for which they qualify. In phase 3 
appendices, assignment to a symptom cluster may be more limited. Refer to appendices for details. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, and eligibility criteria.  
 
5.5 
STUDY DEFINITION OF ENROLLMENT 
For this study, enrollment is defined as signing consent and completing randomization.  
 

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5.6 
STRATEGIES FOR RECRUITMENT AND RETENTION 
The RECOVER Clinical Trial Data Coordinating Center (CT-DCC) will use an integrated strategy of 
coordinating with community organizations, the public, and clinical trial sites to identify and retain study 
participants. To ensure a diverse population is enrolled, strategies from prior successful initiatives will be 
refined and utilized. The study team will develop a comprehensive communication strategy involving 
print and social media, as well as leveraging existing organizational structures where possible, to 
educate the public on concerns about PASC and opportunities for clinical trial participation. Interested 
members of the public will be provided with information to contact a local site for potential 
participation.  
Participants can be recruited and identified through participating site outreach. Site investigators, or 
their designee, may contact eligible participants to introduce the study and discuss study participation.  
Participants may be recruited from other ongoing COVID-19 trials if they opted-in to be contacted about 
future research opportunities. Patient advocates that represent a diverse PASC community will be 
engaged in the study at every step. Patient advocates will serve as consultants to inform study design, 
protocol development, and recruitment and retention strategies.  
During active study, study sites will maintain close connections with study participants.  
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
See appendices. 
6.1.2 DOSING AND ADMINISTRATION 
 
See appendices.  
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Receipt and use of study drug will be handled, tracked by the sites, and stored in a safe, secure, and 
temperature-monitored location to which only the investigator and designated personnel have access. 
Use of study drug will be tracked by the sites. At minimum, the sites will check intervention adherence 
at the Drug Dosing Midpoint Clinic Visit to monitor compliance with study drug administration. 
Participants will also be asked to bring all unused drug with them to the clinic during their End of Dosing 
Visit.  

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See appendices for further details.  
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
See appendices.  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Upon receipt, study drug should be stored according to the instructions specified on the label. See 
appendices.  
 
6.2.4 PREPARATION 
 
See appendices.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
To achieve blinding and an equitable randomization probability, a two-step randomization process will 
be used.  
 
At the first step, each participant will be assigned with equal probability to one of the appendices for 
which the participant is eligible after applying any appendix-level exclusion criteria. At the second step, 
if the appendix includes 𝑘𝑘 dose levels of active intervention plus a control group, participants will be 
assigned with probability 1/(𝑘𝑘+ 1) to one of the  (𝑘𝑘+ 1) available treatment options.   
 
For simplicity, the text below assumes that 𝑀𝑀1 active appendices will have no sharing of control 
participants and that an additional 𝑀𝑀2 active appendices each involve a single intervention dose level 
and will use a single pooled control group among them. Let 𝑘𝑘𝑖𝑖 be the number of dose levels in the 𝑖𝑖-th 
appendix where no restriction is placed on 𝑘𝑘1, … , 𝑘𝑘𝑀𝑀1and 𝑘𝑘𝑀𝑀1+1 = 𝑘𝑘𝑀𝑀1+2 = ⋯= 𝑘𝑘𝑀𝑀1+𝑀𝑀2 = 1. 
Randomization will proceed as follows for a participant who is eligible for 𝑚𝑚1 of the 𝑀𝑀1 appendices with 
no sharing of controls and 𝑚𝑚2 of the 𝑀𝑀2 appendices with sharing of controls. At the first stage, the 
participant will be assigned with probability 1 (𝑚𝑚1 + 𝑚𝑚2)
⁄
 to one of the appendices for which the 
participant is eligible. If the randomly assigned intervention is unable to use a pooled control group, the 
second stage randomization will assign the participant with probability 1 (𝑘𝑘𝑖𝑖+ 1)
⁄
 to one of the 
available intervention groups, where 𝑖𝑖 denotes the randomly assigned appendix. If the randomly 
assigned intervention is one that will use a pooled control group, the second stage randomization will 
assign the participant to active intervention or control at an 𝑚𝑚2: 1 ratio, where 𝑚𝑚2 is defined above.  
 
Sites will be informed to which study intervention appendix the participant is randomized, but not 
whether they are allocated to one of the active intervention dose levels or control within that appendix. 
The participants and investigators will be blinded throughout the study.  
 
6.3.1 UNBLINDING 
 
For each sub-study, the participant, treating clinicians, and study personnel will remain blinded to study 
intervention versus control assignment until after the database is locked and blinded analysis for that 
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being used by another ongoing sub-study. Only the biostatistical team who is preparing closed interim 
reports will be unblinded. Specifically, study intervention/control will be dispensed with packaging and 
labelling that blinds treatment assignment. Unblinding will occur only if required for participant safety or 
treatment, at the request of the treating clinician. Refer to the Manual of Procedures (MOP) for further 
details. 
 
6.4 
STUDY INTERVENTION ADHERENCE 
 
Participants will be notified of the importance of completing the full treatment course.  
 
6.5 
CONCOMITANT THERAPY 
 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
relevant concomitant prescription medications, over-the-counter medications, and supplements. 
Baseline concomitant medications will include all concomitant therapies taken by the participant within 
14 days of informed consent. Concomitant medications will be reviewed through the End of Study.  
 
6.5.1 SYMPTOMATIC THERAPY 
 
Drugs administered for symptomatic treatment and initiated prior to screening may be continued as 
long as there is no contraindication due to drug-drug interaction with the study intervention and there is 
no change in dose or administration during the study period. Administration of the following therapies 
for each symptom cluster will be carefully documented and closely monitored during the study period 
because of the potential for changes in these therapies to alter study results:  
 
Cognitive dysfunction: prescribed or illicit stimulants, amantadine, N-methyl-D-aspartate receptor 
antagonists (e.g., memantine, dissociative drugs). 
 
Autonomic dysfunction: ephedrine, midodrine, amphetamine/attention deficit hyperactivity disorder 
medications, tricyclic antidepressants, florinef, sympathomimetics, Adderall, methylphenidate, 
atomoxetine, or other serotonin and norepinephrine reuptake inhibitors.  
 
Exercise intolerance: none 
 
6.5.2 RESCUE MEDICINE 
 
Participants who require a rescue medication to treat a non-study-related acute condition during the 
study period should proceed with treatment for the acute condition, as prescribed by their treating 
clinician. They may continue to receive study drug as long as the rescue medication is not listed as a 
contraindication in any of the active study appendices. If the rescue medication is contraindicated, the 
participant will discontinue the use of the study intervention, but will continue to be followed per the 
Schedule of Procedures (Table 2). These participants will be considered evaluable for the analysis.  
 
 
 

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7 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
 
7.1 
PARTICIPANT DISCONTINUATION FROM STUDY DRUG 
 
Discontinuation from study intervention does not mean discontinuation from the study, and remaining 
study procedures should be completed as indicated by the appendix protocol. If a clinically significant 
finding is identified after enrollment, such as changes from baseline, the investigator or qualified 
designee will determine if any change in participant management is needed.  
 
An investigator may discontinue a participant from the study intervention at their discretion, for any 
reason including, but not limited to, one of the following: 
 
• 
Significant study intervention non-compliance  
• 
If any clinical AE, laboratory abnormality, or other medical condition or situation occurs such 
that continued participation in the study or intervention would not be in the best interest of the 
participant 
• 
Confirmed new case of acute SARS-CoV-2 
Participants who discontinue due to an AE will be followed until resolution of the AE.  The reason for 
participant discontinuation from study intervention will be recorded on the CRF. Participants who are 
discontinued from the study intervention but not withdrawn from the study will continue to be followed 
for all study procedures. If a participant discontinues the study intervention, but does not withdraw 
consent, they will be followed for safety for at least 28 days after the final study intervention 
administration.  
7.2 
PARTICIPANT WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. The study 
team will attempt to determine a reason for withdrawal; however, participants are not obligated to 
provide a reason for withdrawal. If obtained, the reason for withdrawal will be recorded on the CRF. No 
further study procedures will be performed and no further data will be collected from the participant 
following study withdrawal. All of the data collected up until the time of withdrawal will be maintained 
in the study database and will be used as the participant’s data are evaluable for analysis.    
7.3 
LOST TO FOLLOW-UP 
 
Participants will be considered lost to follow-up if they fail to return for any scheduled visit and if they 
are unable to be contacted after multiple attempts and methods by the study site staff and/or a central 
search company.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant or next of kin (where possible, telephone calls and, 

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if necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record or 
study file.  
• 
Should the participant continue to be unreachable, after exhausting all methods, the participant 
will be considered to have withdrawn from the study with a primary reason of lost to follow-up. 
 
7.4 
STUDY HALTING RULES 
Study intervention dosing and enrollment will be temporarily suspended pending review of the Data and 
Safety Monitoring Board (DSMB) based on appendix-specific criteria. The DSMB recommendations will 
be considered by the NIH and the study Principal Investigator prior to making any decisions regarding 
study continuation or discontinuation.  
 
 

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8 
STUDY ASSESSMENTS AND PROCEDURES FOR PHASE 2 STUDY DESIGNS 
 
8.1 
SCHEDULE OF PROCEDURES  
Table 2. Schedule of study procedures 
 
Screening Baseline 
Drug Dosing 
Midpoint 
Clinic Visit 
End of 
Dosing 
Clinic Visit  
Follow-up  
Through day 179 
End of Study
Visit4 
PROCEDURE 
Day -14 to 
0 
Day -2 to 
0 
Refer to 
appendix1 
 
Day EOD + 
3 days 
Day 45 ± 
5 days 
Day 60 ± 
5 days  
Day 903 ± 
5 days  
Day 120 ± 5 
days 
Day 183 ± 7 
Days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PROMIS-29+2 
 
X 
Weekly2 
X 
Weekly2 Weekly2 
X 
Weekly2 
X 
PASC Symptom Questionnaire 
 
X 
Weekly2 
 
Weekly2 Weekly2 
 
Weekly2 
 
CTCSQ 
X 
 
 
X 
 
 
X 
 
X 
Performance Measure Symptom 
Cluster Assessment(s) (Table 4) 
 
X8 
 
X8 
 
 
X8 
 
 
ISWT (Exercise Intolerance Cluster 
Only) 
X8,9 
 
 
 
 
 
 
 
 
PRO Symptom Cluster Assessment(s) 
(Table 4) 
X 
 
Weekly2 
X 
Weekly2 Weekly2 
X 
Weekly2 
X 
Appendix-Level Eligibility Criteria 
X 
 
 
 
 
 
 
 
 
Pregnancy Test 
 
X 
 
 
 
 
 
 
 
Blood Collection5 
 
X 
X 
X 
X6 
X6 
X 
X6 
 
Nasal Swab 
 
X 
X7 
X7 
X6,7 
X6,7 
X7 
X6,7 
 
Stool Collection 
 
X 
 
 
 
 
X 
 
 
Height and weight 
 
X 
 
 
 
 
 
 
 
BP and Pulse (supine & standing) 
 
X 
 
X 
 
 
X 
 
 
Randomization  
 
X 
 
 
 
 
 
 
 
Study Drug Administration 
 
 
X 
 
 
 
 
 
 
SAEs, SUSARs 
 
X10 
X10 
X10 
X 
X 
X 
X 
X 
Healthcare Utilization 
 
 
X 
X 
 
 
X 
 
X 
ESIs 
 
 
X 
X 
X 
X 
X 
X 
X 
Drug Adherence  
 
 
X 
X 
 
 
 
 
 
Underlined visits must be done in-person. 
1In-clinic evaluation at the drug dosing midpoint, defined per appendix 
2Remote data collection approximately weekly during drug dosing and follow-up unless presenting to clinic for 
optional blood collection, as applicable. Participants will have 3 days to complete weekly assessments.  
3Primary endpoint assessment 
4End of Study Visit will occur by telephone 

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5 Blood for clinical laboratory assessments, mechanistic evaluation, and biorepository storage for future study will 
be collected at baseline, drug dosing midpoint, end of dosing, and day 90 for all participants.   
6Optional nasal swab and blood draws 
7Nasal swab for RAT and PCR  
8The DSQ-PEM must be completed remotely +1 to 2 days after any visit that includes Performance Measure 
Symptom Cluster Assessment(s) to assess PEM. 
9For participants who are considered for the Exercise Intolerance Symptom Cluster, the ISWT must be completed 
at an in-person screening visit that occurs at least 3 days before the Baseline Visit.  
10Non-serious AEs will be collected from the start of study drug administration through the EOD for select 
appendices. 
 
8.2 
SCREENING (DAY -14 TO 0) 
Information about the study will be presented to potential participants and questions will be asked to 
determine potential eligibility. Study-specific screening procedures will begin only after informed 
consent is obtained.   
Screening procedures may be done over one or two calendar days. However, in many cases (e.g., 
autonomic dysfunction and cognitive dysfunction symptom clusters) all the screening assessments can 
be done in < 24 hours.  If that is the case, baseline assessments, specimen collection, and the initial 
study product administration can occur on the same calendar day. 
After the informed consent, the following assessments will be performed at screening to determine 
eligibility: 
• 
Demographics 
• 
Medical History; including SARS-CoV-2 vaccination status and dates, SARS-CoV-2 test result date 
(if available), signs and symptoms, and treatment (including hospitalization, Intensive Care Unit 
(ICU) status, supplemental O2 status) and PASC history (symptoms and duration) 
• 
Collection of concomitant medications taken within 14 days of informed consent   
• 
CTCSQ  
• 
ISWT; for participants who are considered for the Exercise Intolerance Symptom Cluster, the 
ISWT must be completed at an in-person screening visit that occurs at least 3 days before the 
Baseline Visit. The DSQ-PEM must be completed remotely +1 to 2 days after the visit where 
ISWT is performed to assess PEM.  
• 
PRO Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom Cluster Assessments 
• 
Review appendix-level eligibility criteria, refer to appendices 
8.3 
BASELINE (DAY -2 TO 0) 
Baseline assessments will preferably occur on the same day as the first intervention administration and 
may occur on the same day as Screening. In the event that drug dosing does not begin on the same day 
as the Baseline visit, intervention administration must begin within 48 hours of baseline assessments. 
The following will occur at the Baseline visit:  
• 
Concomitant Medication review  

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• 
PROMIS-29+2 
• 
PASC Symptom Questionnaire 
• 
Performance Measure Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom 
Cluster Assessments. The DSQ-PEM must be completed remotely +1 to 2 days after the visit to 
assess PEM. 
• 
Pregnancy test, for individuals capable of becoming pregnant, blood or urine 
• 
Blood Collection for the following evaluations: 
o Local: Comprehensive metabolic panel (if not done within the past 3 months), high-
sensitivity c-reactive protein, D-dimer, coagulation panel (prothrombin time, activated 
partial thromboplastin time, thrombin time), complete blood count with differential (if 
not done within the past 3 months) 
o Send out: Mechanistic evaluation and biorepository storage for future investigation 
o Safety labs, per appendix (local) 
• 
Nasal Swab for SARS-CoV-2 rapid antigen test (RAT), completed locally, and polymerase chain 
reaction (PCR), completed at central lab 
• 
Stool Collection for mechanistic evaluation, processed at central lab 
• 
Height and Weight 
• 
Blood Pressure (BP) and Pulse, supine and standing 
• 
Randomization  
• 
Safety assessment including SAEs and suspected unexpected serious adverse reactions 
(SUSARs), non-serious AE from the start of study drug administration for select appendices 
8.4 
DRUG DOSING MIDPOINT CLINIC VISIT  
Study intervention dosing may begin on the same day as the Baseline Visit, but must occur within 48 
hours of baseline assessments. Refer to appendices for intervention-specific dosing duration.  
At approximately the midpoint of drug dosing, a Drug Dosing Midpoint Clinic Visit will occur. Refer to the 
appendices for the timing of the midpoint visit. At this visit, the following will occur: 
• 
Concomitant Medication review 
• 
Study drug administration, per study drug appendix 
• 
PROMIS-29+2, approximately weekly remotely outside of the in-person visit  
• 
PASC Symptom Questionnaire, approximately weekly remotely outside of the in-person visit 
• 
PRO Symptom Cluster Assessment(s), approximately weekly remotely outside of the in-person 
visit. Refer to Section 8.10.4 for Symptom Cluster Assessments 
• 
Blood Collection, for the following evaluations: 
o High-sensitivity c-reactive protein, D-dimer, coagulation panel (prothrombin time, 
activated partial thromboplastin time, thrombin time), complete blood count with 
differential (local) 
o Mechanistic evaluation  
o Safety labs, per appendix 

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• 
Nasal Swab for SARS-CoV-2 RAT, completed locally, and PCR, completed at central lab 
• 
Safety assessment including SAEs, SUSARs, and ESIs; non-serious AE for select appendices 
• 
Healthcare Utilization 
• 
Drug Adherence 
8.5 
END OF DOSING CLINIC VISIT (DAY END OF DOSING + 3 DAYS) 
The End of Dosing Clinic Visit will occur after the final intervention dose has been administered. The 
following will occur at the End of Dosing Clinic Visit: 
• 
Concomitant Medication review  
• 
PROMIS-29+2 
• 
PASC Symptom Questionnaire 
• 
CTCSQ  
• 
Performance Measure Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom 
Cluster Assessments. The DSQ-PEM must be completed remotely +1 to 2 days after the visit to 
assess PEM. 
• 
PRO Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom Cluster Assessments 
• 
Blood Collection, for the following evaluations: 
o High-sensitivity c-reactive protein, D-dimer, coagulation panel (prothrombin time, 
activated partial thromboplastin time, thrombin time), complete blood count with 
differential (local) 
o Mechanistic evaluation 
o Biorepository storage for future study  
o Safety labs, per appendix 
• 
Nasal Swab for SARS-CoV-2 RAT, completed locally, and PCR, completed at central lab 
• 
Blood Pressure (BP) and Pulse, supine and standing 
• 
Safety assessment including SAEs, SUSARs, and ESIs; non-serious AEs for select appendices 
• 
Healthcare Utilization 
• 
Drug Adherence evaluation based on any doses returned at this visit 
8.6 
FOLLOW-UP [END OF DOSING (+3 DAYS) TO DAY 179] 
The Follow-Up Period will begin after the End of Dosing Clinic Visit. A follow-up clinic visit will occur for 
all participants on Day 90 (± 5 days). All assessments required for the Day 90 visit will occur at the Day 
90 (± 5 days) in-person visit; any assessments completed remotely during the week of the Day 90 visit 
cannot replace the in-person Day 90 assessments. All participants will receive remote follow-up 
approximately weekly with optional in-person visits for blood collection on Days 45 (± 5), 60 (± 5), and 
120 (± 5) days. All assessments that are completed remotely on a weekly basis will be open to the 
participant to complete for 3 days. Any assessments that are not completed within that window will 
expire and will not be collected. The following assessments will occur as part of follow-up: 
• 
Concomitant Medication review  

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• 
PROMIS-29+2  
• 
PASC Symptom Questionnaire + global health question #13 from the CTCSQ 
• 
CTCSQ (Day 90 only) 
• 
PRO Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom Cluster Assessments 
• 
Performance Measure Symptom Cluster Assessment(s). Refer to Section 8.10.4 for Symptom 
Cluster Assessments (Day 90 only). The DSQ-PEM must be completed remotely +1 to 2 days 
after the visit to assess PEM. 
• 
Blood Collection, for the following evaluations:  
o High-sensitivity c-reactive protein, D-dimer, coagulation panel (prothrombin time, 
activated partial thromboplastin time, thrombin time), complete blood count with 
differential (local, Day 90 only) 
o Mechanistic evaluation (required on Day 90, optional on Day 45, 60, and 120) 
o Biorepository storage for future study (required on Day 90, optional on Day 45, 60, and 
120) 
o Safety labs, per appendix (local, Day 90 only) 
• 
Nasal swab for SARS-CoV-2 RAT, completed locally, and PCR, completed at central lab (required 
on Day 90, optional on Day 45, 60, and 120) 
• 
Stool Collection (Day 90 only), processed at central lab 
• 
Blood Pressure (BP) and Pulse, supine and standing (Day 90 only) 
• 
Healthcare Utilization (Day 90 only) 
• 
Safety assessment including SAEs, SUSARs, and ESIs 
8.7 
END OF STUDY VISIT (DAY 183 ± 7 DAYS) 
The End of Study Visit will be a remote visit. The following will occur at the End of Study Visit: 
• 
Concomitant Medication review  
• 
PROMIS-29+2 
• 
CTCSQ  
• 
PRO Symptom Cluster Assessment(s) based on participant cluster assignment. Refer to Section 
8.10.4 for Symptom Cluster Assessments 
• 
Healthcare Utilization 
• 
Safety assessment including SAEs, SUSARs, and ESIs 
8.8 
OPTIONAL BLOOD COLLECTION/NASAL SWAB VISITS 
Participants will be asked to attend optional Follow-up Visits that include blood collection and nasal 
swabs at Days 45 (± 5 days), 60 (± 5 days), and 120 (± 5 days).  Participants opting to attend these 
optional visits will be compensated for their time and effort. 
 
 

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8.9 
CLINICAL LABORATORY ASSESSMENTS 
A comprehensive metabolic panel, high-sensitivity c-reactive protein, D-dimer, coagulation panel 
(prothrombin time, activated partial thromboplastin time, thrombin time), complete blood count with 
differential will be completed as local laboratory assessments at baseline, the drug dosing midpoint 
clinic visit, the end of dosing clinic visit, and at the day 90 follow-up visit. 
For the baseline clinical laboratory assessments, if a participant has these laboratory assessments 
available within 3 months of study enrollment, they do not need to be repeated as part of the study. 
Additional clinical laboratory assessments may be required per appendix, refer to appendices.  
The SARS-CoV-2 RAT will also be completed locally according to the timepoints indicated in Table 2. 
8.10 STUDY ASSESSMENTS  
 
8.10.1 BIOSPECIMEN COLLECTION  
Because a primary focus of this protocol will be to investigate mechanisms underlying PASC and 
improvement with antivirals and other therapies, select biomarkers will be evaluated over time among 
those who receive intervention or control. These biomarkers are targeted towards the leading 
hypotheses for PASC pathogenesis, including viral persistence/reactivation, immune dysregulation, and 
dysregulation of coagulation and will be obtained from blood (~80 ml), stool, and nasal swabs.  
Biomarkers will be collected at various time points that will enable the understanding of potential 
improvement with therapy and rebound, and will be collected at similar time points as PROs and other 
assessments in order to understand the relationship between the biomarkers and clinical findings.  
At minimum, the following biomarkers will be assessed: 
• 
Antigenemia (SARS-CoV-2 antigens), including the S1 subunit of spike, full length spike, and 
nucleocapsid in plasma 
While some important biomarkers will be known at the time of participant enrollment and assays will be 
available, others may not. In addition to biomarkers, peripheral blood mononuclear cells will be 
collected at select sites. Samples collected throughout the course of this study will be stored at the 
RECOVER Biorepository, which is designed to collect and store biospecimens for future research related 
to the various studies of the RECOVER Program. Samples from biorepositories have proven to be 
enormously important in the last 20 years, as information on the components of blood has expanded 
rapidly. Important insights have been gained from biorepository samples from clinical trials and the 
stored samples from the RECOVER Program will prove equally productive and important. This 
biorepository will be conducted under the coordination of the Duke Clinical Research Institute (DCRI) 
which serves as the CT - DCC for all RECOVER clinical trials.  
Samples will be collected for storage at -80°C and will be stored at the Biorepository in a lab at the Mayo 
Clinic in Rochester, MN for up to 7 years. 

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8.10.2 PROMIS-29+2 (PROPR) 
Patient-Reported Outcomes Measurement Information System (PROMIS-29) global health scale: The 
PROMIS was developed out of the “Roadmap for Medical Research” created by the NIH in 2002 as valid, 
generalizable items to standardize clinical research across NIH-funded research dealing with PROs. 
Multiple PROMIS scales have been validated across many clinical populations.22 The PROMIS-29 consists 
of 29 items that assess general domains of health and functioning, including overall physical health, 
mental health, social health, pain, fatigue, and overall perceived quality of life. The PROMIS global 
health scales has been correlated against the EuroQol EQ-5D. 23 Additionally, PROMIS scales have been 
used with PASC patients.24 
The PROMIS-29+2 is used to calculate a preference score (PROPr) by the addition of two Cognitive 
Function Ability items. Preference-based scores provide an overall summary of HRQOL on a common 
metric. Preference-based scores summarize multiple domains on a metric ranging from 0 (as bad as 
dead) to 1 (perfect or ideal health). Scores can be used in comparisons across groups and for cost-utility 
analyses. 25 
8.10.3 CLUSTER TARGETED COVID-19 SYMPTOM QUESTIONS (CTCSQ) 
 
The CTCSQ is a set of thirteen questions with the first twelve items rated none, mild, moderate, or 
severe. The final item is a global symptom question. Participants must report having at least two 
moderate symptom(s) from the same Symptom Cluster or one severe symptom in order to meet 
eligibility criteria. If a participant reports a moderate or severe item #1-3, they will complete the 
exercise intolerance and autonomic dysfunction cluster assessments at Baseline. If a participant reports 
a moderate or severe item #4-8, they will complete the autonomic dysfunction cluster assessments at 
Baseline. If a participant reports a moderate or severe item #9-12, they will complete the cognitive 
dysfunction cluster assessments at Baseline. Item #13 is not associated with specific symptom clusters 
and will not have any influence on symptom cluster assignment. After cluster assignment, the CTCSQ 
will not result in any alterations to cluster assignment, but will be used as a symptom tracking tool.  
Table 3. CTCSQ items #1-13 and associated symptom cluster(s) 
Please rate the level of 
severity you experienced of 
the following symptoms in 
the last 7 days: 
None 
Mild 
Moderate 
Severe 
Associated 
Symptom 
Cluster 
1. Fatigue (being tired) 
 
 
 
 
Exercise 
Intolerance/ 
Autonomic 
Dysfunction 
2. Post-exertional malaise 
(symptoms worse after 
even minor physical or 
mental effort) 
 
 
 
 
3. Weakness in your arms 
and/or legs 
 
 
 
 
4. Pain in your limbs 
 
 
 
 
Autonomic 
Dysfunction 
 
5. Faintness (light-
headedness) 
 
 
 
 
6. Gastrointestinal upset  
 
 
 
 
7. Color changes of the skin  
 
 
 
 

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8. Dry mouth  
 
 
 
 
9. Problems with thinking 
or concentrating (brain 
fog)  
 
 
 
 
Cognitive 
Dysfunction 
10. Confusion 
 
 
 
 
11. Forgetfulness  
 
 
 
 
12. Difficulty focusing  
 
 
 
 
GLOBAL QUESTION 
Improved a 
lot 
Improved 
somewhat 
Stayed 
about the 
same 
Worsened 
somewhat 
Worsened a 
lot 
13. Compared to the start 
of the study, the overall 
severity of your Long 
COVID symptoms have: 
 
 
 
 
 
 
8.10.4 SYMPTOM CLUSTER ASSESSMENT 
 
As part of screening, potential participants will answer the CTCSQ. Eligible participants will complete 
Symptom Cluster assessments based on their CTCSQ responses (see Table 3) and will subsequently be 
assigned to one or more of the three Symptom Clusters based on the baseline assessments. Participants 
must meet criteria for the PRO within a specific symptom cluster in order to be included in the cluster, 
see italicized text within each cluster for inclusion reference points. After study enrollment and initial 
cluster assignment, further assessments will be performed among participants who meet the symptom 
cluster criteria. Participants whose answers qualify them for additional screening for multiple Symptom 
Clusters will undergo assessments for those Symptom Clusters. Refer to Figure 3.  
Table 4. Symptom cluster assessments schedule 
 
Screening Baseline 
Drug 
Dosing 
End of Dosing 
Clinic Visit 
Follow-up 
Through day 179 
End of Study 
Visit 
 
PROCEDURE 
Day -7 to 0 Day -2 to 
0 
Day 0 to 
EOD 
Day EOD + 3 
days 
Day 45 ± 
5 days 
Day 60 ± 
5 days  
Day 90 ± 
5 days  
Day 120 ± 
5 days 
Day 183 ± 7 
Days 
 
DSQ-PEM (+1 to 2 days 
following visit where 
Performance Measures 
are completed) 
 
X 
 
X 
 
 
X 
 
 
All 
Clusters 
DSQ-PEM 
X 
X 
Weekly1 
 
Weekly2 
X 
Exercise 
Intolerance 
ISWT 
X 
 
 
 
 
 
 
 
 
ESWT 
 
X 
 
X 
 
 
X 
 
 
Cardiopulmonary test 
(select sites) 
 
X 
 
X 
 
 
X 
 
 
PROMIS-Cognitive 8a 
X 
 
Weekly1 
 
Weekly2 
X 
Cognitiv
e 
Dysfunc
ECOG 2 
X 
 
Weekly1 
 
Weekly2 
X 
Neurocognitive battery 
 
X 
 
X 
 
 
X 
 
 
COMPASS 31 
X 
 
Weekly1 
 
Weekly2 
X 
Aut
ono
mic 
OHQ 
X 
 
Weekly1 
 
Weekly2 
X 

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Active Stand Test 
 
X 
 
X 
 
 
X 
 
 
Full Autonomic Testing 
(select sites) 
 
X 
 
X 
 
 
X 
 
 
1Must also be completed at the Drug Dosing Midpoint Clinic Visit 
2Must also be completed at the Day 90 ± 5 days in-person visit 
• 
Cognitive dysfunction:  
o PROMIS – cognitive 8a26 (PRO assessment). Part of the PROMIS test battery, the 
cognitive function is a quantitative measure of current cognitive function. A PROMIS – 
cognitive 8a function T-score < 40 will include a participant in this cluster and trigger 
other baseline assessments listed below.  
o ECOG 2 (PRO assessment). The Everyday Cognition 2 is a self-report, 41-item 
questionnaire used to measure the participant’s perceived capacity to perform activities 
related to cognitive function, which could impact major activities of daily living and 
independence. It has been used for patients with mild cognitive impairment, 
Alzheimer’s Disease, and dementia. It takes approximately 15 minutes to complete. 
o Neurocognitive battery (performance measure) to assess various elements related to 
cognition. The neurocognitive battery consists of a cognitive assessment sequence of 
the following: WHO/UCLA Auditory Verbal Learning Test (WHO/UCLA AVLT) and Symbol 
Digit Modalities Test. The entire battery takes approximately 30 minutes to complete.   
• 
Autonomic dysfunction:  
o COMPASS 3127 (PRO assessment). COMPASS 31 is a measure of autonomic symptoms 
across multiple domains commonly seen in patients with PASC. A COMPASS 31 score ≥ 
25 in combination with OHQ requirements will include a participant in this cluster. 
o Orthostatic Hypotension Questionnaire (OHQ) [PRO assessment]. The OHQ is a measure 
of orthostatic intolerance, which has been the primary presentation of patients with 
PASC-related autonomic dysfunction. This measure includes the Orthostatic Intolerance 
Daily Activity Scale (OIDAS) and the Orthostatic Intolerance Symptom Assessment 
(OISA), and prior data in patients with PASC suggests that this measure well-
discriminates those with symptoms compared to healthy controls. For this study and to 
reduce participant burden, the participants will be asked to complete the OIDAS and to 
rate only their most severe symptom on the OISA each time they complete the OHQ. At 
each visit where the OHQ is conducted, participants will complete the OHQ at the start 
of the visit and then repeat it at approximately 30 minutes after completing all other 
visit activities. A value ≥ 4 on question 1 of the OISA of the OHQ in combination with 
COMPASS 31 requirements will include a participant in this cluster. 
o Active stand test (performance measure). The active stand test is a well-characterized 
measure of short-term neurologic and cardiovascular function that requires limited 
resources and aids in diagnosis of patient symptoms of orthostatic intolerance.  
o Full autonomic testing (exploratory performance measure) consists of two 
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maneuver, and a head up tilt test and will be completed at select sites. The entire 
battery takes approximately 90 minutes to complete.   
• 
Exercise intolerance:  
o The Modified DePaul Symptom Questionnaire Post Exertional Malaise (DSQ-PEM) PRO 
assessment.28 Some patients have experienced debilitating PEM that may occur 
following exertion or on the day after exertion. To assess PEM, the DSQ-PEM short form 
will be adapted. This scale assesses symptom frequency and severity over a 6-month 
look back period; however, for the purposes of this study, it will be modified to assess 
over a 1-week look back period. It was previously validated in patients with myalgic 
encephalomyelitis/chronic fatigue syndrome. Frequency is rated on a 5-point Likert 
scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of 
the time, and 4 = all of the time. Severity is also rated on a 5-point Likert scale: 0 
= symptom not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe. Post-
Exertional Malaise (PEM) will be deemed to be present for participants reporting at least 
one moderate (rated severity ≥ 2) PEM symptom for a frequency rated ≥ 2. At least one 
moderate symptom (severity ≥ 2, frequency ≥ 2) on the DSQ-PEM in questions 1-5 will 
include a participant in this cluster and trigger other baseline assessments listed below. 
o Endurance shuttle walk test (performance measure). The ESWT consists of timed 
walking on a 10 meter course.29  The result is expressed as total walking time after an 
initial 2-minute warm-up. In order to determine walking speed, the baseline ESWT will 
be performed in combination with the ISWT.30 Walking speed for the ISWT will increase 
every minute until the participant is too breathless or fatigued to continue walking at 
the required speed. The ESWT will then be performed as 85% of the maximum walking 
speed achieved on the ISWT.29  
o Cardiopulmonary exercise testing (exploratory performance measure) will be completed 
at select sites. This is an exercise test that measures exercise abilities. The test involves a 
2 to 3-minute warm-up, followed by 8 to 12 minutes of progressively harder work on a 
treadmill or stationary bike. The goal is to exercise until the participant is no longer able 
to continue. The final outcome for this measure will be the maximum rate of oxygen 
consumption (VO2 max). 
• 
All Clusters 
o The DSQ-PEM will be performed remotely approximately 1-day (+1 day) after 
assessment of Performance Measures. For the purposes of assessing PEM related to the 
specific activity, it will be modified to assess PEM related specifically to the activity that 
occurred the previous day. 
Each assessment will occur according to Table 2 and Table 4. Procedures may be completed during the 
study as part of regular standard of clinical care. Training to standardize these assessments will be 
provided to participating sites by the RECOVER CT-DCC and protocol study teams.  
 
 
 
 

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8.10.5 PASC SYMPTOM QUESTIONNAIRE 
 
Participants will be asked to complete a questionnaire that asks about the presence of PASC symptoms.  
This questionnaire includes additional symptoms that are not directly related to the Symptom Clusters 
in this study.  
 
 
9 
SAFETY ASSESSMENTS AND REPORTING 
 
9.1 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
9.1.1 DEFINITION OF ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)  
 
An AE is any untoward medical occurrence in humans, whether or not considered drug-related, which 
occurs during the conduct of a clinical trial. An AE can therefore be any change in clinical status, routine 
labs, x-rays, physical examinations, etc., that is considered clinically significant by the study investigator.  
An SAE or serious suspected adverse reaction (SAR) or serious adverse reaction, as determined by the 
investigator or the sponsor, is an AE that results in any of the following serious outcomes:  
• 
Death  
• 
Life-threatening AE (“life-threatening” means that the study participant was, in the opinion of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred and 
required immediate intervention)  
• 
Persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
Congenital abnormality or birth defect  
• 
Important medical event that may not result in one of the above outcomes, but may jeopardize 
the health of the study participant or require medical or surgical intervention to prevent one of 
the outcomes listed in the above definition of serious event 
Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline does 
not meet the definition of an SAE. Hospitalization is defined as a stay in the hospital exceeding 24 hours.  
An unexpected AE is defined as any AE, the specificity or severity of which is not consistent with the 
study drugs’ package insert or investigators brochure. 
An unanticipated problem involving risk to participants or non-participants, including an environmental 
exposure and exposure to a breastfeeding infant, will be reported to the sponsor and the site IRB and 
central IRB, as appropriate. The event occurring in the non-participant will not be entered into the 
electronic data capture (EDC) system. Refer to the MOP and/or Safety Management Plan (SMP) for 
details.  
Medication errors with the study drug(s) resulting in an SAE are reportable. The medication error will be 
captured as a protocol deviation and the SAE captured on the SAE electronic case report form (eCRF).   
 
 

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9.1.2 COLLECTION PERIOD FOR AE AND SAE INFORMATION 
 
Safety event collection will occur at the pre-specified study visits but all participants will be instructed to 
self-report concerns by calling the site.  
Serious adverse events (SAEs) or ESIs (per appendix) will be extracted by site personnel from the 
participant’s medical record if the participant seeks medical care or if hospitalization occurs, each of 
which notifies the site to conduct follow-up.  
Medical occurrences that begin before the first invasive study procedure (blood collection or nasal 
swab), but after obtaining informed consent, will not be considered an AE. The medical occurrence or 
condition will be captured on the Medical History eCRF. 
Non-serious AEs that result in study drug discontinuation will be identified as the reason for study drug 
discontinuation within the study database, reported as an AE and collected from the start of study drug 
administration through the end of study drug dosing.  Each study drug appendix will identify whether 
additional non-serious AEs require collection and reporting such as spontaneously reported non-serious 
AEs by the participant at clinic visits that occur during the dosing period, but do not result in study drug 
discontinuation. There is no expectation nor plan by the site nor the DCC to reconcile AEs reported by 
the participant with the patient reported outcome survey.  
Serious adverse events (SAEs) will be collected from the first invasive study procedure (blood collection 
or nasal swab) through the End of Study Clinic Visit (Day 183 ± 7 days).  
Adverse events (AEs) that qualify as an ESI, even if a non-serious AE, will be collected from the start of 
study drug administration through the End of Study Clinic Visit (Day 183 ± 7 days). 
9.1.2.1 SEVERITY OF EVENT 
 
For reportable events, the following guidelines will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating. Of note, the term “severe” does not necessarily equate to “serious” for 
regulatory reporting 
 
9.1.2.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All reportable events must have their relationship to the study intervention assessed by the clinician 
who examines and evaluates the participant based on temporal relationship and his or her clinical 
judgment. The degree of certainty about causality will be graded using the categories below. In a clinical 
trial, the study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
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intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established 
9.1.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE, ESI, or SAE may come to the attention of study personnel during study visits 
and interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All reportable events will be captured on the appropriate CRF. Information to be collected includes 
event description, date/time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), action taken with study 
drug (e.g. study drug discontinuation), and date/time of resolution/stabilization of the event. All events 
occurring within the pre-specified reportable time windows must be documented appropriately 
regardless of relationship.  
 
Any medical condition that is present at the time the participant is screened will be considered as 
baseline and not reported as a safety event. However, if the participant’s condition deteriorates at any 
time during the study, it will be recorded as a safety event.  
 
Changes in the severity of a safety event will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. Safety events characterized as intermittent require 
documentation of onset and duration of each episode. 
The investigator will follow all SAEs until resolution, stabilization, or the event is otherwise explained. 
The DCRI Safety Surveillance Team will follow all SAEs until resolution, stabilization, or until otherwise 
explained. 
9.1.4 REPORTING AND MONITORING OF SAES 
All of the study drugs used in this platform protocol will be under an IND and subject to IND regulations 
in 21 CFR 312 since their investigational use for treatment of PASC is not an approved indication. The 
IND sponsor, DSMB, or Study Medical Monitor will review aggregate safety data. The IND sponsor will be 
responsible for determining if the safety reporting criteria are met per 21 CFR 312.32(c)(1)(i)(C) and 21 
CFR 312.32(c)(1)(iv) and will notify the CT-DCC to prepare an aggregate report for submission to the 
FDA. An aggregate safety report will be submitted to FDA as soon as possible, but in no case later than 
15 calendar days after the IND sponsor determination. If the IND sponsor determines that an 
unexpected fatal or life-threatening SAR occurs markedly more frequently in a study drug arm than in 
the control arm, an aggregate safety report will be submitted to the FDA as soon as possible, but in no 
case later than 7 calendar days after the IND sponsor determination. Information on individual SAEs will 
be available upon request from the FDA following the submission of any aggregate reports. 
Individual SAEs must be entered into the data system within 24 hours of site awareness. The DCRI Safety 
Surveillance team will notify pharmaceutical partners of SAEs within 1 to 2 business days of their receipt 
that occur involving the specific appendix of the supplied study drug/control, as required. Serious 
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sponsor will be reported to the FDA as SUSARs; as 7-day reports for unexpected fatal or life-threatening 
adverse reactions and 15-day reports for serious and unexpected adverse reactions. The SUSARs will be 
shared with the pharmaceutical partner of the supplied study drug according to the same timelines. If 
the IND sponsor, DSMB, or FDA note a clinically important increase in the rate of a SUSAR, the IND 
sponsor or designee will notify investigators no later than 15 calendar days after determining that the 
information qualifies for reporting. The investigators will notify their local IRB according to local 
guidelines if applicable. The CT-DCC will notify the central IRB. Refer to the Safety Management Plan for 
details regarding specific reporting timelines.  
Investigators are not obligated to actively seek information on AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has completed the study (but before the study itself has ended), and they 
consider the event to be reasonably related to the study intervention, the investigator must promptly 
report the SAE to the sponsor via EDC entry.  
9.1.5 EVENTS OF SPECIAL INTEREST  
Each study drug may have a unique list of ESIs. Refer to the relevant Appendix. 
9.1.6 REPORTING OF PREGNANCY  
 
Pregnancies that occur following the first study drug administration while on-study will be collected. If 
included in the study drug appendix that pregnant participants are excluded, the participant will be 
advised to discontinue study drug(s). Pregnancies will be followed until pregnancy outcome unless the 
participant refuses to provide consent. Pregnant participants will be asked to complete a pregnancy-
specific consent form if the final outcome of the pregnancy is not reached while the participant is on-
study. Any pregnancy-associated ESI or SAE should be reported if information can be collected and 
entered into the CRF. The DCRI Safety Surveillance team will notify study drug supplying partners of a 
pregnancy within 1 to 2 business days after learning about the pregnancy, as required. 
 
 
10 STATISTICAL CONSIDERATIONS FOR PHASE 2 DESIGN 
 
10.1 STATISTICAL HYPOTHESES 
 
Primary Endpoint: 
• 
Improvement in symptom cluster-specific patient-reported outcome measures, including the 
DSQ-PEM, PROMIS-cognitive 8a, or OHQ at Day 90 compared to baseline in intervention(s) vs. 
control 
 
For each pairwise comparison between an intervention and control group, the primary null hypothesis 
to be tested is that the probability of meeting a specified degree of improvement in symptom cluster-
specific primary outcome measures (including the DSQ-PEM, PROMIS-cognitive 8a, or OHQ) at Day 90 
compared to baseline is the same for intervention and control. The alternative hypothesis is that the 
probability of meeting a specified degree of improvement in symptom cluster-specific primary outcome 
measures at Day 90 compared to baseline differs for intervention and control. If 𝜋𝜋𝐷𝐷 denotes the 

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probability of improvement if randomized to intervention and 𝜋𝜋𝐶𝐶 denotes probability of improvement if 
randomized to control, then the primary null and alternative hypotheses may be expressed as follows: 
𝐻𝐻0: 𝜋𝜋𝐷𝐷−𝜋𝜋𝐶𝐶= 0     versus     𝐻𝐻1: 𝜋𝜋𝐷𝐷−𝜋𝜋𝐶𝐶≠0.  
 
Secondary:  
• 
Improvement in performance-based outcomes, including the ESWT, active stand test, and/or 
neurocognitive battery in intervention(s) vs. control  
• 
intervention(s) are safe in the PASC population 
 
The null hypothesis to be tested is that there is no difference between intervention and control group. 
 
Exploratory:  
• 
Improvement in viral, immune, and other mechanistic biomarkers over the course of the study 
in intervention(s) vs. control 
 
The null hypothesis to be tested is that there is no difference between intervention and control group. 
 
10.2 PRIMARY ESTIMAND 
 
A separate pairwise comparison between intervention and control will be performed for each 
combination of study appendix, dose level, and symptom cluster. For each of these, the primary 
estimand will be the intention-to-treat treat between-group difference in marginal probabilities of 
improvement, defined as 
ΔITT = 𝑃𝑃(𝑌𝑌= 1|𝐴𝐴= 1) −𝑃𝑃(𝑌𝑌= 1|𝐴𝐴= 0), 
where 𝑌𝑌 denotes the primary outcome (1 = improvement, 0 = no improvement) and 𝐴𝐴 denotes 
randomization assignment (1 = active treatment, 0 = control). This quantity will be estimated without 
regard to adherence and will implicitly average over observed patterns of concomitant therapies. In the 
unlikely event that follow-up data collection is prevented by death or hospitalization, the participant will 
be classified as not improving. The trial's SAP will provide further clarification of Δ𝐼𝐼𝑇𝑇𝑇𝑇 and may specify 
additional secondary and supplementary estimands, for example, the hypothetical ideal between-group 
difference that would be observed in a setting of high treatment adherence. 
 
10.3 SAMPLE SIZE DETERMINATION 
 
This study uses an adaptive platform trial design that will allow study interventions to be added or 
dropped from consideration based on accruing evidence of futility or efficacy. In such a design, the 
required sample size depends on both the number of interventions tested and the ability to pool their 
control arms for analysis. Initial sample size estimates are based on a single appendix with a 1:1:1 
allocation to each of two dose levels of an active intervention and control. If additional study 
interventions are added later that can contribute to pooled control, the sample size will be adjusted 
accordingly. 
 
The sample size is based on a design that will evaluate treatment effects separately within three co-
primary symptom cluster populations (cognitive dysfunction, autonomic dysfunction, and exercise 
intolerance) with a Holm-type adjustment to control the overall type-I error across them (see Section 
10.5.1 for details). The Holm procedure will initially allocate alpha equally across symptom clusters 
(0.0166, 0.0166, 0.0166), with a total type-I error probability of 0.05. If the null hypothesis is initially 

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rejected for some but not all symptom clusters, the Holm procedure will allow the non-rejected 
hypotheses to be re-tested at an updated, less stringent significance level.  
 
Accounting for the Holm procedure's stepwise alpha selection in power calculations is complicated 
because the final significance threshold is partly random and depends on the unknown configuration of 
treatment effects across all 3 symptom clusters considered jointly. As a simple conservative 
approximation, power was calculated for each symptom cluster individually assuming a specified 
treatment effect for that single symptom cluster and assuming 0.0166 for the Holm procedure's final 
significance threshold.   
 
Analysis within each symptom cluster population will control the type-I error across multiple dose levels 
by analyzing them in a pre-specified hierarchical testing procedure in order from highest to lowest dose. 
For simplicity, the total sample size was obtained by calculating sample size for a simple two-group 
comparison and multiplying by 3/2.  
 
Sample size was chosen to provide 80% power to detect a difference of 25 percentage points in the 
proportion of participants who experience the binary primary outcome for each pairwise comparison 
between a treatment group and control within each symptom cluster, assuming a two-sided test with 
alpha = 0.0166. Specifically, a sample size of 82 per group yields 80% power assuming the true outcome 
probabilities are 37.5% in the control group and 62.5% in the active treatment group. This sample size 
was inflated by 1/0.82 = 1.22 to account for potential 18% dropout/loss to follow-up. 
 
The final required sample size per symptom cluster was calculated as 82 x 3 x 1.22 = 300. The total 
number of participants that will need to be randomized across 3 symptom cluster populations will 
depend on the proportion of participants who meet criteria for >1 symptom cluster population. 
Assuming no overlap, the maximum sample size will be 900 (300 × 3). 
 
Table 5 illustrates the magnitude of treatment effects that will be detectable with 80% or 90% power 
under the study's planned sample size if the primary outcome occurs with probabilities ranging from 
0.05 to 0.35 in the placebo group.  
Table 5. Minimum treatment effects for 80% or 90% power 
Probability of 
Improvement 
with Placebo  
Minimum Treatment 
Effect Difference for 
80% Power* 
Minimum Treatment Effect Difference for 90% Power* 
0.05 
0.17 (0.22 vs 0.05) 
0.20 (0.25 vs 0.05) 
0.10 
0.20 (0.30 vs 0.10) 
0.23 (0.33 vs 0.10) 
0.15 
0.22 (0.37 vs 0.15) 
0.25 (0.40 vs 0.15) 
0.20 
0.23 (0.43 vs 0.20) 
0.27 (0.47 vs 0.20) 
0.25 
0.24 (0.49 vs 0.25) 
0.28 (0.53 vs 0.25) 
0.30 
0.25 (0.55 vs 0.30) 
0.28 (0.58 vs 0.30) 
0.35 
0.25 (0.60 vs 0.35) 
0.28 (0.63 vs 0.35) 
* Power for pairwise comparison between single dose level of active intervention versus control 
assuming 100 participants per treatment group (82 participants per treatment group with non-missing 
outcome data) and two-sided alpha = 0.0166.  
 

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10.4 POPULATIONS FOR ANALYSES 
 
The primary analysis of all study data will be based on a modified intent-to-treat population (mITT), 
consisting of all randomized participants who receive at least part of one dose of the study 
intervention or control. The mITT population will be used when analyzing efficacy as well as safety 
outcomes. Participants will be analyzed according to their randomly assigned intervention group. A 
separate mITT population will be defined for each pairwise comparison between treatment groups 
within each co-primary symptom cluster population. 
 
10.5 STATISTICAL ANALYSES  
 
This section describes analysis methods for primary, secondary, and exploratory efficacy outcomes. 
Unless otherwise specified, analysis will be based on the mITT population. Full details will be provided in 
the SAP.  
 
Because each sub-study is designed to address a separate set of questions pertaining to distinct agents, 
no multiplicity adjustments will be made across sub-study appendices. Plans for controlling type-I error 
within each sub-study are described below.  
 
For each appendix, a separate analysis of the primary outcome will be performed in parallel for each of 
three primary symptom cluster populations. Participants who meet criteria for > 1 symptom cluster will 
be included in the data collection and analysis for all symptom clusters for which criteria are met. A 
Holm-type multiplicity adjustment will be used to control the type-I error probability at 0.05 for analysis 
of primary outcomes across the 3 symptom clusters. If there are multiple dose levels of an intervention, 
analysis of primary outcomes will be performed sequentially in order from highest to lowest dose. At 
each dose level, if the comparison between active intervention versus control is significant for all 3 
symptom clusters, then testing of primary outcomes will proceed to the next lower dose level. 
Otherwise, testing will stop and primary outcome comparisons at lower dose levels will be regarded as 
exploratory. Comparisons between active intervention dose levels will be performed last and will be 
regarded as exploratory. 
 
Figure 4 illustrates the protocol's multiple testing strategy for an appendix with two active dose levels. 
Hypotheses are grouped into a family ℱ1 = {𝐻𝐻11, 𝐻𝐻12, 𝐻𝐻13} for the higher dose level and a family ℱ2 =
{𝐻𝐻21, 𝐻𝐻22, 𝐻𝐻23} for the lower dose level. Here, 𝐻𝐻𝑑𝑑𝑑𝑑 refers to the primary outcome analysis for symptom 
cluster 𝑐𝑐 at dose level 𝑑𝑑. Testing begins with ℱ1 and initially assigns local significance level α/3 to each 
member of ℱ1. After rejecting a hypothesis within ℱ1, its local alpha is reallocated equally within ℱ1. In 
the event that all hypotheses within ℱ1 are rejected, testing proceeds to ℱ2, with alpha reallocated 
equally among its component hypotheses. In general, an appendix with 𝐷𝐷≥1 dose levels will test 
families ℱ1, ℱ2, … , ℱ𝐷𝐷 in order from highest to lowest dose and will proceed to testing ℱ𝑑𝑑+1 if and only if 
all hypotheses within ℱ𝑑𝑑 have been rejected.  
 

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Figure 4. Multiple testing flowchart 
The multiplicity procedure described above provides strong family-wise type-I error control across 3 
symptom clusters and 𝐷𝐷 dose levels for the primary outcomes. For secondary outcomes, the multiple 
testing strategy is less conservative. For each symptom cluster and dose level, if the hypothesis 
pertaining to the primary outcome is rejected, then the symptom cluster's major secondary outcome 
will be tested at the same significance level as the primary outcome. This does not strictly control type-I 
error across all primary and secondary outcomes, but does offer some protection by using the primary 
outcome as a gatekeeper for secondary outcomes within each symptom cluster. This less conservative 
approach is motivated by viewing the study design as a separate trial for each symptom cluster 
population. Of note, a finding of benefit in a particular symptom cluster population will only pertain to 
that symptom cluster population and will not be extrapolated to other symptom cluster populations.  
 
10.5.1 PRIMARY EFFICACY ANALYSIS  
 
Each of the three Symptom Cluster-specific primary endpoints is binary.  
 
• 
For cognitive dysfunction, the primary endpoint is improvement of at least 5 T-score points on 
the PROMIS-cognitive 8a as measured at Day 90 compared to baseline. The proposed difference 
of 5 T-score points is derived from a body of literature that has specifically evaluated the 
minimally important difference using distribution- and anchor-based approaches across a 
number of disease processes (e.g., cancer, stroke, low back pain, osteoarthritis) and PROMIS 
measures (e.g., pain intensity, depression, physical functioning, anxiety, fatigue, etc.). These 
varied populations consistently report a minimally important difference of 2 to 6.31-33 Moreover, 
a value of 5 represents one-half the standard deviation for PROMIS measures in the US general 
population and is recommended as a starting point when no empirical data are available.34,35 
• 
For autonomic dysfunction, the primary endpoint is improvement as defined by a ≥ 1-point 
decrease in the OHQ question 1 at Day 90 compared to baseline. At least 1-point change on 
question 1 has been determined to be clinically meaningful and resulted in previous updates to 
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• 
For exercise intolerance, the primary endpoint is improvement in PEM, defined as having no 
symptoms of moderate or greater severity with 50% or more frequency as determined by the 
DSQ-PEM short form at Day 90.  
 
A separate pairwise comparison between intervention and control will be performed for each 
combination of study appendix, dose level, and symptom cluster. Analysis will target the intention-to-
treat between-group difference in marginal probabilities of improvement, defined as 
ΔITT = 𝑃𝑃(𝑌𝑌= 1|𝐴𝐴= 1) −𝑃𝑃(𝑌𝑌= 1|𝐴𝐴= 0), 
where 𝑌𝑌 denotes the primary outcome (1 = improvement, 0 = no improvement) and 𝐴𝐴 denotes 
randomization assignment (1 = active treatment, 0 = control).  
 
To improve precision, the estimate of ΔITT may be adjusted for a small number of pre-specified baseline 
covariates using the method of Ge et al. 2011 or similar (see SAP for details).36 Covariates will be 
selected based on having a suspected strong association with primary outcomes and high likelihood of 
complete data capture. Inference for ΔITT will be based on Wald-type test statistics and associated 
confidence intervals. 
 
Significance levels for the primary analysis will be determined by the multiplicity procedure described in 
above Section 10.5. Briefly, alpha will initially be equally allocated across symptom clusters (0.0166, 
0.0166, 0.0166), with a total type-I error probability of 0.05.  If the primary outcome comparison 
exceeds the critical threshold for some but not all symptom clusters, the procedure will allow non-
significant comparisons to be re-tested using an updated, less stringent critical threshold.  
 
The primary endpoints for the cognitive and autonomic symptom clusters were created by 
dichotomizing an underlying quantitative PRO outcome. An exploratory analysis of these outcomes will 
also be performed using the underlying quantitative measurements. While exploratory, these 
continuous outcomes may be estimated with greater precision compared to binary outcomes and will 
provide important context for the overall results interpretation. Methods for exploratory endpoints are 
described below.  
 
10.5.2 ANALYSIS OF SECONDARY ENDPOINTS 
 
Secondary outcomes are binary and will be analyzed using methods identical to the primary outcomes.  
 
Secondary endpoint:  
Meeting pre-specified change from baseline to Day 90 on cluster-specific performance outcome 
(yes/no).  
 
Secondary cluster-specific performance outcomes: 
Cognitive dysfunction symptom cluster: neurocognitive battery  
Autonomic dysfunction symptom cluster: active stand test 
Exercise intolerance symptom cluster: endurance shuttle walk test (ESWT)  
 
10.5.3 ANALYSIS OF SAFETY ENDPOINTS 
 
Safety endpoints include the proportion of participants who experience individual SAEs and the 
proportion who experience any one or more SAEs. Each of these will be compared pairwise between 

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each active intervention dose level and control. Events of Special Interest (ESIs) will be summarized by 
study drug appendix and duration. Incidence of AEs/SAEs leading to discontinuation of study 
intervention will also be summarized. 
 
10.5.4 ANALYSIS OF EXPLORATORY ENDPOINTS 
 
Exploratory endpoints that are binary will be analyzed using methods identical to the primary outcomes. 
Exploratory endpoints that are continuous will be analyzed via ANCOVA/regression with adjustment for 
pre-specified baseline covariates and with treatment effects expressed as differences in means. 
Covariates in each model will include an indicator of intervention group, the baseline value 
corresponding to the secondary outcome (e.g., adjust for baseline ESWT when analyzing End of Study 
ESWT as secondary outcome), and other pre-specified baseline factors. 
 
10.5.5 EXPLORATORY LONGITUDINAL ANALYSES 
 
Active intervention group comparisons of binary and continuous secondary outcomes will be assessed at 
multiple time points simultaneously by fitting longitudinal logistic (binary outcomes) and linear 
(continuous outcomes) regression models. Either hierarchical modeling with participant-specific random 
effects or Generalized Estimating Equations (GEE) methodology will be used to account for statistical 
dependence between repeated outcomes measured on the same participant over time.  
 
Exploratory analysis will include analysis of symptom burden, PROs, exploratory performance measures 
at select sites, and healthcare utilization. Biomarkers will be explored to investigate mechanisms of 
potential intervention efficacy and to determine associated with PASC symptom clusters and 
intervention response. Symptom burden analysis will be presented with consideration to subgroups by 
baseline symptoms, racial and ethnic subgroup, sex, acute COVID-19 severity, and timing after acute 
infection. Refer to the SAP for details. 
 
10.5.6 EXPLORATORY BAYESIAN ANALYSES 
To enhance interpretation, a subset of primary, secondary, and exploratory outcomes described above 
will be re-analyzed in a Bayesian statistical framework. The Bayesian statistical paradigm is an attractive 
framework for exploratory analyses because it provides a direct quantification of the likelihood of 
various hypotheses that are relevant when considering whether and how to design a subsequent phase 
3 evaluation. Traditional frequentist analyses assess evidence indirectly by positing a null hypothesis and 
calculating the probability of observing data at least as extreme as what was observed if the null 
hypothesis was true. Such an approach is indirect because it doesn't directly quantify the likelihood that 
a hypothesis is true or the likelihood that the trial will be successful. In contrast, Bayesian analysis can 
answer relevant questions exactly as they are posed. In particular, it can calculate the likelihood that a 
treatment is sufficiently effective to merit studying in a confirmatory phase 3 study. The output of a 
Bayesian analysis is a posterior probability distribution describing the relative likelihood of different 
numerical estimates of unknown quantities. This distribution can be used to determine the post-trial 
probability of a clinically important treatment effect in light of the study data. An additional advantage 
of Bayesian analysis is the ability to incorporate external information in the form of a prior distribution. 
For example, the prior may be formulated to reflect information from other RECOVER and non-RECOVER 
trials.   
 

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10.5.7 ANALYSIS OF TREATMENT EFFECT HETEROGENEITY 
In addition to estimating the overall difference in outcome between intervention groups, exploratory 
analyses will assess whether and how the treatment effect differs according to a set of prospectively 
defined participant baseline factors, most importantly, vaccination status, duration of PASC symptoms, 
and selected virologic and/or inflammatory biomarkers (e.g., positive assay for antigenemia at baseline 
for antiviral agents). These analyses will be performed one-at-a-time for each subgroup variable using 
logistic regression for binary outcomes and linear regression for continuous outcomes. A treatment-by-
covariate interaction test will be used to assess whether variation in the estimated treatment effect 
across levels of the covariate is consistent with chance.  
As a further exploratory analysis, a Bayesian multivariable modeling strategy will be used to estimate 
the treatment effect for selected outcomes as a function of a small number of prospectively defined 
baseline covariates (e.g., duration of treatment, selected biomarkers). The analysis will improve on 
conventional subgroup analyses by analyzing multiple subgroup factors jointly in a single multivariable 
model and providing treatment effect estimates tailored to a specific combination of multiple relevant 
covariates. The analysis will also permit estimating treatment effects as a function of dose level in sub-
studies investigating multiple intervention dose levels. The Bayesian prior distribution will place low 
prior probability on the hypothesis of extreme treatment effect variation across subgroups (i.e., a 
shrinkage prior) and will thereby reduce the probability of obtaining highly noisy and extreme estimates 
of treatment effect heterogeneity. Before developing these models, Monte Carlo simulations based on 
blinded RECOVER data will be used to shed light on the maximum feasible number of model covariates 
and will reduce the number of candidate covariates ahead of time if simulation results suggest a high 
potential for noisy estimates or false discoveries. 
10.5.8 MISSING DATA 
A particularly strong effort will be made to prevent participant’s loss to follow-up and missing outcome 
data. However, in case of missing outcome data, patterns of missingness between intervention groups 
will be examined and compared to baseline characteristics and outcomes available in the missing and 
not missing groups to evaluate any systematic differences. The analysis strategy for the primary 
outcome analysis will be a covariate-adjusted logistic regression combined with direct 
standardization.36,37 If outcome data are missing, participants with non-missing outcomes will be 
weighted to resemble the overall mITT population. Estimates will be unbiased under the assumption 
that outcome data are missing at random conditional on baseline covariates appearing in the weighting 
procedure. Sensitivity analyses will be performed under a range of missing data assumptions and may 
include multiple imputation, weighting, and likelihood-based methods. See SAP for details.  
10.5.9 PLANNED INTERIM ANALYSIS 
Interim examination of clinical endpoints and key safety events will be performed at regular intervals 
during the course of each sub-study/appendix. An independent, NIH-appointed, DSMB will monitor 
participant safety and review participant enrollment and performance of the trial. The primary objective 
of these interim analyses will be to ensure the safety of the participants enrolled in the trial and 
evaluate the accumulating endpoint data by treatment group. In addition, interim monitoring will 
involve a review of participant recruitment, compliance with the study protocol, status of data 
collection, and other factors which reflect the overall progress and integrity of the study. 

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There are no planned early stopping rules for efficacy in this protocol. Because PASC presentations and 
outcomes are highly varied, an important study objective is to estimate the effect of treatment on a 
wide range of participant-relevant outcomes. If the study were to be stopped early with less than the 
full sample size, it would decrease precision and reduce the study's ability to characterize treatment 
risks and benefits based on important secondary effectiveness and safety outcomes. It would also limit 
the collection of data that are critical for planning future trials in similar patient populations. 
Early stopping for rules for futility may be incorporated on a sub-study/appendix specific basis. Such 
rules will be documented in the sub-study appendices.  
 
11 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
11.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
11.1.1 INFORMED CONSENT PROCESS 
 
11.1.1.1 INSTITUTIONAL REVIEW BOARD (IRB) 
 
The protocol, informed consent form(s) [ICF(s)], recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board(s) [IRB(s)] of record for review and approval. This 
approval must be obtained before any participant is enrolled. Any amendment to the protocol will 
require review and approval by the IRB(s) before being implemented in the study. All changes to the 
consent form will also be IRB-approved and a determination will be made regarding whether previously 
consented participants need to be re-consented. 
 
11.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
All consenting will occur either via an electronic consent process or a paper process. Consent forms 
describing in detail the study intervention/control, study procedures, and risks will be given to the 
participant and documentation of informed consent is required prior to starting study procedures. 
Informed consent is a process that is initiated prior to the individual’s agreement to participate in the 
study and continues throughout the individual’s study participation. A description of risks and possible 
benefits of participation will be provided to the participants. Consent forms will be IRB-approved and 
the participant will be asked to read and review the document. The participant will be provided contact 
information in the event they have questions about study participation. This will allow them to 
communicate with the investigators (or their delegate), for further explanation of the research study 
and to answer any questions that may arise, as necessary. Participants will have the opportunity to 
carefully review the consent form and ask questions prior to signing. 
 
The participants should have the opportunity to discuss the study and think about it prior to agreeing to 
participate. The participant will sign the informed consent document prior to any procedures being done 
specifically for the study. The participants may withdraw consent at any time throughout the course of 
the study. A copy of the informed consent document will be provided to the participants for their 
records. The rights and welfare of the participants will be protected by emphasizing to them that the 
quality of their medical care will not be adversely affected if they decline to participate in this study. 
 

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The study team will distinguish between the desire to discontinue study intervention(s) and the desire 
to withdraw consent for study follow-up.  
11.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the sponsor to study participants, site investigators, the central IRB, and the US FDA. Study 
participants will be contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or FDA. 
 
11.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples in 
addition to the clinical and private information relating to participants. Therefore, the study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor. The study participant’s contact information will be securely stored 
in the clinical study database. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the CT-DCC. The study data entry and study management systems used 
by clinical sites and by research staff will be secured and password protected. At the end of the study, all 
study-related data storage systems will be archived according to local processes. 
 
11.1.4 KEY ROLES AND STUDY GOVERNANCE 
The RECOVER program is overseen by the RECOVER Executive Committee, the NIH RECOVER Program, 
and the RECOVER Senior Oversight Committee Co-Chairs. The RECOVER program also includes a Clinical 
Trial Steering Committee, which is a multi-stakeholder committee that oversees the study and includes 
patients, the CT-DCC, the NIH, the FDA, and academic and subject matter experts.  
The CT-DCC is overseen by a Principal Investigator. The CT-DCC is responsible for study coordination, site 
management, communication, financial administration, treatment allocations, receipt and processing of 
data, quality control programs, and statistical analysis and reporting.  

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The DSMB will oversee the safety and welfare of trial participants as well as provide recommendations 
for continuation, discontinuation, or revision of the trial. 
11.1.5 DATA AND SAFETY MONITORING BOARD 
 
Safety oversight will be under the direction of the RECOVER DSMB composed of individuals with the 
appropriate expertise. Members of the DSMB should be independent from the study conduct and free 
of conflict of interest, or measures should be in place to minimize perceived conflict of interest. The 
DSMB will meet at least semi-annually to approve protocols, assess safety and efficacy data, and at 
appropriate intervals to meet requirements for the Interim Analyses on each arm of the study. The 
DMSB will operate under the rules of an approved charter that will be written and reviewed at the 
organizational meeting of the DSMB. At this time, each data element that the DSMB needs to assess will 
be clearly defined. The DSMB will provide its input to the NIH. 
 
11.1.6 CLINICAL MONITORING 
 
This study will employ a centralized risk-based approach to monitoring with routine and periodic review 
of site-submitted data to review the informed consent process, select eligibility criteria, medical history, 
identify and follow-up on missing data, inconsistent data, data outliers, etc. and ensure completion of 
administrative and regulatory processes. The study team will facilitate regular communication through 
training sessions, teleconferences, videoconferencing, email, etc. Using quality-by-design principles, 
steps will be taken at the study design stage to foresee and limit significant problems that might occur 
during the study conduct. Follow-up from the sites is expected to keep participants engaged.  
 
11.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study team will work in tandem to ensure that the data collected in this study are as complete and 
correct as possible. A four-step, multi-functional approach to quality control will be implemented: 
 
• 
Training: Prior to the start of enrollment, the clinician investigators and key study personnel at 
each site will be trained with the clinical protocol and data collection procedures, including how 
to use the EDC system. Follow-up training and training for new study personnel or new versions 
of the protocol will be conducted as needed. 
 
• 
Monitoring: The RECOVER CT-DCC will ensure that data collection is handled properly, will 
provide in-service training, and will address questions from site investigators and coordinators. 
Electronic review of data quality and completeness will occur on a regular and ongoing basis. 
Any issues will be addressed.  
 
• 
Managing data: After the data have been transferred for statistical summarization, data 
description, and data analysis, further crosschecking of the data will be performed with 
discrepant observations being flagged and appropriately resolved through a data query system. 
 
• 
Reviewing data: Data regarding events of interest will be reviewed to ensure appropriate 
documents are collected for DSMB review. The CT-DCC will monitor study data and contact site 
study teams when events comprising the primary endpoint are not complete. 
 

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11.1.8 DATA HANDLING AND RECORD KEEPING  
 
11.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Streamlining research activities and conducting the trial in a pragmatic manner will increase the ability 
to complete the trial in the face of strained clinical and research resources. Data may be collected by 
electronic methods, supplemented by telephone or videophone follow-up, and from the electronic 
health record.  
 
Data will be collected directly from participants using REDCap through text messaging or email with a 
survey link, or phone call as back up. The process for using text messaging and email is Health Insurance 
Portability and Accountability Act (HIPAA) compliant.  
 
Site personnel or participants will enter study data into a secure online database. Data will be 
maintained in a secure online database until the time of study publication. At the time of publication, 
the CT-DCC will generate a de-identified version of the database for archiving (see Section 11.1.10). All 
source documents at the sites should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  
 
11.1.8.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of six years after the study has ended. However, if 
required by local regulations or the US FDA, these documents should be retained for a longer period. No 
records will be destroyed without the written consent of the sponsor. It is the responsibility of the 
sponsor to inform the investigator when these documents no longer need to be retained. 
11.1.9 PROTOCOL DEVIATIONS  
A protocol deviation is defined as non-compliance with the clinical study protocol or GCP requirements. 
The non-compliance may be on the part of the participant, site investigator, or the site staff.  
A major protocol deviation is a significant divergence from the protocol that may have significant effect 
on the participant’s safety, rights, or welfare and/or on the integrity of the study data. Major protocol 
deviations must be sent to the study IRB and local IRB per their guidelines, recorded in source 
documents, and reported to the coordinating center. All protocol deviations will be documented. For 
this study, any missed or delayed survey completion will not be considered a major protocol deviation, 
unless it is a study procedure that is required for the primary endpoint.  
 
11.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 
 
 
 

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11.1.11 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study leadership 
in conjunction with the NIH has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all reported 
dualities of interest. 
 
11.2 ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Transaminase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase  
BP 
Blood Pressure 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
Coronavirus Disease of 2019 
CRF 
Case Report Form 
CTCSQ 
Cluster Targeted COVID-19 Symptom Questions 
CT-DCC 
Clinical Trial – Data Coordinating Center 
DCRI 
Duke Clinical Research Institute  
DILI 
Drug-Induced Liver Injury 
DSMB 
Data Safety Monitoring Board 
DSQ - PEM 
DePaul Symptom Questionnaire Post Exertional Malaise 
DUA 
Data Use Agreement 
ECOG 2  
Everyday Cognition 2 
eCRF 
Electronic Case Report Forms 
EOD 
End of Dosing 
ESI 
Events of Special Interest 
ESWT 
Endurance Shuttle Walk Test 
EUA 
Emergency Use Authorization  
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act  
HIV 
Human Immunodeficiency Virus 
HRQOL 
Health-Related Quality of Life 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization  
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISWT 
Incremental Shuttle Walk Test 
LFT 
Liver Function Test 
mITT 
Modified Intention-To-Treat  
MOP 
Manual of Procedures 
NCT 
National Clinical Trial 

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NIH  
National Institutes of Health 
OHQ 
Orthostatic Hypotension Questionnaire 
OIDAS 
Orthostatic Intolerance Daily Activity Scale 
OISA 
Orthostatic Intolerance Symptom Assessment 
PASC 
Post-acute Sequelae of SARS-CoV-2 Infection 
PCR 
Polymerase Chain Reaction 
PEM 
Post-Exertional Malaise 
PHI 
Personal Health Information 
PRO 
Patient Reported Outcome  
RAT 
Rapid Antigen Test 
RECOVER 
Researching COVID to Enhance Recovery 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3  
Triiodothyronine 
T4 
Thyroxine 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal 
US 
United States 
VO2 max 
Maximum Rate of Oxygen Consumption 
 
11.3 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
1.0 
10OCT2022 
None, original protocol 
2.0 
09MAR2023 
• 
Updated study description, background, and rationale;  
• 
Moved biomarker objective to exploratory, added an 
additional biomarker exploratory objective (exploratory 
objective #6), and added more details around exploratory 
biomarker outcome measures;  
• 
Adjusted sample size from 1700 to 900;  
• 
Added reference to and description of potential phase 2 and 
phase 3 study design within the appendices;  
• 
Extended follow-up to 6 months; 
• 
Study Schema updated to align with study design changes; 
• 
Symptom cluster assignment flow updated; 
• 
Limits were placed on the number of participants with 
suspected and probable COVID-19 on or after May 1, 2021; 
• 
Two moderate symptoms from the same Symptom Cluster or 
one severe symptom required for inclusion; 
• 
End of Study has been extended to 183 days from the original 
90 days; 
• 
PROMIS 29+2, PASC Symptom Questionnaire, and PRO 
Symptom Cluster Assessment(s) will be done weekly as 
opposed to every 2 weeks; 

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• 
Stool collection added; 
• 
Updated clinical laboratory assessments; 
• 
Optional blood collection/nasal swab visits added to Days 45, 
60, and 120; details on biospecimen collection added; 
• 
Added ECOG 2 to the cognitive dysfunction PRO assessment; 
• 
Non-serious AEs that result in study drug discontinuation will 
now be reposted separately as an AE; 
• 
Statistical considerations updated to align with study design 
changes; 
• 
PAXLOVID dosing modified to 15 days of active DOI 
(nirmatrelvir/ritonavir) with 10 days of control (ritonavir), 25 
days of active DOI, or 25 days of control (1:1:1); 
• 
Dose-related exploratory objectives have been added to 
Appendix A (PAXLOVID Phase 2); 
• 
Thyroid function added as an Event of Special Interest to 
Appendix A (PAXLOVID Phase 2); and 
• 
Other administrative changes throughout. 
3.0 
18MAY2023 
• 
Updated schema to align with changes to study procedures; 
• 
Clarified study endpoints, referred to stats section for details; 
• 
Updated exploratory objectives; 
• 
Added the collection of non-serious AEs to the protocol, non-
serious AEs will be assessed from start of study drug 
administration to the EOD for select appendices;  
• 
Participants will have 3 days to complete remote weekly 
assessments; 
• 
DSQ-PEM completed after performance measures will occur at 
1 (+ 1 day) after performance measure;  
• 
Updated statistical considerations; 
• 
Removed exclusion #9 because it duplicates exclusion #8; 
• 
Added a row for "Healthcare Utilization" to the Schedule of 
study procedures; 
• 
Clarified that stool collection will be processed at a central lab; 
• 
Added that peripheral blood mononuclear cells will be 
collected at select sites; 
• 
Added additional appendix-level study assessments to 
Appendix A; 
• 
Updated drug storage specifications for Appendix A; and  
• 
Other administrative changes throughout. 
 
 
 

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[https://doiorg/1021203/rs3rs-1139035/v1]. 2021; 
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Zollner A, Koch R, Jukic A, et al. Postacute COVID-19 is Characterized by Gut Viral Antigen Persistence in 
Inflammatory Bowel Diseases. Gastroenterology. May 1 2022;163(2):495-506.e8. doi:10.1053/j.gastro.2022.04.037 

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2022;22(1):211. doi:10.1186/s12879-022-07153-4 
17. 
Cheshire WP, Freeman R, Gibbons CH, et al. Electrodiagnostic assessment of the autonomic nervous 
system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, 
and the International Federation of Clinical Neurophysiology. Clin Neurophysiol. Feb 2021;132(2):666-682. 
doi:10.1016/j.clinph.2020.11.024 
18. 
Organization; PAH. Case definitions for COVID-19 surveillance. Accessed August 25, 2022, 2022. 
https://www.paho.org/en/case-definitions-covid-19-surveillance 
19. 
Soriano JB, Murthy S, Marshall JC, Relan P, Diaz JV. A clinical case definition of post-COVID-19 condition by 
a Delphi consensus. Lancet Infect Dis. Apr 2022;22(4):e102-e107. doi:10.1016/s1473-3099(21)00703-9 
20. 
Organization; WH. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. 
Vitamin and Mineral Nutrition Information System. . 
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21. 
Prevention; CfDCa. Alcohol and Public Health Updated April 19, 2022. Accessed August 25, 2022. 
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0when%20alcohol%20is%20consumed 
22. 
Cella D, Yount S, Rothrock N, et al. The Patient-Reported Outcomes Measurement Information System 
(PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Med Care. May 2007;45(5 
Suppl 1):S3-s11. doi:10.1097/01.mlr.0000258615.42478.55 
23. 
Hays RD, Bjorner JB, Revicki DA, Spritzer KL, Cella D. Development of physical and mental health summary 
scores from the patient-reported outcomes measurement information system (PROMIS) global items. Qual Life 
Res. Sep 2009;18(7):873-80. doi:10.1007/s11136-009-9496-9 
24. 
Ganesh R, Ghosh AK, Nyman MA, et al. PROMIS Scales for Assessment of Persistent Post-COVID 
Symptoms: A Cross Sectional Study. J Prim Care Community Health. Jan-Dec 2021;12:21501327211030413. 
doi:10.1177/21501327211030413 
25. 
PROMIS ADULT PROFILE INSTRUMENTS. Accessed November 16, 2022. 
https://staging.healthmeasures.net/images/PROMIS/manuals/PROMIS_Adult_Profile_Scoring_Manual.pdf 
26. 
The Patient Reported Outcomes Measurement Information System (PROMIS): A Walk Through the First 
Four Years, (2009).  
27. 
Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and abbreviated 
Composite Autonomic Symptom Score. Mayo Clin Proc. Dec 2012;87(12):1196-201. 
doi:10.1016/j.mayocp.2012.10.013 
28. 
Cotler J, Holtzman C, Dudun C, Jason LA. A Brief Questionnaire to Assess Post-Exertional Malaise. 
Diagnostics (Basel). Sep 11 2018;8(3)doi:10.3390/diagnostics8030066 
29. 
Goldstein RAEaRS. Comprehensive Biomedical Physics. vol 10. Elsevier; 2014. 
30. 
Revill SM, Morgan MD, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: a new field test for 
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Yost KJ, Eton DT, Garcia SF, Cella D. Minimally important differences were estimated for six Patient-
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32. 
Kroenke K, Stump TE, Chen CX, et al. Minimally important differences and severity thresholds are 
estimated for the PROMIS depression scales from three randomized clinical trials. J Affect Disord. Apr 1 
2020;266:100-108. doi:10.1016/j.jad.2020.01.101 
33. 
Terwee CB, Peipert JD, Chapman R, et al. Minimal important change (MIC): a conceptual clarification and 
systematic review of MIC estimates of PROMIS measures. Qual Life Res. Oct 2021;30(10):2729-2754. 
doi:10.1007/s11136-021-02925-y 
34. 
University; N. Meaningful Change for PROMIS(R). Accessed January 20, 2023. 
https://www.healthmeasures.net/score-and-interpret/interpret-scores/promis/meaningful-change 
35. 
Norman GR, Sloan JA, Wyrwich KW. Interpretation of changes in health-related quality of life: the 
remarkable universality of half a standard deviation. Med Care. May 2003;41(5):582-92. 
doi:10.1097/01.Mlr.0000062554.74615.4c 
36. 
Ge M, Durham L, Meyer D, Xie W, Thomas N. Covariate-Adjusted Difference in Proportions from Clinical 
Trials Using Logistic Regression and Weighted Risk Differences. Drug Information Journal - DRUG INF J. 07/01 
2011;45:481-493. doi:10.1177/009286151104500409 
37. 
Benkeser D, Díaz I, Luedtke A, Segal J, Scharfstein D, Rosenblum M. Improving precision and power in 
randomized trials for COVID-19 treatments using covariate adjustment, for binary, ordinal, and time-to-event 
outcomes. Biometrics. Dec 2021;77(4):1467-1481. doi:10.1111/biom.13377 
38. 
Pfizer. PAXLOVID - nirmatrelvir and ritonavir. Updated June 28, 2022. Accessed July 20, 2022. 
https://labeling.pfizer.com/ShowLabeling.aspx?id=16474 
39. 
Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults 
with Covid-19. N Engl J Med. Apr 14 2022;386(15):1397-1408. doi:10.1056/NEJMoa2118542 
40. 
Catlin NR, Bowman CJ, Campion SN, et al. Reproductive and developmental safety of nirmatrelvir (PF-
07321332), an oral SARS-CoV-2 M(pro) inhibitor in animal models. Reprod Toxicol. Mar 2022;108:56-61. 
doi:10.1016/j.reprotox.2022.01.006 
41. 
Sathish JG, Bhatt S, DaSilva JK, et al. Comprehensive Nonclinical Safety Assessment of Nirmatrelvir 
Supporting Timely Development of the SARS-COV-2 Antiviral Therapeutic, Paxlovid™. Int J Toxicol. Aug 
2022;41(4):276-290. doi:10.1177/10915818221095489 
42. 
Singh RSP, Toussi SS, Hackman F, et al. Innovative Randomized Phase I Study and Dosing Regimen 
Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir. Clin Pharmacol Ther. Jul 
2022;112(1):101-111. doi:10.1002/cpt.2603 
43. 
Peluso MJ, Anglin K, Durstenfeld MS, et al. Effect of Oral Nirmatrelvir on Long COVID Symptoms: 4 Cases 
and Rationale for Systematic Studies. Pathog Immun. 2022;7(1):95-103. doi:10.20411/pai.v7i1.518 
44. 
Ford ES, Simmons W, Karmarkar EN, et al. Successful treatment of prolonged, severe COVID-19 lower 
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Clin Infect Dis. Nov 3 2022;doi:10.1093/cid/ciac868 
 
 

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13 APPENDIX A (PAXLOVID PHASE 2)  
 
This appendix describes a prospective, multi-center, double-blind, randomized controlled phase 2 trial 
evaluating nirmatrelvir/ritonavir (PAXLOVID) in two dosing durations for PASC. Within this study, 
participants will be randomized 1:1:1 to 15 days of active intervention (nirmatrelvir/ritonavir) with 10 
days of control (placebo/ritonavir), 25 days of active intervention, or 25 days of control, within three 
symptom clusters. The intervention will be administered in two kits (15 days followed by 10 days). For 
this appendix, the midpoint of drug dosing is approximately 13 days; the Drug Dosing Midpoint Clinic 
Visit will occur at Day 15 (-5 days).  
  
13.1 RISK ASSESSMENT  
 
Serious and unexpected AEs may occur that have not been previously reported with PAXLOVID use.38 
Previously reported AEs were identified in the EPIC-HR study, which was a phase 2/3 randomized, 
controlled trial in non-hospitalized adults with a laboratory confirmed diagnosis of SARS-CoV-2.39 EPIC-
HR AEs included (incidence ≥ 1% and ≥ 5 subject difference) dysgeusia, diarrhea, hypertension, and 
myalgia. Following Emergency Use Authorization (EUA) use of PAXLOVID, hypersensitivity reactions, 
abdominal pain, nausea, and malaise have been reported. Otherwise, any reported AEs in humans are 
related either to nirmatrelvir or ritonavir use. For example, in patients receiving ritonavir, hepatic 
transaminase elevations, clinical hepatitis, and jaundice have occurred. 
 
No PAXLOVID human data are currently available to evaluate for a drug-associated risk of major birth 
defects, miscarriage, adverse maternal or fetal outcomes, or lactation effects. However, one study is 
currently recruiting pregnant women with mild or moderate COVID-19 (NCT05386472), and another 
study will be examining PAXLOVID in healthy lactating women (NCT05441215). Pre-clinical data indicate 
that there are no clinically relevant risks associated with PAXLOVID administration during pregnancy and 
in males and females of reproductive age.40 Published observational studies on ritonavir use in pregnant 
women have not identified an increased risk of major birth defects. Published studies with ritonavir are 
insufficient to identify a drug-associated risk of miscarriage. The benefit of taking PAXLOVID during 
pregnancy may be greater than the risk from the treatment; however, the risk/benefit of treatment for 
PASC during pregnancy has not been established.  
 
13.2 ADDITIONAL APPENDIX-LEVEL EXPLORATORY OBJECTIVE(S) 
 
OBJECTIVE(S) 
OUTCOME MEASURES 
ENDPOINTS  
Exploratory 
Describe the effect of dose on 
efficacy of intervention within 
each PASC symptom cluster 
Cognitive dysfunction 
symptom cluster: PROMIS – 
cognitive 8a 
Autonomic dysfunction 
symptom cluster: OHQ 
Exercise intolerance symptom 
cluster: DSQ-PEM  
 
Cognitive dysfunction symptom 
cluster: Participants meeting pre-
specified change from baseline to 
Day 90 on PROMIS - cognitive 8a 
T-score  
Autonomic dysfunction 
symptom cluster: Participants 
meeting pre-specified change 
from baseline to Day 90 on the 
OHQ 

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OBJECTIVE(S) 
OUTCOME MEASURES 
ENDPOINTS  
Exercise intolerance symptom 
cluster: Participants meeting pre-
specified change from baseline to 
Day 90 on the DSQ-PEM  
Characterize the effect of dose 
on safety and tolerability of 
intervention in PASC 
• Serious adverse events 
(SAEs) 
• Events of Special Interest 
(ESIs)  
• Adverse events (AEs) 
• Number of missed doses 
(adherence) 
• Occurrence of individual SAEs 
and AEs 
• Occurrence of any one or 
more SAEs and AEs 
• Occurrence of AEs and SAEs 
leading to discontinuation 
• Occurrence and duration of 
ESIs Number of missed doses 
(adherence) 
 
Refer to the SAP for analysis details.  
 
13.3 ADDITIONAL APPENDIX-LEVEL EXCLUSION CRITERIA 
 
1. Known pregnancy1 
2. Active or expected breastfeeding during the study 
3. Known eGFR < 30 mL/min 
4. Known severe hepatic impairment (Child-Pugh Class C) 
5. Current use of drugs highly dependent on CYP3A for clearance2 and for which elevated 
concentrations are associated with serious and/or life-threatening reactions and which cannot 
be interrupted during the time of study administration and within seven days before and after 
study drug administration 
6. Current use of potent CYP3A inducers2 where significantly reduced nirmatrelvir or ritonavir 
plasma concentrations may be associated with the potential for loss of virologic response and 
possible resistance 
 
1A pregnancy test must be performed at the Baseline Visit for participants who are capable of becoming 
pregnant. 
2A guide of drugs that may be contraindicated are listed in Section 4 CONTRAINDICATIONS of the Full 
Prescribing Information of the EUA for PAXLOVID. 
 
13.4 ADDITIONAL APPENDIX-LEVEL STUDY ASSESSMENTS 
 
Safety Labs for appendix A are drawn in addition to platform protocol labs at the following time points 
and are run locally at the site. All non-serious AEs will be collected and reported from start of study drug 
dosing to end of study drug administration for this appendix at all timepoints that designate collection of 
non-serious AEs in Table 2. 
 
Baseline Visit 
• 
Pregnancy test (for participants who are capable of becoming pregnant) 
• 
Thyroid stimulating hormone (TSH) 

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• 
Total and free triiodothyronine (T3, total and free) 
• 
Total and free thyroxine (T4, total and free) 
 
Drug Dosing Midpoint Visit  
• 
Thyroid stimulating hormone (TSH) 
• 
Total and free triiodothyronine (T3, total and free) 
• 
Total and free thyroxine (T4, total and free) 
• 
Comprehensive metabolic panel 
 
End of Dosing Visit 
• 
Thyroid stimulating hormone (TSH) 
• 
Total and free triiodothyronine (T3, total and free) 
• 
Total and free thyroxine (T4, total and free) 
• 
Comprehensive metabolic panel 
 
90 Day Visit  
• 
Thyroid stimulating hormone (TSH) 
• 
Total and free triiodothyronine (T3, total and free) 
• 
Total and free thyroxine (T4, total and free) 
• 
Comprehensive metabolic panel 
 
13.5 PAXLOVID INFORMATION  
 
In December 2021, the US FDA issued an EUA for use of the unapproved PAXLOVID, which includes 
nirmatrelvir and ritonavir for the treatment of mild-to-moderate COVID-19 in adults and pediatric 
patients (12 years of age and older weighing at least 40 kg) who test positive for SARS-CoV-2 and are at 
high risk for progression to severe COVID-19.38 Authorized dosing includes 300 mg nirmatrelvir with 100 
mg ritonavir twice daily for five days.  
 
PAXLOVID is nirmatrelvir tablets co-packaged with ritonavir tablets. Nirmatrelvir is a SARS-CoV-2 main 
protease inhibitor. Ritonavir is an HIV-1 protease inhibitor and CYP3A inhibitor. Since CYP3A metabolizes 
nirmatrelvir, ritonavir produces higher systemic concentrations and longer half-life of nirmatrelvir.   
  
13.5.1 PRECAUTIONS  
 
The healthcare provider should consult other appropriate resources such as the prescribing information 
for the interacting drug for comprehensive information on dosing or monitoring with concomitant use of 
a strong CYP3A inhibitor such as ritonavir. No dosage adjustment is required when co-administered with 
other products containing ritonavir or cobicistat. Participants on ritonavir- or cobicistat-containing 
Human Immunodeficiency Virus (HIV) or Hepatitis C viral regimens should continue their treatment as 
indicated. 
 
Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of 
PAXLOVID, respectively. These interactions may lead to:  
• 
Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal 
events from greater exposures of concomitant medications  

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• 
Clinically significant adverse reactions from greater exposures of PAXLOVID  
• 
Loss of therapeutic effect of PAXLOVID and possible development of viral resistance   
 
13.5.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
PAXLOVID is a combination of nirmatrelvir and ritonavir tablets.  
 
Formulation:  
• 
Nirmatrelvir is available as immediate-release, film-coated tablets. Each tablet contains 150 mg 
nirmatrelvir with the following inactive ingredients: colloidal silicon dioxide, croscarmellose 
sodium, lactose monohydrate, microcrystalline cellulose, and sodium stearyl fumarate. The 
following are the ingredients in the film coating: hydroxy propyl methylcellulose, iron oxide red, 
polyethylene glycol, and titanium dioxide. 
• 
Ritonavir is available as film-coated tablets. Each tablet contains 100 mg ritonavir with the 
following inactive ingredients: anhydrous dibasic calcium phosphate, colloidal silicon dioxide, 
copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating may include 
the following ingredients: colloidal anhydrous silica, colloidal silicon dioxide, hydroxypropyl 
cellulose, hypromellose, polyethylene glycol, polysorbate 80, talc, and titanium dioxide. 
 
Appearance:  
• 
Nirmatrelvir is supplied as oval, pink, film-coated tablets.  
• 
Ritonavir is supplied as ovaloid, white, film-coated tablets.  
 
13.5.3 DRUG DISPENSING, STORAGE, AND STABILITY  
 
Store at 15°C to 30°C (59°F to 86°F). Participants will receive two kits. Kit 1 will be provided at the 
Baseline Visit to cover days 1 to 15. Kit 2 will be provided at the midpoint dosing visit to cover days 16 to 
25. 
 
13.5.4 DOSING AND ADMINISTRATION 
 
PAXLOVID dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet). 
All three tablets (two of nirmatrelvir and one of ritonavir) must be taken together and no more than 15 
minutes apart. For this appendix, all three tablets are taken together twice daily by mouth for 25 days. 
PAXLOVID tablets can be taken with or without food, however, taking with food may improve 
tolerability. PAXLOVID tablets should be swallowed whole, not chewed, broken, or crushed.  
 
All participants will undergo dosing for 25 days. Those randomized to PAXLOVID for 15 days will receive 
15 days of active intervention (nirmatrelvir/ritonavir) and 10 days of control (placebo/ritonavir). Those 
randomized to PAXLOVID for 25 days will receive 25 days of active intervention.  
 
Each participant will receive two kits that include a combination of blister cards and bottles. All 
participants will be instructed to take two tablets from the blister cavities and one tablet from the bottle 
for each dose. Refer to the MOP for details. 
 
A dose reduction is necessary for participants with moderate renal impairment (eGFR ≥ 30 to < 60 
mL/min): reduce to 150 mg nirmatrelvir (one 150 mg tablet) with 100 mg ritonavir (one 100 mg tablet), 

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with both tablets taken together twice daily for the dosing period. No dose reduction is needed in 
participants with mild renal impairment (eGFR ≥ 60 to < 90 mL/min). 
 
If the participant misses a dose of PAXLOVID within 8 hours of the time it is usually taken, the participant 
should take it as soon as possible and resume the normal dosing schedule. If the participant misses a 
dose by more than 8 hours, the participant should not take the missed dose but instead take the next 
dose at the regularly scheduled time. The participant should not double the dose to make up for a 
missed dose. 
 
For this study, any dose of nirmatrelvir greater than 900 mg (6 nirmatrelvir tablets) or ritonavir greater 
than 300 mg (3 ritonavir tablets) within a 24-hour time period will be considered an overdose. There is 
no specific treatment for an overdose. Overdose is reportable to Pfizer Safety by DCRI Safety 
Surveillance only when associated with an SAE. In the event of an overdose, the investigator should: 
1. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities for at least 5 half-
lives or 28 calendar days after the overdose of study intervention (whichever is longer).  
2. Document the quantity of the excess dose as well as the duration of the overdose in the CRF. 
3. If there is an associated SAE, the SAE is reported within the CRF within 24 hours of site 
awareness. 
Decisions regarding dose interruptions or modifications will be made by the site investigator based on 
the clinical evaluation of the participant.   
 
13.5.5 RATIONALE FOR SELECTION OF DOSE 
 
Pre-clinical studies: 
Nirmatrelvir has been characterized in nonclinical safety pharmacology and repeat-dose toxicity studies 
in the rat and non-human primate. Ritonavir was not included in pre-clinical safety studies for multiple 
reasons, as noted by Sathish et al.41:  
• 
ritonavir is a marketed drug with a well-characterized pre-clinical and clinical safety profile, and 
no overlapping or additive toxicities between nirmatrelvir and ritonavir are expected;  
• 
the exposure-enhancing effects of ritonavir seen in humans do not translate completely in 
animals;  
• 
high exposures of nirmatrelvir in pre-clinical studies were achieved through use of solvate and 
formulations approaches. 
 
High-dose nirmatrelvir administration (75 mg/kg per dose twice daily, by mouth) over a 5-day treatment 
period in cynomolgus monkeys produced cardiovascular effects limited to transient increases in BP and 
decreases in heart rate. Cardiovascular effects were not observed in low dose (20 mg/kg per dose twice 
daily, by mouth). Additionally, no adverse findings were observed in repeat dose toxicity studies up to 
29 days in rats (up to 1,000 mg/kg daily, by mouth) or monkeys (up to 600 mg/kg daily, by mouth). 
 
Clinical studies: 
A first-in-human study (NCT04756531) assessed nirmatrelvir safety, tolerability, and pharmacokinetics 
following single-ascending doses including food effect, multiple-ascending doses, and at supra-
therapeutic exposure in healthy 18 to 60-year-old patients.42 Participants who received multiple-
ascending doses were randomly assigned to control or escalating nirmatrelvir dose levels (75, 250, and 
500 mg), all administered twice daily as a suspension for 10 days with ritonavir 100 mg, under fasting 
conditions. At all dose levels, nirmatrelvir plasma concentrations reached steady state by Day 2 and 

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remained steady through Day 10. Across all multiple-ascending dose groups and control, treatment-
related AEs included mild dysgeusia (n = 3) and mild increases in blood thyroid stimulating hormone (n = 
5). No severe AEs or SAEs were reported. 
 
Moreover, a supra-therapeutic oral dose of nirmatrelvir as a 2,250-mg suspension (dosed as 3 split 
doses of 750 mg administered at 0, 2, and 4 hours) enhanced with 100 mg ritonavir increased the mean 
plasma concentration ~ 5 times higher than that of the 500 mg nirmatrelvir multiple-ascending dose 
cohort on Day 1. Even with this high concentration, only one case of mild nausea in the treatment group 
was observed. No severe AEs or SAEs were reported. 
 
In clinical studies in participants at high risk of progression to severe COVID-19 illness, PAXLOVID, as 
compared to placebo, was associated with an approximately 0.9 log10 copies/mL greater decline in viral 
RNA levels in nasopharyngeal samples through Day 5,38 which is the approved dosing duration for acute 
COVID-19.38  
 
To date the appropriate duration of therapy for PASC remains unknown. This study will test two dosing 
durations, 15 days and 25 days, which have been chosen to enable evaluation of dose response of 
prolonged therapy within the range of dosing durations previously used in select clinical practice (e.g., 
immunosuppression).  
 
No randomized clinical trial has been performed to study PAXLOVID in patients with PASC. Case studies 
of patients with PASC taking PAXLOVID over 5 days show equivocal improvements in symptom 
resolution.43   
 
The planned dosing duration in this study (15 and 25 days) is nearly three and five times that typically 
administered and currently under EUA for administration to those with acute SARS-CoV-2 infection for 
prevention of severe disease. Previous clinical trials have confirmed the safety of PAXLOVID treatment 
up to a duration 10 days and data suggests similar safety/tolerability of 5- and 10-day treatment 
durations. In addition, prolonged durations of PAXLOVID (up to 20 days) have been used in heavily 
immunosuppressed patients with persistent SARS-CoV-2 infection,44 and for other disease processes 
where viral persistence and reactivation are of concern (e.g., herpes simplex virus, especially neonatal 
herpes simplex virus), prolonged durations of antivirals (sometimes up to 1 year) are standard. 
Moreover, more prolonged durations might increase the probability of viral eradication. Viral 
eradication is the mechanism by which antivirals are believed to potentially mitigate PASC.  
 
13.6 CONTROL INFORMATION  
 
In order to maintain blinding with the distinct taste of ritonavir, the control for this appendix will be the 
combination of ritonavir and placebo. Data obtained from a mouse study show no evidence of an 
antiviral effect of ritonavir alone (see Figure 5). As such, ritonavir with placebo is expected to be an 
appropriate control for the PAXLOVID appendix.  
 

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Figure 5. Effect of PAXLOVID (PF-07321332) on lung viral titers following oral administration in BALB/c mice 
infected with SARS-COV-2-MA10  
Twice daily oral administration of PF-07321332 alone at 300 mg/kg or at 300 mg/kg in the presence of 50 mg/kg 
ritonavir reduced SARS-CoC-2 lung viral titer in mice. Mice (N=12) were inoculated with MA-SARS-CoV-2. 
***p<0.0005; ****p<0.0001; PF-3 = PF-07321332; R = ritonavir. 
13.6.1 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The control formulation includes two placebo tablets and one ritonavir tablet. The following ingredients 
are in a 210 mg placebo tablet: microcrystalline cellulose, NF (MC-102); pregelatinized starch, NF (Starch 
1500); croscarmellose sodium, NF (Vivasol, GF Grade); colloidal silicon dioxide, NF (Aerosil 200); and 
magnesium stearate, NF (2257).  
 
Control appearance will match that of all three PAXLOVID tablets (2 nirmatrelvir tablets and 1 ritonavir 
tablet):  
• 
The placebo for the 150 mg nirmatrelvir tablet is supplied as an oval, pink, film-coated tablets. 
• 
Ritonavir is supplied as ovaloid, white, film-coated tablets. 
 
The control packaging matches the packaging described in Section 13.5.2.  
 
13.6.2 CONTROL DISPENSING, STORAGE, AND STABILITY 
 
Store at 15°C to 30°C (59°F to 86°F). 
 
13.6.3 DOSING AND ADMINISTRATION 
 
Control dosing and administration will occur according to Section 13.5.4 in order to maintain blinding. 
 

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13.7 EVENTS OF SPECIAL INTEREST 
 
Alteration in Thyroid Function 
Alterations in thyroid function have been observed with patients who take PAXLOVID for longer than 10 
days. Therefore, all participants in the study will undergo evaluation of thyroid stimulating hormone 
(TSH), total and free triiodothyronine (T3), and total and free thyroxine (T4) at baseline, drug dosing 
midpoint clinic visit, EOD, and 90 days.  
 
Drug-Induced Liver Injury (DILI) 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt are 
termed “adaptors.” In some participants, transaminase elevations are a harbinger of a more serious 
potential outcome. These participants fail to adapt and therefore are “susceptible” to progressive and 
serious liver injury, commonly referred to as DILI. Participants who experience a transaminase elevation 
above 3 × upper limit of normal (ULN) should be monitored more frequently to determine if they are 
“adaptors” or are “susceptible.” 
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this study. 
However, should an investigator deem it necessary to assess LFTs because a participant presents with 
clinical signs/symptoms, such LFT results should be managed and followed as described below. 
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
transaminase (ALT) precede T bili (bilirubin) elevations (> 2 × ULN) by several days or weeks. The 
increase in T bili typically occurs while AST/ALT is/are still elevated above 3 × ULN (i.e., AST/ALT and T 
bili values will be elevated within the same laboratory sample). In rare instances, by the time T bili 
elevations are detected, AST/ALT values might have decreased. This occurrence is still regarded as a 
potential DILI. Therefore, abnormal elevations in either AST OR ALT in addition to T bili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases and should 
always be considered important medical events, even before all other possible causes of liver injury 
have been excluded. 
The threshold of laboratory abnormalities for a potential DILI case depends on the participant’s 
individual baseline values and underlying conditions. Participants who present with the following 
laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) cases to definitively 
determine the etiology of the abnormal laboratory values: 
1. Participants with AST/ALT and T bili baseline values within the normal range who subsequently 
present with AST OR ALT values ≥ 3 × ULN AND a T bili value ≥ 2 × ULN with no evidence of 
hemolysis and an alkaline phosphatase value < 2 × ULN or not available. 
2. For participants with baseline AST OR ALT OR T bili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on which 
values are above the ULN at baseline: 
a. Preexisting AST or ALT baseline values above the normal range: AST or ALT values ≥ 
2 times the baseline values AND ≥ 3 × ULN; or ≥ 8 × ULN (whichever is smaller). 

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b. Preexisting values of T bili above the normal range: T bili level increased from baseline 
value by an amount of ≥ 1 × ULN or if the value reaches ≥ 3 × ULN (whichever is smaller). 
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed individually based 
on clinical judgment; any case where uncertainty remains as to whether it represents a potential Hy’s 
law case should be reviewed with the sponsor.  
The participant should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include laboratory tests, 
detailed history, and physical assessment.  
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law cases, additional 
laboratory tests should include albumin, creatinine kinase, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time test and INR (PT/INR), total bile acids, and alkaline phosphatase. 
Consideration should also be given to drawing a separate tube of clotted blood and an anticoagulated 
tube of blood for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology. A detailed history, including relevant information, 
such as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated product in 
prescription or over-the-counter medications), recreational drug, or supplement (herbal) use and 
consumption, family history, sexual history, travel history, history of contact with a jaundiced person, 
surgery, blood transfusion, history of liver or allergic disease, and potential occupational exposure to 
chemicals, should be collected. Further testing for acute hepatitis A, B, C, D, and E infection, liver 
imaging (e.g., biliary tract), and collection of serum samples for acetaminophen/paracetamol drug 
and/or protein adduct levels may be warranted.  
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and T bili 
elevation defined above should be considered potential DILI (Hy’s law) cases if no other reason for the 
LFT abnormalities has yet been found. Such potential DILI (Hy’s law) cases are to be reported as SAEs, 
irrespective of availability of all the results of the investigations performed to determine etiology of 
the LFT abnormalities.  
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology. 
13.8 APPENDIX HALTING RULES 
Dosing and enrollment will be temporarily suspended pending review of the DSMB if three or more 
participants experience an SAE of the same type that is determined to be related to study intervention 
(s). The DSMB recommendations will be considered by the NIH and the study Principal Investigator prior 
to making any decisions regarding appendix continuation or discontinuation.