Conditions: Post-acute Sequelae of SARS-CoV-2 Infection Long COVID
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 168
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare whether being treated with nirmatrelvir plus ritonavir for 15 days works better than being treated with placebo plus ritonavir to reduce severe symptoms of Long Covid.

Participants will have 5 planned visits to the study clinic over 15 weeks and will take the drug (or placebo) for the first 15 days.

This study uses the term post-acute sequelae of SARS-CoV-2 (PASC), which is another name for "Long Covid."

Detailed description:
An exploratory sub-study will investigate the correlation of physical activity and biometric parameters from digital wearable devices with the subjective symptom severity and other patient-reported outcomes in the main study. All participants with iPhone 6S Plus or newer will be offered an opportunity to opt-in to this sub-study. An Apple Watch and Bluetooth-enabled blood pressure monitor will be provided to participants and data will be collected for the duration of the main study to track participants' physiological and behavioral trends in the Paxlovid versus placebo groups.

Arms:
arm 1: Participants receive nirmatrelvir plus ritonavir (Paxlovid) for 15 days, and attend follow-up visits through week 15. arm 2: Participants receive placebo to match nirmatrelvir plus ritonavir for 15 days, and attend follow-up visits through week 15.

Interventions: intervention 1: Nirmatrelvir intervention 2: Placebo intervention 3: Ritonavir
Intervention descriptions: intervention 1: Two 150 mg tablets taken by mouth every 12 hours intervention 2: Two tablets containing placebo matching nirmatrelvir taken by mouth every 12 hours intervention 3: One 100 mg capsule taken by mouth every 12 hours

Protocol document:
Prot_SAP_ICF_000.pdf: 
CONFIDENTIAL 
Selective Trial Of Paxlovid for PASC (STOP-PASC) 
Randomized Double-Blind Placebo-Controlled Pilot Trial of Paxlovid for the Treatment 
of PASC 
Protocol Number: 
66994 
IND Number:   
163308 
ClinicalTrials.gov ID: 
NCT05576662 
Study Phase:  
2 
Study intervention:  
nirmatrelvir-ritonavir (Paxlovid) 
Principal Investigator: 
Upinder Singh, M.D. 
Stanford University School of Medicine 
S-143 Grant Building
300 Pasteur Drive
Stanford, California, 94305-5107
Tel. 650-723-4045 | Fax. 650-498-9876
USingh@stanford.edu
Co-Principal Investigator:  Linda N. Geng, M.D., Ph.D. 
IND Sponsor:  
Funded by:   
Version Number:  
Date:  
Stanford University School of Medicine 
211 Quarry Rd. Ste 305 
MC 5987 
Palo Alto, California, 94304 
Tel. 650-723-4000 | Fax. 650-725-7078 
Geng@stanford.edu 
Upinder Singh, M.D. 
Pfizer Inc. 
1.8 
5 May 2023 


ii 
Document History 
Document 
Version Date 
Protocol version 1.8 
5 May 2023 
Protocol version 1.7 
27 March 2023 
Protocol version 1.6 
20 January 2023 
Protocol version 1.5 
5 December 2022 
Protocol version 1.4 
10 November 2022 
Protocol version 1.3 
31 October 2022 
Protocol version 1.2 
25 October 2022 
Protocol version 1.1 
14 October 2022 
Original Protocol 
30 August 2022 


  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................. 1 
1 
PROTOCOL SUMMARY ............................................................................................................................... 1 
1.1 
Synopsis ................................................................................................................................................ 1 
1.2 
Schema ................................................................................................................................................. 8 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 9 
2 
INTRODUCTION .......................................................................................................................................... 10 
2.1 
Study Rationale .................................................................................................................................. 10 
2.2 
Background ......................................................................................................................................... 10 
2.3 
Risk/Benefit Assessment .................................................................................................................. 12 
2.3.1 
Known Potential Risks ................................................................................................... 12 
2.3.2 
Known Potential Benefits .............................................................................................. 13 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 14 
3 
OBJECTIVES AND ENDPOINTS .............................................................................................................. 14 
4 
STUDY DESIGN ........................................................................................................................................... 17 
4.1 
Overall Design .................................................................................................................................... 17 
4.2 
Scientific Rationale for Study Design .............................................................................................. 18 
4.3 
Justification for Dose ......................................................................................................................... 19 
4.4 
End of Study Definition ..................................................................................................................... 19 
5 
STUDY POPULATION ................................................................................................................................ 20 
5.1 
Inclusion Criteria ................................................................................................................................ 20 
5.2 
Exclusion Criteria ............................................................................................................................... 21 
5.3 
Screen Failures .................................................................................................................................. 21 
5.4 
Strategies for Recruitment and Retention ...................................................................................... 22 
6 
STUDY INTERVENTION ............................................................................................................................ 23 
6.1 
Study Intervention(s) Administration ............................................................................................... 23 
6.1.1 
Study Intervention Description ..................................................................................... 23 
6.1.2 
Dosing and Administration ............................................................................................ 24 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 24 
6.2.1 
Acquisition and accountability ...................................................................................... 25 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 25 
6.2.3 
Product Storage and Stability ....................................................................................... 25 
6.2.4 
Preparation ...................................................................................................................... 25 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 25 
6.4 
Study Intervention Compliance ........................................................................................................ 26 
6.5 
Concomitant Therapy ........................................................................................................................ 26 
6.5.1 
Rescue Medicine ............................................................................................................ 28 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 28 
7.1 
Discontinuation of Study Intervention ............................................................................................. 28 
7.1.1 
Potential Cases of Decreased eGFR .......................................................................... 29 
7.1.2 
Potential COVID-19 reinfection .................................................................................... 29 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 29 
7.3 
Lost to Follow-Up ............................................................................................................................... 30 
8 
STUDY ASSESSMENTS AND PROCEDURES ...................................................................................... 30 
8.1 
Efficacy Assessments ....................................................................................................................... 30 
8.1.1 
PASC symptoms assessment ...................................................................................... 30 


  
 
iii 
8.1.2 
Patient reported outcomes (PRO) ............................................................................... 32 
8.1.3 
Clinical assessments ..................................................................................................... 33 
8.2 
Safety and Other Assessments ....................................................................................................... 34 
8.2.1 
Pregnancy ....................................................................................................................... 34 
8.2.2 
Laboratory tests .............................................................................................................. 34 
8.2.3 
Vital Signs ....................................................................................................................... 35 
8.2.4 
Acute COVID-19 reinfections ....................................................................................... 35 
8.3 
Adverse Events and Serious Adverse Events ............................................................................... 35 
8.3.1 
Definition of Adverse Events (AE) ............................................................................... 36 
8.3.2 
Definition of Serious Adverse Events (SAE) .............................................................. 37 
8.3.3 
Classification of an Adverse Event .............................................................................. 37 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 39 
8.3.5 
Adverse Event Reporting .............................................................................................. 39 
Table 1. Guidelines for reporting adverse events .................................................................................. 40 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 40 
8.3.7 
Reporting Events to Participants ................................................................................. 41 
8.3.8 
Events of Special Interest ............................................................................................. 41 
8.3.9 
Reporting of Exposures (Environmental, Pregnancy, Occupational) ..................... 43 
8.3.10 
Medication Errors ........................................................................................................... 45 
8.3.11 
Lack of Efficacy .............................................................................................................. 46 
8.4 
Unanticipated Problems .................................................................................................................... 46 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................. 46 
8.4.2 
Unanticipated Problem Reporting ................................................................................ 47 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 47 
8.5 
Pharmacokinetics .............................................................................................................................. 47 
8.6 
Genetics .............................................................................................................................................. 48 
8.7 
Biomarkers .......................................................................................................................................... 48 
8.7.1 
Specified Gene Expression (RNA) Research ............................................................ 49 
8.7.2 
Specified Protein Research .......................................................................................... 49 
8.7.3 
Specified Metabolomic Research ................................................................................ 49 
8.7.4 
Viral Load Assessments................................................................................................ 49 
8.7.5 
Retained Research Samples for Biomarkers ............................................................. 49 
8.8 
Digital Wearable Substudy ............................................................................................................... 50 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 51 
9.1 
Statistical Hypotheses ....................................................................................................................... 51 
9.2 
Sample Size Determination .............................................................................................................. 52 
9.3 
Populations for Analyses .................................................................................................................. 53 
9.4 
Statistical Analyses ............................................................................................................................ 53 
9.4.1 
General Approach .......................................................................................................... 53 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................. 54 
9.4.3 
Analysis of the Secondary Endpoint(s) ....................................................................... 54 
9.4.4 
Safety Analyses .............................................................................................................. 55 
9.4.5 
Baseline Descriptive Statistics ..................................................................................... 55 
9.4.6 
Planned Interim Analyses ............................................................................................. 55 
9.4.7 
Sub-Group Analyses ..................................................................................................... 56 
9.4.8 
Exploratory Analyses ..................................................................................................... 56 
9.4.9 
Supplemental Analyses ................................................................................................. 56 


  
 
iv 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 57 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 57 
10.1.1 
Informed Consent Process ........................................................................................... 57 
10.1.2 
Study Discontinuation and Closure ............................................................................. 58 
10.1.3 
Confidentiality and Privacy ........................................................................................... 58 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 59 
10.1.5 
Key Investigators ............................................................................................................ 59 
10.1.6 
Safety Oversight ............................................................................................................. 60 
10.1.7 
Clinical Monitoring .......................................................................................................... 61 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 61 
10.1.9 
Data Handling and Record Keeping ............................................................................ 61 
10.1.10 
Protocol Deviations ........................................................................................................ 62 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 63 
10.1.12 
Conflict of Interest Policy .............................................................................................. 63 
10.2 
Additional Considerations ................................................................................................................. 63 
10.3 
Abbreviations ...................................................................................................................................... 64 
10.4 
Protocol Amendment History ........................................................................................................... 65 
11 
REFERENCES ............................................................................................................................................. 68 
12 
APPENDICES ............................................................................................................................................... 71 
12.1 
Appendix 1. Informed Consent ........................................................................................................ 71 
12.2 
Appendix 2. Contraceptive and Barrier Guidance ...................................................................... 100 
12.2.1 
Male Participant Reproductive Inclusion Criteria .................................................... 100 
12.2.2 
Female Participant Reproductive Inclusion Criteria ................................................ 101 
12.2.3 
Woman of Childbearing Potential .............................................................................. 102 
12.2.4 
Contraception Methods ............................................................................................... 102 
12.3 
Appendix 3. DAIDs Toxicity Table Corrected v2.1 ..................................................................... 104 
12.4 
Appendix 4. IRB Reporting ............................................................................................................. 139 
12.5 
Appendix 5. Genetics ...................................................................................................................... 141 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the 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).  
 
All individuals who are responsible for the conduct, management, or oversight of this study 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 Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form 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 
 
PROTOCOL SUMMARY 
 
1.1 SYNOPSIS  
Brief Title 
Selective Trial of Paxlovid for PASC (STOP-PASC) 
Study Rationale 
Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) 
encompasses a variety of symptoms that persist beyond the acute 
phase of COVID-19 infection and can lead to chronic debilitation. 
There are currently no known effective therapies for PASC and the 
underlying mechanisms of pathogenesis are unclear, but viral 
persistence is one of several leading hypotheses. Thus, the overall 
goal of this study is to investigate the efficacy and safety of ritonavir-
boosted SARS-CoV-2 antiviral medication nirmatrelvir in participants 
with PASC and explore biological and digital wearable biometric 
markers of disease and disease severity.  
Study Description 
This study is an interventional efficacy and safety, phase II, double-
blind, 2-arm pilot study to investigate orally administered nirmatrelvir-
ritonavir (PAXLOVIDTM) compared with placebo-ritonavir (“placebo”) 
in outpatient adult participants with PASC. Eligible participants will 
be randomized 2:1 to receive nirmatrelvir-ritonavir or placebo-
ritonavir q12h for 15 days. Randomization will be stratified by 
vaccination status and number of core symptoms. We hypothesize 
that adult participants with PASC treated with Paxlovid for 15 days 


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will report reduced PASC symptom(s) severity at 10 weeks 
compared to placebo. 
Study Phase 
II 
Primary Objective 
• 
To compare the efficacy of a 15-day course of Paxlovid versus 
placebo in reducing symptom(s) severity of participants with 
PASC 
Secondary 
Objectives 
• 
To compare overall symptom burden of participants with PASC 
treated with Paxlovid versus placebo 
• 
To evaluate other patient-reported outcomes (e.g., functional 
status, global health status, etc.) in participants with PASC 
treated with Paxlovid versus placebo 
• 
To identify which core PASC symptom(s) are most responsive to 
Paxlovid treatment, if any 
Exploratory 
Objectives 
• 
To investigate potential biological biomarkers of PASC in 
participants treated with Paxlovid versus placebo 
• 
To investigate potential digital biometric biomarkers of PASC in 
participants treated with Paxlovid versus placebo 
 
Primary Endpoint 
• 
Core symptoms severity based on Likert-scale score at 10 weeks 
in participants treated with Paxlovid versus placebo. Core 
symptoms defined as: fatigue, brain fog, dyspnea, body aches, 
gastrointestinal symptoms, cardiovascular symptoms 
Secondary 
Endpoints 
• 
Core symptoms severity based on Likert-scale score at 15 days 
in participants treated with Paxlovid versus placebo 
• 
Proportion of participants reporting relief at 10 weeks of at least 
one core symptom for 2 weeks. Relief defined as reduction of 
severity from moderate to none or severe to mild/none, ≥ 2-point 
Likert score change 
• 
Proportion of participants with overall alleviation at 10 weeks in 
Paxlovid versus placebo group for 2 weeks. Overall alleviation 
defined as both: (1) any core symptom(s) that are none/mild 
(Likert 0 or 1) at baseline are none at 10 weeks and (2) any core 
symptom(s) that are moderate/severe (Likert 2 or 3) at baseline 
are none/mild at 10 weeks 
• 
Severity of the most bothersome symptom at 5 weeks, 10 
weeks, and 15 weeks in Paxlovid versus placebo group 
• 
Time to relief of each of the 6 core symptoms. Relief defined as 
above. 
• 
Change in PROMIS Physical Function SF 4a v2.0 from baseline 
to 10 weeks 
• 
Change in PROMIS Fatigue SF 7a v1.0 score between baseline 
and 10 weeks 


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• 
Change in PROMIS Dyspnea-Severity SF 5a v1.0 score 
between baseline and 10 weeks  
• 
Change in PROMIS Cognitive Function Abilities score between 
baseline and 10 weeks  
• 
Change in orthostatic vitals (difference in seated versus standing 
blood pressure and heart rate) from baseline and 10 weeks 
• 
Change in 1-minute sit-to-stand test from baseline and 10 weeks 
• 
Patient Global Impression of Severity scale (PGIS) at 15 days, 5 
weeks, 10 weeks, and 15 weeks in Paxlovid versus placebo 
group 
• 
Patient Global Impression of Change scale (PGIC) at Day 15, 5 
weeks, 10 weeks, and 15 weeks in Paxlovid versus placebo 
group 
Exploratory 
Endpoints 
• 
Clinical laboratory test: d-dimer 
• 
Stool RNA RT-qPCR to assess for presence of SARS-CoV-2 at 
baseline, 7 days, 15 days (immediately after treatment), 10 
weeks (1) 
• 
Difference in drug versus placebo and change from baseline of: 
o O-link cytokine profiles, specific chemokines such as 
CCL11, others (2) 
o Autoantibodies – bead-based, multiplexed assays (3, 4) 
o Bulk RNA-Sequencing (5) 
o Anti-SARS-CoV-2, EBV, CMV and other IgG responses, 
measured in a combined panel of autoantibodies 
described above (3)  
o Proportions of blood cells measured by flow cytometry, 
including anti-SARS-CoV-2 T cell responses measured 
using spheromers (6) 
• 
Other assays that may emerge regarding PASC pathophysiology 
• 
Change in digital biometric wearables measures from baseline to 
15 days, 5 weeks, 10 weeks, and 15 weeks in drug versus 
placebo groups for: 
o Physical activity (PA) measured by hand accelerometer 
o Ratio of daytime versus nighttime PA level 
o Time asleep and time in bed 
o Heart rate and resting heart rate 
o Heart rate variability  
o ECG rhythm abnormalities 
o O2 saturation 
o Blood pressure 
 
Safety Monitoring 
Frequency of adverse events and serious events will be analyzed in 
all study participants 


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Independent 
Oversight 
Committee 
An independent Data and Safety Monitoring Board (DSMB) 
comprised of members with relevant expertise in areas such as 
PASC, clinical trials, statistics, and/or virology will be responsible for 
safeguarding the interests of trial participants, assessing the safety 
and efficacy of the intervention during the trial, and for monitoring the 
overall conduct of the clinical trial. The DSMB will provide 
recommendations about stopping or continuing the trial or other 
protocol recommendations as deemed appropriate to enhance the 
integrity of the trial. 
Study Population 
200 adults with PASC will be randomized 
Study Location 
Single site – Stanford University   
Study Intervention 
• 
Nirmatrelvir (PF- 07321332) 300 mg (two 150mg tablets) plus 
ritonavir 100mg orally q12h for 15 days, OR 
• 
Matched placebo for nirmatrelvir (two tablets) plus ritonavir 
100mg orally q12h for 15 days 
Study Duration 
Entire study is estimated to last up to 12 months from first participant 
enrolled until the end-of-study for the last participant enrolled 
Participant Duration 
For each participant, the study lasts 15 weeks (3.5 months) 
Inclusion Criteria 
1. Adults 18 years and older 
2. Weight > 40 Kg 
3. Normal or near-normal renal function (eGFR ≥60 ml/min) 
4. History of confirmed COVID-19 infection (SARS-CoV-2 positive 
PCR/NAAT, positive antigen, positive nucleocapsid antibodies, 
or positive spike antibodies before vaccination for SARS-CoV-
2) by either documented test result or medical records OR by 
self-report of positive test (e.g., home rapid antigen test) with 
clinical and/or epidemiological features consistent with COVID-
19 infection (the latter group not to exceed 15% of total study 
sample size) 
5. Post-COVID-19 symptoms persisting greater than three months 
(>90 days) since the initial COVID-19 infection that caused the 
Long COVID. Symptoms must be present for more days than 
not, were not present prior to COVID-19 infection, and are not 
explained by another cause 
6. Patient’s post-COVID symptom(s) must be at least 2 of the 
following 6 core symptoms or symptom clusters:  
a. Fatigue 
b. Brain fog (including difficulty with focus, memory, word-
finding, processing, orientation, or multitasking) 
c. Shortness of breath 
d. Body aches (muscle or joint pain) 
e. Cardiovascular symptoms (including chest pain, 
tachycardia, palpitations, or lightheadedness) 


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f. 
Gastrointestinal symptoms (including nausea, vomiting, 
diarrhea, constipation, abdominal pain, or decreased 
appetite) 
7. Severity of at least two of the core PASC symptom(s) above 
must be moderate or severe, 2 or 3 on a Likert-scale of 0 to 3 
(where 0 is absent, 1 is mild, 2 is moderate, and 3 is severe) 
8. Willing to provide vaccination history and report all vaccinations 
received during the study, if any 
9. Women of childbearing potential (not surgically sterile or 2 
years postmenopausal) must use a medically accepted method 
of contraception during the treatment period and must agree to 
continue use of this method for 28 days after the last dose of 
the study intervention 
10. Women of childbearing potential must be agreeable to a urine 
pregnancy screening test 
11. Men whose partners may become pregnant must use adequate 
contraception during the treatment period and must agree to 
continue use of this method for 28 days after the last dose of 
the study intervention 
12. Willing and able to adhere to study procedures and available 
for the duration of the study 
Exclusion Criteria 
1. Suspected or confirmed pregnancy or breastfeeding 
2. Severe liver disease (Child-Pugh class C)  
3. Use of the study drug within past 30 days of randomization or 
planned use of the study drug outside of FDA-authorized 
indication for the duration of the study 
4. Receiving other COVID-19 specific treatments within 30 days 
of randomization 
5. History of hypersensitivity or other contraindication to any 
components of the study drug 
6. Current or expected use of any medications or substances that 
are highly dependent on CYP3A4 for clearance or are strong 
inducers of CYP3A4 or have known drug-drug interactions with 
study drug 
7. Use or planned use of any supplements or herbs during study 
drug administration and potential additional time before and 
after this period as determined necessary by investigators, 
unless medically indicated (e.g., for nutrient deficiency) and 
determined to be safe by investigators 
8. Known Human Immunodeficiency Virus (HIV) infection with 
viral load >50 copies/ml or taking prohibited medications for 
HIV treatment 
9. Suspected or confirmed active SARS-CoV-2 infection within 
past 30 days 
10. New or significant change in dosing as determined by study 
investigators of immune-modulating or immunosuppressive 


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medications within 30 days prior to enrollment until the primary 
endpoint (10 weeks) has been reached 
11. Any other medical condition or concomitant medication/therapy 
that would compromise the patient’s safety or compliance with 
the study protocol or significantly confound interpretation of the 
clinical and research tests, as determined by study 
investigators 
12. History of COVID vaccine received within 28 days prior to 
enrollment or other vaccine (including influenza vaccine, 
shingles vaccine, etc.) within 14 days of enrollment or planned 
use of any investigational, authorized, or approved vaccine until 
the primary endpoint (10 weeks) has been reached 
13. Current enrollment in, or discontinuation within the last 30 days 
from, a clinical trial involving any investigational drug or device, 
or concurrent enrollment in any other type of medical research 
judged not to be scientifically or medically compatible with this 
study  
14. Inability to provide informed consent 
15. Currently hospitalized 
Statistical 
Considerations 
We will evaluate the intention-to-treat (ITT) population, defined as 
the original treatment assignment groups after randomization, for the 
primary efficacy analysis. We will also analyze the per-protocol 
group as supportive evidence for the primary efficacy analysis. 
We plan to enroll 200 participants total with assumption that 180 
participants will complete the follow-up at 10 weeks, i.e., a 10% drop 
off rate. With a planned randomization ratio of 2:1, we expect 
approximately 120 participants receiving Paxlovid and 60 
participants receiving placebo completing the study. The primary 
outcome is symptom severity for the 6 core symptoms: fatigue, brain 
fog, dyspnea, body aches, cardiovascular symptoms, and 
gastrointestinal symptoms based on Likert-scale score (0, 1, 2, and 
3) at 10 weeks. Statistical hypotheses for the primary efficacy 
outcome: 
• 
H0 = There is no difference in the symptom severity in any of 
the 6 core symptoms at 10 weeks between Paxlovid and 
placebo groups. 
• 
H1 = There is a difference in the symptom severity of at least 
one of the 6 core symptoms at 10 weeks between Paxlovid 
and placebo groups. 
For each aforementioned symptom, we plan to use the proportional 
odds regression model for ordinal outcomes to compare the Likert 
scale at 10 weeks (stratified by their baseline level) among 
participants experiencing the corresponding symptoms at the 
baseline. The overall comparison will be made based on averaging 


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regression coefficients from comparisons of individual symptoms 
weighted by the sample size of the regression analysis, i.e., the 
number of participants experiencing the corresponding symptom at 
the baseline. The power estimation is made based on following 
simplified assumptions:  
(a) for each symptom, the Likert-scale at week 10 is 
uniformly distributed over 0, 1, 2, and 3 in the placebo 
group, i.e., the proportions of the participants with a 
Likert-scale being 0, 1, 2, and 3 are 25%, 25%, 25%, and 
25%, respectively, among all participants in the study 
including participants without the symptom at the 
baseline.  
(b) for each core symptom, the proportions of the participants 
in the Paxlovid group with a Likert-scale being 0, 1, 2, and 
3 are 34.8%, 26.8%, 21.2%, and 17.2%, respectively, 
among all study participants.  
(c) The z-scores of comparing 6 symptoms using all 
participants are positively correlated with a pair-wise 
correlation coefficient of 0.25. 
Assumptions (a) and (b) satisfy the proportional odds model with a 
odds ratio of 1.6. Under this assumption, the z-score of individual 
comparison based on 60 participants in the placebo group and 120 
participants in the Paxlovid group follows a normal distribution with 
mean of 1.66 and unit variance. The final test statistic is equivalent 
to the simple average of z-scores from analyses for individual 
symptoms, since the assumed alternatives are identical for all core 
symptoms. Under assumption (c) the Wald test statistic for the 
overall comparison follows a normal distribution with a mean of 2.71 
and unit variance, providing a power of 77% at the two-sided 
significance level of 0.05. The proposed test is expected to have a 
higher power than that of the analysis discussed above for several 
reasons. First, the regression analysis excluding participants without 
the core symptom at the baseline is expected to generate a z-score 
with a greater mean value and a higher power, since the potential 
dilution effect from participants without the core symptom at the 
baseline are reduced. Second, the sample size weighting is 
expected to generate a more efficient combination of test statistics 
from individual test than equal weighting. Lastly, the stratification by 
baseline Likert scale will also increase the power of comparing 
severity of individual symptom and also the power of overall 
comparison.   
 
 


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1.2 SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
Procedures 
Screening 
Day -14 to 0 
Baseline 
Day 0 
Day 7 +/-2 days 
Day 15 +/-2 days 
5 weeks 
Day 35 +/-7 days 
Primary Endpoint 
10 weeks 
Day 70 +/-7 days 
Final Study  
15 weeks 
Day 105 +/-14 day 
 
Unscheduled Visite 
 
Visits (V1-V5 +/-VU) 
 
V1 
 
V2 
V3h 
V4 
V5h 
VU 
Informed consent 
X 
 
 
 
 
 
 
 
Eligibility Assessment 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Concomitant medications 
X 
X --------------------------------------------------------------------------------------X 
X 
Concomitant supplements 
X 
X --------------------------------------------------------------------------------------X 
X 
Treatment 
Administer study 
intervention 
 
X--------15 days-------X 
 
 
 
 
 
Patient-reported outcomes (PROs) 
 
PASC symptoms (6 core) 
assessmenta 
X 
 
 
 X-------------- weekly ---------------X 
Q 2 weeks 
 
PASC symptoms (20 
expanded) assessmenta 
 
X 
X 
X 
X 
X 
X 
(X) 
Patient Global Impression 
of Severity (PGIS) scale 
 
X 
X 
X 
X 
X 
X 
(X) 
Patient Global Impression 
of Change (PGIC) scale 
 
 
X 
X 
X 
X 
X 
(X) 
PROMIS Physical 
Function survey 
 
X 
 
X 
X 
X 
X 
(X) 
PROMIS Fatigue-SF 
survey 
 
X 
 
X 
X 
X 
X 
(X) 
PROMIS Dyspnea severity 
survey 
 
X 
 
X 
X 
X 
X 
(X) 
PROMIS Cognitive 
Function Abilities survey 
 
X 
 
X 
X 
X 
X 
(X) 
Clinical assessments 
 
1-minute sit-to-stand test 
 
X 
 
X 
X 
X 
X 
(X) 
Orthostatics 
 
X 
 
X 
X 
X 
X 
(X) 
Vital signs 
 
X 
 
X 
X 
X 
X 
(X) 
Safety laboratory monitoring 
 
Complete blood countb 
X 
 
 
X 
 
 
 
 
Serum chemistryc,d 
X 
 
 
X 
 
 
 
 
Urine pregnancy test  
 
X 
 
 
 
 
 
 
COVID-19 antigen test 
 
X 
 
 
 
 
 
 
Other sample collection for exploratory measures 
 
D-dimer (blood) 
 
X 
 
X 
 
X 
 
 
Other blood collection (for 
immunologic assays, etc.) 
 
X 
 
X 
X 
X 
X 
(X) 
Nasopharyngeal swab 
 
X 
 
X 
X 
X 
X 
(X) 
Stool collection 
 
X 
Xf 
X 
 
X 
 
 
Other assessments 
 
Complete Case Report 
Forms (CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event review 
 
X -----------------------------------------------------------------------------------------X 
X 
Digital wearable sub-study (optional) 
Apple watch 
 
X ----------------------------------- (continuous)g ----------------------------------X 
X 


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Procedures 
Screening 
Day -14 to 0 
Baseline 
Day 0 
Day 7 +/-2 days 
Day 15 +/-2 days 
5 weeks 
Day 35 +/-7 days 
Primary Endpoint 
10 weeks 
Day 70 +/-7 days 
Final Study  
15 weeks 
Day 105 +/-14 day 
 
Unscheduled Visite 
 
Blood pressure monitor 
 
X ------------------------------- (daily to biweekly)g ------------------------------X 
 
a6 core symptoms are included in the 20 symptoms survey and not collected on the days when 20 symptoms survey is 
collected. 6 core symptoms assessment is collected every week until the primary endpoint (10 weeks) and then every 2 
weeks thereafter until study completion. 
b,cscreening laboratory data can be provided by chart review or patient records if available within the 6 months prior or 
since index COVID-19 infection data, whichever is the shorter timeframe, assuming no major interval medical events 
have occurred since those results. 
dalbumin, AST, ALT, total bilirubin, creatinine 
eif there has been a relevant change in clinical status as determined by investigator and select assessments and 
specimen collection may be performed per investigator’s discretion 
fhome stool collection 
gtarget goal data collection schedule detailed in Section 8.8, as able by participant 
hin-person activities for visits #3 and #5 may be optional for select participants with significant travel or other logistical 
barriers per investigator’s discretion. Relevant electronic PROs will be collected on all participants for all visits.  
 
 
 
 
 
 
2 
 
INTRODUCTION 
2.1 STUDY RATIONALE  
 
Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a major public health crisis in 
the wake of the ongoing pandemic, with estimates of over 27 million PASC cases in the United 
States alone as of August, 2022 (7, 8). PASC encompasses various conditions and symptoms, 
such as fatigue, brain fog, and dyspnea, that develop in about 10-30% of individuals after their 
initial COVID-19 infection and can last for months or longer with significant impact on quality of 
life and function (9-11). The underlying mechanisms of disease are unclear and there are 
currently no known effective therapies to treat PASC. Given the large-scale impact of PASC 
globally on the individual patient and the broader society and economy, there is an urgency for 
rigorous and timely evaluation of potential treatments. 
 
 
2.2 BACKGROUND  
 
Several hypotheses have been proposed to explain the multiple symptoms present in 
PASC, and one of the leading hypotheses is viral persistence. Several diseases are caused by 
persistent viral infections including acquired immune deficiency syndrome (AIDS), AIDS-related 
complexes, chronic hepatitis B and C, Ebola, subacute sclerosing panencephalitis (chronic 
measles encephalitis), herpes viruses, chronic papovaviral encephalitis (progressive multifocal 
leukoencephalopathy), spongiform encephalopathies (caused by prions), several herpesvirus-
induced diseases, and some neoplasia. The pathogenic mechanisms by which these viruses 


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cause disease include disorders of biochemical, cellular, immune, and physiologic processes 
(12-16). 
SARS-CoV-2 infection can exhibit prolonged viral RNA shedding up to 83 days in the upper 
respiratory tract and 126 days in the stool, but no live virus has thus far been isolated from 
culture beyond day 9 of symptoms (17). Although a human SARS-Cov-2 viral reservoir has not 
been identified, periodontal pockets have been hypothesized to be potential anatomical sites for 
the viral reservoir (18). An increasing number of studies have shown the presence and 
persistence of SARS-CoV-2 virus RNA or particles in various tissues (1, 19-22). In autopsy 
specimens, Chertow et al., detected persistent SARS-Cov-2 RNA in multiple anatomical sites 
including the brain for up to 230 days.  Those sites were associated with increased inflammatory 
changes and cytopathological effects (23). The same authors demonstrated different variants in 
the brain than respiratory tract, implying extrapulmonary tissue replication (23). In some 
individuals the viral persistence may drive disruption of immune responses, dysbiosis, and 
PASC symptoms (19, 21, 24). Changes in the bacterial, fungal, and viral gut microbiome have 
been reported as a consequence of SARS-CoV-19 infection (25). Patients with prolonged 
symptoms had demonstrated alterations in the composition of the microbiome with higher levels 
of Ruminococcus and Bacteroides and lower levels of Faecalibacterium (26). We and others 
have reported cases of patients with PASC whose symptoms improved after Paxlovid 
administration, highlighting the need to study this antiviral agent in a controlled and well-
designed clinical trial (27, 28). Unpublished analysis from 140 patients referred to the Stanford 
post-COVID-19 demonstrated the most common symptoms were fatigue (86.5%), post-
exertional malaise (82.8%), brain fog (81.2%), difficulty sleeping (76.7%), and daytime 
sleepiness (74.6%) and frequency correlated with the severity of the illness. 
This study is a randomized, placebo-controlled trial that is designed to assess the efficacy 
of an oral antiviral therapy in reducing severity of specific PASC symptoms and explore 
biological  markers of disease and treatment outcomes. 
 
Investigational product: nirmatrelvir-ritonavir (trade name: PAXLOVID™) 
Nirmatrelvir is a peptidomimetic inhibitor of SARS-CoV-2 main protease (Mpro), also referred to 
as 3C-like protease (3CLpro) or nsp5 protease. Inhibition of SARS-CoV-2 Mpro renders it 
incapable of processing polyprotein precursors, preventing viral replication. Nirmatrelvir is 
boosted with low-dose ritonavir that slows nirmatrelvir metabolism via inhibition of CYP3A4, and 
thereby provides higher systemic exposure. Ritonavir has no direct activity against SARS-CoV-
2. For this study, the dose and exposure is 300 mg nirmatrelvir plus 100 mg ritonavir PO q12h 
for 15 days. 
 
Previous human experience: Briefly, the clinical development program has included Phase 1 
FIH/PK/DDI studies, and several completed phase 2/3 studies, including EPIC-SR (Standard 
Risk), EPIC-HR (High Risk), and EPIC-PEP (Post-Exposure Prophylaxis). An ongoing Phase 2 
study (NCT05438602) is evaluating the efficacy and safety of a 15-day course of PAXLOVID in 
immunocompromised patients with symptomatic COVID-19.  The EPIC-HR study, a large phase 
2-3 double-blind, randomized, controlled trial demonstrated that treatment of symptomatic acute 
COVID-19 in individuals with high risk for progression to severe disease with Paxlovid had an 
89% lower risk of COVID-19-related hospitalization or death (29). In December, 2021, the Food 
and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for 
nirmatrelvir/ritonavir for the treatment of patients: (1) with mild to moderate COVID-19 within five 
days of symptom onset, and (2) at a high risk of progression to severe disease. In the EPIC-HR 


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study, the incidence of adverse events that emerged during the treatment period was similar in 
the two arms (any adverse event, 22.6% with Paxlovid vs. 23.9% with placebo; serious adverse 
events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 
2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more 
frequently with Paxlovid than with placebo (29). Results from the aforementioned studies as well 
as real-world post-authorization use consistently support the safety profile for Paxlovid in the 
treatment of acute COVID-19 (30-32).  
 
Reference to previously submitted IND application(s) and/or marketed products:  
A letter of Cross Reference authorizing the FDA to review Chemistry, Manufacturing and 
Control Information on IND 153517 has been provided by the manufacturer Pfizer, Inc. It is filed 
under Additional Information in this application. 
 
 
2.3 RISK/BENEFIT ASSESSMENT   
 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of nirmatrelvir-ritonavir may be found in the FDA EUA fact sheet (33) and 
investigator’s brochure (IB). The SRSD for ritonavir is the USPI for NORVIR (34).  
 
 
2.3.1 KNOWN POTENTIAL RISKS  
 
As per drug label and EPIC-HR study (29), adverse events (all grades regardless of causality) in 
the PAXLOVID group (≥1%) that occurred at a greater frequency (≥5 subject difference) than in 
the placebo group were dysgeusia (6% and <1%, respectively), diarrhea (3% and 2%), 
hypertension (1% and <1%), and myalgia (1% and <1%). Additional adverse reaction 
considerations are also detailed below. 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) nirmatrelvir (alias: PF-07321332) 
Emesis 
Sporadic emesis was observed at 
≥100 mg/kg/day of PF-07321332 in the 
15-day non-human primate (NHP) 
toxicology study. 
AEs will be monitored and 
participants may receive 
antiemetics. 
Hypertension 
Transient increases in systolic, diastolic, 
and mean blood pressure were 
observed in the preclinical studies. In 
Study C4671005 (adults at high risk for 
severe disease), a small imbalance in 9 
participants with reported events of  
hypertension was reported (1% vs <1%). 
Vital signs will be monitored per 
SoA during the study during any 
in-clinic visits. All AEs will be 
monitored in the study. 
Concomitant medications will 
also be reviewed for potential 
new AEs and worsening of the 
condition. 


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Potential Risk of Clinical 
Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s): Ritonavir 
Gastrointestinal 
disturbances (including 
diarrhea, nausea, vomiting 
and abdominal pain) 
Frequently reported adverse reaction in 
HIV-positive patients who are HIV-
positive at 600 mg BID. 
Lower dose of 100 mg twice daily 
is used in this study. There will be 
close observation of AEs.  
In addition to ongoing review of 
AEs by the sponsor, a DSMB will 
review safety data as described in 
Section 10.1.6. 
Taking study intervention with 
food may improve tolerability. 
Neurological disturbances 
(eg, paresthesia, including 
oral paresthesia, dysgeusia 
and dizziness) 
Frequently reported adverse reaction in 
patients who are HIV-positive at 600 mg 
BID. 
Lower dose used in this study. 
There will be close observation of 
AEs.   
In addition to ongoing review of 
AEs by the sponsor, a DSMB will 
review safety data as described in 
Section 10.1.6.  
Rash (most commonly 
reported as erythematous 
and maculopapular, 
followed by pruritic) 
Frequently reported adverse reaction in 
patients who are HIV-positive at 600 mg 
BID. 
Lower dose used in this study. 
There will be close observation of 
AEs and monitoring through 
targeted clinical exams. If 
needed, therapeutic interventions 
per SoC may be provided. 
Fatigue/Asthenia 
Frequently reported adverse reaction in 
patients who are HIV-positive at 600 mg 
BID. 
Lower dose used in this study. 
There will be close observation of 
AEs. Fatigue will be assessed 
through regular symptoms 
surveys and will also be assessed 
through targeted clinical 
examinations when performed 
during the study visits. 
 
 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
Benefits to individual participants may include: 
• Receipt of a potentially efficacious PASC treatment 


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• Access to COVID-19 diagnostic testing 
• Contributing to research to help others in a time of a public health crisis given the 
millions globally impacted by PASC 
 
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
 
Taking into account the current COVID-19 global pandemic with millions around the world 
impacted by PASC and the high burden on individuals, healthcare systems, and society at 
large, the complete lack of readily available and effective treatment options, the safety data on 
the interventional product, and the measures taken to minimize risk to participants in this study, 
the potential risks identified in association with nirmatrelvir-ritonavir are justified by the 
anticipated benefits that may be afforded to participants with PASC. An independent DSMB will 
be responsible for monitoring the safety of participants at regularly scheduled intervals 
throughout the duration of the study and for assessing safety and futility using conditional power 
at the time of the interim analysis according to the DSMB charter. 
 
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
Primary 
 
 
To compare the efficacy of a 
15-day course of Paxlovid 
versus placebo in reducing 
symptom(s) severity of 
participants with PASC 
 
Core symptoms severity based on 
Likert-scale score at 10 weeks in 
participants treated with Paxlovid 
versus placebo. Core symptoms 
defined as: fatigue, brain fog, 
dyspnea, body aches, gastrointestinal 
symptoms, cardiovascular symptoms 
The primary endpoint 
was chosen for the 
following 
considerations: 
clinically meaningful, 
patient-centered, 
accounts for 
heterogeneous 
spectrum of PASC 
while focusing on 
symptoms that are 
most prevalent, most 
disruptive to patients, 
and most likely to be 
proximal in the 
hypothesized disease 
mechanism targeted 
by intervention 
(without knowing a 
priori which 
symptom(s) may be 
most impacted, if 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
the primary endpoint 
was selected to 
ensure sufficient 
follow-up after 
treatment to assess 
durability of response 
(if any) while also 
considering public 
health urgency of 
study and potential 
for confounding 
events to occur as 
time elapses. 
Secondary 
 
 
To compare other measures 
of symptoms severity and 
overall symptom burden of 
participants with PASC 
treated with Paxlovid versus 
placebo 
 
To identify which core PASC 
symptom(s) are most 
responsive to Paxlovid 
treatment, if any  
• 
Core symptoms severity based on 
Likert-scale score at 15 days in 
participants treated with Paxlovid 
versus placebo 
• 
• Proportion of participants reporting 
relief at 10 weeks of at least one 
core symptom for 2 weeks. Relief 
defined as reduction of severity from 
moderate to none or severe to 
mild/none, ≥2-point Likert score 
change from baseline 
• Proportion of participants with 
overall alleviation at 10 weeks in 
Paxlovid versus placebo group for 2 
weeks. Overall alleviation defined as 
both: (1) any core symptom(s) that 
are none/mild (Likert 0 or 1) at 
baseline are none at 10 weeks and 
(2) any core symptom(s) that are 
moderate/severe (Likert 2 or 3) at 
baseline are none/mild at 10 weeks 
• Severity of the most bothersome 
symptom, designated by patient at 
baseline, at 5 weeks, 10 weeks, and 
15 weeks in Paxlovid versus 
placebo group 
•Time to relief of each of the 6 core 
symptoms. Relief defined as above. 
 
Other measures of 
patient-reported 
symptoms such as 
summative symptom 
burden, proportion of 
participants achieving 
relief, and time-to-
relief are also 
clinically meaningful 
efficacy measures 
and may be 
responsive to the 
intervention that offer 
additional support to 
effect of intervention. 
 
Additional secondary 
endpoints were also 
chosen to assess 
each of the core 
symptoms 
individually to identify 
best responders who 
may be enriched in 
enrollment in follow-
on studies. 
 
 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
To evaluate other patient-
reported outcomes (e.g., 
functional status, global 
health status, etc.) in 
participants with PASC 
treated with Paxlovid versus 
placebo 
 
• Change in PROMIS Physical 
Function SF 4a v2.0 from baseline 
to 10 weeks 
• Change in PROMIS Fatigue SF 7a 
v1.0 score between baseline and 10 
weeks 
• Change in PROMIS Dyspnea-
Severity SF 5a v1.0 score between 
baseline and 10 weeks  
• Change in PROMIS Cognitive 
Function Abilities score between 
baseline and 10 weeks 
• Patient Global Impression of 
Severity scale (PGIS) at 15 days, 5 
weeks, 10 weeks, and 15 weeks in 
Paxlovid versus placebo group 
• Patient Global Impression of 
Change scale (PGIC) at 15 days, 5 
weeks, 10 weeks, and 15 weeks in 
Paxlovid versus placebo group 
 
 
Given the paucity of 
PASC-specific PROs, 
these broadly used 
and validated PROs 
were chosen as 
secondary efficacy 
measures and to 
correlate with PASC 
symptoms 
assessments in 
global or specific 
domains. 
To evaluate clinical 
measures related to core 
symptoms in participants 
with PASC treated with 
Paxlovid versus placebo 
 
• Change in orthostatic vitals 
(difference in seated versus 
standing blood pressure and heart 
rate) from baseline and 10 weeks 
• Change in 1-minute sit-stand test 
from baseline and 10 weeks 
 
These are potential 
objective surrogate 
clinical measures of 
efficacy outcomes 
that match core 
PASC symptom 
domains and deficits. 
Exploratory  
 
 
To investigate potential 
biological biomarkers of 
PASC in participants treated 
with Paxlovid versus placebo 
 
• Clinical laboratory tests including d-
dimer  
• Stool RNA RT-qPCR to assess for 
presence of SARS-CoV-2 at 
baseline, 7 days, 15 days 
(immediately after treatment), 10 
weeks (1)  
• Difference in drug versus placebo 
and change from baseline of: 
o O-link cytokine profiles, specific 
chemokines such as CCL11, 
others (2) 
o Autoantibodies – bead-based, 
multiplexed assays (3, 4) 
There are no known 
biological markers of 
PASC or PASC 
severity. These 
exploratory measures 
were chosen based 
on mechanistic 
rationale related to 
viral and 
immunological 
factors that may be 
associated with 
PASC and respond 
to the study 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
FOR ENDPOINTS 
o Bulk RNA-Sequencing (5) 
o Anti-SARS-CoV-2, EBV, CMV 
and other IgG responses, 
measured in a combined panel 
of autoantibodies described 
above (3)  
o Proportion of blood cells 
measured by flow cytometry, 
including anti-SARS-CoV-2 T 
cell responses measured using 
spheromers (6) 
• Other assays that may emerge 
regarding PASC pathophysiology  
 
exploration of new 
hypotheses of 
underlying disease 
mechanisms and 
identification of novel 
and objective 
biomarkers of 
disease. 
To investigate potential 
digital biometric markers of 
PASC symptom severity and 
correlate with intervention 
outcomes 
 
(substudy) 
• Change in digital wearable biometric 
measures over time in drug versus 
placebo groups for: 
o Physical activity (PA) measured 
by hand accelerometer 
o Ratio of daytime versus 
nighttime PA level 
o Time asleep and time in bed 
o Heart rate and resting heart rate 
o Heart rate variability  
o ECG rhythm abnormalities 
o O2 saturation 
o Blood pressure 
 
These physiological 
and behavioral 
biometric endpoints 
were chosen as 
correlates to 
symptom domains 
(e.g., cardiovascular, 
dyspnea, fatigue) and 
to explore additional 
objective measures 
of PASC severity and 
functional debilitation. 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
This is a phase 2, single-center, randomized, double-blind, placebo-controlled pilot trial to 
evaluate the efficacy and safety of nirmatrelvir-ritonavir (Paxlovid) in treating PASC in adults 
and to explore potential biological and digital wearable biometric markers of disease. A total of 
200 participants with PASC who meet all the inclusion criteria will be randomized 2:1 to a 15-
day course of twice-daily (a) Paxlovid (nirmatrelvir 300 mg – ritonavir 100 mg), or (b) placebo 
(placebo 0 mg – ritonavir 100 mg). A total of ~133 and ~67 participants will be enrolled in the 
two arms above, respectively. Randomization will be stratified by the number of moderate or 


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severe core symptoms (2 or 3 vs >3) and vaccination status (completed primary series vs not 
completed as defined by CDC (35)). The randomization list for each stratum will be generated 
by block randomization with block size randomly selected from 6 and 9. Symptoms severity 
assessments, patient-reported outcomes (PROs), clinical assessments, and specimen 
collection will be performed at the time points shown in SoA.  
 
Hypothesis: Adult PASC patients treated with Paxlovid for 15 days will report reduced PASC 
symptoms severity at 10 weeks compared to placebo. 
 
Interim analysis is planned and detailed in Section 9.4.6 “Planned Interim Analysis.” 
 
Sub-study: An exploratory sub-study will investigate the correlation of physical activity and 
biometric parameters from digital wearable devices with the subjective symptom severity and 
other patient-reported outcomes in the main study. All participants with iPhone 6S Plus or newer 
will be offered an opportunity to opt-in to this study. An Apple Watch and Bluetooth-enabled 
blood pressure monitor will be provided to participants and data will be collected for the duration 
of the main study to track participants’ physiological and behavioral trends in the Paxlovid 
versus placebo groups. About 100-120 participants are expected to enroll into the substudy 
based on regional iPhone use rates. 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
General considerations:  There are currently major challenges facing any clinical trial 
designed to address interventions in PASC: (1) There is not a precise clinical definition of PASC 
and it is currently defined by a time-frame rather than specific clinical criteria or diagnostic test, 
(2) heterogeneity is a hallmark of this condition, (3) there are no known biomarkers or other 
objective measures of PASC or PASC severity, (4) the underlying disease mechanism(s) is/are 
unclear, (5) there are no standard eligibility criteria or standard endpoints for PASC trials, and 
(6) there are no validated, disease-specific symptom assessment tools that have been used in 
published clinical research studies for PASC. This trial was designed with these limitations in 
mind and comprises significant exploratory components that will help address these gaps in 
knowledge and inform follow-on studies. 
 
Specific considerations: 
Placebo arm – The study intervention is nirmatrelvir that is pharmacologically boosted by low-
dose ritonavir. The ritonavir has no activity against SARS-CoV-2 but accounts for the dysgeusia 
that is reported in a small percentage of individuals who take nirmatrelvir-ritonavir (29). In order 
to avoid unblinding to the participant based on this side effect, the placebo arm is a placebo 
(matched to nirmatrelvir) given with ritonavir. The current standard of care for PASC is based on 
expert consensus recommendations of supportive lifestyle measures such as pacing, healthy 
diet, etc. There are no known effective therapeutic interventions for PASC. 
 
Patient population – The eligibility criteria were selected with consideration of balancing 
inclusivity and precision, prioritizing safety (e.g., drug-drug interactions), and taking into account 
significant confounding factors that will impact interpretation of outcomes (e.g., acute infections, 
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Randomization ratio – Although a 1:1 ratio would have been selected under the assumption of 
equipoise, based on our experience with PASC patients, we anticipate that many participants 
may not want to have a 50% chance of being randomized to placebo given the significant 
debilitation of PASC in many individuals and their urgency to find effective therapies. We, 
therefore, increased the ratio (2:1 drug:placebo) to reduce the chance of being randomized to 
placebo to 33% to mitigate potential enrollment barriers.  
 
Randomization stratification variables – Total core symptom burden and vaccination history are 
likely to influence treatment responsiveness and, therefore, randomization will be stratified by 
these variables in a binary fashion to ensure balance in the treatment groups with respect to 
each of these variables. 
 
Endpoints – See Section 3 “Objectives and Endpoints” for details on justifications of primary, 
secondary, and exploratory endpoints.  
 
Duration of treatment and follow-up – These timeframes were determined based on 
considerations of existing safety data, the chronicity of PASC, and also reported potential 
rebound of symptoms in the acute COVID-19 treatment setting (36).  
 
 
 
4.3 JUSTIFICATION FOR DOSE 
 
An oral dosing regimen of 300 mg nirmatrelvir administered with 100 mg ritonavir q12h 
administered orally for 15 days will be evaluated in this study. Dose selection for this study 
included consideration of all relevant available preclinical and clinical data, including repeat-
dose toxicology studies, clinical safety, and PK data from Phase 1 study and in vitro 
pharmacology studies with nirmatrelvir.  
 
The selected duration is based on effectiveness of 5-day administration of study drug used in 
treatment of acute SARS-CoV-2 and the hypothesized need for longer duration in treatment of a 
persistent viral reservoir causing chronic symptoms. Additionally, there is consideration of 
potential rebound symptoms that have been reported for the 5-day course (36). Safety data 
from the Phase 1 dosing study in humans included well-tolerated use at 750 mg nirmatrelvir with 
100 mg ritonavir q12h for 10 days which is higher dosing than in this study (30). There is also 
currently an ongoing clinical trial evaluating nirmatrelvir-ritonavir 300mg-100mg q12hr up to 15 
days for treating COVID-19 in adults and adolescents who are immunocompromised 
(NCT05438602). Please see above Section 2.2 Background regarding previous human 
experience. 
 
 
4.4 END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 


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Activities (SoA), or has withdrawn from the study, or is lost to follow-up as defined in Section 
7.3.  
 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in 
the trial globally. 
 
 
 
 
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. Adults 18 years and older 
2. Weight > 40 Kg 
3. Normal or near-normal renal function (eGFR ≥60 ml/min based on CKD-EPI formula as 
per drug label) 
4.  History of confirmed COVID-19 infection (SARS-CoV-2 positive PCR/NAAT, positive 
antigen, positive nucleocapsid antibodies, or positive spike antibodies before vaccination 
for SARS-CoV-2) by either documented test result or medical records OR by self-report of 
positive test (e.g., home rapid antigen test) with clinical and/or epidemiological features 
consistent with COVID-19 infection (the latter group not to exceed 15% of total study 
sample size) 
5. Post-COVID-19 symptoms persisting greater than three months (>90 days) since the initial 
COVID-19 infection that caused the Long COVID. Symptoms must be present for more 
days than not, were not present prior to COVID-19 infection, and are not explained by 
another cause 
6. Patient’s post-COVID symptom(s) must be at least 2 of the following 6 core symptoms or 
symptom clusters:  
a. Fatigue 
b. Brain fog (including difficulty with focus, memory, word-finding, processing, 
orientation, or multitasking) 
c. Shortness of breath 
d. Body aches (muscle or joint pain) 
e. Cardiovascular symptoms (including chest pain, tachycardia, palpitations, 
lightheadedness) 
f. 
Gastrointestinal symptoms (including nausea, vomiting, diarrhea, constipation, 
abdominal pain, decreased appetite) 
7. Severity of at least two of the core PASC symptom(s) above must be moderate or severe, 
2 or 3 on a Likert-scale of 0 to 3 (where 0 is absent, 1 is mild, 2 is moderate, and 3 is 
severe) 
8. Willing to report all vaccinations received prior to and during the study, if any 
9. Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must 
use a medically accepted method of contraception during the treatment period and must 


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agree to continue use of this method for 28 days after the last dose of the study 
intervention 
10. Women of childbearing potential must be agreeable to a urine pregnancy screening test 
11. Men whose partners may become pregnant must use adequate contraception during the 
treatment period and must agree to continue use of this method for 28 days after the last 
dose of the study intervention  
12. Willing and able to adhere to study procedures and available for the duration of the study 
 
5.2 EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1. Suspected or confirmed pregnancy or breastfeeding 
2. Severe liver disease (Child-Pugh class C) 
3. Use of the study drug within past 30 days of randomization or planned use of the study 
drug outside of FDA-authorized indication for the duration of the study 
4. Receiving other COVID-19 specific treatments within 30 days of randomization 
5. History of hypersensitivity or other contraindication to any components of the study drug 
6. Current or expected use of any medications or substances including supplements and 
herbs that are highly dependent on CYP3A4 for clearance or are strong inducers of 
CYP3A4 or have known drug-drug interactions with study drug 
7. Use or planned use of any supplements or herbs during study drug administration and 
potential additional time before and after this period as determined necessary by 
investigators, unless medically indicated (e.g., for nutrient deficiency) and determined to 
be safe by investigators 
8. Known Human Immunodeficiency Virus (HIV) infection with viral load >50 copies/ml or 
taking prohibited medications for HIV treatment 
9. Suspected or confirmed active SARS-CoV-2 infection within past 30 days 
10. New or change in the dosing of immune-modulating or immunosuppressive medications 
within 30 days prior to enrollment until the primary endpoint (10 weeks) has been reached 
11. Any other medical condition or concomitant medication/therapy that would compromise the 
patient’s safety or compliance with the study protocol or significantly confound 
interpretation of the clinical and research tests, as determined by study investigators 
12. History of COVID vaccine received within 28 days prior to enrollment or other vaccine 
(including influenza vaccine, shingles vaccine, etc.) within 14 days of enrollment or 
planned use of any investigational, authorized, or approved vaccine until the primary 
endpoint (10 weeks) has been reached 
13. Current enrollment in, or discontinuation within the last 30 days from, a clinical trial 
involving any investigational drug or device, or concurrent enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study  
14. Inability to provide informed consent 
15. Currently hospitalized 
 
 
5.3 SCREEN FAILURES 


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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. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
an easily modifiable factor (e.g., over-the-counter supplement use) or temporary factor (e.g., 
positive COVID-19 rapid antigen test) may be rescreened at a later time. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
5.4 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Recruitment:  We will employ the following tiered recruitment and screening strategy for our 
target enrollment of 200 participants total in this single-center trial:  
1. We will directly recruit from our Stanford PASC clinic (“Post-Acute-COVID-19 Syndrome 
Clinic”) which follows over 300 patients with PASC and from the long clinic waitlist.  
2. We will recruit from our multiple Stanford research cohorts including patients whom we 
have followed long-term after their initial acute COVID-19 infection. 
3. We will recruit through our Stanford Healthcare network of healthcare professionals who 
may care for or know someone with PASC. 
4. We will recruit through our PASC physician colleagues who lead regional post-COVID 
care centers (e.g., UCSF and UC Davis). 
5. We will recruit through physical and web-based flyers, advertisements including via 
social media outlets and patient advocacy groups. Recruitment materials will be 
available in Spanish and potentially other languages and posted to community clinics to 
promote diversity in enrollment and outreach to historically underrepresented 
populations. 
6. We will screen interested participants with direct phone calls with our study team to 
assess eligibility criteria. We will also utilize a pre-screening self-referral web tool to 
allow more efficient in-flow into our formal screening process. 
 
Specific strategies to recruit diverse populations: Patient-facing materials including study 
advertisements, recruitment materials, patient self-referral form, etc. will be translated to 
Spanish. Additionally, there will be direct outreach to community clinics and county medical 
centers that serve diverse and historically underrepresented populations. 
 
Retention:  Participants will be engaged in the study through multiple channels including: 
• 
Compensation for participants during each study visit 
• 
Visit reminders and multiple contact methods to participants by our clinical research 
coordinators (CRCs) 
• 
Developing participant-centered approaches that recognize the needs and 
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• 
Multifaceted approaches that combine engagement tools, education, effective 
communication, online systems, social media, and advocacy resources. 
 
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. For the purposes of this protocol, study intervention 
refers to: nirmatrelvir (PF-07321332) 150 mg tablets with ritonavir 100 mg capsules or matching 
placebo with ritonavir 100 mg capsules. Nirmatrelvir or placebo will be 150 mg Oval Pink 
Coated Tablets that will be packaged in a blister pack while ritonavir consists of capsules stored 
in a bottle. The participant will receive 3 blister packets and 3 bottles of ritonavir.  
 
Intervention Name 
Nirmatrelvir 
Placebo for nirmatrelvir 
Ritonavir  
ARM Name 
(group of patients 
receiving a specific 
treatment (or no 
treatment)) 
Nirmatrelvir-Ritovanir 
(Paxlovid) 
Placebo 
Both arms 
Type 
drug 
placebo 
drug 
Dose Formulation 
tablet 
tablet 
capsule 
Unit Dose 
Strength(s) 
150 mg  
0 mg 
100 mg 
Dosage Level(s) 
300 mg q12h for 
15 days 
0 mg q12h for 15 days 
100 mg q12h for 
15 days 
Route of 
Administration 
oral 
oral 
oral 
Use 
experimental 
placebo 
experimental/control 
IMP or NIMP 
IMP 
IMP 
IMP 
Sourcing 
Provided by Pfizer, Inc. 
Provided by Pfizer, Inc. 
Provided by Pfizer, Inc. 
Packaging and 
Labeling 
Study intervention will 
be provided in blister 
wallets. Each wallet will 
be labeled as required 
Study intervention will be 
provided in blister 
wallets. Each wallet will 
Study intervention will 
be provided in HDPE 
bottles. Each bottle will 


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per country 
requirement. Products 
will be provided with 
blinded labels. 
be labeled as required 
per country requirement. 
be labeled as required 
per country requirement. 
Current/Former 
Name(s) or 
Alias(es) 
Nirmatrelvir 
PF-07321332 
N/A 
ritonavir 
 
6.1.2 DOSING AND ADMINISTRATION 
 
Nirmatrelvir 150 mg tablets or placebo for nirmatrelvir, will be administered for 15 days with 
ritonavir 100 mg capsules. Participants will be dispensed 1 blister wallet of PF-07321332 150 
mg or placebo for PF-07321332 tablets and 1 bottle of ritonavir capsules. Participants will be 
given clear dosing instruction to take: 
• 
2 tablets of nirmatrelvir 150 mg or placebo q12h 
• 
1 capsule of ritonavir 100 mg q12h 
 
Participants should take nirmatrelvir/placebo and ritonavir at the same time (no more than 
15 minutes apart). The study intervention should be taken every 12 hours (±4 hours), and not 
more than twice in a calendar day. Participants should take the first dose of the study 
intervention on Day 0. Depending on the time of first dose, the timing of the 
subsequent dose may be adjusted slightly to allow the participant/caregiver to select a 
convenient 12 hour dosing schedule as long as the next dose is taken at least 4 hours, but no 
later than 16 hours, after the previous dose. Once adjusted, all subsequent doses should be 
taken every 12 hours (±4 hours). 
 
If a dose is delayed, it should be taken as soon as possible (but no later than 8 hours after the 
scheduled 12-hourly dose time), then resume the normal dosing schedule. If the participant 
misses a dose by more than 8 hours, the participant should not take the missed dose and 
instead take the next dose at the regularly scheduled time. The participant should not double 
the dose to make up for a missed dose. Dosing should be stopped at the end of the treatment 
period (Day 15 or 16). Any remaining tablets and/or capsules at the Day 15 visit should be 
returned. If the Day 15 visit is conducted prior to the last dose of study intervention (i.e., 
Day 16), any remaining tablets or capsules should be collected at the next visit. 
 
If a participant experiences difficulty swallowing the ritonavir capsule, the study team will provide 
guidance on multiple strategies to facilitate swallowing the full-sized capsule. If these strategies 
are unsuccessful, the study team may guide the participant to carefully remove the outer 
encapsulation and take the intact ritonavir tablet that is contained within the encapsulation. The 
outer encapsulation will be discarded. 
 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 


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6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
IDS will receive delivery of study intervention and control product from manufacturer, Pfizer, Inc. 
Study drug accountability and monitoring will be performed by the Stanford Health Care 
Investigational Drug Service (IDS). IDS will maintain accurate, complete, and current records of 
receipt, use, or disposition of study drugs, including: 1) dates of receipt, 2) dates of dispensing, 
3) quantities currently maintained for dispensing, 4) name of participant and amount dispensed, 
and 4) amounts remaining at the end of trial and method of disposition.  
 
All study interventions will be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.  
6) Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. Site staff will instruct participants on the proper storage 
requirements for take-home study intervention. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
See section 6.1.1 Study Intervention Description for details on formulation, packaging, and 
labeling. 
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Medications will be stored at USP controlled room temperature 20○C to 25○C (68○F to 77○F); 
excursions permitted between 15○C to 30○C (59○F to 86○F). 
 
 
6.2.4 PREPARATION 
 
Not applicable 
 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Participants will be randomized 2:1 to drug:placebo. Allocation of participants to treatment 
groups will be conducted in the study’s electronic data capture platform, REDCap Cloud. The 
site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, and the 
participant number. The site personnel will then be provided with a container number(s) to 
indicate the drug product to be supplied to the patient.  
 
The randomization allocation will be generated before the first patient is enrolled and uploaded 
into REDCap Cloud by the unblinded biostatistical team. The unblinded biostatisticians will store 
the randomization allocation in a directory that is inaccessible to blinded personnel. 
 


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Study intervention will be dispensed at the study visits summarized in the SoA. Returned study 
intervention will be disposed immediately by study staff and must not be re-dispensed to the 
study participants. 
 
The participant, treating clinicians, and study personnel will remain blinded to study drug versus 
placebo assignment until after the database is locked and blinded analysis is completed. Only 
the biostatistical team who is generating the randomization allocation and preparing closed 
DSMB interim reports will be unblinded. Specifically, study drug/placebo will be dispensed with 
packaging and labelling that would blind treatment assignment. Unblinding will occur only if 
required for participant safety or treatment at the request of the treating clinician. The date and 
reason that the blind was broken must be recorded in the source documentation and CRF. 
 
 
6.4 STUDY INTERVENTION COMPLIANCE 
 
Study intervention compliance will be assessed by delegated site personnel through the 
accounting of unused study intervention returned by the participant at the study visits and 
discussion with the participant. Participants will also be asked during the 15-day treatment 
period to log their doses taken and missed with their symptom survey every 5 days. Study 
intervention administration, including any deviation(s) from the prescribed dosage regimen, 
should be recorded in the CRF. A record of the number of study intervention tablets/capsules 
dispensed to and taken by each participant must be maintained and reconciled with study 
intervention and compliance records. Intervention start and stop dates will also be recorded in 
the CRF. 
 
The following noncompliance cases will be considered medication errors (see Section 8.3.10): 
• 
Participants interrupting study intervention for 4 consecutive doses; 
• 
Participants taking either nirmatrelvir or ritonavir alone for 4 consecutive doses; 
• 
Participants who have an overall study intervention compliance of <80% or >115%.  
In addition to the above-listed medication errors, any deviation from protocol specified dosing 
(e.g., missed single dose or partial dose) should be recorded as a protocol deviation and the 
investigator or designee is to counsel the participant and ensure steps are taken to improve 
compliance. 
 
 
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 concomitant prescription medications, over-the-counter medications, herbs, 
and supplements. 
 
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 2). 
 
Permitted During the Study 


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All participants may receive standard of care (SoC) therapy for acute COVID-19 re-infection if 
they qualify under the current emergency use authorization (EUA) indications, unless listed as 
prohibited medication on latest FDA Paxlovid Fact Sheet or as defined in Section 5.2. SoC 
therapy is defined as any therapy that is approved and used as indicated by the local regulatory 
authorities (including approvals for emergency use, compassionate use, or through similar 
regulatory guidance), or any therapy as recommended by a relevant national (or a reputable 
international) scientific body (eg, WHO, ECDC, CDC, NIH). Investigator will ensure that any 
recommended SoC therapy is not a strong inducer of CYP3A4 or highly dependent on CYP3A4 
for clearance. 
 
Prohibited During the Study 
Nirmatrelvir and ritonavir are both primarily metabolized by CYP3A4. Therefore, 
concomitant use of any medications or substances that are strong inducers of CYP3A4 and 
that are contraindicated in combination with nirmatrelvir/ritonavir are prohibited without the 
appropriate washout prior to the first dose of study intervention. 
 
Additionally, nirmatrelvir and ritonavir are inhibitors of CYP3A4. Therefore, medications highly 
dependent on CYP3A4 for clearance and for which elevated plasma concentrations may be 
associated with serious and/or life-threatening events are not permitted during dosing of 
nirmatrelvir-ritonavir and for 4 days after the last dose of nirmatrelvir-ritonavir. Because ritonavir 
100 mg every 12 hours is being used to boost the exposure of nirmatrelvir, no additional DDIs 
are expected other than those associated with ritonavir 100 mg q12h based on in vitro 
assessments of nirmatrelvir.  
 
A nonexhaustive list of prohibited and precautionary medications is provided on the latest FDA 
Paxlovid Fact Sheet for Prescribers (FDA.gov), which may be further updated and revised 
during the course of the study. If a medication is not listed, it should not automatically be 
assumed it is safe to coadminister. Appropriately qualified site staff will review all concomitant 
medications (prescription medications, over-the-counter medications, herbs, and supplements) 
during pre-screening intake, during screening, and before the first dose of study intervention is 
administered to determine if they are prohibited. The investigator will make a judgement on the 
ongoing participation of any participant with prohibited medication use during the study. 
At least two qualified study team members must independently review all concomitant 
medications before the first dose of study intervention is administered. Participants should not 
stop any medically-necessary medications and, therefore, will be ineligible to participate in the 
study if they are on such medications that are both medically-necessary for comorbid 
condition(s) and prohibited in the study. Participants who are on non-essential prohibited 
medications may stop these medications to participate in the study at the discretion of  their 
prescribing clinician with appropriate wash-out period if needed and resumption timeline after 
completion of study drug. 
 
Due to safety concerns regarding supplements and herbs and potential interactions with the 
study drug, use or planned use of any supplements or herbs during study drug administration 
and potential additional time before and after this period as determined necessary by 


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investigators is prohibited, unless medically indicated (e.g., for nutrient deficiency) and 
determined to be safe by investigators. 
 
 
Vaccination: COVID vaccination is prohibited within 28 days prior to enrollment. Other types of 
vaccination (including COVID vaccine, influenza vaccine, shingles vaccine, etc.) are prohibited 
within 14 days prior to enrollment. Planned use of any investigational, authorized, or approved 
vaccine (including for COVID, influenza, and others) during the duration of the study through the 
primary endpoint (10 weeks) is also part of the exclusion criteria for the trial (see Section 5.2), 
but all participants may receive vaccinations including COVID-19 vaccination as part of SoC 
indications if their plans and intentions have changed since screening.  
 
Immune-related medications: New or significant change in the dosing of immune-modulating or 
immunosuppressive medications as determined by investigators are prohibited within 30 days 
prior to enrollment and through the primary endpoint (10 weeks).  
 
 
6.5.1 RESCUE MEDICINE 
 
Standard medical supportive care may be provided to manage AEs. 
 
 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
 
It may be necessary for a participant to permanently discontinue study intervention. Reasons for 
permanent discontinuation of study intervention include the following.   
• 
AE (including Grade 3 severity or greater and considered by the investigator to be 
related to study intervention); 
• 
SAE considered by the investigator to be related to the study intervention; 
• 
Requirement for prohibited concomitant medication; 
• 
Death; 
• 
Pregnancy; 
• 
Study terminated by sponsor; 
• 
Withdrawal by participant or legally authorized representative 
• 
Hospitalization during the active treatment period; 
• 
Miss more than 4 consecutive doses of study intervention. 
• 
Determination by the study team that the participant cannot appropriately participate in 
the study 
 
Note that discontinuation of study intervention does not represent withdrawal from the study. If 
study intervention is permanently discontinued, the participant will remain in the study to be 


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evaluated for all subsequent scheduled assessments. See the SoA for data to be collected at 
the time of discontinuation of study intervention and follow-up for any further evaluations that 
need to be completed. In the event of discontinuation of study intervention, it must be 
documented on the appropriate CRF/in the medical records whether the participant is 
discontinuing further receipt of study intervention or also from study procedures, posttreatment 
study follow-up, and/or future collection of additional information. 
 
7.1.1 POTENTIAL CASES OF DECREASED EGFR 
 
If post-screening eGFR is <60 ml/min/1.73 m2 the participant will be instructed to discontinue 
any remaining study intervention doses as soon as study staff become aware of laboratory 
results.  
 
7.1.2 POTENTIAL COVID-19 REINFECTION 
 
If a participant is acutely infected with SARS-CoV-2 during the 15-day treatment period, and 
they meet criteria for EUA treatment of acute COVID-19 (e.g., high risk for severe infection), the 
participant will be offered unblinding in order to obtain standard of care.  
 
If a participant is acutely infected with SARS-CoV-2 more than 5 days after the 15-day treatment 
period, and they meet criteria for EUA treatment of acute COVID-19 (e.g., high risk for severe 
infection), the participant will be offered a 5-day course of Paxlovid, which is consistent with 
current standard of care.  
 
If a participant is acutely infected with SARS-CoV-2 during the trial duration and is not eligible 
for acute COVID-19 treatments (e.g., he/she is at low risk for severe Covid-19 infection) 
according to standard of care, the investigator will recommend that they continue in the study 
without unblinding and no SARS-CoV-2 therapy will be offered. 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following 
reasons: 
 
• 
Pregnancy 
• 
Significant study intervention or study procedure non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
Disease progression which requires discontinuation of the study intervention 


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• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study intervention for 4 consecutive days. 
• 
Study terminated by sponsor 
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form (ICF) and are 
randomized but do not receive the study intervention will not be replaced.  Subjects who sign 
the informed consent form, and are randomized and receive the study intervention, and 
subsequently withdraw, or are withdrawn or discontinued from the study will not be replaced. 
 
7.3 LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site staff.  
 
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 (where possible, 3 telephone calls and, 
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, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 EFFICACY ASSESSMENTS  
8.1.1 PASC SYMPTOMS ASSESSMENT 
6 “core” PASC symptoms or symptom categories of interest are defined in table below and were 
selected based on a combination of three primary factors: (1) prevalence in patients with PASC 
based on the literature (9, 37, 38) and our clinic cohort data, (2) severity of these symptoms in 
patients with PASC based on our clinic cohort data, and (3) relevance to a putative viral 
persistence mechanism that would be targeted by the intervention drug. This primary efficacy 
assessment is also based on published FDA guidance statements on drug intervention trials for 


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acute COVID-19 and chronic fatigue syndrome/myalgic encephalomyelitis including assessment 
of key symptoms and symptom clusters on a 4-point scale (39, 40). 
20 expanded PASC symptoms encompass the 6 core symptoms, including expanded symptom 
categories of cardiovascular and gastrointestinal symptoms, and additionally encompass 
symptoms that are either highly prevalent (e.g., difficulty sleeping) or less prevalent but more 
likely to be associated with a viral persistence mechanism (e.g., fever). There are hundreds of 
symptoms that have been associated with PASC, and the only validated PASC-specific 
symptom survey instrument currently available is the SBQ-LC which is composed of 17 
independent scales with over 100 items total and has not yet been used in published studies 
(41). This study’s selected symptoms are all contained in the SBQ-LC questionnaire, which 
similarly asks respondents to rate their symptom burden at its worst during the past seven days 
with a 4-point rating scale. 
The severity of the symptoms will be assessed on a 4-point Likert scale (0 = none, 1 = mild, 2 = 
moderate, and 3 = severe) with participants reporting the severity at its worst over the past 7 
days. The 6 core symptoms will be assessed at (1) screening to determine eligibility, (2) every 
week until the primary endpoint at 10 weeks, and (3) every 2 weeks until the end of the study at 
15 weeks. The 20 core symptoms will be assessed at each of the 5 in-person visits: baseline, 
V1, V2, V3, V4, V5, and during any unscheduled visits as shown in SoA. Because the 6 core 
symptoms are contained within the 20 expanded symptoms, the 6 core symptoms survey will 
not be redundantly collected during the in-person visits or Day 7 when the 20 expanded 
symptoms are assessed. At enrollment, participants will be asked to select their one most 
bothersome symptom from the expanded 20 symptoms list. 
PASC Symptoms Assessed 
Participants will be asked, “For each symptom below, please indicate how severe it was for you at 
its worst in the last 7 days. Please answer ALL the questions.” 
  
  
0  
none 
1  
mild 
2  
moderate 
3  
severe 
1 
Fatigue* (low energy, tiredness, or exhaustion) 
  
  
  
  
2 
Brain Fog* (including difficulty with focus, or memory, or 
word-finding, or processing, or orientation, or multitasking) 
  
  
  
  
3 
Shortness of breath* (including difficulty breathing, or 
feeling breathless, or air hunger) 
  
  
  
  
4 
Body aches* (including pain in joints or muscles) 
 
 
 
 
5 
Heart symptoms* (including chest pain, or dizziness, or 
heart racing, or fast heart rate, or palpitations) 
  
  
  
  
6 
Gastrointestinal symptoms* (including nausea, vomiting, 
diarrhea, constipation, abdominal pain, or decreased 
appetite) 
  
  
  
  
7 
Post-exertional malaise (worsening of symptoms or feeling 
unwell after physical or mental activity) 
 
 
 
 
8 
Headache 
 
 
 
 
9 
Cough 
  
  
  
  
10 
Fever (mild <101 deg F; moderate 101-103 deg F; severe 
>103F) 
  
  
  
  


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11 
Sore Throat 
  
  
  
  
12 
Difficulty Sleeping 
  
  
  
  
13 
Chest pain 
 
 
 
 
14 
Heart racing (fast heart rate or palpitations) 
 
 
 
 
15 
Dizziness (including lightheadedness or feeling faint) 
 
 
 
 
16 
Nausea or vomiting 
 
 
 
 
17 
Diarrhea 
 
 
 
 
18 
Constipation 
 
 
 
 
19 
Abdominal pain 
 
 
 
 
20 
Decreased appetite 
 
 
 
 
*6 core symptoms (assessed weekly until primary endpoint at 10 weeks then every two weeks thereafter 
until study end);  
20 expanded symptoms which includes the 6 core symptoms (assessed at each of the 5 in-person visits 
and day 7 as shown in SoA) 
 
8.1.2 PATIENT REPORTED OUTCOMES (PRO) 
This study will utilize patient-reported outcomes (PRO) in electronic format at each of the 5 
scheduled visits. PROs are valuable tools to collect patient-centered data and provide unique 
information on the impact of the intervention from the patient’s perspective (42). The PROs were 
selected to capture both global and symptom domain-specific outcomes. 
8.1.2.1 PGIC AND PGIS 
 
The self-report measure Patient Global Impression of Change (PGIC) reflects a participant's 
perception about the overall efficacy of treatment and their overall status since the start of the 
treatment. It is widely used in chronic pain clinical trials and has been used as a co-primary or 
key secondary outcome for trials in conditions with similar features to PASC such as 
fibromyalgia (43, 44). PGIC is a 7-point scale depicting a patient's rating of overall health status 
improvement. Patients rate their change as “very much improved,” “much improved,” “minimally 
improved,” “no change,” “minimally worse,” “much worse,” or “very much worse.” The PGIC will 
be assessed on Day 7, Day 15, Week 5, Week 10, and Week 15. 
 
The related self-report measure Patient Global Impression of Severity (PGIS) reflects a 
participant’s perception about the overall severity of their disease symptoms at that time on a 6-
point scale (45, 58). PGIS in this study is asked in regards to the overall severity of their Long 
COVID symptoms rated as “not present,” “very mild,” “mild,” “moderate,” “severe,” or “extremely 
severe.” The PGIS will be assessed on Day 0 and in parallel with the PGIC on Day 7, Day 15, 
Week 5, Week 10, and Week 15. 
 
8.1.2.2 PROMIS FATIGUE 
Patient-Reported Outcomes Measurement Information System (PROMIS) instruments are a set 
of highly reliable, widely used, publicly available, and precise tools used to measure patient-


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reported health symptoms and health-related quality of life domains relevant to many diseases 
including chronic conditions. PROMIS instruments are accessible through the HealthMeasures 
website (47) and are available for use in clinical research and care. 
The PROMIS Fatigue-Short Form v1.0 7a (PROMIS Fatigue SF) is a reliable and validated 
instrument across diverse clinical populations (48, 49). The PROMIS Fatigue SF consists of 7 
items that measure both the patient-reported experience of fatigue and the interference of 
fatigue on daily activities over the past week with each item scored on 5-point Likert scale. The 
PROMIS Fatigue SF instrument will be administered on the visit days as detailed in SoA for all 
participants. 
8.1.2.3 PROMIS DYSPNEA 
The PROMIS Dyspnea Severity Short Form v1.0 5a (PROMIS Dyspnea Severity) is part of the 
set of PROMIS dyspnea instruments that have been used across different clinical populations 
including in the post-COVID-19 setting (50). The PROMIS Dyspnea Severity 5a consists of 5 
items scored on 4-point Likert scale with a 7-day recall period. The PROMIS Dyspnea Severity 
instrument will be administered on visit days as detailed in the SoA for all participants. 
8.1.2.4 PROMIS COGNITIVE FUNCTION ABILITIES 
The PROMIS Cognitive Function Abilities Short Form v2.0 4a (PROMIS Cognitive Function 
Abilities) is a brief, standardized, reliable, and validated test of self-perceived cognitive 
functioning in various clinical populations (51, 52). The PROMIS Cognitive Function Abilities 
consists of 4 items scored on 5-point Likert scale with a 7-day recall period. The PROMIS 
Cognitive Function Abilities instrument will be administered on visit days as detailed in the SoA 
for all participants. 
8.1.2.5 PROMIS PHYSICAL FUNCTION 
The PROMIS Physical Function Short Form v2.0 4a (PROMIS Physical Function) is part of the 
PROMIS Physical Function question bank of variable-length instruments that have been used 
across different clinical populations and different levels of ability (57). The Short Form 4a is a 
concise fixed-length form that assesses difficulty level performing activities of daily living such 
as doing chores, climbing stairs, walking, and running errands on a 5-point scale (46). The 
PROMIS Physical Function instrument will be administered on visit days as detailed in the SoA. 
 
8.1.3 CLINICAL ASSESSMENTS 
8.1.3.1 1 MINUTE SIT-TO-STAND TEST 
 


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The 1 minute sit-to-stand test is a widely used clinical assessment to evaluate exercise 
tolerance and involves an armless chair and the performance of as many sit-to-stand actions as 
possible in 1 min without using the upper limbs (53). It will be assessed on all participants at the 
select in-person visits as shown in the SoA.  
8.1.3.2 VITAL SIGNS AND ORTHOSTATIC VITALS 
 
Basic vital signs are measured while patient is seated at rest and orthostatic blood pressure and 
heart rate are measured again after 1 minute of standing up. It will be assessed on all 
participants at the select in-person visits as shown in the SoA. 
 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
8.2.1 PREGNANCY 
 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 25 mIU/mL. 
Urine pregnancy test will be required as part screening for the eligibility criteria and must be 
completed on-site on the same day as enrollment and prior to randomization (Day 0). Following 
a negative pregnancy test result at screening, appropriate contraception must be commenced.  
 
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected). Pregnancy tests may 
also be repeated if requested by IRBs or if required by local regulations. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded if the serum pregnancy result is positive. 
 
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant to 
perform the test at home, if compliant with local regulatory requirements. The pregnancy test 
outcome should be documented in the participant’s source documents/medical records. If the 
pregnancy test is positive, the EDP should be reported (Section 8.3.9). Confirm that the 
participant is adhering to the contraception method(s) required in the protocol 
 
8.2.2 LABORATORY TESTS 
 
Screening laboratory tests including hematology (completely blood count) and serum 
chemistries (complete metabolic panel) will be required to ensure eligibility is met. This data 
may be obtained from participant medical records if available within the preceding 6 months or 
since index COVID-19 infection data, whichever is shorter time-frame, assuming no major 
interval medical events have occurred since those results.  
 
Hematology and serum chemistries will be repeated immediately post-treatment (Day 15) for 
safety monitoring. Hematology and serum chemistries may also be performed in the future on 


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retained blood samples as deemed necessary by investigators as relevant to understanding the 
safety or complications of PASC and/or the study intervention. 
 
8.2.3 VITAL SIGNS 
 
In addition to the orthostatic blood pressure and heart rate measurements described above 
under efficacy assessments, additional vital signs such as temperature and pulse oximetry will 
also be collected during each in-person visit. 
 
8.2.4 ACUTE COVID-19 REINFECTIONS 
 
Rapid COVID-19 antigen testing will be required as part screening for the eligibility criteria and 
must be completed on-site on the same day as enrollment and prior to randomization (Day 0). If 
patient is positive and, therefore, does not meet eligibility criteria at that time, they may be 
retested after 30 days later to reassess eligibility. 
 
Each participant will also be provided to take home rapid COVID-19 antigen tests and instructed 
to self-test if they develop new symptoms consistent with acute COVID-19 re-infection (e.g., 
fever, cough, dyspnea, rhinorrhea, sore throat, headache, loss of smell or taste, body aches). If 
the rapid antigen test is positive or as clinically determined by the investigator, the participant 
will be asked to present for an unscheduled visit for assessments as detailed in SoA. If the 
antigen test is negative, the participant will perform a second home test 48 hours later to confirm 
that it remains negative. If the second test is positive, the patient will be asked to present for an 
unscheduled visit. SARS-CoV-2 reinfection will be recorded as an event of special interest (ESI) 
in the CRF as discussed in Section 8.3.8. 
 
If the participant is low-risk for progression to severe acute COVID-19 and, as per standard of 
care (SoC), would not qualify for currently available acute COVID-19 treatments, then we will 
recommend that they continue in the study. 
 
If the patient is high risk for progression to severe acute COVID-19 and, as per SoC, would 
qualify for currently available acute COVID-19 treatments, then the following actions will be 
taken depending on the timing within the study: 
• 
If the participant is reinfected within the 15-day treatment period or within 5 days after 
the last dose, he/she will be offered unblinding and to seek SoC options for acute 
COVID-19 treatment. 
• 
If the participant is reinfected during the follow-up period >5 days after the last study 
intervention dose, then we will provide him/her a 5-day course of Paxlovid as per SoC 
and continue their follow-up in the study. 
 
   
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 


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8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
 
AE Definition 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
 
Events Meeting the AE Definition 
Any abnormal laboratory test results (e.g., hematology, clinical chemistry, etc.) or other 
safety assessments (e.g., vital sign measurements, etc.), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of 
the investigator. Any abnormal laboratory test results that meet any of the conditions 
below must be recorded as an AE: 
• 
Is associated with accompanying symptoms. 
• 
Requires additional diagnostic testing or medical/surgical intervention. 
• 
Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
Exacerbation of a chronic or intermittent preexisting condition, including either an increase 
in frequency and/or intensity of the condition. 
New condition detected or diagnosed after study intervention administration, even though 
it may have been present before the start of the study. 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 
Events NOT Meeting the AE Definition 


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Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the participant and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
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 package insert. 
 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
An adverse event (AE) severity grading scale, based on toxicity grading scales developed by 
the NIH Divisions of AIDS (DAIDS) Toxicity Tables, will be used to grade severity of all 
symptoms, physical exam findings, and laboratory results (Appendix 3). For AEs not included in 
the protocol defined grading system, the following guidelines will be used to describe severity.  


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• 
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”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories 
below:  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should be 
clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the 
influence of other factors is unlikely. The clinical event, including an abnormal laboratory 
test result, occurs within a reasonable time after administration of the study intervention, 
is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly related” 
soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There must 
be an alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  


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Study investigators will be responsible for determining whether an adverse event (AE) is 
expected or unexpected.  An AE will be considered unexpected if the nature, severity, or 
frequency of the event is not consistent with the risk information previously described for the 
study intervention. The Investigator’s Brochure will serve as the SRSD for this trial.  
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an adverse event (AE) or serious adverse event (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 AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, 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), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
 Study personnel will record all reportable events with start dates occurring any time after 
informed consent is obtained until the last day of study participation. Adverse event monitoring 
will occur during the period when study drugs are given and through until the end of the study 
duration (15 weeks).  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, and 
he/she considers the event to be reasonably related to the study intervention, the investigator 
must promptly report the SAE to Pfizer using the CT SAE Report Form (Pfizer ISR/CRC 
Interventional SAE Report form). 
 
 
8.3.5 ADVERSE EVENT REPORTING  
At each scheduled and unscheduled visit to the clinic, study clinicians will assess patients 
according to a standardized case record form.  A severity grading scale, based on toxicity 
grading scales developed by the NIH Divisions of AIDS (DAIDS) Toxicity Tables, will be used to 
grade severity of all symptoms, physical exam findings, and laboratory results (Appendix 3).  All 
participants, regardless of treatment arm, will be assessed using the same standardized case 


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record form.  Adverse event monitoring will occur during the period when study drugs are given 
and through until the end of the study duration (15 weeks).  
Data will be captured on the incidence of all adverse events as defined in Section 8.3.1, 
regardless of severity. Adverse events identified and graded as severe or life threatening and 
felt to be possibly, probably or definitely related to study drugs will be reported to regulatory 
authorities as per Table 1 below.  In addition, an adverse event form will be completed for all 
captured adverse events in the CRF, regardless of severity and expectedness.  The following 
information will be recorded for all adverse experiences that are reported:  
1) Description of event  
2) Date of event onset 
3) Date event reported 
4) Maximum severity of the event 
5) Maximum suspected relationship of the event to study drugs (either SP or DP)   
6) Whether the event is a serious adverse event 
7) Initials of the person reporting the event 
8) Outcome  
9) Date event resolved 
Guidelines for reporting of adverse events provided by the Stanford Institutional Review Board 
and the Food and Drug Administration (FDA) in the U.S. will be followed as summarized in 
Table 1 below.  
Table 1. Guidelines for reporting adverse events 
Institution 
Type of Adverse Events 
When to Report 
Stanford IRB  
Adverse event that Stanford PI determines: 
• 
changes the study risks or benefits, 
OR 
necessitates modification to the IRB-
approved consent document(s) and/or the 
IRB-approved application/protocol 
• 
Within 10 working days of PI’s 
awareness 
• 
Unexpected deaths or life-
threatening experiences related 
to the research must be reported 
to the IRB within 5 working days 
from PI learning of event 
FDA 
• 
Definitely, Probably or Possibly related 
AND BOTH Serious* AND 
Unexpected± 
• 
For fatal or life-threatening 
events, by telephone or fax within 
7 calendar days of first 
awareness 
• 
All other reportable events within 
15 calendar days of first 
awareness 
 
If a participant permanently discontinues or temporarily discontinues study intervention because 
of an AE or SAE, the AE or SAE will be recorded on the CRF and the SAE also reported to 
Pfizer safety using the CT SAE Report Form (Pfizer ISR/CRC Interventional SAE Report form). 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 


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The study clinician will immediately record any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the 
study intervention caused the event. All serious adverse events (SAEs) will be followed until 
satisfactory resolution or until the investigator deems the event to be chronic or the participant is 
stable.  
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of 
any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in 
no case later than 7 calendar days. 
 
Any SAE, whether or not considered study intervention related, will also be reported to Pfizer 
Safety on the CT SAE Report Form (Pfizer ISR/CRC Interventional SAE Report form) 
immediately upon awareness and within 24 hours. Follow-up on SAEs may also be requested 
by Pfizer Safety. 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, and he/she 
considers the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form (Pfizer ISR/CRC 
Interventional SAE Report form).  
 
Overdose is reportable to Pfizer Safety only when associated with an SAE. Any dose of 
nirmatrelvir greater than 900 mg or ritonavir greater than 300 mg within a 24-hour period will be 
considered an overdose.  
 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
The study clinician will review clinical and laboratory data at each scheduled visit and inform 
participants about SAEs within 24 hours.  
 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and 
medical interest specific to the sponsor’s product or program, for which ongoing monitoring and 
rapid communication by the investigator to the sponsor can be appropriate. Such an event might 
warrant further investigation in order to characterize and understand it.  
An ESI relevant to this protocol is acute re-infection with SARS-CoV-2. If patient shows 
symptoms that may indicate COVID-19, an AE will be reported on CRF based on the symptoms. 
Home antigen tests performed as described in Section 8.2.4 “Acute COVID-19 Reinfections”. If 
COVID-19 reinfection is confirmed by rapid antigen testing, the event will be reported as 
“COVID-19 reinfection” with start date of symptoms onset (and remove symptoms AEs if 
entered). If COVID-19 testing is negative, the AE will be updated with a syndromic diagnosis 
(e.g., upper respiratory infection, gastroenteritis, etc.) after monitoring symptoms.  


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Drug Induced Liver Injury may also be considered an ESI. 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 × ULN should be monitored more frequently to determine if they are “adaptors” or are 
“susceptible.” 
 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 AST and/or ALT precede T bili 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 (ie, 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: 
• 
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. 
• 
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: 
• 
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). 
• 
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 
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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, CK, direct and indirect bilirubin, GGT, 
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 (eg, 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. 
 
8.3.9 REPORTING OF EXPOSURES (ENVIRONMENTAL, PREGNANCY, 
OCCUPATIONAL)  
8.3.9.1 ENVIRONMENTAL EXPOSURE 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure. 
Any such exposure to the study intervention under study are reportable to Pfizer Safety within 
24 hours of investigator awareness. 


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8.3.9.2 EXPOSURE DURING PREGNANCY 
Exposure during pregnancy (EDP) occurs if:  
• 
A female participant is found to be pregnant while receiving or after discontinuing study 
intervention.  
• 
A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception.  
• 
A female is found to be pregnant while being exposed or having been exposed to study 
intervention due to environmental exposure. Below are examples of environmental EDP:   
• 
A female family member or healthcare provider reports that she is pregnant after having 
been exposed to the study intervention by ingestion. 
• 
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion then exposes his female partner prior to or around the time of 
conception.  
EDPs will be recorded and reported on the CT SAE form (Pfizer ISR/CRC Interventional SAE 
Report form) and an EDP supplemental form within 24 hours of the investigator’s awareness, 
irrespective of whether an SAE has occurred (see below for information related to termination of 
pregnancy). The initial information recorded should include the anticipated date of delivery. 
Follow up is conducted to obtain general information on the pregnancy and its outcome for all 
EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and record outcome. In the case of a live birth, the 
structural integrity of the neonate can be assessed at the time of birth. In the event of a 
termination, the reason(s) for termination should be specified and, if clinically possible, the 
structural integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (i.e., ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, 
neonatal death, or congenital anomaly in a live born baby, a terminated fetus, an intrauterine 
fetal demise, or a neonatal death), the investigator will follow the procedures for reporting SAEs. 
Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs when 
the investigator assesses the infant death as related or possibly related to exposure to the study 
intervention. 
Further follow up of birth outcomes will be handled on a case-by-case basis (e.g., follow up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information Form 
to deliver to his partner. The investigator must document in the source documents that the 
participant was given the Pregnant Partner Release of Information Form to provide to his 
partner. 
 
 


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8.3.9.3 EXPOSURE DURING BREASTFEEDING 
 
An exposure during breastfeeding occurs if:  
• A female participant is found to be breastfeeding while receiving or after discontinuing 
study intervention. 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental exposure 
during breastfeeding is a female family member or healthcare provider who reports that 
she is breastfeeding after having been exposed to the study intervention by ingestion.   
 
The investigators will report exposure during breastfeeding to Pfizer Safety within 24 hours of 
the investigator’s awareness, irrespective of whether an SAE has occurred. The information 
must be reported using the CT SAE Report Form (Pfizer ISR/CRC Interventional SAE Report 
form). When exposure during breastfeeding occurs in the setting of environmental exposure, the 
exposure information does not pertain to the participant enrolled in the study, so the information 
is not recorded on a CRF. However, a copy of the completed CT SAE Report Form is 
maintained in the investigator site file. 
An exposure during breastfeeding report is not created when a Pfizer drug specifically approved 
for use in breastfeeding women (eg, vitamins) is administered in accord with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the exposure during breastfeeding. 
 
8.3.9.4 OCCUPATIONAL EXPOSURE 
 
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form (Pfizer ISR/CRC 
Interventional SAE Report form), regardless of whether there is an associated SAE. Since the 
information about the occupational exposure does not pertain to a participant enrolled in the 
study, the information is not recorded on a CRF; however, a copy of the completed CT SAE 
Report Form must be maintained in the investigator site file. 
 
 
8.3.10 MEDICATION ERRORS 
 
Medication errors may result from the administration or consumption of the study intervention by 
the wrong participant, or at the wrong time, or at the wrong dosage strength.  
 
Medication errors include: 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant; 
• The administration of expired study intervention; 
• The administration of an incorrect study intervention; 
• The administration of an incorrect dosage; 


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• The administration of study intervention that has undergone temperature excursion from 
the specified storage range, unless it is determined by the sponsor that the study 
intervention under question is acceptable for use; 
• The administration of study intervention consistent with the medication error descriptions 
in Section 6.4. 
 
In the event of a medication dosing error, the investigator should be notified by the study team 
(including Clinical Research Coordinators within 24 hours. Such medication errors occurring to a 
study participant are to be captured on the medication error page of the CRF, which is a specific 
version of the AE page and, if applicable, any associated AE(s), serious and nonserious, are 
recorded on the AE page of the CRF. 
 
Medication errors will also be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form (Pfizer ISR/CRC Interventional SAE Report form) only when associated with an SAE. 
 
8.3.11 LACK OF EFFICACY 
The investigators will assess signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.   
 
 
8.4 UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems 
involving risks to participants or others to include, in general, any incident, experience, or 
outcome that meets all of the following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
Unanticipated problems include both serious adverse events and other adverse events if those 
events suggest that the research places subjects or others at a greater risk of physical or 


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psychological harm than was previously known or recognized [45 CFR 46.103(d)(5)]; [21 CFR 
56.1069(b)(1)]. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB). The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB within 5 working 
days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 
working days of the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within <insert timeline in 
accordance with policy> of the IRB’s receipt of the report of the problem from the 
investigator.  
 
Further details are available from Stanford IRB reporting policy statement (Appendix 4). 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
Reporting of AEs and SAEs to participants will follow section 8.3.7. Institutional IRB will 
determine additional requirement for action in follow-up to reporting of UPs, including potential 
notification and reconsenting of current participants, when such information might be related to 
their willingness to continue to take part in the study. 
 
 
8.5 PHARMACOKINETICS 
 
Blood samples of approximately 4 mL, to provide a minimum of 1.5 mL plasma will be collected 
at day 15 and stored to allow potential future measurement of plasma concentrations of 
nirmatrelvir. The date and time of each sample and the time of last drug dose taken will be 
recorded. Samples collected for analyses of nirmatrelvir concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study, for 


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metabolite identification and/or evaluation of the bioanalytic method, or for research related to 
the study intervention and PASC. 
 
 
8.6 GENETICS 
HLA haplotypes will be evaluated in this study. 
Retained Research Samples for Genetics: A 4 mL blood sample optimized for DNA isolation 
Prep D1 will be collected according to the SoA, as local regulations and IRBs allow.  
Retained Research Samples may be used for research related to the study intervention(s) and 
COVID-19/PASC. Genes and other analytes (eg, proteins, RNA, nondrug metabolites) may be 
studied using the samples.  
See Appendix 4 for information regarding genetic research. Details on processes for collection 
and shipment of these samples can be found in in the laboratory manual. 
 
8.7 BIOMARKERS 
 
Collection of samples for biomarker research is also part of this study.  
 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA: 
 
• NP/nasal swab will be collected to measure SARS CoV-2 viral load by RT-PCR. NP 
swab RT-PCR will be performed at the Stanford clinical laboratory with FDA-approved 
assay. Rapid antigen tests will be performed using commercially available tests that 
are FDA-authorized 
• Residual NP/nasal viral load samples may be used for SARS CoV-2 viral sequencing. 
Any positive RT/PCR will be further evaluated by viral genome sequencing by Stanford 
research laboratories. 
• Residual NP/nasal viral load samples may be used for SARS CoV-2 infectivity assays 
and phenotypic analyses.  
• 10 mL blood optimized for plasma may be utilized for proteomics and immunologic 
studies. Anti-SARS-CoV-2 antibody measurements will be performed by Stanford 
research laboratories which have been at the forefront of developing such assays 
since the start of the pandemic, and has performed many thousand assays. T cell 
responses, EBV antibodies, and CMV antibodies will be measured using research-
grade assays. CLIA assays for T cells have not yet been developed by any institutions. 
CLIA-certified CMV and EBV assays can be conducted if research-grade assays 
demonstrate differences between groups. Autoantibody profiling and cellular analyte 
measurements will be performed by Stanford research laboratories and Stanford core 
facilities using research-grade assays 


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• 40 ml blood optimized for peripheral blood mononuclear cells (PBMCs) may be utilized 
for characterization of blood cells. T cell assays will be performed using spheromers, a 
research-grade assay developed in Stanford research laboratories that has pioneered 
sensitive detection of SARS-CoV-2-specific T-cell responses. 
• 2.5 ml blood optimized for RNA isolation may be utilized to analyze transcript profiles 
of blood cells. 
• 5 ml blood will be collected to measure d-dimer levels. 
• 15 ml blood will be collected for biobanking for future assays. 
• Stool samples will be collected for SARS CoV-2 RT-PCR. RT/PCR will be performed in 
stool samples using methods developed in Stanford research laboratories. Stool will 
also be processed and stored for potential future metagenomic shotgun sequencing if 
a signal is identified in the trial. 
 
 
8.7.1 SPECIFIED GENE EXPRESSION (RNA) RESEARCH 
 
Specified gene expression (RNA) research is not included in this study. 
 
8.7.2 SPECIFIED PROTEIN RESEARCH 
 
Blood will be collected for plasma biomarkers as specified in the SoA and may be used for 
proteomics, immunologic studies, as well as markers associated with coagulation, organ or 
endothelial cell dysfunction. Residuals of all samples may be banked for future research. 
Storage and shipping instructions will be in accordance with the laboratory manual. 
8.7.3 SPECIFIED METABOLOMIC RESEARCH 
 
Specified metabolomic research is not included in this study. 
 
8.7.4 VIRAL LOAD ASSESSMENTS 
 
An NP/nasal swab will be collected per the SoA, and may be analyzed to measure SARS-CoV-2 
RNA by RT-PCR. Residual viral load samples may be utilized for viral sequencing to assess for 
signs of viral evolution and evaluation of potential genetic viral variants (e.g., 3CL gene) or 
immune responses, SARS CoV-2 infectivity assays, and additional molecular analysis.  
Residuals of all samples may be banked for future research. Storage and shipping instructions 
will be in accordance with the laboratory manual. 
 
8.7.5 RETAINED RESEARCH SAMPLES FOR BIOMARKERS 
 
These Retained Research Samples will be collected in this study: 
• 10 mL whole blood optimized for serum Prep B2. 
• 10 mL blood optimized for plasma may be utilized for proteomics and immunologic 
studies. 
• 40 ml blood optimized for peripheral blood mononuclear cells (PBMCs) may be utilized 
for characterization of blood cells. 


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• 2.5 ml blood optimized for RNA isolation may be utilized to analyze transcript profiles 
of blood cells. 
 5 ml blood for d-dimer testing. 
 15 ml blood for biobanking for future emerging assays. 
 
 
Retained Research Samples will be collected as local regulations and IRB allow according to 
the SoA. Retained Research Samples may be used for research related to the study 
intervention(s) and COVID-19 or PASC or their associated risks and complications. Genes and 
other analytes (eg, proteins, RNA, nondrug metabolites) may be studied using the retained 
samples. Additional assays that emerge regarding PASC pathophysiology may be performed. 
 
See Appendix 5 for information regarding genetic research. Details on processes for collection 
and shipment of these samples can be found in the laboratory manual. 
 
8.8 DIGITAL WEARABLE SUBSTUDY 
 
Exploratory sub-study:  For participants who opt-in to the exploratory sub-study, the following 
will be collected from baseline until end of study using the Apple Watch wearable device and the 
Welch Allyn Bluetooth-enabled blood pressure (BP) monitor with target goal frequencies as able 
by the participant:   
 
Measure  
Mode  
Data collection frequency  
Apple Watch  
Accelerometer data (physical activity 
(PA))  
Passive  
Continuous  
Heart rate and resting heart rate  
Passive  
Continuous  
Heart rate variability  
Passive  
Continuous  
Oxygen saturation level  
Passive  
Continuous or periodic  
Time asleep  
Passive  
Continuous  
Time in bed  
Passive  
Continuous  
ECG rhythm  
Active  
Daily (D0-15), Weekly (D16-W10), 
Biweekly (W11 – W15) minimum  
Welch Allyn BP Monitor  
Blood pressure (BP) 
Active  
Daily (D0-15), Weekly (D16-W10), 
Biweekly (W11 – W15) minimum  
 
Target Schedule of data collection:  
 
Active   
Passive  
Day 0 – Day 15 (treatment period)  ECG daily, BP daily  
PA, O2sat, HR, HRV, sleep  
Day 16 – 10 weeks (primary 
endpoint)  
ECG weekly, BP weekly  
PA, O2sat, HR, HRV, sleep  
Week 11 – 15 weeks   
ECG biweekly, BP biweekly  PA, O2sat, HR, HRV, sleep  
 
Passive: No action is required by the patient for the data collection. 
Active: Action is required by the patient to collect the data.  


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• 
For the ECG rhythm, the participant will need to press a button on their Apple Watch. 
• 
For the blood pressure, the participant will need to take their blood pressure and record 
the value. 
 
The schedule above shows the minimum target goal data collection schedule. Participants may 
check and collect their data more frequently if they desire.  
Participants may miss periods of data collection and the study team will reach out to participants 
to troubleshoot any technical issues and encourage resumption to target goal data collection 
schedule. 
 
Specific data analysis parameters and analytics algorithms will be defined in a detailed analysis 
plan prior to data unblinding. 
 
 
 
 
9 
STATISTICAL CONSIDERATIONS  
The statistical analysis will be conducted following the intention to treat principle. Randomization 
will be stratified by vaccination status (completed primary series vs not completed) and the 
number of symptoms at the baseline (2 or 3 symptoms vs >3 symptoms).  
 
9.1 STATISTICAL HYPOTHESES 
For the primary endpoint: 6 core symptoms severity at 10 weeks 
• 
H0 = There is no difference in the symptom severity in any of the 6 core symptoms at 10 
weeks between Paxlovid and placebo groups. 
• 
H1 = There is a difference in the symptom severity of at least one of the 6 core 
symptoms at 10 weeks between Paxlovid and placebo groups 
Secondary endpoints include 
• 
Core symptoms severity based on Likert-scale score at 15 days in participants treated 
with Paxlovid versus placebo 
• 
 Proportion of participants reporting relief at 10 weeks of at least one core symptom for 2 
weeks. Relief defined as reduction of severity from moderate to none or severe to 
mild/none, ≥ 2-point Likert score change 
• 
Proportion of participants with overall alleviation at 10 weeks in Paxlovid versus placebo 
group for 2 weeks. Overall alleviation defined as both: (1) any core symptom(s) that are 
none/mild (Likert 0 or 1) at baseline are none at 10 weeks and (2) any core symptom(s) 
that are moderate/severe (Likert 2 or 3) at baseline are none/mild at 10 weeks 
• 
Severity of the most bothersome symptom at 5 weeks, 10 weeks, and 15 weeks in 
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• 
    Time to relief of each of the 6 core symptoms. Relief defined as above. 
• 
Change in PROMIS Physical Function SF 4a v2.0 from baseline to 10 weeks 
• 
Change in PROMIS Fatigue SF 7a v1.0 score between baseline and 10 weeks 
• 
Change in PROMIS Dyspnea-Severity SF 5a v1.0 score between baseline and 10 
weeks  
• 
Change in PROMIS Cognitive Function Abilities score between baseline and 10 weeks  
• 
Change in orthostatic vitals (difference in seated versus standing blood pressure and 
heart rate) from baseline and 10 weeks 
• 
Change in 1-minute sit-to-stand test from baseline and 10 weeks 
• 
Patient Global Impression of Severity scale (PGIS) at 15 days, 5 weeks, 10 weeks, and 
15 weeks in Paxlovid versus placebo group 
• 
Patient Global Impression of Change scale (PGIC) at Day 15, 5 weeks, 10 weeks, and 
15 weeks in Paxlovid versus placebo group 
The null hypothesis is that there is no difference in the corresponding secondary endpoint 
between Paxlovid and Placebo groups. The alternative hypothesis is that there is a difference in 
the corresponding secondary endpoint. 
 
9.2 SAMPLE SIZE DETERMINATION 
We plan to enroll 200 patients total with 180 patients completing the 10-week follow-up, i.e., a 
10% drop off rate. With a planned randomization ratio of 2:1, we expect approximately 120 
patients receiving Paxlovid and 60 patients receiving placebo completing the 15 weeks follow-up 
at the end of the study. The primary outcome is symptom severity for fatigue, brain fog, dyspnea, 
body aches, CV symptoms, and GI symptoms in Likert-scale (0, 1, 2, and 3) at 10 weeks. For 
each aforementioned symptom, we plan to use the proportional odds regression model for ordinal 
outcomes to compare the Likert scale at week 10 (stratified by their baseline level) among patients 
experiencing the corresponding symptoms at the baseline. The overall comparison will be made 
based on averaging regression coefficients from comparisons of individual symptoms weighted 
by the sample size of the regression analysis, i.e. the number of patients experiencing the 
corresponding symptom at the baseline (55, 56). The power estimation is made based on 
following simplified assumptions:  
(a) for each symptom, the Likert-scale at week 10 is uniformly distributed over 0, 1, 2, and 3 in 
the placebo group, i.e., the proportions of the patients with a Likert-scale being 0, 1, 2, and 3 are 
25%, 25%, 25%, and 25%, respectively, among all patients in the study including patients without 
the symptom at the baseline.  
(b) for each core symptom, the proportions of the patients in the Paxlovid group with a Likert-
scale being 0, 1, 2, and 3 are 34.8%, 26.8%, 21.2%, and 17.2%, respectively, among all study 
patients.  
(c) The z-scores of comparing 6 symptoms using all patients are positively correlated with a pair-
wise correlation coefficient of 0.25. 


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Assumptions (a) and (b) satisfy the proportional odds model with a odds ratio of 1.6. Under this 
assumption, the z-score of individual comparison based on 60 patients in the placebo group and 
120 patients in the Paxlovid group follows a normal distribution with mean of 1.66 and unit 
variance. The final test statistic is equivalent to the simple average of z-scores from analyses for 
individual symptoms, since the assumed alternatives are identical for all core symptoms. Under 
assumption (c) the Wald test statistic for the overall comparison follows a normal distribution with 
a mean of 2.71 and unit variance, providing a power of 77% at the two-sided significance level of 
0.05. The proposed test is expected to have a higher power than that of the analysis discussed 
above for several reasons. First, the regression analysis excluding patients without the core 
symptom at the baseline is expected to generate a z-score with a greater mean value and a higher 
power, since the potential dilution effect from patients without the core symptom at the baseline 
are reduced. Second, the sample size weighting is expected to generate a more efficient 
combination of test statistics from individual test than equal weighting. Lastly, the stratification by 
baseline Likert scale will also increase the power of comparing severity of individual symptom and 
also the power of overall comparison.   
The interim analysis is mainly for assessing futility using conditional power and safety and thus 
does not affect the sample size calculation.  For estimating the timing of the interim and final 
analysis, we project to enroll one patient per day. Therefore, the interim analysis is expected to 
be conducted approximately 24 weeks after the first patient in, by which, the outcomes at 10-
week follow up will be available for approximately 90 patients. Complete data collection for the 
outcomes through the 15-week follow up is projected to occur approximately 46 weeks after the 
first patient in.  
Since this is a phase II study, the proposed sample size doesn’t necessarily guarantee sufficient 
power for all secondary endpoints.    
 
9.3 POPULATIONS FOR ANALYSES 
 
The intent-to-treat (ITT) population will include all randomized patients. Patients will be analyzed 
according to their assigned treatment arm. All efficacy analyses will be completed in the ITT 
population. The per-protocol (PP) population will include all randomized patients who completed 
follow-up, adhered to study procedures, and did not have acute COVID-19 reinfection during the 
study. All efficacy analyses also be completed in the PP population as supportive evidence for 
the primary efficacy analysis. 
 
The safety population will include all patients who received at least one dose of study treatment. 
Patients will be analyzed according to actual treatment received. All safety analyses will be 
completed in the safety population. 
 
 
9.4 STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 


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Descriptive statistics (proportions for categorical variables, means, medians, standard 
deviations and/or interquartile ranges for continuous variables) will be reported for all key patient 
variables, including baseline and demographic characteristics, use of medications, compliance, 
and study completion status. Data that are missing on key patient characteristics and the 
outcome will be fully described, including any patterns of missingness (i.e., any relationships 
between missingness of a variable and patient characteristics). 
 
A CONSORT diagram displaying the number of patients screened, eligible, and consented 
along with reasons for ineligibility will be provided. Graphical tools such as histograms, boxplots, 
and scatterplots will be created to assess quality of data and to display patterns over time. 
 
All tests will be two-sided and performed at the alpha = 0.05 level of significance unless 
otherwise noted. 
 
Additional details will be described in a statistical analysis plan (SAP). 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
The primary endpoint is the Likert-scale of 6 core symptoms at week 10 follow-up. In the 
subgroup of patients having a positive Likert-scale for each core symptom, we will compare the 
Likert-scale of the same symptom at week 10 stratified by the baseline Likert-scale between 
patients receiving Paxlovid for 15 days and patients receiving placebo using the stratified 
proportional odds regression for each core symptom(s). The estimated regression coefficient of 
the treatment, i.e., log-transformed odds ratio, is obtained, for measuring the treatment benefit 
of Paxlovid for the corresponding core symptom.  The overall comparison will be made based 
on a weighted average of the regression coefficient for each core symptom weighted by the 
sample size of the subgroup in which the regression analysis is conducted, i.e., the number of 
patients having the corresponding symptom at the baseline, i.e., Likert-scale > 0.    A 
permutation test will be used to generate the null distribution accounting for correlations among 
estimated regression coefficients for different symptoms (55, 56). This test aggregates the 
statistical evidence of treatment benefit for each core symptoms and is more powerful if the 
Paxlovid has a moderate beneficial effect in treating most or all six core symptoms.   
Note that since the comparison is stratified by the baseline Likert scale, comparing the symptom 
severity at the week 10 is equivalent to comparing the change in severity from baseline to week 
10.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The key secondary endpoints include core symptoms severity at 15 days, severity of most 
bothersome symptom at 5 weeks, 10 weeks and 15 weeks, , proportion of subjects reporting 
relief for 2 weeks of at least one core symptom (reduction of severity from moderate to none or 
severe to mild/none, a 2-point or greater Likert score change) at 5 weeks, 10 weeks and 15 
weeks, and time to relief of at least one core symptom without other symptom worsening, and 
time to relief of the most bothersome symptom. We will use the proportional odds model to 
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Likert-scale. The subgroup analysis will be repeated according to the most bothersome 
symptom at the baseline. The analysis of covariance will be used to compare the global 
symptom severity at follow-up visits adjusting for baseline severity.  The same analysis will be 
used to compare the global impression as well.  The logistic regression will be used to compare 
the probability of experiencing relief for at least one core symptoms, the probability of 
experiencing relief for the most bothersome symptoms, and the probability of experiencing relief 
for each core symptom adjusting for baseline Likert-scale of core symptoms.  For 
aforementioned secondary endpoints, we will also use mixed effects model for repeated 
measurements (MMRM) to compare the longitudinal endpoints across 5-weeks, 10 weeks, and 
15 weeks follow-up visits at the same time.  The MMRM analysis can borrow additional 
information from subjects not completing all follow-up visits in two group comparisons and also 
allow comparing the average endpoints across all longitudinal visits. Lastly, we will use discrete 
time logrank test to compare the time to relief of at least one core symptom without other 
symptom worsening, and time to relief of the most bothersome symptom. Patients who don’t 
experience any symptom relief will be treated as right censoring observations. There will be no 
formal adjustment for multiple testing in analyzing the secondary endpoints. The analysis results 
for all secondary endpoints will be reported regardless of their statistical significance level, 
allowing post-hoc adjustment of multiple testing and providing a global picture of the treatment 
benefit of Paxlovid for long covid patients. 
 
9.4.4 SAFETY ANALYSES 
 
The frequency of adverse events and serious adverse events will be tabulated by type and by 
treatment arm. AEs will be compared by arm using the Chi-squared test or Fisher’s exact test, 
as appropriate, in the safety analysis set. 
 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
The patients’ characteristics at baseline will be summarized and compared between two 
treatment arms to examine the balance achieved via the randomization. The categorical 
variables will be summarized by frequency and proportion and the continuous variables will be 
summarized by mean and standard deviation or median and inter-quartile range as appropriate. 
 
9.4.6 PLANNED INTERIM ANALYSES  
We will include an interim analysis for safety assessment and futility assessment utilizing 
conditional power, when 50% of the planned patients’ outcomes at week 10 are available. To 
this end, a mixed effects regression model will be used to include all enrolled subjects who have 
completed at least one follow up visit at the interim analysis. A subject-specific random intercept 
will be included to account for within-subject correlations among symptoms severity at different 
visits.  We will calculate the conditional power based on data available at the interim analysis, 
assuming the underlying treatment effect size is the same as that observed in the interim 
analysis. If the conditional power at the interim analysis is less than 20%, the trial will be 


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stopped for futility. Furthermore, the reinfection rate, early drop off rate, and the proportion of 
participants with SARS-CoV-2 positive PCR/NAAT and/or positive antigen at the study baseline 
will be summarized and their impact on study power will be examined. The DSMB will evaluate 
overall safety and characteristics of the patient population including acute reinfections and 
potentially recommend enrollment adjustments. 
For estimating the timing of the interim and final analysis, we project to enroll one patient per 
day. Therefore, the interim analysis is expected to be conducted approximately 24 weeks after 
the first patient in, by which, the outcomes at 10-week follow up will be available for 
approximately 90 patients. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Subgroup analyses will be conducted to assess potential treatment effect modification on the 
primary and secondary endpoints in following subgroups:  
• 
Race/ethnic groups (non-Hispanic white, Hispanic, other) 
• 
Sex (male vs female),  
• 
Age (< 50 vs ≥ 50),  
• 
Primary vaccination series completion for COVID-19 (complete vs not complete)  
• 
Number of known COVID-19 infection (1 vs > 1),  
• 
Time since index COVID-19 infection (≤ 6 months vs > 6 months),  
• 
Number of core symptoms at baseline (2-3 vs > 3). 
• 
Prior use of any anti-SARS-CoV-2 therapeutic (yes vs no). 
The treatment effects across subgroups will be summarized using a forest plot. The appropriate 
treatment by covariate interaction will be tested for detecting treatment effect heterogeneity.  
 
 
9.4.8 EXPLORATORY ANALYSES 
 
Analyses for exploratory biological and digital wearable biomarkers data to be described in the 
SAP. 
 
9.4.9 SUPPLEMENTAL ANALYSES 
 
We will perform additional variations of the secondary endpoint analyses as part of a 
supplemental SAP that encompass the following: 
 
• 
Proportion of participants reporting relief of most bothersome symptom at 5 weeks, 10 
weeks, and 15 weeks in Paxlovid versus placebo group. Relief defined as above.  


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• 
Proportion of participants reporting relief for 2 weeks for each of the 6 core symptoms at 
5 weeks, 10 weeks, and 15 weeks. Relief defined as above.  
• 
Time to relief for 2 weeks of at least one core symptom without other core symptoms 
worsening. Relief defined as above.  
• 
Time to relief for 2 weeks of the most bothersome symptom. Relief defined as above. 
• 
Summative core symptoms severity measured by summation of Likert scale score of 6 
core symptoms at 5 weeks, 10 weeks, and 15 weeks in Paxlovid versus placebo group 
 
 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted 
with this protocol: informed consent form (Appendix 1). 
 
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
Institutional Review Board (IRB)-approved and the participant will be asked to read and review 
the document. The investigator will explain the research study to the participant and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants.  Participants will have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants should have the 
opportunity to discuss the study with their family or surrogates or 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. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of 
the informed consent document will be given to the participants for their records. The informed 
consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. 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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10.1.2 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 suspending or terminating party to study participants, funder, 
and regulatory authorities.  If the study is prematurely terminated or suspended, the Principal 
Investigator (PI) will promptly inform study participants and the Institutional Review Board (IRB), 
and will provide the reason(s) for the termination or suspension.  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 Food and Drug Administration (FDA). 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical 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.  
 
All research activities will be conducted in as private a setting as possible. 
 
Representatives of the Institutional Review Board (IRB), regulatory agencies or pharmaceutical 
company supplying study product may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB and Institutional policies. 
 
Participants and their research data will be identified by a unique study identification number. 
The study data entry and study management systems used by the research staff will be secured 


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and password protected. At the end of the study, all study databases will be de-identified and 
archived. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be entered in the REDCap Cloud database by research 
coordinators. After the study is completed, the de-identified, archived data will be cleaned, 
frozen, transmitted to and stored at the Stanford Box folder accessible to the Study PIs.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the Stanford Clinical and Translational Research 
Unit (CTRU) Biorepository. These samples could be used to research the causes of PASC, its 
complications and other conditions for which individuals with PASC are at increased risk, and to 
improve treatment. The CTRU Biorepository will also be provided with a code-link that will allow 
linking the biological specimens with the phenotypic data from each participant, maintaining the 
blinding of the identity of the participant. 
 
During the conduct of the study, an individual participant can choose to withdraw consent to 
have biological specimens stored for future research. However, withdrawal of consent with 
regard to biosample storage may not be possible after the study is completed.  
 
 
 
 
 
10.1.5 KEY INVESTIGATORS  
 
 
Role 
Department 
Email Contact 
Upinder Singh, MD 
Principal Investigator 
Medicine 
usingh@stanford.edu 
Linda Geng, MD, PhD 
Co-Principal Investigator 
Medicine 
geng@stanford.edu 
PJ Utz, MD 
Co-Investigator 
Medicine 
pjutz@stanford.edu 
Hector Bonilla, MD 
Co-Investigator 
Medicine 
hbonilla@stanford.edu 
Prasanna Jagannathan, 
MD 
Co-Investigator 
Medicine 
prasj@stanford.edu 
Karen Jacobson, MD 
Co-Investigator 
Medicine 
kjacobs@stanford.edu 
Aruna Subramanian, 
MD 
Co-Investigator 
Medicine 
asubram2@stanford.edu 
Haley Hedlin, PhD 
Biostatistician 
Quantitative  
Sciences 
Unit 
hedlin@stanford.edu 
Lu Tian, PhD 
Biostatistician 
Biomedical 
Data 
Science 
lutian@stanford.edu 
 
 
 


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10.1.6 SAFETY OVERSIGHT 
A DSMB will be established by the study team in cooperation with the sponsor to assess at 
intervals the progress of a clinical trial, safety data, and interim futility analysis using conditional 
power and recommend to the sponsor whether to continue, modify or terminate the trial. The 
DSMB will operate according to guidelines documented in a DSMB charter. Minutes will be 
taken to provide a written record of the DSMB meetings, including interim results; these will be 
available for review when the trial is complete. The DSMB will be a separate entity from the 
Institutional Review Board (IRB). The independence of the DSMB is intended to control the 
sharing of important comparative information and to protect the integrity of the clinical trial from 
adverse impact resulting from access to trial information.  DSMB members will not participate in 
the study as investigators and will not have conflicts of interest regarding the study or the 
investigational product. The composition of the DSMB will include at minimum a DSMB Chair 
having experience and expertise in clinical trials, a Scientist with expertise in viral infectious 
diseases, and a Biostatistician with expertise in clinical trials.   
The DSMB will meet before the study, during an interim analysis, and at the conclusion of the 
trial to review progress of the clinical trial and safety data. The DSMB will review the study for 
progress and safety. The PI will provide information that will allow the DSMB to review and 
assess the following: 
• 
The research protocol, informed consent documents and plans for data safety and 
monitoring;  
• 
Periodic assessments of data quality and timeliness, participant recruitment, accrual and 
retention, participant risk versus benefit, and other factors that can affect study outcome; 
• 
Factors external to the study when relevant information, such as scientific or therapeutic 
developments, may have an impact on the safety of the participants or the ethics of the 
trial;  
• 
Study performance to make recommendations and assist in the resolution of problems;   
• 
The safety of the study participants;  
• 
The safety and scientific progress of the trial; 
• 
The continuation, termination or other modifications of the trial based on the observed 
beneficial or adverse effects of the treatment under study;  
• 
The confidentiality of the data and the results of monitoring; and 
• 
Any problems with study conduct, enrollment, sample size and/or data collection. 
The first meeting of the DSMB will take place prior to the initiation of the study to discuss the 
protocol and the Data Safety Monitoring Plan.  Meetings of the DSMB shall be held according to 
the plan outlined above. Meetings shall be closed to the public because discussions may 
address confidential patient data. Meetings may be convened as conference calls as well as in 
person. An emergency meeting of the Board may be called at any time should questions of 
patient safety arise. The DSMB may request the presence of study investigators at such 
meetings. 
The study PI will distribute study information to the DSMB prior to a scheduled meeting. The 
DSMB may request additions and other modifications to this information on a one‑time or 
continuing basis. This information will consist of two parts: (1) information on study progress 
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any confidential data on study outcomes, including safety data. A formal report from the DSMB 
should be supplied to the PI within 3 days of each meeting. Each report should conclude with a 
recommendation to continue or to terminate the study. This recommendation should be made 
by formal majority vote. A recommendation to terminate the study should be transmitted to the 
PI and IRBs as rapidly as possible, by immediate telephone and fax if sufficiently urgent. In the 
event of a split vote in favor of continuation, a minority report should be contained within the 
regular DSMB report. At the conclusion of the DSMB meeting for the interim safety review 
planned at 50% enrollment, the DSMB chair will convey the DSMB’s recommendation to the 
study PI in order to minimize the amount of time enrollment is paused. 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with the currently approved protocol/amendment(s), with 
International Conference on Harmonisation Good Clinical Practice (ICH GCP), and with 
applicable regulatory requirement(s). This study will be subject to internal monitoring and to 
external monitoring by DSMB and inspection by regulatory agencies. 
 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The study Data Manager will perform internal quality management of study conduct, data and 
biological specimen collection, documentation and completion.   
 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the study CRC for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the 
clinical trial is conducted and data are generated and biological specimens are collected, 
documented (recorded), and reported in compliance with the protocol, International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements 
(e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities. 
 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 


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Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents will be completed in a neat, legible manner or electronically to ensure 
accurate interpretation of data.  Hardcopies of the study visit worksheets will be provided for use 
as source document worksheets for recording data for each participant enrolled in the study.  
Data recorded in the electronic case report form (eCRF) derived from source documents should 
be consistent with the data recorded on the source documents.  
All subjects will be given a study ID.  Symptom questionnaires and CRFs used at clinic visits will 
be completed by subjects and or study personnel using only study ID.   Specimen containers will 
be labeled by the CRC only with study ID and date, time of collection.   Virologic measurements 
will be provided back to the study team electronically once available, and entered into a 
REDCap Cloud database by a CRC. 
Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into REDCap Cloud, a 21 CFR Part 
11-compliant data capture system. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, 
incomplete, or inaccurate. Clinical data will be entered directly from the source documents. 
Electronic data including all study databases and supporting electronic documentation will be 
archived to cloud-based servers on a daily basis.  All data will be kept in secured REDCap Cloud 
and Box servers.  Only the research team will have access to the data.     
 
10.1.9.2 
STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an International Conference on Harminosation (ICH) region and until 
there are no pending or contemplated marketing applications in an ICH region or until at least 2 
years have elapsed since the formal discontinuation of clinical development of the study 
intervention. These documents should be retained for a longer period, however, if required by 
local regulations. No records will be destroyed without the written consent of the sponsor, if 
applicable. It is the responsibility of the sponsor to inform the investigator when these 
documents no longer need to be retained. 
 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures 
(MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  


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• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 working 
days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents and reported to sponsor.  Protocol deviations must be sent to the reviewing 
Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling of 
protocol deviations will be included in the MOP. 
 
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will comply with the Clinical Trials Registration and Results Information Submission 
rule (FDAAA 801) and will be registered at ClinicalTrials.gov, and results information from this 
trial will be submitted to ClinicalTrials.gov. Data from this study may be shared with the drug 
manufacturer Pfizer, Inc. under a research collaborative agreement. In addition, study results 
will be disseminated to the public and the medical community through presentations at scientific 
meetings and publishing manuscripts in peer-reviewed journals. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
Any 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 
and sponsor institution have 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. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
We will engage a community advisory board (comprised of stakeholders such as patients, 
advocates, external experts, etc.) for independent feedback and input about the trial as soon as 
knowledge of this trial is in the public domain.  
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
CFR 
Code of Federal Regulations 
CONSORT 
Consolidated Standards of Reporting Trials 
CRC 
Clinical Research Coordinator 
CRF 
Case Report Form 
CTRU 
Clinical and Translational Research Unit 
DDI 
Drug Drug Interaction 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
ESI 
Event of Special Interest 
EUA 
Emergency Use Authorization 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 
2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HIPAA 
Health Insurance Portability and Accountability Act  
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
MOP 
Manual of Procedures 
NHP 
Non-Human Primate 
NIH  
National Institutes of Health 
OHRP 
Office for Human Research Protections 
NIMP 
Non-Investigational Medicinal Product 
PASC 
Post-Acute Sequelae of SARS-CoV-2 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PRO 
Patient Reported Outcome 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOA 
Schedule of Activities 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
SRSD  
Single Reference Safety Document 
UP 
Unanticipated Problem 
US 
United States 
WOCBP 
Women of Childbearing Potential 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
1.1 
Oct 14, 2022 
Major changes include: Wearables sub-
study removed, added day 7 home 
stool collection time-point, added Hy’s 
law provision on potential drug-induced 
liver injury, collapsing day 5 and day 10 
survey timepoints into day 7.  
 
Minor changes include: added day 15 
symptom severity secondary endpoint, 
added more subgroup analyses,  
adjusted reporting parameters to 
manufacturer, removed certain 
exploratory labs/assays such as 
cortisol, etc., and adjusted total blood 
volume for biobanking. 
Incorporating additional 
suggestions from FDA Antiviral 
Division, IRB, manufacturer, and 
DSMB to help improve the 
scientific rigor, quality, safety, 
and patient experience the 
study. 
 
Substudy removed from this 
version while pending additional 
internal regulatory review. 
 
Some exploratory assays were 
removed due to budgetary 
limitations, but blood volume 
adjusted to allow for biobanking 
for emerging assays 
1.2 
October 25, 
2022 
Major changes include: switched PCFS 
instrument to PROMIS Physical 
Function instrument, included PGIS 
global impression scale, shifted several 
secondary endpoints to supplemental 
SAP given their similarity and slight 
variation in analysis to others. 
 
Minor changes include: symptoms 
survey query “at its worst” instead of 
“on average” in last 7 days, added 
individual items in parantheses after 
some broad symptoms to clarify, added 
2 weeks duration to relief and 
alleviation endpoints, reduced number 
of items classified as key secondary 
endpoints. 
Incorporating additional 
suggestions from FDA DCOA 
Division regarding the clinical 
outcomes assessments, in 
particular patient reported 
outcomes and clarifications or 
adjustments in analyses. 
1.3 
October 31, 
2022 
Major change includes: re-added 
exploratory wearables sub-study 
 
Minor change: secondary endpoints’ list 
in SAP copy-edited for consistency with 
rest of document; stool collection 
schedule updated 
Wearables sub-study passed 
internal regulatory data and 
privacy review 
 
Stool collection schedule 
updated per FDA as prior and 
budget 
1.4 
November 10, 
2022 
Minor changes: stool collection during 
unscheduled visit adjusted to at 
investigator’s discretion, removed 
redundant exclusion criteria #10, 
adjusted supplements exclusion criteria 
timeframe to per investigator’s 
discretion given variability in type and 
Minor updates and clarifications  


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safety profile of supplements, clarified 
vaccine exclusion criteria timeline for 
COVID vs other vaccines, updated 
Pfizer safety reporting form name and 
clarified redundant reporting text, 
updated prohibited medications 
appendix per latest FDA fact sheet, 
clarified wearables trend over time 
endpoint, typographical edits. 
1.5 
December 5, 
2022 
Major changes include: Final study visit 
at 15 weeks instead of 18 weeks, drug-
drug interaction appendix removed with 
reference to latest FDA Fact Sheet 
instead. 
 
Minor changes include: Increased 
screening period to 14 days from 10, 
modified unscheduled visit to 
investigators’ discretion, added 
exclusion criteria for planned study 
drug use during study outside of FDA 
authorized indication, modified 3-
minute standing orthostatics test to 
simple sit-stand orthostatics. 
Final study duration changed 
due to patient experience, 
adherence, and potential 
confounding events that occur 
during longer follow-up. 
 
Drug-drug interaction appendix 
is not easily kept up-to-date as 
referencing the latest FDA Fact 
Sheet and updated, reliable 
online interaction checker, and 
investigator’s discretion on 
drugs with minimal interaction 
data. 
 
1.6 
January 20, 
2023 
Major changes include: AE definition 
further clarified in Section 8.3 
 
Minor changes: modified screening lab 
chemistries, added process for 
managing difficulty swallowing ritonavir, 
clarified wearables schedules as target 
goals and added process for following 
up with patients who may miss periods 
of wearable data collection, schema 
figure stool schedule error fixed, 
deleted numbers to home antigen kits. 
AE capture threshold clarified to 
capture what is more clinically 
significant, relevant, and 
meaningful. 
 
Minor updates to chemistries 
and pill swallowing management 
done to improve patient 
experience and participation. 
Substudy update to clarify data 
collection. Antigen kit number 
flexibility for package variations. 
1.7 
March 27, 
2023 
Minor changes include: Schedule of 
Activities footnote added for optional in-
person activities for visits #3 and #5 for 
select participants with significant travel 
or logistical barriers; inclusion criteria 
clarification for confirmation of testing 
either by documentation or self-report 
(latter not to exceed 15% of 
enrollment); $250 additional 
compensation offered for participants 
traveling in from out of the area 
To expand recruitment and 
promote participant engagement 
and retention, particularly for 
those with significant travel or 
logistical barriers. 
1.8 
May 5, 2023 
Minor changes include: Clarification of 
the analysis plan for interim analysis 
including futility assessment and 
conditional power threshold 
Efficacy is understood to 
represent interim futility 
analysis, which is to be 
conducted utilizing Conditional 


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on alpha. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Microbiology. Galveston (TX)1996. 
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Brun P, Conti J, Zatta V, Russo V, Scarpa M, Kotsafti A, et al. Persistent Herpes Simplex Virus 
Type 1 Infection of Enteric Neurons Triggers CD8(+) T Cell Response and Gastrointestinal 
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12 APPENDICES 
 
12.1 APPENDIX 1. INFORMED CONSENT 
 
. Are you participating in any other research studies? _____ Yes _____No 
 
CONCISE SUMMARY 
 
We are asking your consent in order to participate in a RESEARCH study.  
It is very important to know that your participation is entirely VOLUNTARY.  
 
The purpose is to study whether PAXLOVID can reduce or eliminate Long 
COVID (a.k.a., PASC) symptoms and whether it causes any side effects. We do 
not know whether this medication will be effective for PASC. 
The duration of your participation in the study would be 15 weeks (3.5  
months). 


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If you are eligible to participate, you will be randomly selected to receive either 
the drug or placebo at a 2:1 ratio which means twice as many participants 
will receive the drug as the placebo. 
The test treatment involves taking the study drug orally twice a day for 15 
days. 
There are a total of 5 clinic visits scheduled for in-person, including at 
enrollment (study entry), then approximately at 15 days, 5 weeks, 10 weeks, 
and 15 weeks after enrollment. Requirement for in-person activities for Week 5 
and Week 15 visits may be discussed with study team for individuals who have 
significant travel or other logistical barriers to come in person.  
You will be asked to do the following: 
Symptoms surveys up to weekly throughout the study (online) 
Other questionnaires by/at each clinic visit (online or in person) 
Blood collection at each clinic visit 
Nasopharyngeal (deep nose) swab at each clinic visit 
Stool collection at 3 visits and a week into study (kit given for home collection) 
Vital signs and a 1-minute sit-stand test at each clinic visit 
Your medications and supplements will be reviewed carefully and frequently 
throughout the study and all changes must be alerted to the study team for your 
safety. 
Optional sub-study: If you have an iPhone, you may be invited to participate 
in a sub-study to track your digital health data such as physical activity and heart 
rate from a wearable device (a smartwatch – this will be provided to you if you 
wish to participate in this sub-study). Participating in this sub-study is optional.  
Possible risks may include discomfort from study procedures, side effects from 
the drug, and unforeseeable consequences as with any research study.  
Possible benefits may include taking a potentially effective medication for 
PASC, but we cannot and do not guarantee or promise that you will receive any 
benefits from this study. 
Alternative to the study is to not participate in the study.  
  
 
PURPOSE OF RESEARCH 
 


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You are invited to participate in a research study of PAXLOVID (nirmatrelvir and ritonavir) 
to treat Long COVID (also called Post-Acute Sequelae of Sars-CoV2 or PASC). The U.S. 
Food and Drug Administration (FDA) has issued an Emergency Use Authorization (EUA) 
for the emergency use of PAXLOVID for the treatment of mild-to-moderate COVID-19 in 
adults and pediatric patients at high risk for severe COVID-19 infection. However, 
PAXLOVID has not been approved by the FDA. The use of PAXLOVID for PASC has not 
been tested yet and there are some potential risks with taking this drug.  We will hope to 
learn whether 15 days of oral administration of this medicine will decrease or eliminate 
your Long COVID symptoms and whether it causes any side effects.  In addition, if there 
is a benefit, we will hope to learn the possible reason for this observation. You were 
selected as a possible participant in this study because you have been diagnosed with 
Long COVID and have had symptoms lasing for at least 3 months.    
   
If you decide to terminate your participation in this study, you should notify Dr. Upinder 
Singh and Dr. Linda Geng at 650-723-4045.   
   
This research study is looking for 200 adults diagnosed with Long COVID in the US. 
Stanford expects to enroll all 200 research study participants. 
 
VOLUNTARY PARTICIPATION  
 
Your participation in this study is entirely voluntary.  Your decision not to participate will 
not have any negative effect on you or your medical care.  You can decide to participate 
now, but withdraw your consent later and stop being in the study without any loss of 
benefits or medical care to which you are entitled. 
 
DURATION OF STUDY INVOLVEMENT  
 
This research study will recruit 200 participants to complete 15 weeks (3.5 months) of 
follow-up. 
 
 


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PROCEDURES 
This study will assess whether PAXLOVID (nirmatrelvir and ritonavir) can alleviate or 
resolve your Long COVID symptoms. Nirmatrelvir has activity against the SARS-CoV-2 
virus and ritonavir does not have any biological activity against SARS-CoV-2 but is given 
with nirmatrelvir to increase its level in the body. The PAXLOVID medication is given as 
300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet) 
with all three tablets taken together by mouth twice daily for 15 days. We will also 
assess whether this medication and dose causes any side effects.  
PAXLOVID, tested in over 4000 healthy people, was highly effective in reducing the risk 
of severe COVID-19 and death. As a result, the U.S. Food and Drug Administration 
(FDA) has issued an Emergency Use Authorization (EUA) for the emergency use of 
PAXLOVID, which includes the treatment of mild-to-moderate COVID-19 in adults and 
pediatric patients.  
Because we do not know if PAXLOVID will work for Long COVID, participants will be 
selected at random to receive PAXLOVID or a placebo (inactive) medication. The 
placebo group will also receive ritonavir which has no activity against SARS-CoV-2, but 
it is given to match the ritonavir given in the PAXLOVID group. The participants, doctors 
and staff involved in the study will not know who is receiving the drug or the placebo. 
The PAXLOVID and placebo groups will be compared after the study has completed to 
see whether the medication is more effective than the placebo medication. For each 
participant, there is a 2/3 chance of getting PAXLOVID and a 1/3 chance of getting 
placebo. So, you will have a two times higher chance of receiving PAXLOVID than a 
placebo drug.  
Study overview 


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If you choose to participate, you will be asked to do the following.  
• Before the first (enrollment) visit: The study team will review with you ALL of 
your prescribed and over-the-counter medications and supplements. It is very 
important for your safety that the study team is informed of everything you 
are taking. 
May request that you hold certain supplements and herbs before enrollment and after 
this period as determined necessary by investigators, unless medically indicated (e.g., 
for nutrient deficiency) and determined to be safe by investigators. 
Supplements and herbs include a wide range of products including vitamins, minerals, 
probiotics, botanicals, amino acids, enzymes, tinctures, etc. 
Request that you and your doctor(s) do not plan to add new or significantly changed 
doses of immune-related medications from 30 days prior to enrollment until 10 weeks 
after enrollment.  
Immune-related medications include immunosuppressants and immunomodulators such 
as steroids (e.g., prednisone), biologics (e.g., infliximab), azathioprine, low-dose 
naltrexone, etc.  


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You should NOT stop any medications that are medically necessary for your health 
conditions. If you are currently taking any medically necessary medications that interact 
with the study drug, you may not be able to participate in the study. If later during the 
study you need to start taking any medically necessary medications that interact with 
the study drug, you may be asked to stop the study treatment. 
 
• At the first (enrollment) visit:  
The study team will 
Review the informed consent with you, answer any questions you may have, and 
confirm that you fully understand it.   
Assess eligibility including asking about your Long-Covid symptoms and reviewing your 
medical records to ensure that you are eligible for the study 
Assess your current medications, including prescribed and over the counter 
medications, supplement, and herbs to ensure that you can safely participate in the 
study. 
Give you an ID number that we ask you to save for future use. 
Collect urine for a pregnancy test if you a woman of reproductive age and have the 
potential to have children. A negative test during this study visit is required before 
receiving the study drug even if you already know you are not pregnant. During follow-
up phone calls and visits, the study doctor or staff may ask and talk to you about any 
possible pregnancy.  
Perform a rapid antigen COVID-19 test  
Collect 80 ml (about five and a half tablespoons) of your blood by venipuncture. This 
blood will be used for biological tests. Any remaining blood will be stored for future 
studies in the Biobank facility at Stanford University.  
Swab your nasopharynx (deep inside your nose) for SARS-CoV2 and potentially other 
viruses     
Provide you a kit to collect a stool sample at home which will be mailed back to us 
Ask that you complete questionnaires including about your symptoms and overall health 


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Check your vital signs (including blood pressure and heart rate lying down and standing 
up, temperature, and blood oxygen saturation level) 
Perform a physical function test (asking you to sit and stand from a chair as many times 
as you are able in 1 minute) 
The study team will provide you a Medication Alert bracelet and wallet card to use while 
you are taking the study drug.  
If you agree to participate in the Digital Wearable portion of the study, please see 
additional details on page 18.  
If you are eligible for the trial, you will be randomly assigned to either receive 
PAXLOVID or placebo. You will be instructed on how to take the pills and keep track of 
the number of medications. If you have any questions or concerns about taking your 
medications or missed doses, please contact the study team at 
TreatCOVID@stanford.edu or call 650-308-6788. 
• Online symptoms questionnaire: 
At home, after the first visit and periodically throughout the trial, you will complete an 
online questionnaire accessible by computer or cell phone. On this questionnaire, you 
will be asked to respond to questions about symptoms of Long COVID or of medication 
effects that you may experience.  
During the first 10 weeks, the questionnaire will weekly.  
After 10 weeks, the questionnaire will occur every 2 weeks through the end of the trial 
at 15 weeks. 
 
• Home stool collection: 
At home, a week after the first visit, you will be asked to collect a sample of your stool:  
7 (+/- 2 days) after enrollment (kit provided for you to collect stool sample at 
home and mail back) 
• Returning visits to the clinic for assessments: 


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There are 5 scheduled in-person visits for the study: enrollment, and 15 days, 5 weeks, 
10 weeks, and 15 weeks after starting therapy. Additional visits may be required per 
the discretion of the investigator (if you develop any symptoms consistent with acute 
COVID reinfection, have a positive SARS-CoV-2 test, or have other new concerning 
symptoms, etc.) for clinical assessment, nasopharyngeal swab, and blood sample 
collection. *Requirement for in-person activities for Week 5 and Week 15 visits may be 
discussed with study team for individuals who have significant travel or other logistical 
barriers to come in person. 
We will provide you with a calendar and appointments for these visits. All visits will be 
during Mon-Friday and no visits will be on the weekend. These return visits will occur 
at:  
15 days (+/- 2 days) after enrollment  
5 weeks* (+/- 7 days) after enrollment 
10 weeks (+/- 7 days) after enrollment  
15 weeks* (+/- 14 days) after enrollment 
At each return in-person clinic visit, the following will be performed: 
Blood collection of 80 ml (about five and a half tablespoons) by venipuncture. These 
samples will be used to look for medication effects and to store for future work on 
immune responses and viral biology in the Biobanking facility at Stanford University.  
Nasopharyngeal (deep nose) swab for SARS-CoV2 (the virus that causes COVID-19) 
and potentially other viruses    
Stool sample collection around days 15 and week 10 (kit provided for you to collect at 
home and mail back) 
Questionnaires including symptoms of Long COVID and overall health 
Vital signs including blood pressure and heart rate sitting down and standing up, 
temperature, and blood oxygen saturation level 
Physical function test (asking you to sit and stand from a chair as many times as you 
are able in 1 minute) 


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You will be tested for communicable diseases (COVID-19) as part of this research 
study. If your test results are positive, the results will be reported to health authorities 
as required by law. 
We will also ask you to return any unused medication to us so it can be properly 
disposed. 
At the end of the study, if you are also participating in the Digital Wearable sub-study, 
we will ask you to return the Apple Watch and blood pressure monitor. See page 18 
regarding details of the Digital Wearable sub-study. 
Your specimens may be sent outside of Stanford for analysis. This research might 
include whole genome sequencing of specimens. Any of your samples that are used in 
the study may result in new products, tests, or discoveries. In some instances, these 
may have potential commercial value and may be developed and owned by the 
Investigators, Stanford University, and/or others. However, donors of specimens do not 
retain any property rights to the materials. Therefore, you would not share in any 
financial benefits from these products, tests, or discoveries.   
Women of Childbearing Potential  
If you are a woman who is able to become pregnant, it is expected that you will use an 
effective method of birth control to prevent exposing a fetus to a potentially dangerous 
agent with unknown risk. If you are pregnant or currently breastfeeding, you may not 
participate in this study. You understand that if you are pregnant, if you become 
pregnant, or if you are breastfeeding during this study, you or your child may be 
exposed to an unknown risk.  
To confirm to the extent medically possible that you are not pregnant, you agree to 
have a pregnancy test done before beginning this research study. You must agree to 
avoid sexual intercourse or use a birth control method judged to be effective by the 
investigator and which will not interfere with the proposed investigation for at least one 
months after receiving PAXLOVID or Placebo. You must accept the risk that pregnancy 
could still result despite the responsible use of a reliable method of birth control. You 
agree to notify the investigator as soon as possible of any failure of proper use of your 
birth control method or if you become pregnant. Due to safety reasons, pregnancy may 
result in your being withdrawn from the study.  
If you are a man participating in this study and your partner is able to become 
pregnant, you and your partner must use adequate contraception while you are 
participating in the study and for at least one month. Your doctor will discuss with you 


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what methods of birth control are considered adequate. You should inform your study 
doctor if your partner becomes pregnant.  
 
 
 
Future Use of Private Information and/or Specimens  
Research using private information and/or specimens is an important way to try to 
understand human disease. You are being given this information because the 
investigators want to save private information and/or specimens for future research.    
Your specimens will be stored with a study ID. After the study is complete, all personal 
identifiers linked to the study ID will be destroyed. Because your specimens will not be 
linked to your name after they are stored, you cannot withdraw your consent to the use 
of the specimens after they are taken.   
Identifiers might be removed from identifiable private information and/or identifiable 
specimens, and, after such removal, the information and/or specimens could be used 
for future research studies or distributed to another investigator for future research 
studies without additional informed consent from you.  
 
Genetic Testing and Future Research 
 
As part of the analysis on your specimens, the investigators may do genetic testing.  
Genetic research is research that studies genes, including gene characteristics and gene 
versions that are transmitted by parents to children.  Genetic research may include 
looking at information, such as personal appearance and biochemistry, gene sequences, 
genetic landmarks, individual and family medical histories, reactions to medications and 
responses to treatment.  Genetic research raises certain questions about informing you 
of any results.  Possible risks of knowing results include:  anxiety; other psychological 
distress; and the possibility of insurance and job discrimination.  A possible risk of not 
knowing includes being unaware of the need for treatment.  These risks can change 
depending on the results of the research and whether there is a treatment or cure for a 
particular disease.  


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Sometimes patients have been required to furnish information from genetic testing for 
health insurance, life insurance, and/or a job.  A Federal law, the Genetic Information 
Nondiscrimination Act of 2008 (GINA), generally makes it illegal for health insurance 
companies, group health plans, and employers with 15 or more employees to 
discriminate against you based on your genetic information.  
 
The process of determining all or nearly all of your DNA sequence is called whole 
genome sequencing. It is different from genetic testing that does not involve whole 
genome sequencing because it provides a much more detailed snapshot of your 
genome. This research might include whole genome sequencing. 
 
The results of the study of your data and/or specimens from this project will be 
used for research purposes only, and you will not be told the results of the tests.  
 
 
PARTICIPANT RESPONSIBILITIES           
 
As a participant, your responsibilities include:  
 
Follow the instructions of the Protocol Director and study staff. 
Keep your study appointments.  If it is necessary to miss an appointment, please 
contact the Protocol Director or research study staff. 
Complete the smart phone/computer questionnaire as requested by study staff. 
Tell the Protocol Director or research study staff about any side effects, 
medication changes, illness, doctor visits, or hospitalizations that you may have. 
Tell the Protocol Director or research staff if you believe you might be pregnant 
or gotten your partner pregnant. 
Ask questions as you think of them. 
Tell the Protocol Director or research staff if you change your mind about staying 
in the study. 
 


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WITHDRAWAL FROM STUDY 
 
If you first agree to participate and then you change your mind, you are free to 
withdraw your consent and discontinue your participation at any time.  Your decision 
will not affect your ability to receive medical care for your disease and you will not lose 
any benefits to which you would otherwise be entitled. 
  
If you decide to withdraw your consent to participate in this study, you should notify Dr. 
Upinder Singh and Dr. Linda Geng at 650-723-4045. 
 
The Protocol Director may also withdraw you from the study without your consent for 
one or more of the following reasons:   
Failure to follow the instructions of the Protocol Director and study staff. 
The Protocol Director decides that continuing your participation could be harmful 
to you. 
Pregnancy 
You need treatment not allowed in the study. 
The study is cancelled. 
Other administrative reasons. 
Unanticipated circumstances. 
 
POSSIBLE RISKS, DISCOMFORTS, AND INCONVENIENCES  
 
There are risks, discomforts, and inconveniences associated with any research study.  
These deserve careful thought.  You should talk with the Protocol Director if you have 
any questions. 
You will be asked to come to our research clinic on five (5) occasions. (Additional 
office visits may be scheduled up to discretion of the investigator team as 
necessary for safety or other medically related events). 


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We will collect blood samples on up to five occasions. Blood draws can cause 
discomfort, bruising and very, very rarely, infection at the needle site.  Some 
people also feel faint. We will try to minimize these risks by having well-trained 
blood drawing staff draw your blood. 
We will collect nasopharyngeal swabs on up to five occasions. Nasopharyngeal 
swabs can cause discomfort. We will try to minimize this risk by having well-
trained staff using proper techniques perform the swabs. 
2/3 of subjects will receive nirmatrelvir and 1/3 will receive placebo (inactive) 
drug. All subjects will receive ritonavir. Known potential risks associated with 
nirmatrelvir include vomiting and headache. Known potential risks associated 
with ritonavir include gastrointestinal disturbances (including diarrhea, nausea, 
vomiting and abdominal pain), Neurological disturbances (eg, tingling sensation, 
altered taste, and dizziness), Rash, and Fatigue. Other less common side effects 
may include diarrhea, high blood pressure, muscle aches, abdominal pain, 
nausea, malaise. Other risks or side effects may include: Risk of Serious Adverse 
Reactions Due to Drug Interactions, Allergic Reactions/ Hypersensitivity, 
Hepatotoxicity, and Risk of HIV-1 Resistance Development. For individuals with 
undiagnosed or uncontrolled HIV, administration of this drug could lead to 
resistance of HIV to protease inhibitors. 
We do not know if this medication will be effective for Long-Covid.  All subjects, 
whether receiving treatment or the standard-of-care, may have worsening of 
symptoms.  Because we will be monitoring your symptoms, and because you can 
contact us with any concerns, you will have rapid access to further medical care 
Any study may have unforeseeable consequences to subjects.  By carefully 
monitoring the progress of this study, we will be able to respond to these 
problems in a timely manner. 
 
POTENTIAL BENEFITS                              
The main purpose of this study is research. Because of this, you may or may not get 
any health benefit from being in the study. PAXLOVID may reduce the duration and 
severity of symptoms related to Long COVID.  
We cannot and do not guarantee or promise that you will receive any benefits from this 
study. 
 
ALTERNATIVES 


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The alternative to participating is not to participate. 
 
PARTICIPANT’S RIGHTS 
 
You should not feel obligated to agree to participate.  Your questions should be 
answered clearly and to your satisfaction.  If you decide not to participate, tell the 
Protocol Director.   
 
You will be told of any important new information that is learned during the course of 
this research study, which might affect your condition or your willingness to continue 
participation in this study. 
 
ClinicalTrials.gov 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This Web site will not include information that can identify you.  
At most, the Web site will include a summary of the results.  You can search this Web 
site at any time. 
 
CONFIDENTIALITY 
 
The results of this research study may be presented at scientific or medical meetings or 
published in scientific journals.  Your identity and/or your personal health information 
will not be disclosed except as authorized by you or as required by law.  However, there 
is always some risk that even de-identified information might be re-identified. 
 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect research 
records and learn your identity if this study falls within its jurisdiction. 
  


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The purpose of this research study is to learn whether 15 days of oral administration of 
PAXLOVID will reduce or eliminate your Long COVID symptoms and whether it causes 
any side effects. The results will be provided to the sponsor, the Food and Drug 
Administration and other federal and regulatory agencies as required. 
 
 


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Authorization To Use Your Health Information For 
Research Purposes  
Because information about you and your health is personal and private, it 
generally cannot be used in this research study without your written 
authorization.  If you sign this form, it will provide that authorization.  The 
form is intended to inform you about how your health information will be 
used or disclosed in the study.  Your information will only be used in 
accordance with this authorization form and the informed consent form 
and as required or allowed by law.  Please read it carefully before signing 
it.   
 
What is the purpose of this research study and how will my health 
information be utilized in the study? 
 
The purpose of this study is to see if the drug, PAXLOVID can reduce or 
eliminate the symptoms of Long COVID.  Health information you provide 
will determine whether you are eligible to participate in the study and 
whether the medication has affected your symptoms in any way.  Blood, 
stool, and nasopharyngeal samples you provide will help determine 
whether the medication can change possible biomarkers of persistent 
SARS-CoV-2.   
 
Do I have to sign this authorization form? 
You do not have to sign this authorization form.  But if you do not, you will 
not be able to participate in this research study, including receiving any 


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research-related treatment.  Signing the form is not a condition for 
receiving any medical care outside the study. 
 
If I sign, can I revoke it or withdraw from the research later? 
If you decide to participate, you are free to withdraw your authorization 
regarding the use and disclosure of your health information (and to 
discontinue any other participation in the study) at any time.  After any 
revocation, your health information will no longer be used or disclosed in 
the study, except to the extent that the law allows us to continue using 
your information (e.g., necessary to maintain integrity of research).  If you 
wish to revoke your authorization for the research use or disclosure of your 
health information in this study, you must write to: Upinder Singh at Lane 
Building, Room L134, 300 Pasteur Dr., Stanford University, Stanford CA. 
94305-5107.  
 
What Personal Information Will Be Obtained, Used or Disclosed? 
Your health information related to this study, may be used or disclosed in 
connection with this research study, including, but not limited to, name and 
initials, address, email, phone number(s), date of birth, age, sex, race, 
ethnicity, medical record number, health history and information related to 
COVID-19 disease and symptoms, questionnaires, symptoms that might 
relate to medication side effects, vital signs including temperature and 
blood oxygen saturation levels, laboratory and radioimaging investigation 
reports, pregnancy test and tests of viral shedding of COVID-19 and other 
viruses, medication received including study drug, and phone call records.   
 


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The Digital Wearables sub-study will also have the AiCare app collect the 
following data: physical activity, heart rate, heart rate variability, BP, step 
count and ECG via the smartwatch. 
 
Who May Use or Disclose the Information? 
The following parties are authorized to use and/or disclose your health 
information in connection with this research study: 
The Protocol Director, Dr. Upinder Singh 
The Stanford University Administrative Panel on Human Subjects in 
Medical Research and any other unit of Stanford University as 
necessary 
Research Staff 
  
Who May Receive or Use the Information? 
The parties listed in the preceding paragraph may disclose your health 
information to the following persons and organizations for their use in 
connection with this research study:  
 
The Office for Human Research Protections in the U.S. Department of 
Health and Human Services 
Pfizer, the manufacturer of PAXLOVID 
AiCare, Inc.  
The Food and Drug Administration 
The study’s Institutional Data Monitoring Committee at Stanford 
  


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Your information may be re-disclosed by the recipients described above, if 
they are not required by law to protect the privacy of the information. 
 
When will my authorization expire? 
Your authorization for the use and/or disclosure of your health information 
will end on May 1, 2050 or when the research project ends, whichever is 
earlier.  
 
Will access to my medical record be limited during the study? 
To maintain the integrity of this research study, you may not have access 
to any health information developed as part of this study until it is 
completed.  At that point, you would have access to such health 
information if it was used to make a medical or billing decision about you 
(e.g., if included in your official medical record).  
 
 
________________________________             
  ______________ 
Signature of Adult Participant                                        Date 
 
 
________________________________             
 
Print Name of Adult Participant  
 
FINANCIAL CONSIDERATIONS 


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Payment/ Reimbursement 
You will be paid 
 for each visit to the clinical site to compensate you for travel 
expenses and inconvenience. If you live greater than 2-hour driving distance away 
(about 100 miles) from the clinical site, you will be paid an additional 
 for each 
completed in-person visit to off-set additional travel expenses. You will be paid 
 for 
completing the Day 7 home activities.  Preferred method of payment is gift card after 
the completion of each study visit.  
 
Payments may only be made to U.S. citizens, legal non-citizens, and those who have a 
work eligible visa. You may need to provide your social security number to receive 
payment.   
 
Costs 
If you participate in this study, the study will pay for those services, supplies, 
procedures, and care associated with the study that are not a part of your routine 
medical care.  However, there may be additional costs to you.  These include basic 
expenses like transportation and the personal time it will take to come to the study 
visits.  You and/or your health insurance must pay for services, supplies, procedures, 
and care that are required during this study for routine medical care.  You will also be 
responsible for any co-payments and/or deductibles as required by your insurance.  
Participation in this study is not a substitute for health insurance.   
 
Sponsor 
Pfizer will be providing the medications, PAXLOVID and Placebo, for this study.  Pfizer is 
providing funding for the conduct of this study. 
 
Consultative or Financial Relationships 
None of the protocol directors and study investigators have any consultative or financial 
relationships with Pfizer, Inc.  
 
 
COMPENSATION for Research-Related Injury 
All forms of medical diagnosis and treatment – whether routine or experimental – 
involve some risk of injury.  In spite of all precautions, you might develop medical 
complications from participating in this study.  If such complications arise, the Protocol 
Director and the research study staff will assist you in obtaining appropriate medical 


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treatment.  In the event that you have an injury or illness that is directly caused by 
your participation in this study, reimbursement for all related costs of care first will be 
sought from your insurer, managed care plan, or other benefits program.  You will be 
responsible for any associated co-payments or deductibles as required by 
your insurance. 
If costs of care related to such an injury are not covered by your insurer, managed care 
plan or other benefits program, you may be responsible for these costs.  If you are 
unable to pay for such costs, the Protocol Director will assist you in applying for 
supplemental benefits and explain how to apply for patient financial assistance from the 
hospital. 
You do not waive any liability rights for personal injury by signing this form. 
Due to the coronavirus public health emergency, the federal government has issued a 
Declaration that may limit your right to sue if you are injured or harmed while 
participating in this COVID-19 study. If the Declaration applies, it limits your right to sue 
researchers, healthcare providers, any study sponsor, manufacturer, distributor or any 
other official involved with the study. However, the federal government has a program 
that may provide compensation to you or your family if you experience serious physical 
injuries or death. To find out more about this “Countermeasures Injury Compensation 
Program” please go to https://www.hrsa.gov/cicp/about/index.html or call 1-855-266-
2427. 
 
 
 
STOP-PASC Digital Wearable Sub-Study 
 
This is an optional sub-study within the main STOP-PASC trial. You may still participate 
in the main STOP-PASC trial regardless of whether or not you decide to participate in 
this digital wearable sub-study. 
 


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Purpose:  Digital wearable devices such as smartwatches are electronic devices that 
people wear to track personal health data, such as monitoring their heart rate and how 
many steps they have taken in a day. The purpose of this sub-study is to track changes 
in participant’s health condition over time and better understand the impact of 
treatments using these quantitative measures such as heart rate and physical activity. 
 
Eligibility: To enroll in this digital wearable study, you must meet all of the following 
criteria: 
consent to the main STOP-PASC trial 
currently own an Apple iPhone 8 or newer (or iOS 16) with a data plan and is the 
sole user of that iPhone 
agree to download and maintain the free third-party AiCare and Welch Allyn 
apps, as needed, onto the iPhone for the duration of the study 
able to read and speak English 
are able and willing to comply with all study procedures 
do NOT have known hypersensitive skin, allergies to wristbands of Apple 
Watches or wristbands of similar products, or severe allergy to nickel or metal 
jewelry 
 
Devices provided: We will loan these devices to you to take home for the duration of 
the study: 
one (1) smartwatch:  Apple Watch Series 7 or newer 
one (1) blood pressure (BP) monitor:  Welch Allyn 1500 Series with Bluetooth 
You may use your own device if you already own these models or have an 
equivalent or newer model that is compatible with our system. 
 
Procedures: 
Wearing the smartwatch: You will be asked to wear, or continue to wear, the 
smartwatch (Apple Watch) on your wrist, 24/7 (around the clock) as possible for the 
duration of the study which is 15 weeks (3.5 months) except when charging and during 


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water activities if desired. The smartwatch is water resistant and can be worn in shallow 
water activities such as showering, bathing, or swimming in the pool or ocean, but can 
be removed temporarily during those activities if you prefer. You will be asked to 
charge the smartwatch for 1 hour daily. 
 
Installing the apps: The clinical study coordinator will assist you to download and install 
the free AiCare and Welch Allyn apps on your smartphone. The smartwatch will allow 
Bluetooth signaling to be picked up by the AiCare app on your smartphone. You may be 
asked to review and agree to any Privacy Policies, Terms of Service, or End User 
Licensing Agreements when downloading the apps onto your phone. This is separate 
from this consent form. You should review these terms carefully prior to agreeing to 
them. You do not have to agree to these agreements/terms. If you do not, you cannot 
participate in the sub-study but can still participate in the main study.  
 
Data collection: Your physical activity, heart rate, heart-rate variability, and blood 
oxygen saturation level will be collected continuously for the duration of the study. 
Other data from the smartwatch such as sleep patterns may also be collected. These 
are passive data collection which means no action is required from you to collect this 
data. Your smartwatch data is collected securely by the AiCare phone app and AiCare 
website, and it can also be viewed by the clinical trial study coordinator. AiCare will 
securely transmit your smartwatch data to the Stanford study team for further research 
analysis. 
 
You will be asked to check your ECG rhythm (press of a button on smartwatch)  and 
also check your blood pressure (BP) with the home BP monitoring kit at this following 
schedule at a minimum: 
Day 0 – ~Day 15 (during the study drug administration period): daily the same 
time each morning 
~Day 16 – Week 10: every week 
Week 11 – 15 weeks (end of study): every two weeks 


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You are welcome to check more frequently than the above schedule if desired but this 
is not required. Blood pressure checks should be performed according to manufacturer’s 
instructions to ensure accurate measurements. 
 
Monitoring: Please note that your smartwatch data will not be continuously monitored 
in real-time by a medical professional. If you have any concerns or questions about 
your health-related smartwatch values, please call your doctor and seek medical care. 
The clinical research coordinator may contact you via email and/or phone if there are 
significant changes in the data recordings based on automated data completeness 
parameters set by AiCare. If there is no data transmitted for 24 hours, the study 
coordinator will contact you to answer simple questions and clarify proper use of the 
smartwatch. If the research team is unable to reach you, the back-up contact person 
will be contacted.  
 
Return of devices: After completing the study, you will return any loaned devices 
(smartwatch and/or blood pressure monitor) as directed by the study coordinator. 
 
Risks and benefits: 
There is a small risk of irritation or allergic reaction from wearing the smartwatch. 
These are usually well tolerated and worn by millions of people. A prior clinical trial did 
not demonstrate any significant adverse skin effect to anyone. Please let us know if 
there is any irritation to your wrist or any skin changes.   
  
The sub-study may help with detecting changes in PASC symptom severity, overall 
health status, and potential responses to treatment. 
 
We cannot and do not guarantee or promise that you will receive any benefits from this 
sub-study.   


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Participant’s rights: Your participation in this sub-study is voluntary and you have the 
right to withdraw your consent or discontinue participation at any time without penalty 
or loss of benefits to which you are otherwise entitled. You may still continue to 
participate in the main STOP-PASC trial if you withdraw from the Digital Wearable sub-
study. See pages 10 and 22 in the main study for additional participant’s rights. 
 
Confidentiality:  The results of this research study may be presented at scientific or 
medical meetings or published in scientific journals.  Your identity and/or your personal 
health information will not be disclosed except as authorized by you or as required by 
law.  However, there is always some risk that even de-identified information might be 
re-identified.  
 
Patient information may be provided to Federal and other regulatory agencies as 
required.  The Food and Drug Administration (FDA), for example, may inspect research 
records and learn your identity if this study falls within its jurisdiction. 
 
The purpose of this research sub-study is to explore the correlation between the digital 
biometric data collected via the AiCare platform and PASC symptoms; the results will be 
provided to the sponsor, the Food and Drug Administration and other federal and 
regulatory agencies as required. 
 
Identifiers might be removed from identifiable private information and/or identifiable 
specimens and, after such removal, the information and/or specimens could be used for 
future research studies or distributed to another investigator for future research studies 
without additional informed consent from you.  
 
Conflict of interest:   
 


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The Protocol Directors and the rest of the investigators have no financial interest in 
AiCare. 
 
☐ _________ (initials and date) Yes, I wish to participate in the STOP-PASC Digital 
Wearable Sub-Study. 
 
☐ _________ (initials and date) No, I do not wish to participate in the STOP-PASC 
Digital Wearable Sub-Study. 
 
 
 
CONTACT INFORMATION  
 
Questions, Concerns, or Complaints:  If you have any questions, concerns or complaints 
about this research study, its procedures, risks and benefits, or alternative courses of 
treatment, you should ask the Protocol Directors, Dr. Upinder Singh, or Dr. Linda Geng. 
You may contact her now or later at 650-723-4045. 
  
Injury Notification:  If you feel you have been hurt by being a part of this study, please 
contact the Protocol Director, Upinder Singh, or page Dr. Linda Geng, at 650-723-4045. 
  
Independent Contact:  If you are not satisfied with how this study is being conducted, 
or if you have any concerns, complaints, or general questions about the research or 
your rights as a participant, please contact the Stanford Institutional Review Board 
(IRB) to speak to someone independent of the research team at (650)-723-5244 or toll 
free at 1-866-680-2906.  You can also write to the Stanford IRB, Stanford University, 
1705 El Camino Real, Palo Alto, CA 94306. 


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Appointment Contact: If you need to change your appointment, please contact the 
study team at 
.  
  
Alternate Contact:  If you cannot reach the Protocol Directors, please contact Dr. Hector 
Bonilla at 
. 
EXPERIMENTAL SUBJECT’S BILL OF RIGHTS 
 
As a research participant you have the following rights.  These rights include but are 
not limited to the participant's right to: 
be informed of the nature and purpose of the experiment;  
be given an explanation of the procedures to be followed in the medical 
experiment, and any drug or device to be utilized;  
be given a description of any attendant discomforts and risks reasonably to be 
expected;  
be given an explanation of any benefits to the subject reasonably to be 
expected, if applicable;  
be given a disclosure of any appropriate alternatives, drugs or devices that might 
be advantageous to the subject, their relative risks and benefits; 
be informed of the avenues of medical treatment, if any available to the subject 
after the experiment if complications should arise;  
be given an opportunity to ask questions concerning the experiment or the 
procedures involved;  
be instructed that consent to participate in the medical experiment may be 
withdrawn at any time and the subject may discontinue participation without 
prejudice;  
be given a copy of the signed and dated consent form; and  
be given the opportunity to decide to consent or not to consent to a medical 
experiment without the intervention of any element of force, fraud, deceit, 
duress, coercion or undue influence on the subject's decision. 
 


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May we contact you about future studies that may be of interest to you?    
____ Yes  ____ No 
 
Signing your name below means you agree to be in the STOP-PASC study and that you 
will receive a copy of this signed and dated consent form. 
 
 
_____________________________________       
        ____________ 
Signature of Adult Participant                              
      
   Date 
 
  
_____________________________________           __________________ 
Print Name of Adult Participant                                       Time of Consent  
  
Legally Authorized Representative  
The legally authorized representative should sign if the participant is unable to sign for 
themselves. The relationship between the study participant and the representative 
should be stated. 
 
 
_____________________________________                ____________         
Signature of Legally Authorized Representative (LAR)  
  Date  


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(e.g., parent, guardian or conservator)    
 
_____________________________________              
Print Name of LAR                                         
                               
_____________________________________ 
LAR’s Authority to Act for Participant  
 
 
(e.g., parent, guardian or conservator) 
 
 
Person Obtaining Consent 
 
_____________________________________       
        ____________ 
Signature of Person Obtaining Consent                  
   Date 
  
  
_____________________________________            
Print Name of Person Obtaining Consent 
 
 
The following witness line is to be signed only if the consent is provided as a summary 
form and accompanied by a short form foreign language consent. 
 


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_____________________________________                     ____________ 
Signature of Witness                                                              Date 
 
__________________________________             
 
Print Name of Witness                                         
 
(e.g., staff, translator/interpreter, family member) 
 
Translated short form must be signed and dated by both the participant (or their LAR) 
AND the witness. 
The English consent form (referred to as the "Summary Form" in the regulations): 
Must be signed by the witness AND the Person Obtaining Consent (POC). 
The non-English speaking participant/LAR does not sign the English consent. 
The non-English speaking participant/LAR should not sign the HIPAA participant line 
If the participant or the LAR is non-English speaking, the Person Obtaining Consent (POC) must 
ensure that 1) the LAR's Description of Authority is completed and 2) that any questions or options 
presented by the consent form are documented and initialed by the POC on the Summary Form, 
per the participant's wishes, as they are understood during the consent process. 
 
 
 
 
12.2 APPENDIX 2. CONTRACEPTIVE AND BARRIER GUIDANCE 
12.2.1 MALE PARTICIPANT REPRODUCTIVE INCLUSION CRITERIA 
 


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Male participants are eligible to participate if they agree to the following requirements during the 
intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study intervention(s): 
 
• 
Refrain from donating sperm 
PLUS either: 
• 
Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent.  
 
OR 
• 
Must agree to use contraception/barrier as detailed below: 
• 
Agree to use a male condom when having sexual intercourse with a woman of 
childbearing potential who is not currently pregnant. 
• 
In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly 
effective methods below in Section 12.2.4). 
12.2.2 FEMALE PARTICIPANT REPRODUCTIVE INCLUSION CRITERIA 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 
1 of the following conditions applies: 
• 
Is not a WOCBP (see definitions below in Section 12.2.3). 
OR 
• 
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), as described below, during the intervention period and for at 
least 28 days after the last dose of study intervention, which corresponds to the time 
needed to eliminate any reproductive safety risk of the study intervention(s). If a 
highly effective method that is user dependent is chosen, a second effective method 
of contraception, as described below, must also be used. The investigator should 
evaluate the effectiveness of the contraceptive method in relationship to the first 
dose of study intervention.  
Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents are 
coadministered, a barrier method or other nonhormonal method of contraception must also be 
used if the participant is using estradiol-containing contraceptives.  


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The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
12.2.3 WOMAN OF CHILDBEARING POTENTIAL 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP: 
1. Premenopausal female with 1 of the following:  
• 
Documented hysterectomy; 
• 
Documented bilateral salpingectomy; 
• 
Documented bilateral oophorectomy. 
 
2. For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
 
2. Postmenopausal female: 
• 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  In addition: 
o A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 50 years of age and not using hormonal 
contraception or HRT.  
o A female on HRT and whose menopausal status is in doubt will be required to 
use one of the non-estrogen hormonal highly effective contraception methods if 
they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
12.2.4 CONTRACEPTION METHODS 
 


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Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation. 
2. Intrauterine device. 
3. Intrauterine hormone releasing system. 
4. Bilateral tubal occlusion (eg, bilateral tubal ligation). 
5. Vasectomized partner: 
o A vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the woman of childbearing potential and 
the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. The spermatogenesis cycle is 
approximately 90 days. 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
o Oral; 
o Intravaginal; 
o Transdermal. 
 
7. Progestogen only hormone contraception associated with inhibition of ovulation: 
o Oral; 
o Injectable. 
8. Sexual abstinence: 
o Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant. 
In addition, one of the following effective barrier methods must also be used when option 
6 or 7 are chosen above:  
• 
Male or female condom with or without spermicide; 
• 
Cervical cap, diaphragm, or sponge with spermicide; 
• 
A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 


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Because ritonavir may reduce the effect of estradiol-containing contraceptives when agents are 
co-administered, a barrier method or other nonhormonal method of contraception must also be 
used if the participant is using estradiol-containing contraceptives. 
 
12.3 APPENDIX 3. DAIDS TOXICITY TABLE CORRECTED V2.1 
Division of AIDS Table for Grading the Severity of ADULT AND PEDIATRIC Adverse Events Corrected 
Version 2.1, July 2017 
The Division of AIDS (DAIDS) oversees more than 300 clinical trials domestically and internationally, which evaluate 
the safety and efficacy of therapeutic products, vaccines, and other preventive modalities.  Adverse event (AE) 
data collected during these clinical trials form the basis for subsequent safety and efficacy analyses of 
pharmaceutical products and medical devices.  Incorrect and inconsistent AE severity grading can lead to 
inaccurate data analyses and interpretation, which in turn can impact the safety and well-being of clinical trial 
participants and future patients using pharmaceutical products.   
Over the years, DAIDS scientific knowledge and experience have expanded, necessitating revisions of the DAIDS 
grading table which serves as a guide for assessing the severity of AEs (including clinical and laboratory 
abnormalities) in participants enrolled in DAIDS-sponsored and -supported clinical trials.  The Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 (July 2017) 
updates and replaces version 2.1 (March 2017).  
Glossary/Definitions of terms used in tables: 
AE  
Adverse event; Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure regardless of whether it is considered related to the medical treatment or 
procedure.  
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC  
Absolute neutrophil count  
AST (SGOT)  
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase)  
AV  
Atrioventricular  
Basic Self-care 
Functions  
Adult  
Activities such as bathing, dressing, toileting, transfer or movement, continence, and 
feeding.  
  
Young Children  


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Activities that are age and culturally appropriate, such as feeding one’s self with culturally 
appropriate eating implements.  
BMI z-score  
Body mass index z- score; A body reference norm. Specifically, the number of standard 
deviations a participant's BMI differs from the average BMI for their age, sex, and ethnicity.  
BMD t-score  
Bone mineral density t-score; The number of standard deviations above or below the mean 
bone mineral density of a healthy 30 year old adult of the same sex and ethnicity as the 
participant.  
BMD z-score  
Bone mineral density z-score; The number of standard deviations a participant's BMD 
differs from the average BMD for their age, sex, and ethnicity.  
BPAP  
Bilevel positive airway pressure; A mode used during noninvasive positive pressure 
ventilation.  
Chemical 
Pregnancy  
A pregnancy in which a positive pregnancy test is followed by a negative pregnancy test 
without evidence of a clinical pregnancy loss.  
CNS  
Central nervous system  
CPAP  
Continuous positive airway pressure  
DAERS  
DAIDS Adverse Experience Reporting System; An internet-based  
system developed for clinical research sites to report Expedited Adverse Events (EAEs) to 
DAIDS.  It facilitates timely EAE report submission and serves as a centralized location for 
accessing and processing EAE information for reporting purposes.  
Disability  
A substantial disruption of a person’s ability to conduct normal life functions.  
ECG  
Electrocardiogram  
eGFR  
Estimated glomerular filtration rate  
Hospitalization  
Does not include the following hospital admissions: under 24 hours, unrelated to an adverse 
event (e.g., for labor and delivery, cosmetic surgery, social or administrative for temporary 
placement [for lack of a place to sleep]), protocol-specified, and for diagnosis or therapy of 
a condition that existed before the receipt of a study agent and which has not increased in 
severity or frequency.   
INR  
International normalized ratio   


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Intervention  
Medical, surgical, or other procedures recommended or provided by a healthcare 
professional for the treatment of an adverse event.   
IV  
Intravenous  
IVIG  
Intravenous immune globulin  
LDL  
Low density lipoprotein  
LLN  
Lower limit of normal  
Life-threatening 
AE  
Any adverse event that places the participant, in the view of the investigator, at immediate 
risk of death from the reaction when it occurred (i.e., it does not include a reaction that 
would have caused death if it had occurred in a more severe form).  
NA  
Not applicable  
Participant ID 
The identification number assigned to a study participant which is used to track study-
related documentation, including any reported AEs.  
PR Interval 
The interval between the beginning of the P wave and the beginning of the QRS complex of 
an electrocardiogram that represents the time between the beginning of the contraction of 
the atria and the beginning  of the contraction of the ventricles.  
PT  
Prothrombin time  
PTT  
Partial thromboplastin time  
QTc Interval  
The measure of time between the onset of ventricular depolarization and completion of 
ventricular repolarization corrected for ventricular rate.  
RBC  
Red blood cell  
SI  
Standard international unit  
ULN 
Upper limit of normal 
Usual Social & 
Functional 
Activities  
Activities which adults and children perform on a routine basis and those which are part of 
regular activities of daily living, for example:  
  
Adults  
Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, or pursuing a hobby.  


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Young Children  
Activities that are age and culturally appropriate, such as social interactions, play activities, 
or learning tasks.  
WBC 
White blood cell 
WHO  
World Health Organization   
WNL 
Within normal limits 
 
Instructions for use 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.1 
consists of parameters, or AEs, with severity grading guidance that are to be used in DAIDS clinical trials for safety 
data reporting to maintain accuracy and consistency in the evaluation of AEs.  The term “severe” is not the same as 
the term “serious” in classifying AEs.  The severity of a specific event describes its intensity, and it is the intensity 
which is graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory definition.  
  
Clinical sites are encouraged to report parameters in the DAIDS grading table as they are written to maintain data 
consistency across clinical trials.  However, since some parameters can be reported with more specificity, clinical 
sites are encouraged to report parameters that convey additional clinical information.  For example, diarrhea could 
be reported as neonatal diarrhea; seizures, as febrile seizures; and pain, as jaw pain.  
General Considerations  
The DAIDS grading table provides an AE severity grading scale ranging from grades 1 to 5 with descriptions for each 
AE based on the following general guidelines:   
Grade 1 indicates a mild event  
Grade 2 indicates a moderate event  
Grade 3 indicates a severe event  
Grade 4 indicates a potentially life-threatening event  
Grade 5 indicates death (Note: This grade is not specifically listed on each page of the grading table).  
  
Determining Severity Grade for Parameters “Between Grades” 


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If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either 
Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory value that is graded as a 
multiple of the ULN or LLN falls between two grades, select the higher of the two grades for the AE. For example, 
Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a parameter. If the lab value is 2.53 x ULN (which is between the 
two grades), the severity of this AE would be Grade 2, the higher of the two grades. 
Values Below Grade 1 
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded. 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should not be reported to 
DAIDS in an expedited timeframe unless it meets protocol-specific reporting requirements.  Sites should refer to 
the applicable network standards for reporting abnormal laboratory findings on the clinical case report forms.   
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high values) or the LLN and 
grade 1 (for low values) should not be graded or reported as an AE.  Sites should consult the Manual for Expedited 
Reporting of Adverse Events to DAIDS, Version 2.0 and their protocol when making an assessment of the need to 
report an AE.  
 Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory normal values fall 
within grading table laboratory ranges, the severity grading is based on the ranges in the grading table unless there 
is a protocol-specific grading criterion for the laboratory value.  For example, “Magnesium, Low" has a grade 1 
range of 1.2 to < 1.4 mEq/L, while a particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  
If a study participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as grade 1.  
Estimating Severity Grade for Parameters Not Identified in the Grading Table  
The functional table below should be used to grade the severity of an AE that is not specifically identified in the 
grading table.  In addition, all deaths related to an AE are to be classified as grade 5.   
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY  
LIFE-THREATENING  
Clinical adverse  
event NOT  
identified 
elsewhere in 
the grading 
table  
Mild symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated  
Moderate 
symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated  
Severe symptoms  
causing inability to 
perform usual social 
& functional activities 
with intervention or 
hospitalization 
indicated  
Potentially life-
threatening symptoms 
causing inability to 
perform basic self-care 
functions with 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death  


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Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Arrhythmia   (by ECG or 
physical examination) 
Specify type, if 
applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention 
indicated 
Non-life-threatening 
symptoms AND Non-
urgent 
intervention 
indicated  
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities1  
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
mmHg diastolic 
diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg 
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile  
+ 5 mmHg adjusted 
for age, height, and 
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension 
(e.g., malignant 
hypertension) OR 
Hospitalization 
indicated 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular
Health and Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 
2011; DOI: 10.1542/peds.2009-2107C.  


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Hypotension  
No symptoms  
Symptoms corrected 
with oral fluid 
replacement  
Symptoms AND IV  
fluids indicated  
Shock requiring use of 
vasopressors or 
mechanical assistance 
to maintain blood 
pressure  
Cardiac Ischemia or  
Infarction  
Report only one  
NA  
NA  
New symptoms with 
ischemia (stable  
angina) OR New  
testing consistent 
with ischemia   
Unstable angina OR 
Acute myocardial 
infarction  
Heart Failure  
No symptoms AND  
Laboratory or 
cardiac imaging 
abnormalities  
Symptoms with mild 
to moderate activity 
or exertion  
Symptoms at rest or 
with minimal activity  
or exertion (e.g., 
hypoxemia) OR  
Intervention 
indicated (e.g., 
oxygen)  
Life-threatening 
consequences OR 
Urgent intervention 
indicated (e.g., 
vasoactive 
medications, 
ventricular assist 
device, heart 
transplant)  
Hemorrhage  
(with significant acute 
blood loss)  
NA  
Symptoms AND No  
transfusion 
indicated  
Symptoms AND  
Transfusion of  ≤ 2 
units packed RBCs 
indicated   
Life-threatening 
hypotension OR  
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs  
> 10 cc/kg) indicated  
Prolonged PR Interval  
or AV Block  
Report only one  
> 16 years of age  
PR interval 0.21 to 
< 0.25 seconds  
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block  
Type II 2nd degree  
AV block or 
ventricular delay of 
3.0 seconds  
Complete AV block   
≤ 16 years of age  
1st degree AV block 
(PR interval  > 
normal for age and 
rate)  
Type I 2nd degree 
AV block   
Type II 2nd degree  
AV block of 
ventricular delay of 
3.0 seconds  
Complete AV block  


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Prolonged QTc  
Interval2  
0.45 to 0.47 
seconds  
> 0.47 to 0.50 
seconds  
> 0.50 seconds OR ≥ 
0.06 seconds above 
baseline  
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated 
serious ventricular 
dysrhythmia)  
Thrombosis or 
Embolism  
Report only one  
NA  
Symptoms AND No  
intervention 
indicated   
Symptoms AND  
Intervention 
indicated   
Life-threatening 
embolic event (e.g., 
pulmonary embolism, 
thrombus)   
 
  
Dermatologic  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Alopecia (scalp only)   
Detectable by 
study  
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Obvious on visual 
inspection AND 
Causing greater 
than minimal 
interference with 
usual social & 
functional activities  
NA  
NA  
 
 
2 As per Bazett’s formula.  


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Bruising  
Localized to one 
area  
Localized to more 
than one area  
Generalized  
NA  
Cellulitis  
NA  
Non-parenteral 
treatment 
indicated  
(e.g., oral 
antibiotics,  
antifungals, 
antivirals)  
IV treatment 
indicated (e.g., IV 
antibiotics, 
antifungals, 
antivirals)  
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis)  
Hyperpigmentation  
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
NA  
NA  
Hypopigmentation  
Slight or localized 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Marked or 
generalized causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
NA  
NA  
Petechiae  
Localized to one 
area  
Localized to more 
than one area  
Generalized  
NA  
Pruritus3  
(without skin lesions)  
Itching causing no 
or minimal 
interference with 
usual social & 
functional 
activities  
Itching causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Itching causing 
inability to perform 
usual social & 
functional activities   
NA  
 
 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).  
 


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Rash  
Specify type, if 
applicable  
Localized rash   
Diffuse rash OR  
Target lesions   
Diffuse rash AND 
Vesicles or limited 
number of bullae or  
superficial  
ulcerations of  
mucous membrane  
limited to one site  
Extensive or 
generalized bullous 
lesions OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Stevens-Johnson 
syndrome OR Toxic 
epidermal necrolysis   
 
Endocrine and Metabolomic 
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Diabetes Mellitus  
Controlled without 
medication  
Controlled with 
medication OR 
Modification of 
current medication 
regimen  
Uncontrolled despite 
treatment 
modification OR  
Hospitalization for 
immediate 
glucose 
control 
indicated  
Life-threatening 
consequences 
(e.g., 
ketoacidosis, 
hyperosmolar 
nonketotic coma, end 
organ  
failure)   
Gynecomastia  
Detectable by study  
participant,  
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Obvious on visual 
inspection 
AND 
Causing pain with 
greater 
than 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Disfiguring 
changes 
AND Symptoms  
requiring 
intervention 
or 
causing inability to 
perform usual social 
& functional activities  
NA  
Hyperthyroidism  
No symptoms AND 
Abnormal 
laboratory value  
Symptoms causing 
greater 
than 
minimal 
interference 
with 
usual social &  
functional activities  
OR Thyroid 
suppression therapy 
indicated  
Symptoms causing 
inability to perform 
usual social &  
functional activities 
OR 
Uncontrolled 
despite treatment 
modification   
Life-threatening 
consequences (e.g., 
thyroid storm)  


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Hypothyroidism  
No symptoms AND 
Abnormal 
laboratory value  
Symptoms causing 
greater 
than 
minimal 
interference 
with 
usual social &  
functional activities  
OR Thyroid 
replacement therapy 
indicated  
Symptoms causing 
inability to perform 
usual social &  
functional activities 
OR 
Uncontrolled 
despite treatment 
modification   
Life-threatening 
consequences 
(e.g., 
myxedema 
coma)  
Lipoatrophy4  
Detectable by study  
participant,  
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Obvious on visual 
inspection 
AND 
Causing 
greater 
than 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Disfiguring changes  
NA  
Lipohypertrophy5  
Detectable by study  
participant,  
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional 
activities  
Obvious on visual 
inspection 
AND 
Causing 
greater 
than 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Disfiguring changes   
NA  
 
 
 
 
 
 
 
 
 
 
 
 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.  
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
=  


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Gastrointestinal  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Anorexia  
Loss of appetite 
without decreased 
oral intake  
Loss of appetite 
associated with 
decreased oral 
intake without 
significant weight 
loss  
Loss of appetite 
associated with 
significant weight 
loss  
Life-threatening 
consequences OR  
Aggressive 
intervention indicated 
(e.g., tube feeding, 
total parenteral 
nutrition)  
Ascites  
No symptoms  
Symptoms AND  
Intervention 
indicated (e.g., 
diuretics, 
therapeutic 
paracentesis)  
Symptoms recur or 
persist despite 
intervention  
Life-threatening 
consequences  
Bloating or Distension  
Report only one  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional 
activities  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  
Cholecystitis  
NA  
Symptoms AND  
Medical 
intervention 
indicated  
Radiologic, 
endoscopic, or 
operative 
intervention 
indicated  
Life-threatening 
consequences (e.g., 
sepsis, perforation)   
Constipation  
NA  
Persistent 
constipation 
requiring regular 
use of dietary 
modifications, 
laxatives, or enemas  
Obstipation with 
manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction)  


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Diarrhea 
≥ 1 year of age 
Transient or 
intermittent 
episodes of 
stools over 
baseline per 24-
hour period 
Persistent episodes 
of unformed to 
watery stools OR 
Increase of 4 to  6 
stools over baseline 
per 24-hour period 
Increase of  ≥ 7 
stools per 24-hour 
period OR IV fluid 
replacement 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number 
of stools OR Mild 
dehydration 
Liquid stools with 
moderate 
dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting 
in severe dehydration, 
hypotensive shock) 
Dysphagia or  
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary 
intake with no 
intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention 
indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention 
indicated 
Transfusion 
indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema  Patchy 
pseudomembranes 
or ulcerations  
Confluent 
pseudomembranes
or ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding  
Nausea  
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in 
decreased oral 
intake for 24 to 48 
hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration 
indicated (e.g., IV 
fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated  
Life-threatening 
consequences (e.g., 


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circulatory failure, 
hemorrhage, sepsis)  
Perforation  
(colon or rectum)  
NA  
NA  
Intervention 
indicated  
Life-threatening 
consequences  
Proctitis  
Rectal discomfort 
with no 
intervention 
indicated  
Symptoms causing 
greater than 
minimal 
interference with 
usual social &  
functional activities  
OR Medical 
intervention 
indicated   
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention 
indicated   
Life-threatening 
consequences (e.g., 
perforation)  
Rectal Discharge  
Visible discharge  
Discharge requiring 
the use of pads  
NA  
NA  
Vomiting  
Transient or  
intermittent AND 
No or minimal 
interference with 
oral intake  
Frequent episodes 
with no or mild 
dehydration  
Persistent vomiting  
resulting in  
orthostatic 
hypotension OR 
Aggressive  
rehydration 
indicated  
(e.g., IV fluids)  
Life-threatening 
consequences (e.g., 
hypotensive shock)  
 
 
Musculoskelatal 
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  


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Arthralgia  
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional 
activities  
Joint pain causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Joint pain causing 
inability to perform 
usual social & 
functional activities  
Disabling joint pain 
causing inability to 
perform basic self-
care functions  
Arthritis  
Stiffness or joint 
swelling causing 
no or minimal 
interference with 
usual social & 
functional 
activities  
Stiffness or joint 
swelling causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities  
Disabling joint 
stiffness or swelling 
causing inability to 
perform basic self-
care functions   
Myalgia (generalized)  
Muscle pain 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Muscle pain 
causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Muscle pain causing 
inability to perform 
usual social & 
functional activities  
Disabling muscle pain 
causing inability to 
perform basic self-
care functions  
Osteonecrosis  
NA  
No symptoms but 
with radiographic 
findings AND No  
operative 
intervention 
indicated  
Bone pain with 
radiographic 
findings OR 
Operative 
intervention 
indicated  
Disabling bone pain 
with radiographic 
findings causing 
inability to perform 
basic self-care 
functions  
Osteopenia6 ≥ 30 
years of age  
BMD t-score   
-2.5 to -1  
NA  
NA  
NA  
   < 30 years of age  
BMD z-score   
-2 to -1  
NA  
NA  
NA  
 
 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment  
of osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for 
Metabolic Bone Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.   


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Osteoporosis6 ≥ 30 
years of age  
NA   
BMD t-score < -2.5  
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height)  
Pathologic fracture 
causing life-
threatening 
consequences   
< 30 years of age  
NA  
BMD z-score < -2  
Pathologic fracture 
(e.g., compression 
fracture causing 
loss of vertebral 
height)  
Pathologic fracture 
causing life-
threatening 
consequences   
  
Neurologic  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Acute CNS Ischemia  
NA  
NA  
Transient ischemic 
attack  
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit)  
Altered Mental Status  
(for Dementia, see  
Cognitive, Behavioral, 
or Attentional 
Disturbance below)   
Changes causing 
no or minimal 
interference with 
usual social & 
functional 
activities  
Mild lethargy or 
somnolence 
causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Confusion, memory 
impairment, 
lethargy, or  
somnolence 
causing inability to 
perform usual 
social & functional 
activities  
Delirium OR   
Obtundation OR   
Coma  
Ataxia   
Symptoms 
causing no or 
minimal 
interference with 
usual social &  
functional 
activities  
OR No symptoms  
with ataxia 
detected on 
examination  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities   
Disabling symptoms 
causing inability to 
perform basic self-
care functions  


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Cognitive, Behavioral, 
or Attentional  
Disturbance (includes 
dementia and 
attention deficit 
disorder)  
Specify type, if 
applicable  
Disability causing 
no or minimal 
interference with 
usual social &  
functional 
activities OR 
Specialized 
resources not 
indicated  
Disability causing 
greater than 
minimal 
interference with 
usual social &  
functional activities 
OR Specialized 
resources on 
parttime basis 
indicated  
Disability causing 
inability to perform 
usual social &  
functional activities 
OR Specialized 
resources on a 
fulltime basis 
indicated  
Disability causing 
inability to perform 
basic self-care 
functions OR 
Institutionalization 
indicated  
Developmental Delay  
< 18 years of age  
  
Specify type, if 
applicable  
Mild 
developmental 
delay, either 
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for 
the setting   
Moderate  
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting   
Severe  
developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting   
Developmental 
regression, either 
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting  
Headache   
Symptoms 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities   
Symptoms causing 
inability to perform 
basic self-care 
functions OR 
Hospitalization 
indicated  OR 
Headache with 
significant 
impairment of 
alertness or other 
neurologic function   
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy)  
Specify type, if 
applicable  
Minimal muscle 
weakness causing 
no or minimal 
interference with 
usual social & 
functional 
activities OR No 
symptoms with 
Muscle weakness 
causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Muscle weakness  
causing inability to 
perform usual 
social & functional 
activities   
Disabling muscle 
weakness causing 
inability to perform 
basic self-care 
functions OR 
Respiratory muscle 
weakness impairing 
ventilation  


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decreased 
strength on 
examination  
Neurosensory  
Alteration (includes 
paresthesia and painful 
neuropathy)  
Specify type, if 
applicable  
Minimal 
paresthesia 
causing no or 
minimal  
interference with 
usual social & 
functional 
activities  
OR No symptoms 
with sensory 
alteration on 
examination  
Sensory alteration 
or paresthesia 
causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Sensory alteration 
or paresthesia 
causing inability to 
perform usual 
social & functional 
activities  
Disabling sensory 
alteration or  
paresthesia causing 
inability to perform 
basic self-care 
functions  
 
Seizures  
New Onset Seizure  
≥ 18 years of age  
NA  
NA   
1 to  3 seizures   
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR  
Difficult to control 
(e.g., refractory 
epilepsy)  
< 18 years of age 
(includes new or 
preexisting febrile 
seizures)  
Seizure lasting < 5 
minutes with < 24 
hours postictal 
state  
Seizure lasting 5 to 
<  
20 minutes with  < 
24 hours postictal 
state  
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal 
state  
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR  
Difficult to control 
(e.g., refractory 
epilepsy)  
Pre-existing Seizure  
NA  
Increased 
frequency from 
previous level of 
control without 
Change in seizure 
character either in 
duration or quality  
Prolonged and 
repetitive seizures 
(e.g., status 
epilepticus) OR  


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change in seizure 
character  
(e.g., severity or  
focality)  
Difficult to control 
(e.g., refractory 
epilepsy)  
Syncope   
Near syncope 
without loss of 
consciousness 
(e.g., pre-syncope)  
Loss of 
consciousness with 
no intervention 
indicated  
Loss of  
consciousness AND 
Hospitalization or 
intervention 
required  
NA  
  
Psychiatric  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Insomnia   
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities   
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing more than 
minimal 
interference with 
usual social & 
functional activities  
Severe difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing inability to 
perform usual 
social & functional 
activities requiring 
intervention or 
hospitalization  
NA  
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) Specify 
disorder  
Symptoms with 
intervention not 
indicated OR 
Behavior causing 
no or minimal 
interference with 
usual social & 
functional 
activities  
Symptoms with 
intervention 
indicated OR 
Behavior causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities  
Threatens harm to 
self or others OR 
Acute psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions  
Suicidal Ideation or 
Attempt  
Report only one  
Preoccupied with 
thoughts of death 
AND No wish to  
kill oneself  
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
Thoughts of killing 
oneself with partial 
or complete plans 
but no attempt to 
do so OR 
Suicide attempted  


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specific plan or 
intent  
Hospitalization 
indicated  
  
Respiratory  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Acute Bronchospasm  
Forced expiratory 
volume in 1 
second or peak 
flow reduced to   
≥ 70 to < 80% OR 
Mild symptoms 
with intervention 
not indicated  
Forced expiratory 
volume in 1 second 
or peak flow 50 to   
< 70% OR 
Symptoms  
with intervention 
indicated OR 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Forced expiratory 
volume in 1 second  
or peak flow 25 to  
< 50% OR  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or  
hemodynamic 
compromise OR  
Intubation   
Dyspnea or 
Respiratory Distress  
Report only one  
Dyspnea on 
exertion with no 
or minimal  
interference with 
usual social &  
functional 
activities  
OR Wheezing OR 
Minimal increase 
in respiratory rate 
for age  
Dyspnea on 
exertion causing 
greater than 
minimal 
interference with 
usual social &  
functional activities 
OR Nasal flaring OR  
Intercostal 
retractions  
OR Pulse oximetry  
90 to < 95%  
Dyspnea at rest 
causing inability to 
perform usual 
social & functional 
activities OR Pulse 
oximetry < 90%  
Respiratory failure 
with ventilator 
support indicated 
(e.g., CPAP, BPAP, 
intubation)  
  
Sensory  


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PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Hearing Loss ≥ 12 
years of age  
  
NA  
  
Hearing aid or 
intervention not 
indicated  
  
Hearing aid or 
intervention 
indicated  
  
Profound bilateral 
hearing loss (> 80 dB 
at 2 kHz and above) 
OR  
Non-serviceable 
hearing (i.e., >50 dB 
audiogram and <50% 
speech 
discrimination)  
< 12 years of age  
(based on a 1, 2, 3, 4,  
6 and 8 kHz 
audiogram)  
> 20 dB hearing 
loss at  ≤ 4 kHz  
> 20 dB hearing 
loss at > 4 kHz  
> 20 dB hearing loss 
at  ≥ 3 kHz in one 
ear with additional 
speech language 
related services 
indicated (where 
available) OR 
Hearing loss 
sufficient to 
indicate 
therapeutic 
intervention, 
including hearing 
aids  
Audiologic indication 
for cochlear implant 
and additional 
speechlanguage 
related services 
indicated (where 
available)  
Tinnitus  
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional 
activities with 
intervention not 
indicated  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  
Uveitis  
No symptoms 
AND  
Detectable on 
examination  
Anterior uveitis 
with symptoms OR  
Posterior or 
panuveitis OR 
Operative 
Disabling visual loss in 
affected eye(s)   


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Medical 
intervention 
indicated  
intervention 
indicated  
Vertigo  
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional 
activities  
Vertigo causing 
greater than 
minimal 
interference with 
usual social & 
functional activities  
Vertigo causing 
inability to perform 
usual social & 
functional activities  
Disabling vertigo 
causing inability to 
perform basic self-
care functions  
Visual Changes  
(assessed from 
baseline)  
Visual changes 
causing no or 
minimal 
interference with 
usual social & 
functional 
activities  
Visual changes 
causing greater 
than minimal 
interference with 
usual social & 
functional activities  
Visual changes 
causing inability to 
perform usual 
social & functional 
activities  
Disabling visual loss in 
affected eye(s)  
  
Systemic  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Acute Allergic  
Reaction   
Localized urticaria 
(wheals) with no 
medical intervention 
indicated  
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with 
no intervention 
indicated  
Generalized urticaria 
OR Angioedema with 
intervention 
indicated OR 
Symptoms of mild 
bronchospasm  
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema  
Chills  
Symptoms causing 
no  
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities   
Symptoms causing 
inability to perform 
usual social & 
functional activities  
NA  


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Cytokine Release  
Syndrome7  
Mild signs and  
symptoms AND  
Therapy (i.e., 
antibody infusion)  
interruption not 
indicated  
Therapy (i.e., 
antibody infusion)  
interruption 
indicated AND 
Responds 
promptly to 
symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours  
Prolonged severe 
signs and symptoms 
OR Recurrence of 
symptoms following 
initial improvement  
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support)  
Fatigue or Malaise  
Report only one  
Symptoms causing 
no  
or minimal 
interference with 
usual social & 
functional activities  
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities  
Symptoms causing 
inability to perform 
usual social & 
functional activities  
Incapacitating 
symptoms of fatigue or 
malaise causing inability 
to perform basic self-
care functions  
Fever (non-axillary 
temperatures only)  
38.0 to < 38.6°C or 
100.4 to < 101.5°F  
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  < 
102.7°F  
≥ 39.3 to < 40.0°C or  
≥ 102.7 to < 104.0°F  
≥ 40.0°C or ≥ 104.0°F  
Pain8 (not associated 
with study agent 
injections and not 
specified elsewhere)  
Specify location  
Pain causing no or 
minimal interference 
with usual social & 
functional activities  
Pain causing 
greater than 
minimal 
interference with 
usual social & 
functional 
activities   
Pain causing inability 
to perform usual 
social & functional 
activities   
Disabling pain causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  
 
 
 
7 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.  
8 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).    


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Serum Sickness9  
Mild signs and 
symptoms  
Moderate signs 
and  
symptoms AND  
Intervention 
indicated (e.g., 
antihistamines)  
Severe signs and 
symptoms AND  
Higher level 
intervention 
indicated (e.g., 
steroids or IV fluids)  
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support)  
Underweight10 > 5 
to 19 years of age  
WHO BMI z-score  
< -1 to -2  
WHO BMI z-score  
< -2 to -3  
WHO BMI z-score   
< -3  
WHO BMI z-score   
< -3 with life-
threatening 
consequences  
2 to 5 years of age  
WHO Weight-for- 
height z-score   
< -1 to -2  
WHO Weight-for- 
height z-score   
< -2 to -3  
WHO Weight-for- 
height z-score < -3  
WHO Weight-for-
height z-score < -3 with 
lifethreatening 
consequences  
< 2 years of age  
WHO Weight-for- 
length z-score   
< -1 to -2  
WHO Weight-for- 
length z-score   
< -2 to -3  
WHO Weight-for- 
length z-score < -3  
WHO Weight-for-
length z-score < -3 with 
lifethreatening 
consequences  
Unintentional  
Weight Loss  
(excludes 
postpartum  
weight loss)  
NA  
5 to < 9% loss in 
body weight from 
baseline  
≥ 9 to < 20% loss in 
body weight from 
baseline  
≥ 20% loss in body 
weight from baseline 
OR  Aggressive 
intervention indicated 
(e.g., tube feeding, 
total parenteral 
nutrition)  
  
Urinary  
 
 
9 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or 
dyspnea.  
10 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:   
http://www.who.int/growthref/who2007_bmi_for_age/en/ 
for 
participants 
> 
5 
to 
19 
years 
of 
age 
and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  
DAIDS AE Grading Table Corrected Version 2.1- July 2017  


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PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Urinary Tract  
Obstruction   
NA  
Signs or symptoms 
of urinary tract 
obstruction 
without  
hydronephrosis or 
renal dysfunction  
Signs or symptoms 
of  
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction  
Obstruction causing  
life-threatening 
consequences  
  
 
 
 
 
 
Site Reactions to Injections and Infusions  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Injection Site Pain or  
Tenderness  
Report only one  
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb  
Pain or tenderness 
causing greater than 
minimal limitation 
of use of limb   
Pain or tenderness 
causing inability to 
perform usual social 
& functional 
activities  
Pain or tenderness 
causing inability to 
perform basic self-care  
function OR 
Hospitalization 
indicated  


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Injection Site Erythema 
or Redness11 Report 
only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 
to < 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
to 
< 100 cm2 surface 
area OR Symptoms 
causing greater than 
minimal 
interference with 
usual social & 
functional activities 
surface area OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially 
lifethreatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue)  
≤ 15 years of age 
≤2.5 cm in 
diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the 
extremity segment 
involved (e.g., upper 
arm or thigh) 
≥50% surface area 
of the extremity 
segment involved 
(e.g., upper arm or 
thigh) OR Ulceration 
OR Secondary 
infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Potentially 
lifethreatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
11 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.


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Injection Site Pruritus   
  
Itching localized to 
the injection site 
that is relieved 
spontaneously or 
in < 48 hours of 
treatment   
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment   
Generalized itching 
causing inability to 
perform usual social 
& functional 
activities   
NA  
  
Laboratory Values*   
Chemistries  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Acidosis  
NA  
pH ≥ 7.3 to < LLN  
pH < 7.3 without 
lifethreatening 
consequences  
pH < 7.3 with 
lifethreatening 
consequences  
Albumin, Low  
(g/dL; g/L)  
3.0 to < LLN  
30  to < LLN  
≥ 2.0 to < 3.0   
≥ 20  to < 30   
< 2.0   
< 20   
NA  
Alkaline Phosphatase,   
High  
1.25  to < 2.5   
x ULN  
2.5  to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Alkalosis  
NA  
pH > ULN to ≤ 7.5  
pH > 7.5 without 
lifethreatening 
consequences  
pH > 7.5 with 
lifethreatening 
consequences   
ALT or SGPT, High  
Report only one  
1.25  to < 2.5   
x ULN  
2.5 to < 5.0 x ULN  
5.0  to < 10.0 x ULN  ≥ 10.0 x ULN  
Amylase (Pancreatic) 
or Amylase (Total), 
High  
Report only one  
1.1  to < 1.5 x ULN  1.5  to < 3.0 x ULN  
3.0  to < 5.0 x ULN  
≥ 5.0 x ULN  
AST or SGOT, High  
Report only one  
1.25  to < 2.5   
x ULN  
2.5  to < 5.0 x ULN  
5.0  to < 10.0 x ULN  ≥ 10.0 x ULN  
Bicarbonate, Low  
(mEq/L; mmol/L)  
16.0 to <  LLN  
16.0 to <  LLN  
11.0  to < 16.0   
11.0  to < 16.0   
8.0  to < 11.0   
8.0  to < 11.0   
< 8.0   
< 8.0   


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Bilirubin 
Direct Bilirubin13, 
High 
> 28 days of age 
  
NA 
NA 
> ULN with other 
signs and 
symptoms of 
hepatotoxicity.  
> ULN with 
lifethreatening 
consequences (e.g., 
signs and symptoms 
of liver failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL 
> 2 mg/dL 
Total Bilirubin, High > 
28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN  
≥ 5.0 x ULN  
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates  
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates  
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates  
See Appendix A. Total 
Bilirubin for Term 
and 
Preterm Neonates 
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be reported to 
DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements. 
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total 
bilirubin.
PARAMETER 
GRADE 1 MILD 
GRADE 2 
MODERATE 
GRADE 3 SEVERE 
GRADE 4 
POTENTIALLY LIFE- 
THREATENING 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5  
2.88  to < 3.13 
12.5   to < 13.5  
3.13  to < 3.38 
< 7 days of age 
11.5  to < 12.4  
2.88  to < 3.10 
12.4  to < 12.9  
3.10  to < 3.23 
12.9  to < 13.5  
3.23  to < 3.38 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0 
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8  
≥ 7.2 
≥ 1.8  


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Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4  
1.95  to < 2.10 
7.0   to < 7.8  
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1  < 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized), Low 
(mg/dL; mmol/L) 
< LLN  to 4.0  
< LLN  to 1.0 
3.6 to < 4.0  
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9  
< 3.2 
< 0.8  
Cardiac Troponin I, 
High  
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
*Report only one 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase to 1.3 to 
< 1.5 x participant’s 
baseline 
> 1.8  to < 3.5  
x ULN OR Increase to 
1.5 to < 2.0 x 
participant’s baseline 
Increase of  ≥ 2.0 x 
participant’s baseline 
Creatinine Clearance12
or eGFR, Low *Report 
only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2  
OR 
10 to < 30% decrease 
from participant’s 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 
OR 
30 to < 50% decrease 
from participant’s 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 
participant’s baseline or 
dialysis needed 
Glucose 
(mg/dL; mmol/L) Fasting, 
High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500  
13.89 to < 27.75 
≥  500  
≥ 27.75 
Nonfasting, High 
116 to 160 
6.44 to < 8.89  
> 160 to 250 
8.89 to < 13.89 
> 250  to 500 
13.89  to < 27.75  
≥  500 
≥ 27.75  
12 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in mL/min/1.73m2). Sites should 
choose the method defined in their study and when not specified, use the method most relevant to the study population. 
  
*Reminder: Choose the method that selects for the higher grade.


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Glucose, Low   
(mg/dL; mmol/L)  
≥ 1 month of age  
55  to 64   
3.05  to <3.55   
40  to < 55  
2.22  to < 3.05   
30  to < 40  
1.67 to < 2.22   
< 30  
< 1.67   
< 1 month of age  
50 to 54  
2.78  to < 3.00   
40 to < 50  
2.22 to < 2.78   
30 to < 40  
1.67 to < 2.22   
< 30  
< 1.67   
Lactate, High  
ULN to  < 2.0 x 
ULN without 
acidosis  
≥ 2.0 x ULN without 
acidosis  
Increased lactate 
with pH < 7.3 
without 
lifethreatening 
consequences   
Increased lactate 
with pH < 7.3 with 
lifethreatening 
consequences   
Lipase, High  
1.1  to < 1.5 x ULN  1.5  to < 3.0 x ULN  
3.0  to < 5.0 x ULN  
≥ 5.0 x ULN  
Lipid Disorders   
(mg/dL; mmol/L)  
Cholesterol, Fasting,  
High  
≥ 18 years of age  
  
200  to < 240  
5.18  to < 6.19   
  
240  to < 300   
6.19  to < 7.77   
  
≥  300  
≥  7.77   
  
NA  
< 18 years of age  
170  to < 200  
4.40  to < 5.15   
200 to < 300  
5.15  to < 7.77   
≥  300   
≥  7.77   
NA  
LDL, Fasting, High ≥ 18 
years of age  
  
130  to < 160   
3.37  to < 4.12   
  
160 to < 190   
4.12  to < 4.90   
  
≥ 190   
≥ 4.90   
  
NA  
> 2 to < 18 years of age  110  to < 130   
2.85  to < 3.34   
130 to < 190   
3.34  to < 4.90   
≥ 190  
≥ 4.90   
NA  
Triglycerides, Fasting,  
High  
150 to 300   
1.71 to 3.42   
>300  to 500   
>3.42 to 5.7   
>500 to < 1,000   
>5.7 to 11.4   
> 1,000   
> 11.4  
Magnesium13, Low 
(mEq/L; mmol/L)  
1.2   to < 1.4   
0.60  to < 0.70   
0.9  to < 1.2   
0.45  to < 0.60   
0.6  to < 0.9   
0.30  to < 0.45   
< 0.6   
< 0.30   
Phosphate, Low   
(mg/dL; mmol/L)  
> 14 years of age  
2.0 to < LLN  
0.65 to < LLN  
1.4 to < 2.0  
0.45 to < 0.65   
1.0 to < 1.4  
0.32 to < 0.45   
< 1.0  
< 0.32   
 
 
13 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  


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1 to 14 years of age  
3.0  to < 3.5  
0.97  to < 1.13   
2.5  to < 3.0  
0.81  to < 0.97   
1.5  to < 2.5  
0.48  to < 0.81   
< 1.5  
< 0.48   
< 1 year of age  
3.5  to < 4.5  
1.13  to < 1.45   
2.5  to < 3.5  
0.81  to < 1.13   
1.5  to < 2.5  
0.48  to < 0.81   
< 1.5  
< 0.48   
Potassium, High 
(mEq/L; mmol/L)  
5.6  to < 6.0  
5.6  to < 6.0   
6.0  to < 6.5  
6.0  to < 6.5   
6.5  to < 7.0  
6.5  to < 7.0   
≥ 7.0  
≥ 7.0   
Potassium, Low 
(mEq/L; mmol/L)  
3.0  to < 3.4  
3.0  to < 3.4   
2.5  to < 3.0  
2.5  to < 3.0  
2.0  to < 2.5  
2.0  to < 2.5   
< 2.0  
< 2.0   
Sodium, High (mEq/L; 
mmol/L)  
146  to < 150  
146  to < 150   
150  to < 154  
150  to < 154   
154  to < 160  
154  to < 160   
≥ 160  
≥ 160   
Sodium, Low (mEq/L; 
mmol/L)  
130  to < 135  
130  to < 135   
125  to < 130  
125  to < 130  
121  to < 125  
121  to < 125   
≤ 120  
≤ 120   
Uric Acid, High (mg/dL; 
mmol/L)  
7.5  to < 10.0  
0.45  to < 0.59   
10.0  to < 12.0  
0.59  to < 0.71   
12.0  to < 15.0  
0.71  to < 0.89   
≥ 15.0  
≥ 0.89   
 
 
Hematology  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Absolute CD4+ Count,  
Low  
(cell/mm3; cells/L)  
> 5 years of age   
(not HIV infected)  
  
  
  
300 to < 400  
300 to < 400  
  
  
  
200 to < 300  
200 to < 300  
  
  
  
100 to < 200  
100 to < 200  
  
  
  
< 100  
< 100  
Absolute Lymphocyte  
Count, Low   
(cell/mm3; cells/L)  
> 5 years of age   
(not HIV infected)  
  
  
  
600 to < 650  
0.600 x 109 to  
< 0.650 x 109  
  
  
  
500 to < 600  
0.500 x 109 to  
< 0.600 x 109  
  
  
  
350 to < 500  
0.350 x 109 to  
< 0.500 x 109  
  
  
  
< 350  
< 0.350 x 109  


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Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 
1.000 x 109 
600 to 799 
0.600 x 109 to 0.799 
x 109 
400 to 599 
0.400 x 109 to 0.599 
x 109 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 
1.500 x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 
x 109 
750 to 999 
0.750 x 109 to 0.999 
x 109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 
x 109 
1,500 to 2,999 
1.500 x 109 to 2.999 
x 109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100 to < 200 
1.00 to < 2.00  
OR 
0.75 to < 1.00 x 
LLN 
75 to < 100 0.75  to 
< 1.00  
x LLN  
50 to < 75 
0.50  to < 0.75  
OR 
0.25 to < 0.50 x LLN 
< 50 
< 0.50  
OR 
< 0.25 x LLN OR 
Associated with gross 
bleeding 
Hemoglobin14, Low 
(g/dL; mmol/L)15
≥ 13 years of age  
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age  
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
Hematology 
14 Male and female sex are defined as sex at birth. For transgender participants ≥13 years of age who have been on hormone 
therapy for more than 6 consecutive months, grade hemoglobin based on the gender with which they identify (i.e., a transgender 
female should be graded using the female sex at birth hemoglobin laboratory values). 
15 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading hemoglobin results obtained by 
an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using appropriate conversion 
factor for the particular laboratory.  


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PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
57 days of age to < 13 
years of age  (male and 
female)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to < 9.5  
5.25 to < 5.88  
6.5 to < 8.5  
4.03 to < 5.25  
< 6.5  
< 4.03  
36 to 56 days of age  
(male and female)  
8.5 to 9.6  
5.26 to 5.99  
7.0 to < 8.5  
4.32 to < 5.26  
6.0 to < 7.0  
3.72 to < 4.32  
< 6.0  
< 3.72  
22 to 35 days of age  
(male and female)  
9.5 to 11.0  
5.88 to 6.86  
8.0 to < 9.5  
4.94 to < 5.88  
6.7 to < 8.0  
4.15 to < 4.94  
< 6.7  
< 4.15  
8 to ≤ 21 days of age  
(male and female)  
11.0 to 13.0  
6.81 to 8.10  
9.0 to < 11.0  
5.57 to < 6.81  
8.0 to < 9.0  
4.96 to < 5.57  
< 8.0 < 4.96  
≤ 7 days of age  
(male and female)  
13.0 to 14.0  
8.05 to 8.72  
10.0 to < 13.0  
6.19 to < 8.05  
9.0 to < 10.0  
5.59 to < 6.19  
< 9.0  
< 5.59  
INR, High   
(not on anticoagulation 
therapy)  
1.1  to < 1.5 x ULN  1.5  to < 2.0 x ULN  
2.0  to < 3.0 x ULN  
≥  3.0 x ULN  
Methemoglobin  (% 
hemoglobin)  
5.0  to < 10.0%  
10.0  to < 15.0%  
15.0  to < 20.0%  
≥  20.0%  
PTT, High   
(not on anticoagulation 
therapy)  
1.1  to < 1.66   
x ULN  
1.66 to < 2.33   
x ULN  
2.33 to < 3.00   
x ULN  
≥  3.00 x ULN  
Platelets, Decreased 
(cells/mm3; cells/L)  
100,000  to  
< 125,000   
100.000 x 109  to  
< 125.000 x 109  
50,000  to  
< 100,000  
50.000 x 109  to  
< 100.000 x 109  
25,000  to  
< 50,000   
25.000 x 109  to   
< 50.000 x 109  
< 25,000   
< 25.000 x 109  
PT, High   
(not on anticoagulation 
therapy  
1.1  to < 1.25   
x ULN  
1.25  to < 1.50   
x ULN  
1.50  to < 3.00   
x ULN  
≥  3.00 x ULN  
WBC, Decreased  
(cells/mm3; cells/L)  
> 7 days of age  
  
  
2,000 to 2,499  
2.000 x 109 to 
2.499 x 109  
  
  
1,500 to 1,999  
1.500 x 109 to 
1.999 x 109  
  
  
1,000 to 1,499  
1.000 x 109 to 
1.499 x 109  
  
  
< 1,000  
< 1.000 x 109  


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≤ 7 days of age  
5,500 to 6,999  
5.500 x 109 to 
6.999 x 109  
4,000 to 5,499  
4.000 x 109 to 
5.499 x 109  
2,500 to 3,999  
2.500 x 109 to 
3.999 x 109  
< 2,500  
< 2.500 x 109  
 
 
Urinalysis  
PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
Glycosuria (random 
collection tested by 
dipstick)  
Trace to 1+ or  
≤ 250 mg  
2+ or ˃ 250 to    
≤ 500 mg  
> 2+ or > 500 mg  
NA  
Hematuria (not to be 
reported based on 
dipstick findings or on 
blood believed to be of 
menstrual origin)  
6  to < 10 RBCs per 
high power field  
≥ 10 RBCs per high 
power field  
Gross, with or 
without clots OR  
With RBC casts OR  
Intervention 
indicated  
Life-threatening 
consequences  
Proteinuria (random 
collection tested by 
dipstick)  
1+  
2+  
3+  or higher  
NA  
  
 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates  
 
  PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  


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Total Bilirubin16, High 
(mg/dL; µmol/L)17
Term Neonate18
< 24 hours of age 
4 to < 7  
68.4 to < 119.7  
7 to < 10  
119.7 to < 171  
10 to < 17  
171 to < 290.7  
≥ 17 
≥ 290.7  
24 to < 48 hours of age 5 to < 8  
85.5 to < 136.8  
8 to < 12  
136.8 to < 205.2  
12 to < 19  
205.2 to < 324.9  
≥ 19  
≥ 324.9  
48 to < 72 hours of age 8.5 to < 13  
145.35 to < 222.3  
13 to < 15  
222.3 to < 256.5  
15 to < 22  
256.5 to < 376.2  
≥ 22  
≥ 376.2  
72 hours to < 7 days of 
age 
11 to < 16  
188.1 to < 273.6  
16 to < 18  
273.6 to < 307.8  
18 to < 24  
307.8 to < 410.4 
≥ 24  
≥ 410.4  
7 to 28 days of age 
(breast feeding) 
5 to < 10  
85.5 to < 171  
10 to < 20  
171 to < 342  
20 to < 25  
342 to < 427.5  
≥ 25  
≥ 427.5  
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥ 5.0 x ULN 
Preterm Neonate20  
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate 
(based on days of 
age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
32 to < 35 weeks 
gestational age and  < 7 
days of age 
NA 
NA 
10 to < 14  
171 to < 239.4 
≥ 14  
≥ 239.4 
28 to < 32 weeks 
gestational age and  < 7 
days of age 
NA 
NA 
6 to < 10  
102.6 to < 171  
< 28 weeks 
gestational age and  < 7 
days of age 
NA 
NA 
5 to < 8  85.5 to < 
136.8  
16 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first 
week of life followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this 
appendix corresponds approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 
4. 
17 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
18 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks gestational age; preterm, as < 35 weeks 
gestational age; and neonate, as 0 to 28 days of age.


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7 to  28 days of age  
(breast feeding)  
5 to < 10   
85.5 to < 171   
10 to < 20   
171 to < 342   
20 to < 25   
342 to < 427.5   
≥ 25   
≥ 427.5   
7 to 28 days of age  
(not breast feeding)  
1.1 to < 1.6 x ULN  
1.6 to < 2.6 x ULN  
2.6 to < 5.0 x ULN  
≥  5.0 x ULN  
 
 
 
12.4 APPENDIX 4. IRB REPORTING 
 
This guidance applies to Stanford University human subject research and details events or 
circumstances that must be promptly reported to the IRB during the conduct of human subject 
research.  
 
Events and information which require prompt reporting to the IRB 
 
1) Unanticipated Problems Involving Risks to Participants or Others (UPs) 
Events (internal or external, deaths, life-threatening experiences, injuries, or other) occurring 
during the research study, which in the opinion of the Monitoring Entity or the PD meet all of 
the following criteria: 
 
• 
Unexpected 
in terms of nature, severity, or frequency, given (a) the research procedures described in 
the protocol-related documents such as the IRB-approved research protocol and 
informed consent document or the Investigator's Brochure, and (b) the characteristics of 
the subject population being studied; 
AND 
• 
Related or Possibly Related to participation in the research or there is a reasonable 
possibility or likelihood that the incident, experience, or outcome may have been 
caused by the procedures involved in the research; 
AND 
• 
Places Subjects or Others at a Greater Risk of Harm  
the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm, including harm related to breaches of privacy) 
than was previously known or recognized. 
 
NOTE: 
 A “UP” generally will warrant consideration of substantive changes in the research 
protocol or informed consent process/document, or other corrective actions, in order to 
protect the safety, welfare, or rights of subjects or others. 


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2) New Information that indicates a change to the risks or potential benefits of the 
research in terms of severity or frequency or impacts the subject’s willingness to 
participate (e.g., DSMB/DSMC Report, other safety information or publication, 
suspension or premature termination by the sponsor or investigator). 
 
3) Noncompliance: An action, inaction, or activity, whether by the investigator, study staff, 
or others involved in human subject research, that is at variance with the approved IRB 
protocol, other requirements and determinations of the IRB, the HRPP Policy Manual 
and other applicable policies of Stanford University, SHC, LPCH, VAPAHCS (e.g., VHA 
Handbook 1200.5), Palo Alto Veterans Institute for Research (PAVIR) or relevant state 
or federal laws. The following are always considered noncompliance: human subjects 
research conducted without IRB approval, or approved by an outside IRB, without prior 
notice to Stanford’s IRB (or Stanford IRB approval, if required under Stanford policies); 
or change(s) to the research implemented without IRB approval except when necessary 
to eliminate apparent immediate hazards to the subject. 
 
When the event is: 
 
o Possibly serious: Any behavior, action, inaction, or omission in the conduct or 
oversight of human research that, in the judgment of the IRB, has been 
determined to: 
 
adversely affect or compromise the rights or welfare of participants; 
 
harm or materially increase exposure to significant risk of harm to a 
research participant(the IRB does not have to find that harm has 
occurred, or was likely to occur, to make a determination of serious 
noncompliance); 
 
result in a detrimental change to a participant’s clinical or emotional 
condition or status; or 
 
compromise the integrity or validity of the research. 
 
o Possibly continuing: A pattern of repeated instances of noncompliance that: 
 
Continues to occur after discovery of noncompliance or implementation of 
a preventive action plan; or 
 
Results from failure to implement a preventive action plan approved by 
the IRB; or 
 
A circumstance in which an investigator or other study staff fails to 
cooperate with investigating or correcting non-compliance. 
 
4) Complaint unresolved by the research team 
 
5) Incarceration when in the opinion of the PD it is in the best interest of the participant to 
remain on the study. 
 
6) Unanticipated adverse device effect (UADE) 


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Any serious adverse effect on health or safety or any life-threatening problem or death 
caused by, or associated with, a device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the investigational plan or application 
(including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 21 CFR 
812.3(s) 
 
7) Other events or information 
Examples include: a deviation intended to eliminate an immediate hazard to a participant, 
suicide or suicide attempt of a participant, other Audit or Monitoring Visit reports and 
Corrective Action Preventative Action (CAPA) plans. Report only after consulting with the 
IRB Panel Manager. 
 
Timeframes 
• 
Timeframe for UP reports depends on Monitoring Entity 
 
o If PD is the only monitoring entity 
Items 1 - 6 should be reported directly to the IRB within 10 working days from when 
the PD learns of the event or new information. 
 
o If there is a monitoring entity in addition to, or other than, the PD 
Report to the IRB using this form within 10 working days from receiving assessment 
from monitoring entity. The PD should report to the IRB when the event has been 
assessed by the monitoring entity to be a UP. 
 
• 
Timeframe for Reportable Information (items 2 - 7) 
These should always be reported by the PD directly to the IRB within 10 working days from 
when the PD learns of the event or new information. 
 
• 
Unexpected deaths or life-threatening experiences related to the research (at Stanford, or 
when STANFORD is the coordinating institution in a multi-site study) must be reported to the 
IRB within 5 working days from PD learning of event. 
  
 
12.5 APPENDIX 5. GENETICS 
 
Use/Analysis of DNA 
• 
Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Therefore, where local regulations and 
IRBs/ECs allow, a blood sample will be collected for DNA analysis. 


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• 
The scope of the genetic research may be narrow (eg, 1 or more candidate genes) or 
broad (eg, the entire genome), as appropriate to the scientific question under 
investigation. 
• 
The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to study intervention or study interventions of this class to 
understand treatments for the disease(s) under study or the disease(s) themselves. 
• 
The results of genetic analyses may be reported in CSR or in a separate study 
summary, or may be used for internal decision making without being included in a study 
report. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.  
• 
The samples will be retained as indicated: 
o Retained samples will be stored indefinitely or for another period as per local 
requirements.  
• 
Participants may withdraw their consent for the storage and/or use of their Retained 
Research Samples at any time by making a request to the investigator; in this case, any 
remaining material will be destroyed. Data already generated from the samples will be 
retained to protect the integrity of existing analyses.  
Samples for genetic research will be labeled with a code. The key between the code and the 
participant’s personally identifying information (eg, name, address) will be held securely at the 
study site.