Trial of Early Therapies During Non-hospitalized Outpatient Window (TREAT NOW) for COVID-19
Phase: PHASE2
Conditions: COVID-19
Sponsor: Vanderbilt University Medical Center

Protocol 
 Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for 
COVID-19 
 
NCT04372628 
 January 26, 2021 
 

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Trial of Early Antiviral Therapies during Non-hospitalized Outpatient 
Window (TREAT NOW) for COVID-19 
 
 
Funding:  
US Department of Defense and AbbVie  
Network:  
Influenza and other Viruses in the Acutely Ill (IVY) Network 
Protocol:  
Version 1.6 
Date: 
 
January 26, 2021 
 
 
 
 
 
 
 
 
 
 

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TREAT NOW Trial Leadership 
 
 
Principal Investigators 
Adit A. Ginde, MD, MPH 
University of Colorado School of Medicine 
Email: adit.ginde@cuanschutz.edu 
 
Nathan I. Shapiro, MD, MPH 
Beth Israel Deaconess Medical Center 
nshapiro@bidmc.harvard.edu 
 
Lead Biostatistician 
      Alex Kaizer, PhD 
      Colorado School of Public Health 
      alex.kaizer@cuanschutz.edu 
 
Data Coordinating Center at Vanderbilt University Medical Center 
Gordon Bernard, MD 
Chris Lindsell, PhD 
    Frank Harrell, PhD 
Todd Rice, MD 
Wesley H. Self, MD, MPH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Signature of Clinical Study Protocol  
This signatory agrees to the content of the final clinical study protocol as presented.  
Name: Todd Rice, M.D., MSc  
 
 
 Data Coordinating Center Principal Investigator 
 
Date: __________________________ 
 
Signature: ______________________________________ 
 
Name: Adit A. Ginde, M.D., M.P.H. 
 
 Principal Investigator  
 
Date: __________________________ 
 
Signature: ______________________________________ 
 
Name: Nathan I. Shapiro, M.D., M.P.H. 
 
 Principal Investigator 
 
Date: __________________________ 
 
Signature: ______________________________________ 
 
 

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Table of Contents 
 
Signature of Clinical Study Protocol ............................................................................................... 3 
ABBREVIATIONS ...................................................................................................................................... 7 
1. STUDY SUMMARY ................................................................................................................................ 9 
2. TRIAL DESCRIPTION .......................................................................................................................... 13 
2.1 Background ............................................................................................................................... 13 
2.1.1 COVID-19 Infection .................................................................................................................. 13 
2.1.2 Promising Candidate Therapies for COVD-19 .......................................................................... 13 
2.1.3 Rationale for a Randomized Trial Early Treatment among Outpatients .................................... 14 
2.2 Study Aims ................................................................................................................................. 14 
2.2.1 Study aim ................................................................................................................................... 14 
2.2.2 Study hypothesis ........................................................................................................................ 14 
2.3 Study Design .............................................................................................................................. 15 
3. STUDY POPULATION AND ENROLLMENT ................................................................................... 15 
3.1 
Inclusion Criteria ................................................................................................................ 15 
3.2 Exclusion Criteria ..................................................................................................................... 15 
3.3 Justification of Exclusion Criteria ........................................................................................... 16 
3.4 Screening .................................................................................................................................... 16 
3.5 Assessment of Eligibility and Exclusion Tracking ................................................................. 17 
3.6 Process of Obtaining Informed Consent ................................................................................. 17 
3.7 Randomization and Blinding ................................................................................................... 18 
4. STUDY INTERVENTIONS................................................................................................................... 18 
4.1 Treatment of Study Participants ............................................................................................. 18 
4.2 Lopinavir/Ritonavir Group ...................................................................................................... 19 
4.3 Control Group ........................................................................................................................... 20 
4.4 Co-Interventions ....................................................................................................................... 20 
4.5 On-Study Monitoring ............................................................................................................... 20 
4.6 Criteria for Stopping Study Drug ............................................................................................ 21 
5. OUTCOMES........................................................................................................................................... 21 
5.1 Primary Outcome ...................................................................................................................... 21 
5.2 Secondary Outcomes ................................................................................................................ 22 
5.3 Safety outcomes ......................................................................................................................... 22 

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5.4 Rationale for Primary Outcome .............................................................................................. 22 
6. DATA COLLECTION ........................................................................................................................... 23 
6.1 Baseline Variable Collection .................................................................................................... 24 
6.2 Daily Assessments between Randomization and Study Day 16, and then at Day 29 .......... 24 
7. STATISTICAL CONSIDERATIONS .................................................................................................... 25 
8. DATA QUALITY MONITORING AND STORAGE ........................................................................... 26 
8.1 Data Quality Monitoring .......................................................................................................... 26 
8.2 Data Storage .............................................................................................................................. 26 
9. RISK ASSESSMENT ............................................................................................................................. 26 
9.1 Potential Risk to Participants .................................................................................................. 26 
9.1.2 Potential risks of receiving lopinavir/ritonavir .......................................................................... 26 
9.1.3 Potential risks of receiving placebo with COVID-19 ................................................................ 27 
9.2 Minimization of Risk ................................................................................................................ 27 
9.3 Potential Benefit ........................................................................................................................ 28 
9.4 Risk in Relation to Anticipated Benefit ................................................................................... 28 
10. HUMAN SUBJECTS PROTECTIONS ............................................................................................... 28 
10.1 Selection of Subjects................................................................................................................ 28 
10.2 Informed Consent ................................................................................................................... 28 
10.3 Withdrawal of Consent ........................................................................................................... 29 
10.4 Confidentiality ......................................................................................................................... 29 
11. ADVERSE EVENTS ............................................................................................................................ 29 
11.1 Adverse Event Definitions ...................................................................................................... 30 
11.2 Safety Monitoring ................................................................................................................... 30 
11.3 Serious Adverse Events .......................................................................................................... 31 
12. Data and Safety Monitoring Board (DSMB) ........................................................................................ 32 
13. APPENDICES ...................................................................................................................................... 33 
Appendix A. Schedule of Events .................................................................................................... 33 
Appendix B. Potential medication interactions with lopinavir/ritonavir ................................... 34 
Appendix C:  Adverse Event Reporting and Unanticipated Events .......................................... 35 
C.1. Unanticipated Problems (UP) ...................................................................................................... 35 
C.2. Determining Relationship of Adverse Events to Study Drug or Study Procedures .................... 35 
C.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting .................................... 36 
C.4. Decision tree for determining if an adverse event is reportable .................................................. 37 

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14. REFERENCES ..................................................................................................................................... 38 
 
 
 
 
 

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ABBREVIATIONS 
 
 
 
 
 
 
 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
BID 
twice daily 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CYP3A 
Cytochrome P4503A 
DCC 
Data Coordinating Center 
DSMB 
Data safety monitoring board 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report forms 
EKG 
Electrocardiogram 
 EUA 
 Emergency Use Authorization  
FDA 
Food & Drug Administration 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HR 
Hazard ratio 
IC50 
Half maximal inhibitory concentration 
ICU 
Intensive care unit 
ID 
Identification  
IL1 
Interleukin-1 
IL6 
Interleukin-6 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRIS 
Immune reconstitution inflammatory syndrome 
 
 
IVY Network 
Influenza Vaccine Effectiveness in the Critically Ill Network 
KDIGO 
Kidney Disease Improving Global Outcomes 
LFT 
Liver function test 
LPV/r 
Lopinavir/ritonavir 
MERS-CoV 
Middle East respiratory syndrome coronavirus 2 
 
 
NHLBI 
National Heart, Lung, and Blood Institute 

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NIH 
National Institutes of Health 
 
 
 
 
PI 
Principal investigator (a clinician responsible for one site) 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PPE 
Personal protective equipment 
QD 
once daily 
 
 
QR code 
Quick response code 
QTc 
QT interval corrected for heart rate 
 
 
REDCap 
Research Electronic Data Capture 
RT-PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious adverse events 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
 
 
sIRB 
Single IRB 
 
 
 
 
SUSAR 
Suspected unexpected serious adverse reaction 
US 
United States 
VCC 
Vanderbilt Coordinating Center 
VAS 
Visual Analog Scale 
 
 
 
 

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1. STUDY SUMMARY 
Title 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window 
Acronym  
TREAT NOW 
Background 
Effective therapies for COVID-19 are urgently needed. Lopinavir/Ritonavir 
(Kaletra) is an antiviral agent used to treat HIV-1 and is a potent in vitro 
inhibitor of SARS-CoV-2, the virus that causes COVID-19. Initial clinical data 
have suggested possible relevance as a potential therapeutic agent early in the 
course of patients with COVID-19. 
Study Design 
Blinded, multicenter, placebo-controlled randomized clinical trial 
Intervention Group 
Lopinavir/ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses 
(Days 1-14) 
Control Group                      Placebo (unmatched) orally twice daily for 14 days 
Sample Size 
Up to 600 patients 
 
Inclusion Criteria 
1. Age ≥18 years 
2. Laboratory-confirmed SARS-CoV-2 infection by RT-PCR or other 
molecular test, or by antigen test with emergency use authorization or full 
approval and collected within the past 6 days 
3. Current symptoms of acute respiratory infection for ≤6 days, defined as one 
or more of the following: 
o cough 
o fever 
o shortness of breath 
o chest pain 
o abdominal pain 
o nausea/vomiting 
o diarrhea 
o body aches 
o weakness/fatigue 
Exclusion Criteria 
1. Prisoner 
2. Pregnancy  
3. Breast feeding 
4. Two individuals from the same household are not enrolled in the study 
5. Unable to randomize within 6 days after onset of acute respiratory infection 
symptoms 
6. Hospitalization within the 6 days prior to randomization  
7. Inability to swallow oral medications 
8. Refusal or inability to be contacted and participate in daily symptom/safety 
monitoring in English or Spanish during the two-week follow-up period 
9. Previous enrollment in this trial 
10. Known severe chronic kidney disease requiring dialysis 

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11. Known liver disease (cirrhosis or >3 times upper limit of normal for AST 
or ALT in medical record if available) 
12. Known hepatitis B or hepatitis C infection 
13. Known history of jaundice 
14. Current heavy alcohol use, defined as 8 drinks or more per week for 
women or 15 drinks or more per week for men 
15. Known seizure disorder 
16. Known HIV infection 
17. Known history of pancreatitis 
18. Known history of prolonged QT interval (Long QT Syndrome, patient report, 
or QTc >500 milliseconds on most recently available electrocardiogram 
within the past 2 years) 
19. Receipt of >1 dose of lopinavir/ritonavir in the 10 days prior to enrollment 
20. Known allergy to lopinavir/ritonavir 
21. Currently prescribed (with planned continuation) or planned administration 
during 14-day study period of medication at high risk for QT prolongation 
as follows: 
Antiarrhythmics: Amiodarone, disopyramide, dofetilide, dronedarone, 
flecainide, ibutilide, procainamide, propafenone, quinidine, sotalol 
Anti-cancer:  Arsenic trioxide, oxaliplatin, vandetanib 
Antidepressants: Amitriptyline, citalopram, escitalopram, imipramine 
Antimicrobials: azithromycin, ciprofloxacin, clarithromycin, erythromycin, 
fluconazole, levofloxacin, moxifloxacin, pentamidine, hydroxychloroquine 
Antipsychotics:  aloperidol, chlorpromazine, droperidol, olanzapine, 
pimozide, quetiapine, thioridazine, risperidone, ziprasidone 
Others: cilostazol, cimetidine, cisapride, donepezil, methadone, 
ondansetron, sumatriptan  
22. Currently prescribed (with planned continuation) or planned administration 
during 14-day study period of any of the following medications: alfuzosin, 
apalutamide, astemizole, ergot-containing medicines (including 
dihydroergotamine mesylate, ergotamine tartrate, methylergonovine), 
lomitapide, lovastatin, lurasidone, midazolam, phenobarbital, phenytoin, 
ranolazine, rifampin, sildenafil, simvastatin, rivaroxaban, St. John’s Wort, 
terfenadine, triazolam. Patients who are on warfarin or fluticasone will be 
advised to contact their primary care provider to advise them that they are 
in the trial and possibly receiving lopinavir/ritonavir which can influence 
levels of either drug and may require more frequent monitoring. 
Randomization 
Eligible patients will be randomized through a central electronic system in a 1:1 
ratio, to lopinavir/ritonavir (intervention) versus placebo (control). 
Randomization will be stratified by site and age (≥65 years or <65 years). 
Blinding 
Patients, treating clinicians, trial personnel, and outcome assessors will be 
blinded to group assignment. 
Primary Outcome 
Modified COVID Ordinal Outcomes Scale to Study Day 15:  
1. Death 

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2. Hospitalized on mechanical ventilation or ECMO 
3. Hospitalized on supplemental oxygen 
4. Hospitalized not on supplemental oxygen  
5. Not hospitalized with symptoms and limitation in activity 
6. Not hospitalized with symptoms but with no limitation in activity 
7. Not hospitalized without symptoms nor limitation in activity 
Secondary Outcomes 
• Modified COVID Ordinal Outcome Scale to Study Day 8 
• Modified COVID Ordinal Outcome Scale to Study Day 29 
• Proportion of patients hospitalized to Study Day 29 
• Time to hospitalization to Study Day 29 
• Time to symptom resolution to Study Day 29 
• All-cause, all-location mortality to Study Day 29 
• Oxygen-free days through Study Day 29 
• Fever-free days to Study Day 29 
• Ventilator-free days through Study Day 29 
• Vasopressor-free days through Study Day 29 
• ICU-free days through Study Day 29 
• Hospital-free days through Study Day 29 
Safety Outcomes 
• Seizure 
• Atrial or ventricular arrhythmia 
• Cardiac arrest 
• *Elevation in aspartate aminotransferase or alanine aminotransferase to twice 
the local upper limit of normal AND at least doubling over known baseline 
• *Acute pancreatitis 
• *Acute kidney injury by KDIGO criteria 
• Receipt of renal replacement therapy 
• *Symptomatic hypoglycemia 
• *Anemia or thrombocytopenia 
• Severe dermatologic reaction 
 
*For participants whose symptoms are significant enough to trigger a clinical 
work-up and thus have clinically available testing 
Analysis 
Using intention-to-treat principles, we will compare the primary outcome 
(Modified COVID Ordinal Outcomes Scale score on Study Day 15) between 
patients the intervention group (lopinavir/ritonavir) and the control group using a 
proportional odds model, adjusted for the following co-variables: age, gender, 
and duration of acute respiratory infection symptoms prior to randomization. 
With type I error of 0.05, enrolling 540 patients in the primary population will 
provide 90% power to detect an odds ratio of 1.75. Accounting for a 10% loss to 
follow-up rate, we will plan to enroll 600 patients. This sample size and power 
assumes a frequentist analysis, which is generally more conservative than what 
is needed for a Bayesian approach. We will plan an initial DSMB evaluation for  

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safety and feasibility after n=100 patients have been enrolled; efficacy will not 
be considered at this analysis. The trial will then have frequent interim analyses 
with details on specifics on timing of meetings, as well as efficacy and futility 
stopping rules to be detailed in the Statistical Analysis Plan, to be finalized prior 
to the n=100 interim analyses. 
 
 
 

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2. TRIAL DESCRIPTION 
2.1 Background 
Coronavirus Disease 2019 (COVID-19) is an acute respiratory infectious illness caused by severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2).1,2  Although the epidemiology is not fully 
elucidated, most adults with COVID-19 appear to experience fever, cough, and fatigue and then recover 
within 1-3 weeks.  However, a portion of adults with COVID-19 develop severe illness, typically 
manifesting as pneumonia and hypoxemic respiratory failure, with continued progression to acute 
respiratory distress syndrome (ARDS) and death in some cases.1–3  There is an urgent need for outpatient 
therapies with a demonstrated ability to improve recovery progression of COVID-19 to severe illness. 
Based on mechanism of action and early clinical experiences, several agents currently available in the 
U.S. are proposed as potential therapies to prevent disease progression.4–6  Among these potential 
therapies, lopinavir/ritonavir has generated substantial interest due to antiviral and immunomodulatory 
activity and established safety profiles with FDA approval for use in other conditions.  In this trial, we 
will evaluate effectiveness and safety of lopinavir/ritonavir for the early treatment of adults with COVID-
19 in the outpatient setting, prior to hospitalization. 
2.1.1 COVID-19 Infection 
COVID-19 was first identified as a cluster of cases of pneumonia among a group of workers from a 
seafood wholesale market in Wuhan, China in November 2019.7  This observation, along with subsequent 
viral genotyping showing significant genetic similarities to the bat coronaviruses8 suggest a zoonotic 
origin, although the specific reservoir and  intermediary species remain unclear.9  The COVID-19 
infection represents the seventh coronavirus known to cause disease in humans.10  Four of the 
coronaviruses viruses are known to cause symptoms of the common cold in immunocompetent 
individuals while two others (SARS-CoV and MERS-CoV) have caused recent outbreaks of severe and 
sometimes fatal respiratory diseases.11 SARS-CoV-2 appears to exploit the same cellular receptor as 
SARS-CoV and MERS-CoV,12 and its severity may similarly result from a predilection for 
intrapulmonary epithelial cells over cells of the upper airways.13,14  
Since the first documented human case, COVID-19 has spread exponentially with 1,447,412 confirmed 
cases and 93,425 deaths worldwide as of April 9, 2020.  While most patients recover after a mild, brief 
illness with fever and cough, the disease has a clinical spectrum ranging from asymptomatic infection15 to 
ARDS and death.16  The most common reasons for ICU care are respiratory failure and ARDS, with a 
minority developing shock and possibly cardiomyopathy.17 The case fatality rate is estimated to be 0.25% 
to 3.0%.18   
2.1.2 Promising Candidate Therapies for COVD-19 
Several agents currently available in the US are proposed as potential therapies to halt disease 
progression.4-6  
Lopinavir/ritonavir (Kaletra), an antiretroviral medication used to treat HIV-1, also has potent antiviral 
activity and promising early clinical data against coronaviruses, including those causing SARS and 
MERS.22–26 Lopinavir is a HIV type 1 aspartate protease inhibitor; when combined with ritonavir, the 
plasma half-life of lopinavir is increased. Lopinavir was first identified as a potential therapy for severe 

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coronaviruses as demonstrating strong in vitro inhibitory activity against both SARS-CoV, the virus 
which causes Severe Acute Respiratory Syndrome (SARS), and MERS-CoV, the virus which causes 
Middle East Respiratory Syndrome (MERS).27,28 Prior open label studies of lopinavir-ritonavir suggested 
the potential to improve clinical outcomes and decrease viral load in patients with SARS and MERS.29–32  
A recent randomized open-label trial of lopinavir/ritonavir in hospitalized patients with COVID-19 failed 
to demonstrate a treatment benefit.3 However, the trial was underpowered for clinically important 
endpoints and enrolled patients at an advanced stage of disease, a median of 13 days after symptom onset, 
when antiviral activity is likely much less important. Still, the observed mortality in the 
lopinavir/ritonavir group was 5.8% lower than the control group (95% confidence interval, -17.3 to 5.7), 
as well as an observed faster time to clinical improvement that was also not statistically significant (HR 
1.24, 95%CI 0.90-1.72). Accordingly, substantial enthusiasm remains for early treatment of COVID-19, 
particularly prior to hospitalization. 
2.1.3 Rationale for a Randomized Trial Early Treatment among Outpatients 
Initial COVID-19 symptoms develop approximately 2-10 days after infection with the SARS-CoV-2 
virus.33–35 Most adults recover without complications, but hospitalized patients typically experience 
pneumonia leading to acute hypoxemic respiratory compromise/failure, and in some cases, ARDS and 
death. The first 4-8 days of illness typically manifest with conditions consistent with a viral syndrome 
such as fevers and cough. Those experiencing a milder course typically recover after this initial period; 
those on a more severe course will progress to respiratory failure and ARDS, which usually occurs 7-12 
days after the onset of symptoms.36,37   
The period between onset of symptoms and the development of hypoxemia requiring hospitalization is a 
critical therapeutic window for treatment to halt disease progression. Early data suggest that mortality 
rates are highest in the elderly, immunocompromised, and those with chronic cardiopulmonary disease. 
However, young adults remain at high risk of complications, as younger adults (age 20-44 years) 
comprise approximately 25% of COVID-19-hospitalized patients.  
COVID-19 is an unprecedented public health crisis, and there is significant interest in finding effective 
therapies, specifically in repurposing approved medications with widespread availability and known 
safety profiles. Efficacy and safety data for lopinavir/ritonavir from randomized trials are critical to 
provide evidence-based therapy for the ongoing COVID-19 pandemic. Our proposed trial will efficiently 
assess the potential candidate therapy and provide a structure for rapid integration of other candidate 
drugs in future clinical trials. 
2.2 Study Aims  
2.2.1 Study aim 
To determine the effectiveness and safety of early treatment with lopinavir/ritonavir versus placebo in 
outpatient adults with COVID-19. 
2.2.2 Study hypothesis 
Early initiation of lopinavir/ritonavir will reduce disease progression and improve clinical outcomes 
among outpatient adults with COVID-19. 

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2.3 Study Design 
We will conduct an investigator-initiated, multicenter, blinded, placebo-controlled, randomized clinical 
trial evaluating lopinavir/ritonavir vs placebo for early treatment of adults with COVID-19 in the 
outpatient setting prior to hospitalization. Patients, treating clinicians, and study personnel will all be 
blinded to study group assignment.     
3. STUDY POPULATION AND ENROLLMENT 
3.1 Inclusion Criteria 
1. Age ≥18 years 
2. Laboratory-confirmed SARS-CoV-2 by RT-PCR or other molecular test, or by antigen test with 
FDA emergency use authorization or full approval and collected within the past 6 days 
3. Current symptoms of acute respiratory infection for ≤6 days, defined as one or more of the 
following: 
o cough 
o fever 
o shortness of breath 
o chest pain 
o abdominal pain 
o nausea/vomiting 
o diarrhea 
o body aches 
o weakness/fatigue 
3.2 Exclusion Criteria 
1. Prisoner 
2. Pregnancy  
3. Breast feeding 
4. Two individuals from the same household are not enrolled in the study 
5. Unable to randomize within 6 days after onset of acute respiratory infection symptoms 
6. Hospitalization within the 6 days prior to randomization  
7. Inability to swallow oral medications 
8. Refusal or inability to be contacted and participate in daily symptom/safety monitoring in English or 
Spanish during the two-week follow-up period 
9. Previous enrollment in this trial 
10. Known severe chronic kidney disease requiring dialysis 
11. Known liver disease (cirrhosis or >3 times upper limit of normal for AST or ALT in medical record 
if available) 
12. Known hepatitis B or hepatitis C infection 
13. Known history of jaundice 
14. Current heavy alcohol use, defined as 8 drinks or more per week for women or 15 drinks or more 
per week for men 
15. Known seizure disorder 

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16. Known HIV infection 
17. Known history of pancreatitis 
18. Known history of prolonged QT interval (Long QT Syndrome, patient report, or QTc >500 
milliseconds on most recently available electrocardiogram within the past 2 years) 
19. Receipt of >1 dose of hydroxychloroquine, chloroquine, or lopinavir/ritonavir in the 10 days prior to 
enrollment 
20. Known allergy to lopinavir/ritonavir 
21. Currently prescribed (with planned continuation) or planned administration during 14-day study 
period of medication at high risk for QT prolongation as follows: 
Antiarrhythmics: Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, ibutilide, 
procainamide, propafenone, quinidine, sotalol 
Anti-cancer:  Arsenic trioxide, oxaliplatin, vandetanib 
Antidepressants: Amitriptyline, citalopram, escitalopram, imipramine 
Antimicrobials: azithromycin, ciprofloxacin, clarithromycin, erythromycin, fluconazole, 
levofloxacin, moxifloxacin, pentamidine, hydroxychloroquine 
Antipsychotics:  aloperidol, chlorpromazine, droperidol, olanzapine, pimozide, quetiapine, 
thioridazine, risperidone, ziprasidone 
Others: cilostazol, cimetidine, cisapride, donepezil, methadone, ondansetron, sumatriptan  
22. Currently prescribed (with planned continuation) or planned administration during 14-day study 
period of any of the following medications: alfuzosin, apalutamide, astemizole, ergot-containing 
medicines (including dihydroergotamine mesylate, ergotamine tartrate, methylergonovine), 
lomitapide, lovastatin, lurasidone, midazolam, phenobarbital, phenytoin, ranolazine, rifampin, 
sildenafil, simvastatin, rivaroxaban, St. John’s Wort, terfenadine, triazolam. Patients who are on 
warfarin or fluticasone will be advised to contact their primary care provider to advise them that 
they are in the trial and possibly receiving lopinavir/ritonavir which can influence levels of either 
drug and may require more frequent monitoring. 
3.3 Justification of Exclusion Criteria 
Since this is intended as an outpatient trial, patients hospitalized within 6 days prior to 
enrollment/randomization are excluded. The other exclusion criteria are primarily designed for patient 
safety.  In addition to excluding specific vulnerable populations (e.g., prisoners), these criteria are 
designed to exclude patients for whom receipt of lopinavir/ritonavir might increase the risk of serious 
adverse events. Lopinavir/Ritonavir has been routinely prescribed to outpatients with HIV-1 without 
extensive cardiac workups, laboratory testing, or monitoring. In addition, we have incorporated guidelines 
for safe outpatient prescribing of lopinavir/ritonavir without a baseline electrocardiogram or outpatient 
cardiac monitoring40 and have put into place a method of monitoring newly prescribed medications during 
the 14-day intervention period. 
3.4 Screening 
The site investigator or delegate will screen for non-hospitalized patients with laboratory confirmed 
COVID-19 (that is, a positive laboratory test for SARS-CoV-2 by RT-PCR or other molecular method, or 
by antigen test with FDA approval or emergency use authorization and collected within the past 6 days). 
The source of these patients will be primarily patients seen and sent home from the enrolling hospital 

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emergency department, urgent care, primary care, virtual care/telemedicine visits, or testing centers. We 
may also advertise the study at outpatient testing sites and more broadly for self-referral to the study. 
3.5 Assessment of Eligibility and Exclusion Tracking 
For patients who appear to meet eligibility criteria after screening, we will complete an electronic case 
report form to determine eligibility and track exclusions.  We will access and store the electronic case 
report form in the electronic database.  At the time of entry into the screening database, we will assign the 
patient a screening number.  
If a patient appears to meet all eligibility criteria, the site investigator or delegate will approach the patient 
to confirm eligibility, discuss potential study recruitment, and proceed with informed consent. Most 
patients will no longer be in the healthcare setting and therefore we anticipate that this discussion will 
occur primarily by telephone or videophone to the patient’s home (test pending patients are typically 
advised by their clinicians to home quarantine while symptomatic and test results are pending).  We may 
advertise the study at both the testing sites as well as more broadly. 
For all excluded patients, including refusal by the patient to participate, we will collect a small number of 
variables, including month and year patient met screening criteria and reason(s) patient was excluded to 
allow for reporting in the CONSORT diagram of the manuscript. Due to the nature of this trial in the 
outpatient setting and for staff safety and personal protective equipment (PPE) conservation, these 
encounters will usually occur via telephone or videophone.  
3.6 Process of Obtaining Informed Consent 
We will obtain written informed consent from the patient. We will not enroll patients who lack decision-
making capacity due to logistical issues with remote study medication administration, safety monitoring, 
and accurate data collection. 
In-person visits for patients with known COVID-19 who are deemed stable for outpatient management 
and home quarantine would violate infection control principles and policies. Given the infectious risk 
from COVID-19 and potential shortages of personal protective equipment (PPE), there is a moral and 
practical imperative to minimize face-to-face contact between patients and non-clinical personnel. 
Therefore, we will use “no-touch” consent procedures for this trial, employing an electronic remote 
consent process to obtain written informed consent.  
Electronic approach 
1. A link for the electronic consent is sent to the subject. 
2. Research staff contact the patient by telephone or videophone (method dictated by institutional 
policy) to have an informed consent conversation. This step confirms subject identity. 
3. If they consent, the patient signs the consent form. This can be: 
a. an actual signature (often tracing their finger on the screen) OR 
b. a username and password specific to the individual signing 
This approach complies with relevant regulations and sub-regulator guidance at 45 CFR 46.117, 45 CFR 
164.512, 21 CFR 11 Subpart C (11.100–11.300), https://www.hhs.gov/ohrp/regulations-and-

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policy/guidance/use-electronic-informed-consent-questions-and-answers/index.html, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/informed-consent 
We will provide the information for the informed consent discussion in a formal document that has been 
approved by the IRB and in a language comprehensible to the potential participant, using an interpreter if 
necessary. Currently, English and Spanish documents are approved for use in this trial. The information 
presented in the consent form and by the research staff will detail the nature of the trial and what is 
expected of participants, including any potential risks or benefits of taking part. We will clearly state that 
the participant is free to withdraw from the trial at any time for any reason without prejudice to future 
care, and with no obligation to give the reason for withdrawal. Where a patient does not speak English, a 
translated Spanish consent and qualified interpreter will be employed, using similar “no-touch” principles.  
Use of a telephone or video interpreter and the interpreter’s identity will be documented on the electronic 
consent. 
After allowing the potential participant time to read the informed consent document, research staff will 
answer any additional questions.     
3.7 Randomization and Blinding  
We will randomize eligible participants through a central electronic system in a 1:1 ratio to 
lopinavir/ritonavir (intervention) versus placebo (control). A randomized group assignment is provided to 
the site investigator or delegate from a centralized, web-based platform.  Randomization will require 
provision of the screening number and confirmation of patient eligibility. In the future, we may also 
consider adding an intervention group. 
We will perform the randomization in permuted blocks of varying size and stratified by site and age (≥65 
years or <65 years). We will store the randomization sequence allocation on a secure server, which will 
not be available to site study personnel. Each participant will receive a computer-generated study ID 
number.  The computer-generated study ID number and shipping information will be provided to the 
pharmacy who will provide a dose pack containing lopinavir/ritonavir or placebo.  
The participant, treating clinicians, study personnel, and outcome assessors will all remain blinded to 
group assignment until after the database is locked and blinded analysis is completed. Only Belmar 
Pharmacy, who is distributing study medication, and one member of the biostatistical team who is 
preparing closed DSMB interim reports will be unblinded. Specifically, study medication will be 
dispensed with packaging and labelling that would blind treatment assignment. Unblinding will occur 
only if required for subject safety or treatment at the request of the treating clinician.  
4. STUDY INTERVENTIONS 
4.1 Treatment of Study Participants 
A summary of the trial’s schedule of events is included in Appendix A. 
Timing of study procedures is based on the time of randomization, which is defined as “Time 0”. Study 
Day 1 is defined as the day of receipt of the first dose of study drug.  We will assess the primary outcome 
on Study Day 15, which corresponds to 14 days (2 weeks) after the initiation of study drug.  

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A research physician will prescribe a study medication that a central pharmacy (Belmar Pharmacy) will 
fill at no charge to the patient and will arrive through overnight mail (typically next day by 10:00AM). 
The study medication will arrive in blinded blister packs labelled as lopinavir/ritonavir or placebo with 
the appropriate daily instruction for administration. The goal is initiation of treatment within one day of 
randomization (Study Day 1). 
On Study Days 1-15, the patient will complete brief electronic data collection form through a secure 
electronic platform that will confirm receipt and administration of study drug and document the number 
and reason for any missed doses. For those with missing electronic data, telephone follow-up will provide 
an additional opportunity to clarify study drug administration, as needed. If the participant is hospitalized 
prior to completion of the study medication, an attempt will be made to continue study medication. 
However, study medication may be discontinued if felt necessary by the treating clinician in consultation 
with the local investigator. Unblinding will occur only if required for subject safety or treatment at the 
request of the treating clinician. 
4.2 Lopinavir/Ritonavir Group 
Participants assigned to the lopinavir/ritonavir arm will receive lopinavir/ritonavir 400 mg/100 mg orally 
twice daily for 28 doses (Days 1-14). Medication dose packs will contain all 28 doses labelled by Study 
Day. 
Rationale for Drug Selection of Lopinavir/Ritonavir 
We are administering lopinavir/ritonavir (LPR/r) in standard dosing:   lopinavir/ritonavir 400 mg/100 mg 
twice daily for 28 doses (Days 1-14). LPV/r as Kaletra tablets is dosed based upon extensive PK/PD 
study evaluations in healthy  and HIV+ subjects as reported in its US and European labels  (400/100mg 
BID  or 800/200mg QD) - 
see https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021251s052_021906s046lbl.pdf 
and https://www.medicines.org.uk/emc/product/221/smpc. The mean in vitro antiviral IC50 of lopinavir 
against HIV in the absence of human serum, is 6.5 nM. The IC50 of LPV vs SARS viruses and in 
particular SARS-CoV-2 is believed to be approximately 1-10μM.23,25 Comparison of these potencies is 
limited as data are uncontrolled and assay procedure differ, but it suggests SARS-CoV-2 replication is 
approximately  100 - 1000-fold less susceptible to LPV/r-mediated  replication than HIV. PK/PD 
comparisons across unrelated viral infections with overtly different clinical manifestations also presents 
significant translational insight limitations, but the safety/efficacy and PK/PD for LPV/r against HIV is 
well known and enables a guide to a pragmatic and safety-reasoned dosing regimen. A regimen 
of 400/100 mg BID should achieve near steady state concentrations as seen in HIV therapy within 3 to 4 
days. This should align with an acceptable safety profile coupled with rapid achievement of LPV/r 
exposure to efficacious levels associated with HIV clinical antiviral activity, and possibly some effect on 
SARS-C0V-2 replication inhibition in patients. LPV/r dosing BID, or 800/200mg QD in adults enables 
unbound LPV exposure at significantly higher levels than reported by the HIV in vitro antiviral IC50. 
Multiple dosing with 400/100 mg LPV/r twice daily for 14 days produces mean ± SD LPV peak plasma 
concentration (Cmax) of 12.3 ± 5.4 μg/ml. The mean steady-state trough concentration prior to the 
morning dose was 8.1 ± 5.7 μg/ml. LPV AUC over a 12 hour dosing interval averages 113.2 ± 60.5 
μg/h/m. LPV and RTV are 98–99% bound to the blood plasma proteins, which indicates that unbound 
LPV exposure to be approximately 10 - 100-fold greater than the in vitro  HIV IC50 value, and within an 

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order of magnitude as reported for SARS-C0V-2 value, thereby making clinical testing by the regimen 
described as reasoned from a potential antiviral perspective. If unbound drug levels are higher inpatient 
BAL fluid, then a more favourable ratio is potentially achievable. 
4.3 Control Group 
Participants randomized to the control group will receive placebo orally twice daily for 14 days. 
Medication dose packs will contain all 28 doses labelled by Study Day. 
While patients who receive the lopinavir/ritonavir will not have a matched placebo, the packaging would 
indicate study medication (lopinavir/ritonavir, or placebo) and participants will not be aware that there is 
no matched placebo for lopinavir/ritonavir. Thus, even if the participant searches the internet for pill 
markings, it is entirely possible from the patient perspective that this could be a marched placebo.  
Exclusion criteria will be exercised to ensure that two individuals from the same household are not 
enrolled in the study and that telephone assessments during the study avoid discussion of the appearance 
of the study medication.   
4.4 Co-Interventions 
This trial will control the use of lopinavir/ritonavir, or placebo during the 14-day intervention period. 
Enrolled participants will not receive open-label lopinavir/ritonavir during the 14-day intervention period, 
unless the patient is hospitalized, and the treating clinician wishes to unblind the trial and use these 
medications open label. The treating clinicians will make all other treatment decisions without influence 
from the protocol.  Administration of other antiviral, immunomodulatory, or other COVID-19 directed 
novel medications (“rescue therapy”) will be allowed. We will record the co-administered COVID-19 
directed medications in the case report form.  The patient will be allowed to take antipyretics at home as 
needed.   
4.5 On-Study Monitoring 
All participants enrolled in the study will be outpatients (not hospitalized) and therefore initial monitoring 
will be remote as part of routine outpatient clinical care with treating physicians and nurses (we anticipate 
primarily virtual care/telehealth or routine telephone follow-up). The research staff will provide additional 
remote monitoring through daily electronic collection of symptoms, healthcare utilization, clinically 
obtained electrocardiograms, newly prescribed medications, and adverse event reporting with 
supplemental telephone follow-up as needed. The research team may flag potential issues but will defer 
specific decisions about additional care and hospital transfer to usual outpatient clinical care. 
Lopinavir/ritonavir has been used extensively for outpatient treatment of other conditions without the 
need for additional monitoring during short term therapy. 
Between baseline and Study Day 15, study personnel will ascertain and review the initiation of any new 
medications daily and evaluate for potential medication interactions with lopinavir/ritonavir (see 
Appendix B).  If a medication that is considered to be contraindicated with lopinavir/ritonavir is 
discovered, site physician investigator or designee will contact the patient to discuss if stopping study 
drug is appropriate or if the medication in question may be stopped or substituted in consultation with the 
prescribing/treating clinician. If a medication with a potential interaction with lopinavir/ritonavir is 
identified, study personnel will contact the treating clinician to ensure they are aware of the potential 
interaction, as needed.  Treating clinicians will determine whether an alternative medication would be 

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appropriate or whether the risk-benefit ratio favors continuing the medication with the known potential 
interaction. 
4.6 Criteria for Stopping Study Drug 
We will stop administration of the blinded study drug temporarily or permanently for (a) adverse events 
without evidence of an alternative cause to the patient’s symptoms, (b) results of on-study monitoring, or 
(c) clinical deterioration if requested by treating clinician. 
If a patient experiences an adverse event that the patient treating clinicians, or investigators feel merits 
temporarily or permanently stopping the study drug, we will stop the study drug. We will record the 
explanation for stopping the study drug in the case report form, and we will record and report the adverse 
event according to the adverse event guidelines below.  If the adverse event resolves to the extent that the 
patient, treating clinicians, and investigators feel that resuming the study drug is appropriate, we will 
resume the study drug, and we will record this information in the case report form.   
If an EKG is obtained as part of routine clinical care after enrollment and the QTc is greater than or equal 
to 500 ms, we will discontinue the study drug, unless a repeat EKG after at least 24 hours demonstrates 
the QTc is less than 500 ms, at which time we will direct the patient to resume the study drug. We will 
record both the value for the QTc and the decision to continue or stop the study drug in the case report 
form. If the daily on-study monitoring by study personnel for medication interactions indicates a potential 
interaction with a medication that treating clinicians feel is required for the optimal treatment of the 
patient and with which treating clinicians and the investigator feel it would be unsafe to administer 
lopinavir/ritonavir, we will stop study drug and record the reason in the case report form. 
For patients who experience clinical deterioration requiring hospitalization or toxicity potentially related 
to study drug, for which treating clinicians feel optimal care would include stopping the study drug and 
unblinding group assignment, we will stop the study drug, and the site investigator will contact the 
coordinating center to receive the unblinded study group assignment.  We will defer any additional 
treatments to the treating clinicians.  In this situation, we will record the following data in the case report 
form: the criteria met for clinical deterioration; the reason for stopping study drug and unblinding; use of 
other antivirals, and immunomodulators; and study outcomes. Crossovers from placebo to 
lopinavir/ritonavir will be recorded and reported to the DSMB at DSMB reviews and interim analyses. 
The primary analysis will be intention-to-treat.  
5. OUTCOMES 
5.1 Primary Outcome  
The primary outcome is clinical status on the Modified COVID Ordinal Outcomes Scale to Day 15, 
incorporating more granular description of symptoms at the milder end of the scale for this outpatient 
trial. In addition, we collapsed non-invasive ventilation with mechanical ventilation and high flow nasal 
oxygen with supplemental oxygen to improve pragmatism of in-hospital data collection (source data may 
come from the patient or alternate contact if hospital records are not accessible). This outcome is in use 
by COVID-19 trials globally, including those conducted by the World Health Organization, and will 
facilitate pooling and comparison of data across trials.  
1. Death 

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2. Hospitalized on mechanical ventilation or ECMO 
3. Hospitalized on supplemental oxygen 
4. Hospitalized not on supplemental oxygen  
5. Not hospitalized with symptoms and limitation in activity 
6. Not hospitalized with symptoms but with no limitation in activity 
7. Not hospitalized without symptoms or limitation in activity 
5.2 Secondary Outcomes 
• Modified COVID Ordinal Outcome Scale at Study Day 8 
• Modified COVID Ordinal Outcome Scale at Study Day 29 
• Proportion of patients hospitalized to Study Day 29 
• Time to hospitalization to Study Day 29 
• Time to symptom resolution to Study Day 29 
• All-cause, all-location mortality to Study Day 29 
• Oxygen-free days through Study Day 29 
• Fever-free days to Study Day 29 
• Ventilator-free days through Study Day 29 
• Vasopressor-free days through Study Day 29 
• ICU-free days through Study Day 29 
• Hospital-free days through Study Day 29 
5.3 Safety outcomes 
• Seizure 
• Atrial or ventricular arrhythmia 
• Cardiac arrest 
• *Elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper 
limit of normal, AND at least doubling over known baseline 
• *Acute pancreatitis 
• *Acute kidney injury by KDIGO criteria 
• Receipt of renal replacement therapy 
• *Symptomatic hypoglycemia 
• *Anemia or thrombocytopenia 
• *Severe dermatologic reaction 
*For participants whose symptoms are significant enough to trigger a clinical work-up and thus have 
clinically available testing and diagnoses: 
5.4 Rationale for Primary Outcome 
COVID-19 has a broad spectrum of clinical severity. Among non-hospitalized patients, most recover 
without experiencing critical illness.42  Designing a trial with statistical power to detect a meaningful 
difference in hospital-free days, ICU-free days, or mortality might require an unfeasibly large sample size 
and could miss significant morbidity experienced by outpatients with COVID-19. Since the majority of 

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morbidity from COVID-19 relates to hypoxemia, the fact that this outcome is tied to degree of hypoxemic 
respiratory failure increases its face validity and relevance.  For similar reasons, previous trials of severe 
influenza have employed a similar ordinal outcome.43  This ordinal scale was selected as an outcome in 
multiple ongoing COVID-19 trials across a range of illness severity, including outpatients, and is a 
preferred outcome by the World Health Organization Research and Development Blueprint for COVID-
19.44 For our cohort of outpatients, we have enhanced the outcome with the addition of COVID-related 
symptoms to better distinguish recovery in those with milder disease. Use of this standardized outcome 
will increase the potential to compare the results of this trial with other trials and perform meta-analyses. 
6. DATA COLLECTION 
Given the infectious risk from COVID-19 and potential shortages of personal protective equipment 
(PPE), we will have no face-to-face contact between patients and non-clinical staff.  Additionally, 
minimizing research activities and conducting the trial in a pragmatic manner will increase the ability to 
complete the trial in the face of strained clinical and research resources during the COVID-19 pandemic. 
We will emphasize data collection by electronic methods, supplemented by telephone or videophone 
follow-up and from the electronic health record. If the patient is hospitalized, we will attempt to obtain 
permission for accessing these records. We will not collect biological specimens as part of this trial.  
Electronic Data Collection:  
We will collect data directly from patients using MyCap or, if installation and use of an app is not 
possible, through text messaging or email with a survey link, or phone call as back up. MyCap is a secure 
mobile application developed by the REDCap team at Vanderbilt and integrated into the REDCap 
database system. Participants install the application on their personal device. All interaction with the app 
is secure and requires the user to enter a 6-digit pin. Once a patient has consented, they join a study for 
data collection by scanning a unique QR code. Then, patients receive a notification each day to answer 
questions about their current symptom burden, any hospitalizations, and any oxygen requirements. This 
provides the capacity for collecting patient reported outcomes in a secure and robust manner.  If patients 
are unable to use this application or unwilling to install it, they can be asked the same messages using a 
text messaging system will be utilized. Our outcomes are designed such that a text messaging option is 
not overly burdensome and can even be completed in hospitalized patients. The process for using text 
messaging is HIPAA compliant. Finally, we can use standard telephone calls as a back-up method to 
administer the questions. This minimizes loss to follow up and maximizes the efficiency of the study.  
Research teams have had great success using REDCap-based mobile data collection for multiple studies 
including collection of data about quality of life and exercise after heart surgery (NCT03270124), pain 
reporting in sickle cell disease (NCT03629678), and pain using a visual analog scale (VAS) during an 
interventional drug study (NCT03865940). 
Telephone/Videophone Data Collection:  
While primary data collection will be by electronic methods as above, specific circumstances will trigger 
telephone or videophone follow-up, based on the following: 
• 
Participant does not complete daily electronic data collection for two consecutive days. 
• 
Participant does not complete Study Day 29 assessment 
• 
Identification of newly prescribed medication if deemed necessary by site investigator. 
• 
New electrocardiogram 

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• 
Lack of administration of study medication, if unable to confirm plan to resume study medication 
• 
Hospitalization 
• 
Reported adverse events, if deemed necessary by the site investigator 
• 
Clarification or concern by study team 
• 
By request of participant 
6.1 Baseline Variable Collection 
• Informed Consent Document and documentation of consent process 
• Presence or absence of each inclusion and exclusion criterion 
• Date and time of enrollment 
• Day of symptom onset 
• Specimen type, date, and result of SARS-CoV-2 testing conducted clinically.  
• Demographics (age, sex, race, ethnicity, height, weight) 
• Comorbidities: chronic cardiac disease, chronic pulmonary disease, chronic kidney disease, chronic 
liver disease, chronic neurological disease, malignant neoplasm, chronic hematologic disease, 
AIDS/HIV, obesity, diabetes with complications, diabetes without complications, rheumatologic 
disorder, malnutrition, smoking, other 
• Chronic use of medication: ACE inhibitors, angiotensin receptor blockers  
• Receipt of azithromycin in the past week 
• Presenting signs and symptoms, along with self-reported severity 
6.2 Daily Assessments between Randomization and Study Day 16, and then at Day 29 
• Study drug administration and reason for missed doses. 
• Modified COVID Ordinal Outcomes Scale 
• Daily signs and symptoms, along with self-reported severity via electronic log and/or telephone 
interview. 
• Day of symptom resolution 
• Receipt of open label antivirals: chloroquine, hydroxychloroquine, remdesivir, lopinavir/ritonavir, 
other  
• Receipt of open label immunomodulators between enrollment and hospital discharge: 
corticosteroids, tocilizumab, sarilumab, interferon β, other  
• Receipt of azithromycin  
• Study days in hospital (if applicable)  
• Study days receiving supplemental oxygen (if applicable)  
• Study days receiving non-invasive or invasive mechanical ventilation (if applicable)  
• Study days in ICU to Study Day 29  
• Study day of death (if applicable) 
• Safety Outcomes: seizure, atrial or ventricular arrhythmia, cardiomyopathy, cardiac arrest, aspartate 
aminotransferase or alanine aminotransferase levels that are greater than twice the local upper limit 
of normal (or two times higher than known baseline), acute pancreatitis (defined by a clinically 
obtained lipase level above the local upper limit of normal and abdominal pain or vomiting), stage 
II or greater acute kidney injury according to KDIGO criteria45, receipt of new renal replacement 

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therapy, symptomatic hypoglycemia, neutropenia, lymphopenia, anemia, thrombocytopenia, or 
severe dermatologic reaction (e.g., Steven’s Johnson Syndrome).  Since we will not systematically 
obtain laboratory tests to identify asymptomatic changes in laboratory values, we will ask about 
outpatient laboratory testing or obtain the requisite results of laboratory tests from medical records 
if tests were obtained.  
• Prolonged (>500 msec) QTc interval on available electrocardiograms 
• Self-reported adverse events to Study Day 15 
7. STATISTICAL CONSIDERATIONS 
Using intention-to-treat principles, we will compare the primary outcome (Modified COVID Ordinal 
Outcomes Scale score to Day 15) between patients in each intervention group and the control group using 
a proportional odds model, adjusted for the following co-variables: age, gender, and duration of acute 
respiratory infection symptoms prior to randomization. The proportional odds assumption will mainly be 
examined using graphical methods—e. g., the logit of the empirical cumulative distribution function of 
the ordinal scale should be parallel among categories of covariates. If proportionality is clearly violated, 
we will consider partial proportional odds or non-proportional odds models. 
With type I error of 0.05, enrolling 540 patients in the primary population will provide 90% power to 
detect an odds ratio of 1.75. Accounting for a ~10% loss to follow-up rate, we will plan to enroll 600 
patients. This sample size and power assumes a frequentist analysis, which is generally more 
conservative than what is needed for a Bayesian approach. We will plan an initial DSMB evaluation of 
safety and feasibility after n=100 patients have been enrolled; efficacy will not be considered at these 
analyses. The trial will then have frequent interim analyses with details on specifics on timing of 
meetings, as well as efficacy and futility stopping rules to be detailed in the Statistical Analysis Plan, to 
be finalized prior to the first interim analyses. 
Additional analyses will include comparisons of secondary outcomes between treatment groups. We will 
compare the Modified COVID Ordinal Outcome Scale daily over the 14-day intervention period using a 
recently developed longitudinal proportional odds model that can incorporate the information on 
intermediate states between baseline and Study Day 15. For time-to-event outcomes we will utilize 
survival models (e.g., Cox proportional hazards models), continuous outcomes will utilize linear 
regression, and dichotomized outcomes will be evaluated using logistic regression. We will also evaluate 
primary and main secondary outcomes in key subgroups of interest. A priori subgroups for analysis will 
include age, sex, race/ethnicity, facility residence, BMI, baseline renal function, hypertension, diabetes, 
cardiovascular disease, and duration of respiratory symptoms. 
The proposed trial will use a Bayesian approach to implement adaptive elements and to estimate the 
primary outcome using the proportional odds model to calculate the posterior probability that the OR > 1, 
suggesting any benefit. Additionally, we will calculate posterior probabilities to account for the potential 
that a treatment is ineffective (e.g., OR < 1) or causes harm (i.e., safety concerns) and would be of 
consideration to terminate enrollment due to futility. A Bayesian approach provides the ability for 
frequent updating of the posterior probabilities to rapidly identify if a treatment is showing benefit to 
reducing hospitalization and severity of disease, providing the possibility of more quickly identifying 
beneficial treatments. The proposed design may evolve as more is learned about COVID-19 and the 

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treatment responses, with an adaptive Bayesian design that we expect to be more efficient and flexible 
being in active development. 
We expect that given the circumstances of this trial during a rapidly evolving pandemic, the DSMB will 
need maximum latitude in modifying this trial if necessary, based on other studies of lopinavir/ritonavir 
that may be conducted simultaneously and the rate of growth or decline of the epidemic.  Alterations may 
include adding patients, adding arms to the trial, declining to stop for futility, or stopping earlier to make 
the results public if that is necessary. We may also need to collapse categories within the Modified 
COVID Ordinal Scale based on granularity of data or frequency of an individual category. We are 
exploring other possible statistical plans that will be included in a final statistical analysis plan and will be 
presented to the DSMB before the first interim report. 
8. DATA QUALITY MONITORING AND STORAGE 
8.1 Data Quality Monitoring 
We will review data quality remotely using front-end range and logic checks at the time of data entry and 
back-end monitoring of data using application programming interface tools connecting the online 
database to statistical software to generate data reports.   
8.2 Data Storage  
Site personnel will enter study data into a secure online database.  Site personnel will maintain the data in 
the secure online database until the time of study publication.  At the time of publication, DCC will 
generate a de-identified version of the database. 
9. RISK ASSESSMENT 
9.1 Potential Risk to Participants 
Although lopinavir/ritonavir are FDA approved medications with a long history of patient use and well-
established safety profiles, potential risks exist to participating in this study of lopinavir/ritonavir versus 
placebo for the treatment of COVID-19.   
9.1.2 Potential risks of receiving lopinavir/ritonavir 
The safety and tolerability of lopinavir/ritonavir has been well characterized through clinical trials and 
post-marketing experience since first authorization for use in 2001 for the approved HIV indication with 
over 7 million patient years of exposure. Based on clinical trials and post-marketing experience, the most 
frequently reported adverse drug reactions among patients receiving lopinavir/ritonavir were 
gastrointestinal disorders (including diarrhea, nausea, vomiting, and upper and lower abdominal pain), 
fatigue/asthenia, respiratory tract infection (upper and lower), lipid elevations (hypercholesterolemia and 
hypertriglyceridemia), musculoskeletal pain (including arthralgia and back pain), and headache (including 
migraine). Key safety concerns include metabolic abnormalities such as dyslipidemia and insulin 
resistance, pancreatitis, and hepatotoxicity. In addition, in the HIV population, immune reconstitution 
inflammatory syndrome (IRIS) manifesting as autoimmune disorders (such as Grave's disease) has been 
reported.  

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Important potential risks include PR prolongation at therapeutic dosing, and QT prolongation with 
supratherapeutic doses. Lopinavir/ritonavir interacts with several drugs since it is an inhibitor of the P450 
isoform CYP3A and is likely to increase the plasma concentration of drugs that are metabolized by 
CYP3A4.  Therefore, LPV/r should not be co-administered with drugs primarily metabolized by CYP3A 
and for which elevated plasma concentrations are associated with serious and/or life-threatening 
events.  A list of such products is included in the lopinavir/ritonavir label. Rare reports of second- or 
third-degree atrioventricular block in patients with underlying structural heart disease and pre-existing 
conduction system abnormalities, or in patients receiving drugs known to prolong the PR interval such as 
verapamil, have been reported in patients receiving lopinavir/ritonavir.  Lopinavir/ritonavir should be 
used with caution in such patients. In addition, QT prolongation with supratherapeutic doses and when 
lopinavir/ritonavir is co-administered with drugs known to prolong the QT interval has been 
reported.  Because lopinavir/ritonavir is principally metabolized by the liver, caution should be exercised 
when administering this drug to patients with impaired hepatic function. Extra monitoring is 
recommended when diarrhea occurs. The relatively high frequency of diarrhea during treatment with 
lopinavir/ritonavir may compromise the absorption and efficacy (due to decreased compliance) of 
lopinavir/ritonavir or other concurrent drugs.  Serious persistent vomiting and/or diarrhea with 
lopinavir/ritonavir use might also compromise renal function.  The safety of lopinavir/ritonavir for 
treatment of patients with COVID-19 disease is unknown. COVID-19 may be associated with cardiac 
effects. lopinavir/ritonavir may prolong QT at supratherapeutic doses and prolong PR at therapeutic 
doses, resulting in arrhythmias. 
9.1.3 Potential risks of receiving placebo with COVID-19 
One potential risk to participating in this study is receiving placebo rather than lopinavir/ritonavir. This 
risk is only relevant if lopinavir/ritonavir are ultimately found to be an effective therapy for COVID-19 
and is not relevant if lopinavir/ritonavir are both ultimately found to be ineffective therapy for COVID-
19.  This trial protocol minimizes this risk through rigorous design to minimize the number of patients 
that we must enroll to determine whether these therapies are an effective therapy for COVID-19 and 
allocating approximately one-third of eligible patients to placebo (instead of one half in a traditional two-
arm trial). We will also exclude patients who decline to participate because they feel their optimal care 
requires lopinavir/ritonavir, exclude patients whose treating clinicians declines to allow enrollment 
because they feel the patient’s optimal care requires treatment with lopinavir/ritonavir, and specify 
procedures for stopping the study drug, unblinding, and allowing open-label administration of 
lopinavir/ritonavir for patients who experience clinical deterioration during the study period. 
9.2 Minimization of Risk 
Federal regulations at 45 CFR 46.111(a)(1) require that risks to participants are minimized by using 
procedures which are consistent with sound research design.  This trial protocol incorporates numerous 
design elements to minimize risk to patients that meet this human subject protection requirement.  
Lopinavir/ritonavir is approved by the U.S. Food and Drug Administration and have been used in clinical 
practice for decades in a number of patient populations with an established safety profile.  The dose and 
route of administration of both medications in this trial are comparable to the dose and route of 
administration approved for the treatment of other acute infections, such as HIV-1.  The duration of 
treatment in this trial of 14 days is significantly shorter than for treatment of HIV-1 infection, for which 
the drug is frequently administered for multiple years.  To further mitigate risk, we will exclude patients 

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with specific risk factors for adverse events from study medication, we will exclude patients with higher 
risk for adverse events and patients receiving medications that may interact with lopinavir/ritonavir. 
We will collect data on adverse events that are significant enough to warrant health care evaluation.  It 
was determined that transient, and clinically insignificant changes in the electrocardiogram or laboratory 
testing would not be required. In addition, the additional risk to the public and to research personnel by 
exposing them to COVID-19 patients by requiring additional research testing is greater than the benefits 
of this monitoring. The trial protocol includes active monitoring of clinically significant adverse events, 
clinical outcomes, and interim analyses by an independent data and safety monitoring board empowered 
to stop or modify the trial at any time, including the need to request additional safety monitoring if 
determined to be warranted. 
9.3 Potential Benefit 
Study participants may or may not receive any direct benefits from their participation in this study. 
Administration of lopinavir/ritonavir may improve clinical outcomes among outpatient adults with 
COVID-19. 
9.4 Risk in Relation to Anticipated Benefit 
Federal regulations at 45 CFR 46.111 (a)(2) require that “the risks to subjects are reasonable in relation to 
anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be 
expected to result.” Based on the preceding assessment of risks and potential benefits, the risks to subjects 
are reasonable in relation to anticipated benefits.  Lopinavir/Ritonavir has been used in clinical practice 
for decades and previously evaluated for the treatment of patients acutely ill from infection with 
substantial data to support its safety and potential efficacy. 
10. HUMAN SUBJECTS PROTECTIONS 
Each study participant must sign and date an informed consent form or complete the consent in 
accordance with ethics committee guidelines for obtaining consent. Approval of the central institutional 
review board will be required before any participant is entered into the study.  
10.1 Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require the equitable selection of subjects. We will screen non-
hospitalized patients with positive SARS-CoV-2 testing to determine if a patient meets inclusion and 
exclusion criteria. Data that have been collected as part of the routine clinical care of the patient will be 
reviewed to determine eligibility. Study exclusion criteria neither unjustly exclude classes of individuals 
from participation in the research nor unjustly include classes of individuals for participation in the 
research. Hence, the recruitment of participants conforms to the principle of distributive justice. 
10.2 Informed Consent 
Federal regulations 45 CFR 46.111(a)(5) require us to seek informed consent from each patient. Study 
personnel obtaining informed consent are responsible for ensuring that the patient understands the risks 
and benefits of participating in the study, answering any questions the patient may have throughout the 
study and sharing any new information in a timely manner that may be relevant to the patient’s 

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willingness to permit the patient’s continued participation in the trial. The study personnel obtaining 
informed consent will make every effort to minimize coercion. We will inform all patients of the 
objectives of the study and the potential risks. We will use the informed consent document to explain the 
risks and benefits of study participation to the patient in simple terms before the patient is entered into the 
study, and to confirm that the patient is satisfied with his or her understanding of the risks and benefits of 
participating in the study and desires to participate in the study. The investigator is responsible for 
ensuring that informed consent is given by each patient. This includes obtaining the appropriate 
signatures and dates on the informed consent document prior to the performance of any protocol 
procedures including administration of study agent. 
For additional details, see Section 3.6. 
10.3 Withdrawal of Consent 
Participating patients may withdraw or be withdrawn (by the treating physician or investigator) from the 
trial at any time without prejudice. Site personnel will include data up to the point of withdrawal in the 
trial analysis, unless consent to use data is also withdrawn. Site personnel will record consent prior to 
receipt of study drug, which will constitute a screen-failure.  Withdrawal of consent after randomization 
and administration of one or more doses of study drug will lead to discontinuation of study interventions 
but site staff will request access to medical records for data related to the trial.   
10.4 Confidentiality 
Federal regulations at 45 CFR 46 111 (a) (7) requires that when appropriate, there are adequate provisions 
to protect the privacy of participants and to maintain the confidentiality of data. At no time during the 
course of this study, its analysis, or its publication will we reveal patient identities in any manner.  We 
will collect the minimum necessary data containing patient or provider identities.  All patients will be 
assigned a unique study ID number for tracking.  We will enter all data collected for this study into a 
secure online database.  We will maintain all data in the secure online database until the time of study 
publication.  At the time of publication, we will generate a de-identified version of the database. Further, 
we will use tools within the secure online database so that only the coordinating center and investigators 
from the enrolling site will have access to data from participants enrolled at that site. 
11. ADVERSE EVENTS 
Assuring patient safety is an essential component of this protocol.  Lopinavir/ritonavir is approved by the 
Food and Drug Administration and there is an have been used in clinical practice for decades with a well-
established safety profile.  Use of lopinavir/ritonavir for the treatment of acute respiratory infection due to 
COVID-19, however, raises unique safety considerations.  This protocol addresses these considerations 
through: 
1. Exclusion criteria designed to prevent enrollment of patients likely to experience adverse events 
with receipt of lopinavir/ritonavir 
2. On-study monitoring of co-interventions (e.g., newly prescribed medications) and patient 
characteristics (e.g., healthcare utilization, clinically obtained electrocardiogram) to intervene 
before adverse events occur. 
3. Systematic collection of safety outcomes relevant to use of lopinavir/ritonavir in this setting. 

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4. Structured reporting of adverse events 
11.1 Adverse Event Definitions 
Adverse Event: Any untoward medical occurrence associated with the use of a drug or a study 
procedure, whether or not considered drug related. 
Serious Adverse Event: A serious adverse event is any adverse event that results in one of the outcomes 
listed in section 11.3 below.  
Adverse Reaction: An adverse reaction means any adverse event caused by a study intervention. An 
adverse reaction is a subset of all suspected adverse events where there is a reason to conclude that the 
study intervention caused the event.  
Suspected Adverse Reaction: Any adverse event for which there is a reasonable possibility that the 
study procedures caused the adverse event. Reasonable possibility means there is evidence to suggest a 
causal relationship between the study procedures and the adverse event. A suspected adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction.  
Suspected Unexpected Serious Adverse Reaction (SUSAR): An adverse reaction that is both 
unexpected (not consistent with risks outlined in the study protocol or investigator brochure), serious, and 
meets the definition of a suspected adverse reaction. 
11.2 Safety Monitoring 
Assuring patient safety is an essential component of this protocol. Each participating investigator has 
primary responsibility for the safety of the individual participants under his or her care. The Investigators 
will determine daily if any adverse events occur during the period from enrollment through study day 16 
(or 48 hours after completion of the study drug administration) and will determine if such adverse events 
are reportable.  Thereafter, adverse events are not required to be reported to the IRB unless the 
investigator feels the adverse event was related to study drug or study procedures.   
The following adverse events will be considered reportable and thus collected in the adverse event case 
report forms: 
 
 Serious adverse events 
 Non-serious adverse events that are considered by the investigator to be related to study 
procedures or of uncertain relationship (Appendix C) 
 Events leading to permanent discontinuation of study drug. 
Study-specific clinical outcomes (Primary, Secondary and Safety Outcomes and Assessments 
During the Study), including serious outcomes such as organ failures and death, are 
systematically recorded in the case report forms and are exempt from adverse event reporting 
unless the investigator deems the event to be related to the administration of study drug or the 
conduct of study procedures (or of uncertain relationship) as outlined in Appendix C.  
After randomization, adverse events must be evaluated by the investigator. If the adverse event is judged 
to be reportable, as outlined above, then the investigator will report to the VCC their assessment of the 

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potential relatedness of each adverse event to the study drug or protocol procedure via electronic data 
entry. Investigators will assess if there is a reasonable possibility that the study procedure caused the 
event, based on the criteria outlined in Appendix C. Investigators will also consider if the event is 
unexpected.  Unexpected adverse events are events not listed in the study protocol and the investigator 
brochure for Lopinavir/ritonavir. Investigators will also determine if adverse events are unanticipated 
given the patient’s clinical course, previous medical conditions, and concomitant medications.   
If a patient's treatment is discontinued as a result of an adverse event, study site personnel must also 
report the circumstances and data leading to discontinuation of treatment in the adverse event case report 
forms.   
11.3 Serious Adverse Events 
Serious adverse event collection begins after randomization and study procedures have been initiated.  If a 
patient experiences a serious adverse event after consent, but prior to randomization or starting study 
procedures, the event will NOT be collected. Study site personnel must alert the VCC of any serious and 
study procedure related adverse event within 24 hours of awareness of the event regardless of suspected 
causality. The site Investigator must sign off on the initial report within three (3) days of study team’s 
awareness of the SAE.   Alerts issued via telephone are to be immediately followed with official 
notification on the adverse event case report form. See Appendix C for reporting timelines for serious, 
unexpected, study related events (SAEs) and serious, unexpected suspected adverse reactions (SUSARs) 
As per the FDA and NIH definitions, a serious adverse event is any adverse event that results in one of 
the following outcomes: 
 Death 
 A life-threatening experience (that is, immediate risk of dying) 
 Prolonged inpatient hospitalization or re-hospitalization 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if admission 
to the hospital or prolongation of hospitalization was a result of the adverse event. Emergency room 
visits that do not result in admission to the hospital should be evaluated for one of the other serious 
outcomes (e.g., life-threatening; required intervention to prevent permanent impairment or damage; 
other serious medically important event). 
 Persistent or significant disability/incapacity 
As per http://www.fda.gov/Safety/MedWatch/HowToReport/ucm053087.htm: Report if the adverse 
event resulted in a substantial disruption of a person's ability to conduct normal life functions, i.e., 
the adverse event resulted in a significant, persistent or permanent change, impairment, damage or 
disruption in the patient's body function/structure, physical activities and/or quality of life. 
Reportable serious adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse events when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. 
Serious adverse events will be collected through Study Day 16 (or 48 hours after completion of the study 
drug administration), regardless of the investigator's opinion of causation.  

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12. Data and Safety Monitoring Board (DSMB) 
The principal role of the DSMB is to assure the safety of participants in the trial. They will regularly 
monitor data from this trial, review and assess the performance of its operations with respect to:  
• 
Review of adverse events 
• 
Review of every death occurring on study 
• 
Interim results of the study for evidence of efficacy or adverse events 
• 
Possible early termination of the trial because of new external information, early attainment of 
study objectives, safety concerns, or inadequate performance 
• 
Possible modifications in the clinical trial protocol  
• 
Performance of individual centers  
The DSMB will consist of members with expertise in acute infections, acute lung injury, emergency 
medicine, biostatistics, ethics, and clinical trials. Appointment of all members is contingent upon the 
absence of any conflicts of interest. All the members of the DSMB are voting members. The unblinded 
statistician will be responsible for the preparation of all DSMB and adverse event reports and may review 
unblinded data. The DSMB will develop a charter and review the protocol and sample consent form 
during its first meeting. Subsequent DSMB meetings will be scheduled in accordance with the DSMB 
Charter with the assistance of the VCC. When appropriate, conference calls may be held in place of face-
to-face meetings. Recommendations to end, modify, or continue the trial will be prepared by the DSMB 
executive secretary. Recommendations for major changes, such as stopping the trial, will be 
communicated immediately. Other recommendations will be distributed in writing to the VCC and sIRB, 
which will distribute with instructions for reporting to local IRBs when appropriate.   
We will comply with the principles and approaches espoused by the NIH NHLBI guidance found here: 
https://www.nhlbi.nih.gov/grants-and-training/policies-and-guidelines/nhlbi-policy-data-and-safety-
monitoring-extramural-clinical-studies 

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13. APPENDICES  
Appendix A. Schedule of Events 
Schedule of Events 
 
Description: 
Date of Randomization 
Days 1-14 
Days 15-
16 
Day 29 
Confirmation of SAR-CoV-2 positive test result 
X 
 
 
 
Home medications 
X 
 
 
 
Verification of Inclusion/Exclusion Criteria 
X 
 
 
 
Remote consent 
X 
 
 
 
Randomization 
X 
 
 
 
IP shipped to subject 
X 
 
 
 
Self-Administered Dosing 
 
X 
 
 
Self-Reported Symptom Survey 
 
X 
X 
X 
Assessment of Adverse Events 
 
X 
X 
X 
Modified COVID Ordinal Outcome Scale 
 
X 
X 
X 
Ventilator Status 
 
X 
X 
X 
ICU Status 
 
X 
X 
X 
Oxygen Status 
 
X 
X 
X 
Hospital Length of Stay 
 
X 
X 
X 
Vital Status 
 
 
 
X 
End of Study 
 
 
 
X 

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Appendix B. Potential medication interactions with lopinavir/ritonavir 
Medications considered to present a potential interaction with lopinavir/ritonavir, which if ordered during 
the 14-day study period, will prompt study personnel to discuss with treating clinicians the risk-benefit 
assessment of this medication and potential need for additional monitoring: flecainide, mefloquine, 
methotrexate, mexilitine, rifampicin, rifapentine, amiodarone, cimetidine dofetilide, phenobarbital, 
phenytoin, or sotalol, propafenone, astemizole, terfenadine, alfuzosin, apalutamide, ranolazine, 
dronedarone, rifampin, lurasidone, cisapride, pimozide, ergot-containing medicines (including 
dihydroergotamine mesylate, ergotamine tartrate, methylergonovine), lovastatin, simvastatin, lomitapide, 
sildenafil, triazolam, midazolam, rivaroxaban, fluticasone and anticoagulants or St. John’s Wort. 
 
 
 

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Appendix C:  Adverse Event Reporting and Unanticipated Events 
As noted in section 11, investigators will report all “serious adverse events,” defined as adverse events 
that are serious and have a reasonable possibility that the event was due to a study drug or procedure (or 
of uncertain relatedness), to the VCC within 24 hours. The VCC will then notify the single Institutional 
Review Board (sIRB).  
The National/Lead Investigator at the VCC will work collaboratively with the reporting investigator to 
determine if a serious adverse event has a reasonable possibility of having been caused by the study drug 
or study procedure, as outlined in 21 CFR 312.32(a)(1), and below. The CC unblinded statistician will 
also determine if the event is unexpected for lopinavir/ritonavir.   An adverse is considered “unexpected” 
if it is not listed in the investigator brochure or the study protocol (21 CFR 312.32(a)). If a determination 
is made that a serious adverse event has a reasonable possibility of having been caused by a study 
procedure or the study drug, it will be classified as a suspected adverse reaction. If the suspected adverse 
reaction is unexpected, it will be classified as a serious unexpected suspected adverse reaction (SUSAR).  
To enhance safety monitoring, the VCC will report every death by coded group (and potentially 
unblinded group upon request) to the DSMB. The VCC will also report all unexpected deaths, serious and 
treatment related adverse events, and SUSARs to the DSMB, and sIRB within 7 days after receipt of the 
report from a clinical site. A written report will be sent to the DSMB and the sIRB within 15 calendar 
days. The DSMB will also review all reported adverse events and clinical outcomes during scheduled 
interim analyses. The VCC will distribute the written summary of the DSMB’s periodic review of 
reported adverse events to the sIRB. The VCC will provide to AbbVie Pharmacovigilance any safety 
findings for lopinavir/ritonavir (without disclosing protected health information) during the conduct of the 
trial per contractual language.  
C.1. Unanticipated Problems (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, associated with study 
procedures within 24 hours. An unanticipated problem is defined as follows: any incident, experience, or 
outcome that meets all of the following criteria:  
• 
Unexpected, in terms of nature, severity, or frequency, given the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and the characteristics of the subject population being studied.  
• 
Related or possibly related to participation in the research, in this guidance document, 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.  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
C.2. Determining Relationship of Adverse Events to Study Drug or Study Procedures 
Investigators will be asked to grade the strength of the relationship of an adverse event to study drug or 
study procedures as follows:  
• 
Definitely Related: The event follows: a) A reasonable, temporal sequence from a study 
procedure; and b) Cannot be explained by the known characteristics of the patient’s clinical state 

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or other therapies; and c) Evaluation of the patient’s clinical state indicates to the investigator that 
the experience is definitely related to study procedures.  
• 
Probably or Possibly Related: The event should be assessed following the same criteria for 
“Definitely Associated”. If in the investigator’s opinion at least one or more of the criteria are not 
present, then “probably” or “possibly” associated should be selected.  
• 
Probably Not Related: The event occurred while the patient was on the study but can reasonably 
be explained by the known characteristics of the patient’s clinical state or other therapies.  
• 
Definitely Not Related: The event is definitely produced by the patient’s clinical state or by other 
modes of therapy administered to the patient.  
• 
Uncertain Relationship: The event does not meet any of the criteria previously outlined.  
C.3. Clinical Outcomes that may be Exempt from Adverse Event Reporting 
Study-specific outcomes of acute respiratory infection, COVID-19, and critical illness will be 
systematically collected for all patients in both study group and are exempt from adverse event 
reporting unless the investigator considers the event to be Definitely or Possibly Related (or of an 
Uncertain Relationship) to the study drug or study procedures.  Examples of study-specific clinical 
outcomes include: 
• 
Death not related to the study procedures.  
• 
Neurological events 
o Seizure 
• 
Cardiovascular events 
o Receipt of vasopressors 
o Atrial or ventricular arrhythmia 
o Cardiac arrest 
• 
Respiratory events 
o Hypoxemia requiring supplemental oxygen 
o Acute respiratory distress syndrome 
o Receipt of mechanical ventilation 
o Receipt of extra-corporeal membrane oxygenation 
• 
Gastrointestinal events 
o Elevation of aspartate aminotransferase or alanine aminotransferase 
o Acute pancreatitis 
• 
Renal events 
o Acute kidney injury 
o Receipt of renal replacement therapy 
• 
Endocrine events 
o Symptomatic hypoglycemia 
• 
Hematologic or coagulation events 
o Neutropenia, lymphopenia, anemia, or thrombocytopenia 
• 
Dermatologic events 
o Severe dermatologic reaction (e.g., Steven’s Johnson Syndrome) 

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Note: A study-specific clinical outcome may also qualify as a reportable adverse event.  For example, a 
ventricular arrhythmia that the investigator considers Definitely or Possibly Related to the study drug 
would be both recorded as a study-specific clinical outcome and reported as a Serious and Definitely or 
Possibly Related Adverse Event. 
C.4. Decision tree for determining if an adverse event is reportable 
 
 
 
 
 

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