Clinical trial NCT04372628
Conditions: COVID-19
Keywords: Coronavirus
Sponsor: Vanderbilt University Medical Center
Start date: 2020-06-01; Completion date: 2022-01-18
Enrollment: 452 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Blinded, multicenter, placebo-controlled, randomized clinical trial evaluating lopinavir/ritonavir vs placebo in early outpatient treatment of adults with COVID-19

Detailed description:
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.

Arms: arm 1: Lopinavir/Ritonavir 400 mg/100 mg orally twice daily for twenty-eight doses (Days 1-14) arm 2: Placebo unmatched orally twice daily for 14 days
Interventions: intervention 1: Lopinavir/Ritonavir 400 mg/100 mg intervention 2: Placebo
Intervention descriptions: intervention 1: Lopinavir/Ritonavir tablets intervention 2: Unmatched placebo

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
 Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for 
COVID-19 
 
NCT04372628 
 December 23, 2021 
 


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Statistical Analysis Plan 
We would like to acknowledge the Cambridge University Hospitals Clinical Trials Unit for the 
development of the template (version CCTU/TPLV2), which was modified by the Michigan Institute 
for Clinical & Health Research (MICHR). 
 
TRIAL FULL TITLE 
Trial of Early Antiviral Therapies during Non-hospitalized 
Outpatient Window (TREAT NOW) for COVID-19 
SAP VERSION 
1.1 
SAP VERSION DATE 
12/23/2021 
TRIAL STATISTICIAN 
Alexander Kaizer, PhD 
Protocol Version (SAP 
associated with) 
1.6 
TRIAL PRINCIPAL 
INVESTIGATORS 
Adit A. Ginde, MD, MPH 
Nathan I. Shapiro, MD, MPH  
SAP AUTHOR 
Alexander Kaizer 
 
1 SAP Signatures 
I give my approval for the attached SAP for TREAT NOW dated 12/23/2021: 
 
Statistician (Author) 
Name: Alexander M. Kaizer, PhD 
 
Signature: 
                                                
 
Date: 
 
     12/24/2021                         
  
 
 
Principal Investigators 
Name: Adit A. Ginde, MD, MPH 
 
 
Signature: 
                                                
 
Date: 
 
    12/24/2021                         
 
Name: Nathan I. Shapiro, MD, MPH 
 
Signature: 
                                                
 
Date: 
 
    12/24/2021                         
 
 
 


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2 Table of Contents 
 
1 
SAP Signatures ................................................................................................................................ 1 
2 
Table of Contents ............................................................................................................................ 2 
3 
Abbreviations and Definitions ........................................................................................................ 4 
4 
Introduction .................................................................................................................................... 6 
4.1 
Preface .................................................................................................................................... 6 
4.2 
Scope of this statistical analysis plan ...................................................................................... 6 
5 
Study Objectives and Endpoints ..................................................................................................... 6 
5.1 
Study Objectives ..................................................................................................................... 6 
5.2 
Treatment arms ...................................................................................................................... 6 
5.3 
Endpoints/Outcomes .............................................................................................................. 7 
6 
Study Methods ................................................................................................................................ 9 
6.1 
Overview of study Design ....................................................................................................... 9 
6.2 
Inclusion-Exclusion Criteria and General Study Population .................................................... 9 
6.3 
Randomization and Blinding ................................................................................................... 9 
6.4 
Timing of study procedures and outcomes assessments ..................................................... 10 
7 
Sample Size ................................................................................................................................... 10 
8 
General Analysis Considerations ................................................................................................... 10 
8.1 
Timing of Analyses ................................................................................................................ 11 
8.2 
Analysis Populations ............................................................................................................. 11 
8.2.1 
Intention to Treat Population ....................................................................................... 11 
8.2.2 
Per Protocol Population ................................................................................................ 11 
8.2.3 
Safety Population .......................................................................................................... 11 
8.3 
Covariates adjustment .......................................................................................................... 11 
8.4 
Missing Data .......................................................................................................................... 12 
8.5 
Interim Analyses and Data Monitoring ................................................................................. 12 
8.5.1 
Purpose of Interim Analyses ......................................................................................... 12 
8.5.2 
Planned Schedule of Interim Analyses .......................................................................... 12 
8.5.3 
Adaptations ................................................................................................................... 13 
8.5.4 
Stopping Rules ............................................................................................................... 13 
8.5.5 
Considerations for Multiplicity of Testing ..................................................................... 13 
9 
Summary of Study Data ................................................................................................................ 14 
9.1 
Descriptive analysis ............................................................................................................... 14 
9.2 
Subject disposition ................................................................................................................ 15 
9.3 
Derived variables................................................................................................................... 15 


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9.4 
Treatment compliance, protocol deviations and protocol violations .................................. 15 
10 
Efficacy Analyses ....................................................................................................................... 15 
10.1 
Primary Efficacy Analysis ....................................................................................................... 15 
10.1.1 
Secondary Analyses of Primary Efficacy Endpoint ........................................................ 16 
10.2 
Secondary Efficacy Analyses ................................................................................................. 16 
10.2.1 
Analyses of Secondary Endpoints ................................................................................. 16 
10.3 
Subgroup analyses ................................................................................................................ 16 
11 
Safety Analyses ......................................................................................................................... 17 
11.1 
Adverse Events, Serious Adverse Events, and other Events ................................................. 17 
12 
Reporting Conventions ............................................................................................................. 17 
13 
References ................................................................................................................................ 18 
 
 
 


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3 Abbreviations and Definitions 
ACE-I 
Angiotensin-converting-enzyme inhibitor 
ARB 
Angiotensin II receptor blocker 
ADR 
Adverse drug reaction 
ACE 
Angiotensin-converting enzyme 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AR 
Adaptive randomization 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
BAL 
Bronchoalveolar lavage 
BID 
“Bis in die” (twice daily) 
CC 
Coordinating Center 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CYP3A 
Cytochrome P4503A 
DCC 
Data Coordinating Center 
DSMB 
Data and safety monitoring board 
ECMO 
Extracorporeal membrane oxygenation 
eCRF 
Electronic case report form 
EKG 
Electrocardiogram 
FDA 
Food & Drug Administration 
GFR 
Glomerular filtration rate 
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 
IV 
Intravenous 
IVY Network 
Influenza Vaccine Effectiveness in the Critically Ill Network 
KDIGO 
Kidney Disease Improving Global Outcomes 
LFT 
Liver function test 
 
 
 


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LPV/r 
Lopinavir/ritonavir 
MERS-CoV 
Middle East respiratory syndrome coronavirus 2 
MIC 
Minimum inhibitory concentration 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
NSAIDs 
Nonsteroidal anti-inflammatory drug 
pH 
Potential for hydrogen 
PI 
Principal investigator (a clinician responsible for one site) 
PK/PD 
Pharmacokinetics/pharmacodynamics 
PPE 
Personal protective equipment 
PPoS 
Predictive probability of success 
QD 
“quaque die” (once daily) 
QID 
“quater in die” (four times daily) 
QR code 
Quick response code 
QTc 
QT interval corrected for heart rate 
RCT 
Randomized control trial 
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 
S/F 
SpO2/FiO2 ratio 
sIRB 
Single IRB 
SOFA 
Sequential Organ Failure Assessment 
SUSAR 
Suspected unexpected serious adverse reaction 
US 
United States 
VAS 
Visual Analog Scale 
 
 
 
 


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4 Introduction 
4.1 Preface 
Effective therapies for COVID-19 are urgently needed. Lopinavir/ritonavir (Kaletra), an antimicrobial 
agent used to treat HIV-1, has demonstrated in vitro inhibition of SARS-CoV-2, the virus that causes 
COVID-19. Initial clinical data have suggested possible relevance as a therapeutic agent when 
administered early in the disease course of patients with COVID-19. The TREAT NOW study was 
designed to test the hypothesis that lopinavir/ritonavir reduces disease progression and improves 
clinical status measured using a seven point at day 15 following receipt of study drug when 
compared with placebo. The TREAT NOW study is a multicenter, blinded, non-matching placebo-
controlled, randomized clinical trial to evaluate the superiority of active therapy (lopinavir/ritonavir) 
versus placebo control. Briefly, patients testing positive for SARS-CoV-2 infection in an outpatient 
setting are contacted by research coordinators and invited to participate. Adults with a positive 
SARS-CoV-2 test are either self-referred or identified via review of testing records at participating 
sites. Patients who are still symptomatic and who are within six days of symptom onset are invited 
to participate. Eligible participants who provide their consent to participate using an electronic 
system undergo comprehensive baseline data collection via phone survey, the participant is 
randomized, and study drug or placebo is shipped overnight to the participant’s home. The 
participant then completes a daily web-based medication adherence, symptom burden, and 
hospitalization survey for sixteen days. Missed surveys result in telephone follow up to complete 
missing data and to re-engage the participant in completing the study. At day 15, the primary 
outcome is assessed. Patients are followed up once more at 29 days 
4.2 Scope of this statistical analysis plan 
The TREAT NOW clinical protocol was developed to adapt to allow for addition of new agents and 
changing standards of care. In the absence of any planned adaptations, this document is restricted 
to the statistical design and analysis of a comparison between two groups of participants: patients 
randomized to receive lopinavir/ritonavir and patients randomized to receive a placebo. If new 
agents are introduced for testing, or other adaptations are sought, this document will be revised 
accordingly. 
 
Section 5 introduces and defines the study objectives and endpoints. Study methods including the 
overall design, inclusion/exclusion criteria, randomization, and blinding are in Section 6. Sample size 
justifications are in Section 7. Section 8 discusses the analysis populations and planned interim 
analyses. Subject disposition, derived variable definitions, and protocol deviations are defined in 
Section 9. Sections 10 and 11 detail the planned efficacy and safety analyses, respectively. The final 
sections, after Section 12, note reporting conventions, any updates to the SAP and/or protocol after 
SAP approval, and references.  
5 Study Objectives and Endpoints 
5.1 Study Objectives 
To determine whether early treatment with lopinavir/ritonavir improves clinical status at 15 days 
when compared to placebo in outpatient adults with COVID-19. Secondary objectives include 
describing the safety profile of lopinavir/ritonavir, and to determine whether the clinical progression 
is improved through to Day 29. 
5.2 Treatment arms 


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The active treatment arm of lopinavir/ritonavir (LPV/r) consists of standard dosing with 
400mg/100mg taken orally twice daily for 28 doses. Medication dose packs contain all 28 doses 
labelled by study day. The LPV/r dosing is based upon extensive PK/PD study evaluations in healthy 
and HIV+ subjects. 
 
The control arm consists of unmatched placebo taken orally twice daily for a total of 28 doses. 
Medication dose packs will contain all 28 doses labelled by study day. Given the unmatched placebo 
pill to LPV/r, exclusion will be exercised to ensure 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.  
5.3 Endpoints/Outcomes 
In this section endpoints/outcomes are described with how they should be operationalized for 
analysis. Additional information on the study population(s) are defined in Section 8.2 with respect to 
those included for analysis. Per the protocol, timing of study procedures is based on the time of 
randomization, which is defined as Baseline. Study Day 1 is defined as the day of receipt of the first 
dose of the study drug. 
 
Primary outcome: 
The primary outcome is the daily status based on the proposed Modified COVID Ordinal Outcomes 
Scale from Study Day 1 through Study Day 15: 
1. Death 
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 
 
Each daily status is derived primarily from the daily study survey through day 16 after randomization 
and the chart review on day 29 after randomization. This is a longitudinal measure of the ordinal 
outcome from receipt of study medication (Study Day 1) to completion of study treatment (Study 
Day 15). 
 
Secondary outcomes: 
The secondary outcomes are described below with details on operationalization: 
 
• Modified COVID Ordinal Outcome Scale on Study Day 8  
• The ordinal outcome of the previously defined scale on Study Day 8 after one week of 
treatment. 
• Modified COVID Ordinal Outcome Scale on Study Day 15 
• Modified COVID Ordinal Outcome Scale on Study Day 29 
• The ordinal outcome of the previously defined scale on Study Day 29 after one month of 
treatment receipt. 
• Proportion of patients hospitalized through Study Day 29 
• A dichotomous indicator if the participant was hospitalized at any point through Study 
Day 29 as reported on daily surveys or through the Day 29 Chart Review. 
• Time to hospitalization through Study Day 29 
• The number of days from receipt of study medication (Study Day 1) to first 


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hospitalization for any reason through Study Day 29. 
• Time to symptom resolution through Study Day 29 
• The number of days from receipt of study medication (Study Day 1) to resolution of all 
symptoms reported without recurrence. For example, if a participant reports no 
symptoms on the daily survey on Study Day 5, but then symptoms are reported again on 
Study Days 6 through 8 with resolution of all symptoms on Study Day 9, the number of 
days for resolution would be 9 and not 5 to reflect the recurrence of symptoms. 
• All-cause, all-location mortality up to Study Day 29 
• A binary variable indicating death for any reason from receipt of study drug (Study Day 
1) through Study Day 29. 
• Oxygen-free days through Study Day 29 
• The number of days derived from the Modified COVID Ordinal Outcome Scale where 
there is no reported supplemental oxygen, mechanical ventilation, or ECMO from receipt 
of study drug (Study Day 1) to Study Day 29 during hospitalization. Death before Study 
Day 29 will be penalized by using a value of -1 free days. 
• Fever-free days through Study Day 29 
• The number of days where fever is reported as “None” versus “Mild”, “Moderate”, or 
“Severe” based upon daily surveys between receipt of study drug (Study Day 1) and 
Study Day 29. Death before Study Day 29 will be penalized by using a value of -1 free 
days. 
• Ventilator-free days through Study Day 29 
• The number of days derived from the Modified COVID Ordinal Outcome Scale where 
there is no reported mechanical ventilation or ECMO from receipt of study drug (Study 
Day 1) to Study Day 29. Death before Study Day 29 will be penalized by using a value of -
1 free days. 
• Vasopressor-free days through Study Day 29 
• The number of days from receipt of study drug (Study Day 1) to Study Day 29 based 
upon the Study Day 29 Chart Review where no vasopressor use is denoted. Death before 
Study Day 29 will be penalized by using a value of -1 free days. 
• ICU-free days through Study Day 29 
• The number of days from receipt of study drug (Study Day 1) to Study Day 29 based 
upon the Study Day 29 Chart Review where there is no portion of the day spent in the 
ICU. Death before Study Day 29 will be penalized by using a value of -1 free days. 
• Hospital-free days through Study Day 29 
• The number of days from receipt of study drug (Study Day 1) to Study Day 29 based 
upon daily surveys and the Study Day 29 Chart Review where there is no portion of the 
day spent admitted to a hospital setting. Death before Study Day 29 will be penalized by 
using a value of -1 free days. 
 
Safety outcomes: 
Safety outcomes to be included in the safety analysis for this trial include all potentially associated 
adverse events (PAAEs) as well as other events of interest including, but not necessarily limited to: 
 
• Seizure 
• Atrial or ventricular arrhythmia 
• Cardiac arrest 
• Receipt of renal replacement therapy 


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• Severe dermatologic reaction 
• *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 
• *Symptomatic hypoglycemia 
• *Anemia or thrombocytopenia 
* For participants whose symptoms are significant enough to trigger a clinical work-up and thus have 
clinically available testing 
6 Study Methods 
6.1 Overview of study Design  
The study is a multicenter, blinded, non-matching placebo-controlled, randomized clinical trial to 
evaluate the superiority of active therapy (lopinavir/ritonavir) versus placebo control. Patients, 
treating clinicians, and study personnel are blinded to study group assignment. Randomization uses 
permuted blocks and is stratified by site and age (≥65 years or <65 years) in a 1:1 ratio through a 
central electronic system. The primary outcome, measured from Study Day 1 (receipt of study drug) 
to Study Day 15, is a seven-level ordinal scale describing the patient’s clinical status defined in 
Section 5.  The planned analysis is a longitudinal Bayesian proportional odds model with a skeptical 
prior, and is powered to detect an odds ratio of greater than 1.75. 
6.2 Inclusion-Exclusion Criteria and General Study Population 
Patients aged ≥18 years who have laboratory-confirmed SARS-CoV-2 infection by RT-PCR or other 
molecular test within the past 6 days, whose symptoms began ≤6 days previously, and who currently 
remain with at least one symptom are eligible to participate. Qualifying symptoms are cough, fever, 
shortness of breath, chest pain, abdominal pain, nausea/vomiting, diarrhea, body aches, 
weakness/fatigue. 
 
Detailed exclusion criteria are listed in the protocol. They include known contraindications for 
lopinavir/ritonavir, clinical conditions increasing the risk of adverse events associated with 
lopinavir/ritonavir, known pregnancy or breast feeding, known to be a prisoner, inability to comply 
with study procedures, and inability to provide informed consent or complete daily symptom 
surveys in English or Spanish during the two-week observational period.  
6.3 Randomization and Blinding  
Eligible patients will be randomized in a 1:1 ratio to the intervention arm (lopinavir/ritonavir) or the 
control arm (placebo). Randomization is stratified by site and age (≥65 years versus <65 years) and 
uses permuted small block randomization. Patients, treating clinicians, trial personnel, and outcome 
assessors are blinded to group assignment. Only the investigational pharmacy (who is distributing 
study medication), the Data Coordinating Center (who is managing the randomization systems 
including generating the randomization sequence), and one member of the statistical team (who is 
preparing closed DSMB interim reports) are unblinded.  
 
To maintain the blind, study medication is dispensed with packaging and labelling that does not 
indicate whether the drug is a placebo or active treatment. Unblinding will occur only if required for 
subject safety or treatment at the request of the treating clinician and will be done by the 


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Investigational Pharmacy.  
6.4 Timing of study procedures and outcomes assessments 
 
The day of randomization is defined as Baseline and the receipt of the study drug is defined as 
“Study Day 1”.  It is possible for it to take up to two days for study medications to arrive at a 
participant’s home. For the purposes of analysis, Study Day 1 will be counted as the day on which 
study medications are received by the participant. To ensure symptoms are assessed daily while on 
study, and to ensure the primary outcome can be measured through Study Day 15, symptoms are 
collected daily from the day following randomization to sixteen days following randomization. The 
symptoms assessed on Study Day 1 (day of receipt of medication) to Study Day 15 are included in 
the measurements for this trial. At Study Day 15, the primary outcome is assessed. At Study Day 29, 
additional outcomes are assessed. 
7 Sample Size  
This study is designed to be analyzed using a Bayesian approach, accepting the possibility of 
adaptations or sample size adjustments as the trial progresses. Although the design as detailed is 
Bayesian in nature, a frequentist sample size and target power are provided for consistency with 
FDA guidance and recommendations. To provide a sample size estimate, we calculated a sample size 
of 540 patients equally distributed among study arms is needed to have 90% power to detect an 
odds ratio of 1.75 or greater assuming a traditional proportional odds model and a type I error of 
0.05, as proposed by Whitehead (1993). Accounting for an approximate 10% loss to follow-up rate, 
we plan to enroll 600 patients  
 
An example of the difference between study arms resulting in such an odds ratio is shown in the 
table. This is based on recommendations from the World Health Organization for COVID-19 Master 
Protocols that were in place at the time this study was designed  
 
Category 
Placebo Arm Proportion 
Treatment Arm Proportion 
1-Death 
1% 
0.6% 
2-Hospitalized on mechanical 
ventilation or ECMO 
3% 
1.8% 
3-Hospitalized on supplemental 
oxygen 
4% 
2.4% 
4-Hospitalized not on supplemental 
oxygen 
3% 
1.9% 
5-Not hospitalized with symptoms 
and limitation in activity 
10% 
6.6% 
6-Not hospitalized with symptoms 
but with no limitation in activity 
24% 
18.7% 
7-Not hospitalized without 
symptoms nor limitation in activity 
55% 
68.1% 
 
8 General Analysis Considerations 
Here, we describe overarching guidelines that will be followed in the statistical analysis of the TREAT 
NOW study. The timing and scope of each analysis, the analysis datasets, the approach to handling 


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missing data, covariate adjustment, subgroup analysis and stopping guidelines are provided. In 
subsequent sections, the approach to describing the data and modeling the outcomes of interest are 
described. 
8.1 Timing of Analyses 
The final analysis will be performed after all subjects enrolled have completed their Day 29 data 
collection or dropped out prior to their Day 29 data collection, and data are declared query free. 
Interim analyses are detailed below for safety, efficacy, and futility and will be performed for the 
primary outcome based on a database pull for interim analyses. At conclusion of the trial and after 
resolution of all queries, the database will be locked. 
8.2 Analysis Populations 
The analysis populations are defined below. A participant’s inclusion or exclusion status with regard 
to each analysis population will be set prior to breaking the blind for final analyses based on the 
criteria as outlined. 
8.2.1 
Intention to Treat Population 
● All subjects who have receipt of study drug (Study Day 1) based upon their randomized 
allocation. 
● Given the study design whereby patients are shipped study drug from a central pharmacy, 
there might be times when the drug does not get delivered to the patient. In these rare 
instances the patient will be excluded. All other subjects will be included, and they will be 
analyzed according to which group the patient was assigned. Thus, the intent to treat (ITT) 
analysis set includes all subjects who were randomized and received the study drug at their 
provided address. 
8.2.2 
Per Protocol Population 
● All subjects who receive study drug, report taking at least one dose, and who complete their 
Study Day 15 survey will be included in the per protocol population. 
● Patients will be classified according to the treatment they received with confirmation of 
receipt from the study pharmacy. 
8.2.3 
Safety Population 
● All subjects who received any study treatment (including control) and reported taking at 
least one dose but excluding subjects who drop out prior to receipt of the study drug. In the 
unlikely case a participant receives the incorrect study drug, patients will be grouped 
according to the treatments that they received in any safety analyses. If a participant 
receives both placebo and active treatment, they will be considered as receiving active 
treatment. 
8.3 Covariate adjustment 
The main analysis of the primary outcome will be a covariate adjusted proportional odds model. 
Covariates that will be adjusted for include  
• 
Race/ethnicity defined as a single categorical variable for non-Hispanic White/Caucasian, 
non-Hispanic Black/African American, Hispanic, Other.  
• 
Age as a continuous variable in years; modeling will assess for linear effect or cubic splines 
based on the study data. 
• 
Gender as a categorical variable for male, female, undifferentiated, and no answer 
• 
Duration of acute respiratory infection symptoms prior to study drug receipt in days 
calculated as the duration reported at enrollment for randomization plus the additional days 


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until receipt of study drug 
• 
Presence of comorbidities as a dichotomous variable for presence of any or absence of all of 
the following: hypertension, diabetes mellitus, obesity, chronic kidney disease, chronic 
cardiopulmonary conditions, or immunosuppressive conditions.  
• 
Monoclonal antibodies taken for the treatment of COVID-19 prior to randomization defined 
as a binary variable (yes/no) 
• 
SARS-CoV-2 vaccinations were added to the data collection on May 14th, 2021. After that 
time, enrolled subjects will be categorized as fully vaccinated (at least 14 days after 2nd dose 
of SARS-CoV-2 mRNA vaccine or after single dose of J&J vaccine prior to randomization); 
partially vaccinated (receipt of one or more doses of SARS-CoV-2 vaccine but not fully 
vaccinated prior to randomization); and not vaccinated. Between December 14th, 2020 (first 
day of public vaccination in the US under EUA) and May 13th, 2021, vaccination status will be 
recorded as missing. Prior to December 14th, 2020, vaccination status will be recorded as not 
vaccinated. 
• 
Time period when date of randomization occurred defined as a categorical variable in 
quarters (3 month) periods beginning with June 2020-August 2020, September 2020-
November 2020, December 2020-February 2021, etc. 
Center effects will be accounted for with the specification of a random intercept. The defined 
groupings above may be modified to collapse groups pending the available data at time of final 
study analysis. 
8.4 Missing Data 
Missing outcome data for an analysis population will be imputed when necessary using multiple 
imputation. Outcomes using the Bayesian longitudinal proportional odds model, which includes the 
primary outcome, will not use imputation since the model facilitates smoothing over missing 
responses (i.e., the model can still be used even if a participant has missing day(s) of response data). 
Data on age, gender, race/ethnicity, comorbidities, and duration of acute respiratory infection prior 
to randomization should not be missing as they are collected as part of enrollment, however 
imputation procedures will be used in cases of missing values.   
8.5 Interim Analyses and Data Monitoring 
8.5.1 
Purpose of Interim Analyses 
Interim analyses are planned for safety, efficacy, and futility. The results of the interim analyses will 
be reported to the DSMB, along with the stopping guidelines described in this Statistical Analysis 
Plan. The DSMB may request additional interim analyses. Such requests will be fulfilled by the 
unblinded statistician and will not be reported outside of the DSMB meeting. 
8.5.2 
Planned Schedule of Interim Analyses 
The first interim analysis is planned after at least the first 50 participants have been enrolled and 
achieved follow-up through at least Study Day 15. This first analysis will present only safety data to 
the DSMB. The second and subsequent interim analyses will include both safety and efficacy data, 
and are planned to occur after at least 200 participants have been enrolled and have their primary 
outcome observed at Study Day 15. Futility interim analyses will begin after approximately 400 
participants have been observed and will be conducted in addition to interim analyses for safety and 
efficacy. 
 
This trial is planned to be analyzed using a Bayesian approach, and so a strict interim analysis 
schedule is not prespecified. Instead, the schedule for subsequent interim analyses will be decided 
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participants, opportunities to add new agents, and other relevant considerations. 
8.5.3 
Adaptations 
The statistical design of this study is sufficiently flexible to allow for future adaptations. However, no 
adaptations are currently planned. Should new agents become available for inclusion in the study, or 
should there be sufficient evidence to warrant changes in the planned randomization allocation 
probabilities or sample size, the adaptations will be encoded in a revision to this document before 
being implemented.  
8.5.4 
Stopping Rules 
Given the Bayesian nature of the analysis, the posterior probability of the odds ratio for the primary 
outcome exceeding certain thresholds will be used to guide decisions to stop the trial early for 
efficacy or harm. These are: 
 
Probability 
Evidence For 
Action Trigger 
P1 = P(OR > 1 | data) 
Any benefit  
P1 > 0.95 
P2 = P(OR < 1 | data) 
Inefficacy or potential harm 
P2 > 0.90 
 
The criteria for P1 represents scenarios where an intervention arm would stop early for efficacy, 
whereas P2 represents early termination of an intervention arm for inefficacy or potential harm. 
 
Interim monitoring for futility will be based on the posterior predictive probability that P(concluding 
efficacy at N=300 per group|interim data). For the calculation of PPoS, the efficacy threshold on 
study completion will be based on the posterior probability that P(OR > 1 | data) > 0.90. The 
posterior predictive probability of success (PPoS) will be estimated via upstrapping the remaining 
number of participants to be enrolled from participants who have completed through Study Day 15 
regardless of level of missing data (Crainiceanu and Crainiceanu 2020). The PPoS will be based on 
1,000 upstraps of the “completed” trial with stopping rules based on the following table: 
 
Predictive Probability of Success (PPoS) 
Action Trigger 
Action 
PPoS < 0.10 
Stop for futility 
0.10 < PPoS < 0.25 
Consider stopping for futility based on trial 
characteristics (e.g., accrual), secondary 
endpoints, and external factors 
PPoS > 0.25 
Continue trial 
 
8.5.5 
Considerations for Multiplicity of Testing 
Unlike a frequentist design with confidence intervals and p-values relating to the unknown 
parameters, a Bayesian design conditions on the data to estimate the unknown parameters. 
Therefore, the type of control for multiplicity used in a frequentist approach is inappropriate. 
However, it is not uncommon to attempt to understand the frequentist operating characteristics for 
Bayesian designs. We note that a 5% type I error rate with identical assumptions to detect an 
OR=1.75 achieves 86.4% power with a target sample size of 600. With regards to repeated 
evaluations of efficacy using the Bayesian approach, the posterior probability is an estimate of the 
unknown parameter conditional on the data collected thus far and any prior estimates of the 
posterior probability are irrelevant, and so multiplicity adjustments are not warranted and would be 
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9  Summary of Study Data 
All continuous variables will be summarized using the following descriptive statistics: n (non-
missing sample size), mean, standard deviation, median, minimum, 1st quartile, 3rd quartile, and 
maximum. All categorical variables will be reported as the frequency and percentages of 
observed levels with a clear definition of the denominator. In general, summary tables will be 
based on the relevant population (e.g., ITT, safety) and structured with a column for each study 
arm and will be annotated with the total sample size relevant to that table/treatment, including 
the number of missing observations. 
9.1 Descriptive analysis 
Using data pooled across all sites, the study sample will be characterized based on demographic and 
clinical variables measured at randomization, unless otherwise indicated. Specifically, the following 
variables will be described: 
1. Age (years) 
2. Sex (male, female, undifferentiated, no response) 
3. Race (Black/African American, White/Caucasian, American Indian/Alaskan Native, Asian, 
Native Hawaiian/Other Pacific Islander, other, no answer) 
4. Ethnicity (Hispanic, non-Hispanic) 
5. Race/ethnicity (non-Hispanic Black/African American, non-Hispanic White/Caucasian, 
Hispanic, other) 
6. Body mass index (kg/m2) 
7. Presence of comorbidities (yes/no): 
a. chronic cardiac disease 
b. chronic pulmonary disease 
c. chronic kidney disease 
d. chronic liver disease 
e. chronic neurological disease 
f. 
malignant neoplasm 
g. chronic hematologic disease 
h. AIDS/HIV 
i. 
obesity 
j. 
diabetes with complications 
k. diabetes without complications 
l. 
rheumatologic disorder 
m. malnutrition 
n. immunosuppressive conditions 
8. Tobacco product use (current, former, never) 
9. E-cigarette or vaping product use (current, former, never) 
10. Chronic use of medication (yes/no): 
a. ACE inhibitors 
b. angiotensin receptor blockers 
11. Receipt of azithromycin in the past week 
12. Presence of symptoms (yes/no): 
a. Cough 
b. Fever 
c. Shortness of breath 
d. Chest pain 
e. Abdominal pain 


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f. 
Nausea 
g. Diarrhea 
h. Body aches 
i. 
Weakness/fatigue 
13. Total number of symptoms reported (count) 
14. Symptom duration (days) 
9.2 Subject disposition 
The number of participants completing each stage of the trial will be summarized with frequencies 
and percentages to describe the number screened, the number randomized, the number reaching 
target data collection times by arm at Study Day 8, Study Day 15 (primary), and Study Day 29 for 
collection of the primary ordinal outcome status, and the number that dropped out by arm and the 
accompanying reason where known (e.g., death, toxicity, withdrew consent). A CONSORT diagram 
will be generated (Schulz et al. 2010). 
9.3 Derived variables 
This study involves several derived variables, such as body mass index and the seven-level ordinal 
outcome scale. During the data collection process, each component of the derived variable is 
collected and the first stage in data analysis will be to generate and validate the derived variable. 
Depending on the distribution of the seven-category modified COVID-19 ordinal outcomes scale, 
certain categories may need to be combined based upon few or no events.  
 
The primary outcome through Study Day 15 will be derived primarily through the daily surveys (from 
Days 1 to 16 post-randomization) and supplemented by the Study Day 29 Chart Review to verify 
details about hospitalization or other healthcare encounters recorded. The method for derivation of 
other variables not described will be clearly articulated in the analysis report if needed. 
9.4 Treatment compliance, protocol deviations and protocol violations 
Major protocol deviations and violations will be described. Adherence to the schedule for taking 
study medications will be reported. Major protocol deviations that will be reported are failure of 
participant to adhere to the study medication schedule, errors in shipping and handling of study 
medication including shipping the incorrect medication, and other protocol deviations deemed by 
the study executive committee to affect the overall integrity of the data. Any such determination will 
be made before unblinding to treatment arm.  
10 Efficacy Analyses 
All continuous and categorical variables will be summarized as described previously. The analytic 
approach is Bayesian with results presented as credible intervals and posterior probabilities for 
specific hypotheses as defined in the following sections unless otherwise noted. 
10.1 Primary Efficacy Analysis 
The primary outcome of the Modified COVID Ordinal Outcomes Scale from Study Day 1 through 
Study Day 15 will be evaluated in the ITT dataset using a Bayesian longitudinal proportional odds 
model. The model will include a random intercept for each participant to account for the repeated 
measurements over time to calculate the posterior probability that a treatment arm compared to 
the placebo-controlled arm has an OR > 1, suggesting any benefit for the treatment. The 
proportional odds assumption will 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 


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covariates. If proportionality is clearly violated, we will consider partial proportional odds or non-
proportional odds models.  
 
The model will be adjusted for the variables described in Section 8.3. To account for changes in the 
effect size between treatment groups from Study Day 1 to Study Day 15, an interaction between 
randomized group and time will be included. Time will initially be modeled using a cubic spline, but it 
may be modified to a simpler or more complex representation of time if needed to appropriately 
model the effect over time. 
 
The prior for the intercept for the proportional odds regression model will assume a Dirichlet 
distribution. The treatment effect, as defined as a log odds ratio in the model, will have a normal 
prior defined so that 𝑃(𝑂𝑅> 1) = 𝑃(𝑂𝑅< 1) = 0.5 (i.e., equally as harmful as beneficial) and 
𝑃(𝑂𝑅> 2) = 𝑃(𝑂𝑅<
1
2) = 0.025 (i.e., large effects in either direction unlikely), with the variance 
computed to satisfy these criteria. For all other covariates the prior distributions will be normal with 
mean 0 and a larger variance to reflect the uncertainty of their potential effect. 
 
The convergence of the Markov chain Monte Carlo simulations will be checked via diagnostics, with 
alternative priors, models, and chain lengths/burn-ins explored if necessary to achieve convergence 
and satisfy any model assumptions.  
10.1.1 Secondary Analyses of Primary Efficacy Endpoint 
We will replicate the primary analyses using the per protocol dataset and the safety dataset.  
10.2 Secondary Efficacy Analyses 
10.2.1 Analyses of Secondary Endpoints 
For time-to-event outcomes we will utilize survival models (e.g., Cox proportional hazards models), 
and dichotomized outcomes will be evaluated using logistic regression. The continuous outcomes 
such as hospital free days are penalized for death and so an ordinal model will be fit in preference to 
using linear regression. Secondary endpoint models will be fit using normal priors with mean 0 and 
larger variance to reflect the uncertainty of their potential effect on all regression coefficients, with 
convergence evaluated similarly to the primary endpoint.  
10.3 Subgroup analyses 
The currently recommended approach to subgroup analysis is to prespecify subgroups where there 
is a clear biological rationale, and otherwise not to create subgroups unless the data indicate 
differential treatment effects based on potential subgrouping variables.  Given how little is known 
about COVID-19 and possible treatment response, we will examine the potential of differential 
treatment effects in key subgroups of interest based upon previous definitions unless otherwise 
noted: 
• 
Age 
• 
Sex  
• 
Race/ethnicity 
• 
BMI 
• 
Baseline renal function defined as known severe chronic kidney disease requiring dialysis, 
kidney disease not requiring dialysis, no known history of kidney disease 
• 
Hypertension 
• 
Diabetes defined as diabetes with complications, diabetes without complications, not 
diabetic 


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• 
Cardiovascular disease 
• 
Duration of respiratory symptoms prior to randomization 
 
Interactions will not be tested together within the same model but will be tested one by one. 
Potentially significant subgroups will be identified by evaluating the posterior weight assigned to a 
model with and without the interaction by Bayesian stacking. If the model including the interaction 
has a posterior weight of 80% or greater, we will proceed with fitting the model within subgroups. 
For continuous variables, graphical methods will be used to show how the treatment effect changes 
over the range of the continuous variable.  
11 Safety Analyses 
The safety analysis set will be used for safety analyses. Summary statistics will be calculated as 
described in Section 9. When calculating the incidence of adverse events, or any sub-classification 
thereof by treatment, time period, severity, etc., each subject will only be counted once for a given 
safety outcome and any repetitions will be reported separately; the denominator will be the total 
safety population size.  
 
Three tables summarizing adverse events will be created: 
● All-Cause Mortality: A table of all anticipated and unanticipated deaths due to any cause, 
with number and frequency of such events in each arm/group of the clinical study. 
 
● Serious Adverse Events: A table of all anticipated and unanticipated serious adverse events, 
grouped by organ system, with number and frequency of such events in each arm/group of 
the clinical study. 
 
● Other (Not Including Serious) Adverse Events: A table of anticipated and unanticipated 
events (not included in the serious adverse event table) that exceed a frequency threshold 
of 5% within any arm of the clinical study, grouped by organ system, with number and 
frequency of such events in each arm/group of the clinical study. 
11.1 Adverse Events, Serious Adverse Events, and other Events 
The summary statistics will be produced in accordance with section 9. Adverse events, serious 
adverse events, and other events are defined in Appendix C of the study protocol. The 
discontinuation of study medication due to potential adverse events or side effects will be 
summarized by self-reported termination of study treatment and reported adverse events or side 
effects. 
12 Reporting Conventions 
For the purposes of the statistical analysis plan report, posterior probabilities and p-values 
≥0.001 will be reported to 3 decimal places; values less than 0.001 will be reported as “<0.001”. 
The mean, standard deviation, and any other statistics other than quantiles, will be reported to 
one decimal place greater than the original data. Quantiles, such as median, or minimum and 
maximum will use the same number of decimal places as the original data. Estimated 
parameters, not on the same scale as raw observations (e.g. regression coefficients) will be 
reported to 3 decimal places.  


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13 References 
Crainiceanu CM and Crainiceanu A. The upstrap. Biostatistics 21.2 (2020): e164-e166. 
 
Harrell F. rmsb: Bayesian Regression Modeling Strategies. R package version 0.0.1. (2020): 
https://CRAN.R-project.org/package=rmsb 
 
Schulz KF, Altman DG, Moher D, CONSORT Group. CONSORT 2010 Statement: Updated Guidelines 
for Reporting Parallel Group Randomised Trials. PLoS Med 7.3 (2010): e1000251. 
 
Whitehead J. Sample size calculations for ordered categorical data. Statistics in medicine 12.24 
(1993): 2257-2271. 
 
 
 

Prot_001.pdf: 
Protocol 
 Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for 
COVID-19 
 
NCT04372628 
 January 26, 2021 
 


TREAT NOW Protocol Version 1.6 
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Page 1 of 40 
  
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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Page 2 of 40 
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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January 26, 2021 
 
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14. REFERENCES 
 
1.  
Del Rio C, Malani PN. COVID-19-New Insights on a Rapidly Changing Epidemic. JAMA 2020; 
2.  
Fauci AS, Lane HC, Redfield RR. Covid-19 - Navigating the Uncharted. N Engl J Med 2020; 
3.  
Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir–Ritonavir in Adults Hospitalized with Severe 
Covid-19. N Engl J Med [Internet] 2020 [cited 2020 Apr 24];Available from: 
http://www.nejm.org/doi/10.1056/NEJMoa2001282 
4.  
Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently 
emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020;30(3):269–71.  
5.  
World Health Organization (WHO). WHO R&D Blueprint: informal consultation on prioritization 
of candidate therapeutic agents for use in novel coronavirus 2019 infection, Geneva, Switzerland, 
24 January 2020. [Internet]. [cited 2020 Mar 19];Available from: 
https://apps.who.int/iris/handle/10665/330680 
6.  
Li Q, Guan X, Wu P, et al. Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-
Infected Pneumonia. N Engl J Med 2020; 
7.  
Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 
2019. N Engl J Med 2020;382(8):727–33.  
8.  
Perlman S. Another Decade, Another Coronavirus. N Engl J Med 2020;382(8):760–2.  
9.  
Su S, Wong G, Shi W, et al. Epidemiology, Genetic Recombination, and Pathogenesis of 
Coronaviruses. Trends Microbiol 2016;24(6):490–502.  
10.  Cui J, Li F, Shi Z-L. Origin and evolution of pathogenic coronaviruses. Nat Rev Microbiol 
2019;17(3):181–92.  
11.  Zhou P, Yang X-L, Wang X-G, et al. A pneumonia outbreak associated with a new coronavirus of 
probable bat origin. Nature 2020;579(7798):270–3.  
12.  Cheng PK, Wong DA, Tong LK, et al. Viral shedding patterns of coronavirus in patients with 
probable severe acute respiratory syndrome. The Lancet 2004;363(9422):1699–700.  
13.  Hui DS, Azhar EI, Kim Y-J, Memish ZA, Oh M, Zumla A. Middle East respiratory syndrome 
coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. 
Lancet Infect Dis 2018;18(8):e217–27.  
14.  Wang Y, Liu Y, Liu L, Xang X, Luo N, Ling L. Clinical outcome of 55 asymptomatic cases at the 
time of hospital admission infected with SARS-Coronavirus-2 in Shenzhen, China. J Infect Dis 
2020; 
15.  Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome 
and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern 
Med 2020; 


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16.  Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With 
COVID-19 in Washington State. JAMA [Internet] 2020 [cited 2020 Mar 19];(Publised Online). 
Available from: https://jamanetwork-
com.proxy.library.vanderbilt.edu/journals/jama/fullarticle/2763485 
17.  Wilson N, Kvalsig A, Telfar-Barnard L, Baker M. Case-fatality estimates for COVID-19 calculated 
by using a lag time for fatality. Emerg Infect Dis [Internet] 2020 [cited 2020 Mar 18];26(6). 
Available from: https://wwwnc.cdc.gov/eid/article/26/6/20-0320_article 
18.  Al-Bari MAA. Targeting endosomal acidification by chloroquine analogs as a promising strategy 
for the treatment of emerging viral diseases. Pharmacol Res Perspect 2017;5(1):e00293.  
19.  Chu CM, Cheng VCC, Hung IFN, et al. Role of lopinavir/ritonavir in the treatment of SARS: initial 
virological and clinical findings. Thorax 2004;59(3):252–6.  
20.  Chen F, Chan KH, Jiang Y, et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus 
to selected antiviral compounds. J Clin Virol 2004;31(1):69–75.  
21.  Wu C-Y, Jan J-T, Ma S-H, et al. Small molecules targeting severe acute respiratory syndrome 
human coronavirus. Proc Natl Acad Sci U S A 2004;101(27):10012–7.  
22.  de Wilde AH, Jochmans D, Posthuma CC, et al. Screening of an FDA-approved compound library 
identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus 
replication in cell culture. Antimicrob Agents Chemother 2014;58(8):4875–84.  
23.  Chan JF-W, Yao Y, Yeung M-L, et al. Treatment With Lopinavir/Ritonavir or Interferon-β1b 
Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. 
J Infect Dis 2015;212(12):1904–13.  
24.  Wang J. Fast Identification of Possible Drug Treatment of Coronavirus Disease -19 (COVID-19) 
Through Computational Drug Repurposing Study. J Chem Inf Model 2020; 
25.  Martinez MA. Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. 
Antimicrob Agents Chemother 2020;64(5).  
26.  Kim UJ, Won E-J, Kee S-J, Jung S-I, Jang H-C. Combination therapy with lopinavir/ritonavir, 
ribavirin and interferon-α for Middle East respiratory syndrome. Antivir Ther 2016;21(5):455–9.  
27.  Spanakis N, Tsiodras S, Haagmans BL, et al. Virological and serological analysis of a recent Middle 
East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen. Int J 
Antimicrob Agents 2014;44(6):528–32.  
28.  Min C-K, Cheon S, Ha N-Y, et al. Comparative and kinetic analysis of viral shedding and 
immunological responses in MERS patients representing a broad spectrum of disease severity. Sci 
Rep 2016;6:25359.  
29.  Chan JFW, Chan K-H, Kao RYT, et al. Broad-spectrum antivirals for the emerging Middle East 
respiratory syndrome coronavirus. J Infect 2013;67(6):606–16.  
30.  Lauer SA, Grantz KH, Bi Q, et al. The Incubation Period of Coronavirus Disease 2019 (COVID-19) 
From Publicly Reported Confirmed Cases: Estimation and Application. Ann Intern Med [Internet] 


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2020 [cited 2020 Apr 24];Available from: https://annals.org/aim/fullarticle/2762808/incubation-
period-coronavirus-disease-2019-covid-19-from-publicly-reported 
31.  Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel 
Coronavirus–Infected Pneumonia in Wuhan, China. JAMA 2020;323(11):1061.  
32.  Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J 
Med [Internet] 2020 [cited 2020 Apr 24];Available from: 
http://www.nejm.org/doi/10.1056/NEJMoa2002032 
33.  Wu C, Chen X, Cai Y, et al. Risk Factors Associated With Acute Respiratory Distress Syndrome 
and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern 
Med [Internet] 2020 [cited 2020 Apr 24];Available from: 
https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2763184 
34.  Arentz M, Yim E, Klaff L, et al. Characteristics and Outcomes of 21 Critically Ill Patients With 
COVID-19 in Washington State. JAMA [Internet] 2020 [cited 2020 Apr 24];Available from: 
https://jamanetwork.com/journals/jama/fullarticle/2763485 
35.  Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in 
treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 2020;14(1):72–3.  
36.  Woosley R, Heise C, Gallo T, Tate J, Woosley D, Romero K. www.CredibleMeds.org,  QTdrugs 
ListCredibleMeds [Internet]. [cited 2020 Apr 24];Available from: https://www.crediblemeds.org/ 
37.  Sapp JL, Alqarawi W, MacIntyre CJ, et al. Guidance On Minimizing Risk of Drug-Induced 
Ventricular Arrhythmia During Treatment of COVID-19: A Statement from the Canadian Heart 
Rhythm Society. Can J Cardiol [Internet] 2020 [cited 2020 Apr 24];Available from: 
https://linkinghub.elsevier.com/retrieve/pii/S0828282X20303251 
38.  Guan W, Ni Z, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J 
Med 2020; 
39.  Wang Y, Fan G, Salam A, et al. Comparative effectiveness of combined favipiravir and oseltamivir 
therapy versus oseltamivir monotherapy in critically ill patients with influenza virus infection. J 
Infect Dis 2019; 
40.  WHO | Coronavirus disease (COVID-2019) R&D [Internet]. WHO. [cited 2020 Mar 18];Available 
from: http://www.who.int/blueprint/priority-diseases/key-action/novel-coronavirus/en/ 
41.  Kidney Disease Improving Global Outcomes. KDIGO clinical practice guideline for acute kidney 
injury. Kidney Int 2012;2: Suppl:1–138.  
42.  Hydroxychloroquine [Internet]. In: LiverTox: Clinical and Research Information on Drug-Induced 
Liver Injury. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 
2012 [cited 2020 Mar 21]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK548738/ 

ICF_003.pdf: 
Informed Consent Document 
 Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT NOW) for 
COVID-19 
 
NCT04372628 
 January 21, 2021 
 


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
1 
This box is for 
CIRB USE ONLY 
VERSION 6 
Do not edit or delete 
Part 1 of 2: MASTER CONSENT 
 
 
Name of participant: __________________________________________ Age: ___________ 
 
You are being invited to take part in a research study. This study is a multi-site study, meaning it will 
take place at several different locations. Because this is a multi-site study this consent form includes 
two parts. Part 1 of this consent form is the Master Consent and includes information that applies to 
all study sites. Part 2 of the consent form is the Study Site Information and includes information 
specific to the study site where you are being asked to enroll. Both parts together are the legal 
consent form and must be provided to you. 
 
 
 
Key information about this study:  
You are being asked to take part in this research study because you tested positive for SARS Coronavirus 
2 (SARS-CoV-2), which leads to Coronavirus Disease 2019 (COVID-19), and you do not need to be in the 
hospital. This study will enroll up to 600 people. 
 
The symptoms may include fever, cough, shortness of breath or other cold or flu-like symptoms, which 
may appear 2-14 days after exposure. If you develop trouble breathing, persistent pain or pressure in 
the chest, new confusion or trouble waking up or bluish lips or face, get medical attention 
immediately. 
 
COVID-19 illnesses have ranged from very mild (including some with no reported symptoms) to severe, 
including illness resulting in death. While information so far suggests that most COVID-19 illness is mild, 
more serious illness can occur in any person with COVID-19 and lead to hospitalization. Older people 
and people of all ages with severe chronic medical conditions like heart disease, lung disease and 
diabetes, for example, seem to be at higher risk of being hospitalized for COVID-19. 
 
The purpose of this study is to collect information needed to understand if a potential treatment, 
lopinavir/ritonavir, could possibly help people recover faster and/or prevent serious events such as 
hospitalization or death. We do not know if the study drug will make COVID-19 better or worse or have no effect.  
Key Information:  
The first section of this document contains some key points that the research team thought you 
would find important. The study is described in more detail after this section. If you do not 
understand something, please ask someone.  
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
2 
This box is for 
CIRB USE ONLY 
VERSION 6 
Do not edit or delete 
 
If you agree to be in the study, you will be in the study for about 30 days and will take study drug for 14 days.  
 
Although this study is short, we don't want to enroll participants who may be pregnant, become pregnant, or 
breastfeed. 
 
 
 
This study is randomized, blinded, and placebo-controlled, which means that you will either receive 
lopinavir/ritonavir or placebo. A placebo is made to look like the study drug tablet but does not have any 
study drug in it. Researchers use a placebo to see if the study drug works better or is safer than not 
taking any active medication. Randomized means that no one can choose who receives the study drug 
and who receives the placebo. It is up to chance. You have a one in two chance of receiving 
lopinavir/ritonavir or placebo. Blinded means that you, the study doctor and the study team will not 
know which tablet you receive.  
 
Lopinavir/ritonavir is an FDA approved drug used in HIV-1 patients to slow the progression of the HIV-1 virus. 
Laboratory tests and some early human studies suggest it may have activity to fight the SARS-CoV-2 virus.    
 
In this study, lopinavir/ritonavir is considered investigational, which means it has not been approved by the 
U.S. Food and Drug Administration (FDA) for use in COVID-19. 
 
You do not have to be in this research study. You may choose not to be in this study and get other 
treatments without changing your healthcare, services or other rights.  You can stop being in this study 
at any time.  If we learn something new that may affect the risks or benefits of this study, you will be 
told, so that you can decide whether or not you still want to be in this study.    
 
 
Side effects and risks that you can expect if you take part in this study:  
 
Risks of Lopinavir/Ritonavir: 
General Risks  
The most common side effects were diarrhea (loose stools), nausea (feeling sick to your stomach), 
Detailed Information: 
The rest of this document includes detailed information about this study (in addition to the 
information listed above). 
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
3 
This box is for 
CIRB USE ONLY 
VERSION 6 
Do not edit or delete 
vomiting, hypertriglyceridemia (Increased blood level of a form of fat called triglyceride), and 
hypercholesterolemia (Increased blood cholesterol level). Diarrhea, nausea, and vomiting occurred more 
often at the start of therapy while hypertriglyceridemia and hypercholesterolemia generally occurred 
later. Diarrhea was reported more often when this drug was used once a day than when it was used 
twice a day. In this study the study drug is taken twice a day. 
 
The very common side effects (10% or more) are: 
- Diarrhea (loose stools)  
- Nausea (feeling sick to your stomach)  
- Hypertriglyceridemia (Increased blood level of a form of fat called triglyceride) 
- Increased total blood cholesterol level 
- Hypercholesterolemia (Increased blood cholesterol level) 
- Upper Respiratory Infection (upper lung infection) 
 
The most common side effects (less than 10%) are: 
- Vomiting  
- Abdominal Pain (stomach pain) 
- Dyspepsia ( heartburn) 
- Gastroesophageal Reflux Disease (chronic heartburn and indigestion) 
- Flatulence (gas) 
- Headache (pain in the head, including migraine) 
- Dizziness or drowsiness (feeling faint or tired) 
- Pancreatitis (inflammation of the pancreas causing stomach pain) Pancreatitis should be considered 
if clinical symptoms (nausea, vomiting, abdominal pain)  
- Hepatotoxicity (damage to the liver)  
- Lower Respiratory Infection (lower lung infection) 
- Hemorrhoids (a condition that affects the vessels located around the anal area) 
- Gastroenteritis and Colitis (inflammation of the stomach and/or intestines 
- Blood Glucose Disorders (including diabetes mellitus) 
- Musculoskeletal pain [muscle pain including arthralgia (joint pain), back pain] 
- Peripheral Neuropathy [nerve damage (possible numbness, pain, and/or loss of motor function)] 
- Neutropenia (low white blood cell count which increases your risk of infection) 
- Lymphadenopathy (lymph node swelling) 
- Anxiety (feeling of fear, worry, and uneasiness) 
- Insomnia (difficulty sleeping or falling asleep) 
- Cellulitis (an infection of the skin) 
- Dermatitis/Rash (including eczema, seborrheic dermatitis),  
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
4 
This box is for 
CIRB USE ONLY 
VERSION 6 
Do not edit or delete 
- Night sweats  
- Pruritus (itchy skin) 
- Cerebrovascular Accident (stroke) 
- Erectile dysfunction 
- Menstrual Disorders (amenorrhea, menorrhagia) 
 
Uncommon (1% or less) 
- Stomatitis and oral ulcers (sores in the mouth and esophagus, which may be painful and cause 
difficulty swallowing) 
- Duodenitis or Gastritis (inflammation of the intestines and/or stomach) 
- Gastrointestinal Hemorrhage (bleeding of the stomach and/or intestines) 
- Fecal incontinence ( inability to control bowel movements) 
- Lactic Acidosis (abnormal blood acid/base balance) 
- Hyperbilirubinemia (abnormally high levels of bilirubin in the blood) 
- Osteonecrosis (bone destruction) 
- Tinnitus (ringing in the ears) 
- Hemolytic Anemia (anemia due to destruction of red blood cells) 
- Hematuria (blood in the urine) 
- Alopecia (hair loss) 
- Vasculitis (blood vessel inflammation) 
- Deep vein thrombosis [blood clots in a vein (possible pain, swelling, and/or redness)] 
 
Frequency not reported 
- Dysphagia (difficulty swallowing) 
- Eructation (burping) 
- Esophagitis (inflammation, irritation or swelling of the esophagus) 
- Dehydration (Excessive loss of body water) 
- Cholecystitis (an infection of the gallbladder) 
- Dyspnea (shortness of breath) 
- Pulmonary Edema [fluid in the lung (possible difficulty breathing)] 
- Pharyngitis (sore throat) 
Sometimes liver tests are done before starting lopinavir/ritonavir  for long term use, but given the 
quarantine that you are being asked to abide by for your COVID and the short duration of treatment 
being used, it is thought to be safe to give this short treatment course without doing these tests first. 
 
Risks that are not known:  
Because this treatment is investigational, meaning non-FDA approved, there may be risks that we do not 
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
5 
This box is for 
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VERSION 6 
Do not edit or delete 
know about at this time.  
 
Good effects that might result from this study:  
The benefits to science and humankind that might result from this study: 
- 
May help develop important scientific knowledge that could contribute to the development of a 
treatment for patients with COVID-19 and other COVID-like illnesses.   
 
Procedures to be followed: 
Screening/Randomization 
The study team will review your medical record   
 
To confirm a positive SAR-CoV-2 test result  
 
To confirm your medications and medical history and review any available electrocardiograms 
to determine if you are potentially eligible to take part in this study. 
 
The study team will contact you to explain: 
 
The study and what will be required of you.  
 
Review all medications you are taking including prescription medications, over the counter 
medications and supplements. 
 
Ask you general information about yourself including race, ethnicity, and gender.  
 
We will ask you for an alternate contact who can answer questions about you.  
 
We ask you questions about your medical history. 
 
Review the remote consent process. The study team will answer all your questions. You will be 
able to ask any questions that you might have. If you want to take part in this study, you will 
complete the remote consent process. 
 
After you have provided consent and once you are determined to be eligible to take part in this study: 
 
You will be randomized to either lopinavir/ritonavir or placebo.  
 
The study team will review your shipping address and study drug will be shipped to you by 
overnight mail. 
 
Days 1 thru 29  
You will take the study drug twice a day for 14 days. You will complete an electronic daily symptom 
survey or answer questions over the phone about how you are feeling, and we will ask about any new 
medications. We may call and remind you to complete the electronic surveys. If you are unable to 
complete the daily symptom survey electronically, the study team may call you to ask you these survey 
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
6 
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VERSION 6 
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questions over the telephone. We may also call you to ask more questions about your responses or if 
you request that we call you. We also collect information about how you are doing around Day 29.  
 
If you become hospitalized – we may also call your study doctors to see how you are doing.  We will ask 
you to sign a release of information so that we may obtain your medical records if you become 
hospitalized.  We will also ask you for alternative contacts so that we may contact others to see how you 
are doing if you do not answer the questions. If you are hospitalized prior to completion of the study 
medication, an attempt will be made to continue study medication. 
 
If we are unable to reach you by phone, we will contact the alternate contact you have provided to 
obtain information about you. 
 
Reasons why the study doctor may take you out of this study:  
The study doctor may take you out of the study if he or she thinks it is not in your best interest. If the 
sponsor stops the study, you will be taken out of study. If you are taken out of this study, you will be 
told the reason why. 
 
What will happen if you decide to stop being in this study? 
If you decide to stop being part of the study, you should tell your study doctor.  Deciding to not be part 
of the study will not change your regular medical care in any way. 
 
Clinical Trials Registry.   
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by U.S. Law.  This 
website will not include information that can identify you.  At most, the website will include a summary 
of the results.  You can search this Web site at any time. 
 
Privacy: 
Any information about you may be made available to others to use for research.  To protect your 
privacy, we will not release your name.  You will not receive any benefit as a result of the data collected.  
This data may help us, or other researchers learn more about the causes, risks, treatments, or how to 
prevent this and other health problems. 
 
Your study data may be used to make new products or tests.  This data may have value and may be 
developed and owned by the study staff, Vanderbilt University, and/or others.  If this happens, there are 
no plans to provide money to you.  
 
Study Results: 
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022


Institutional Review Board 
Informed Consent Document for Research 
MASTER CONSENT 
 
Study Title: 
Trial of Early Antiviral Therapies during Non-hospitalized Outpatient Window (TREAT 
NOW) for COVID-19 
Version Date: 
October 30, 2020 
  
 
 
 
7 
This box is for 
CIRB USE ONLY 
VERSION 6 
Do not edit or delete 
Study results will not be shared directly with participants but will be available through 
www.clinicaltrials.gov and publication in medical journals. 
Date of IRB Approval: 01/21/2021
Date of Expiration: 01/20/2022