Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial
Phase: PHASE2
Conditions: COVID-19, SARS-CoV-2
Sponsor: University of Washington

Protocol Title: 
Efficacy of Novel Agents for Treatment of 
SARS-CoV- 2 Infection Among High-Risk 
Outpatient Adults: An Adaptive 
Randomized Platform Trial 
 
 
NCT Number: 
 
NCT04354428 
 
Document Date: 
 
Version 2.1; 17 August 2020 
 

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About this Model Protocol 
This model document is a protocol template created to align institutions engaged in evaluating 
hydroxychloroquine (HCQ), HCQ in combination with azithromycin, lopinavir-ritonavir 
(LPV/r), and other therapies for SARS-CoV-2 treatment. It contains the following: 
• Sections written in black text are mandatory and must be consistent across the 
participating institutions to maintain scientific integrity of the project 
• Sections written in italics are optional and may be omitted as required 
(e.g., based on institutional needs and practices) 
• A site-specific protocol addendum template (Appendix 4) is provided to capture 
information that is specific to a given study site 
These materials are provided “AS IS” WITHOUT WARRANTY OF ANY KIND, EITHER 
EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED 
WARRANTIES OF MERCHANTABILITY, FITNESS FOR A PARTICULAR PURPOSE, OR 
NON-INFRINGEMENT. Authors and Sponsors of this document do not accept any 
responsibility for any loss of any kind including loss of revenue, business, anticipated savings or 
profits, loss of goodwill or data, or for any indirect consequential loss whatsoever to any person 
using these materials or acting or refraining from action as a result of the information contained 
in these materials. Any party using these materials bears sole and complete responsibility for 
ensuring that the materials, whether modified or not, are suitable for the particular use and are 
accurate, current, commercially reasonable under the circumstances, and comply with all 
applicable laws and regulations. 
Nothing in this model document should be construed to represent or warrant that persons using 
this document have complied with all applicable laws and regulations. All individuals and 
organizations using this document bear responsibility for complying with the applicable laws and 
regulations for the relevant jurisdiction. 

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CLINICAL STUDY PROTOCOL 
Protocol Title: 
Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient 
Adults: An Adaptive Randomized Platform Trial 
Compound: 
A. Hydroxychloroquine (terminated) 
B. Azithromycin (terminated) 
C. Lopinavir-ritonavir 
D. Ascorbic acid (control) 
E. Folic acid (control) 
Short Title: 
Treatment for SARS-CoV-2 in High-Risk Adult Outpatients 
Protocol Version and Approval Date: 
Version 1.4; 11 April 2020 
Version 2.0; July 29, 2020 
Version 2.1; August 17, 2020 
Protocol Registry Number: 
NCT04354428 
Regulatory Agency Identifying Number(s): 
Not applicable 
Sponsor Name and Legal Registered Address: 
University of Washington 
4333 Brooklyn Ave NE 
Box 359472 
Seattle, WA 98195-9472 
Funding Agency and Legal Registered Address: 
Bill & Melinda Gates Foundation 
1300 I St NW, Washington, DC 20005 
Principal Investigator: 
Dr. Christine Johnston, University of Washington 
Phone: +1 206 520 4318; Email: cjohnsto@uw.edu 

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Sponsor Signatory Name and Title: 
  
 
 
 
 
 
 
Signature 
 
Date 
Medical Monitor name and contact information is provided separately for each site. 

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Table of Contents 
 
1. 
Synopsis............................................................................................................................7 
2. 
Schedule of Activities ....................................................................................................12 
3. 
Introduction ...................................................................................................................14 
3.1. 
Background .....................................................................................................................15 
3.2. 
Study Rationale ...............................................................................................................15 
3.2.1. 
COVID-19 and Antiviral Approaches ............................................................................15 
3.2.2. 
Antiviral Effects of Chloroquine Analogues Against COVID-19 ..................................16 
3.2.3. 
Rationale for Drug Selection of HCQ .............................................................................17 
3.2.4. 
Rationale for Dosing Schedule of HCQ..........................................................................17 
3.2.5. 
Antiviral Effects of Azithromycin Against COVID-19 ..................................................18 
3.2.6. 
Rationale for Drug Selection of Azithromycin ...............................................................18 
3.2.7. 
Rationale for Dose Selection of Azithromycin ...............................................................19 
3.2.8. 
Antiviral Effects of Lopinavir and Ritonavir Analogues Against 
COVID-19.......................................................................................................................19 
3.2.9. 
Rationale for Drug Selection of LPV/r ...........................................................................19 
3.2.10. Rationale for Dose Selection of LPV/r ...........................................................................20 
3.2.11. Rationale for Ascorbic Acid Control as a Comparator for HCQ 
and LPV/r ........................................................................................................................20 
3.2.12. Rationale for Folic Acid Control as a Comparator for 
Azithromycin ..................................................................................................................20 
3.3. 
Benefit/Risk Assessment ................................................................................................21 
4. 
Objectives and Endpoints ............................................................................................22 
5. 
Study Design ..................................................................................................................24 
5.1. 
Overall Design ................................................................................................................24 
5.2. 
Participant and Study Completion ..................................................................................25 
6. 
Study Population ...........................................................................................................26 
6.1. 
Inclusion Criteria ............................................................................................................26 
6.2. 
Exclusion Criteria ...........................................................................................................27 
6.3. 
Screen Failures ................................................................................................................28 
6.4. 
Recruitment .....................................................................................................................28 
6.5. 
Co-enrollment Guidelines ...............................................................................................28 
7. 
Treatments .....................................................................................................................29 
7.1. 
Treatments Administered ................................................................................................29 
7.2. 
Risks to the Participants ..................................................................................................30 
7.2.1. 
Risks Associated Administration with HCQ ..................................................................30 
7.2.2. 
Risks Associated with Azithromycin ..............................................................................30 
7.2.3. 
QT Risks Associated with Coadministration of HCQ and 
Azithromycin ..................................................................................................................30 
7.2.4. 
Risks Associated with LPV/r ..........................................................................................31 
7.2.5. 
Risks Associated with COVID-19 Diagnosis .................................................................31 

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7.3. 
Strategies to Minimize Risk ............................................................................................32 
7.3.1. 
Dose Selection ................................................................................................................32 
7.3.2. 
Management of Participants to Limit Risks of SARS-CoV-2 
Transmission ...................................................................................................................32 
7.4. 
Dose Modification and Toxicity Management ...............................................................32 
7.5. 
Method of Treatment Assignment ..................................................................................35 
7.6. 
Blinding ..........................................................................................................................35 
7.6.1. 
Patient Blinding ..............................................................................................................35 
7.7. 
Preparation/Handling/Storage/Accountability ................................................................36 
7.8. 
Treatment Compliance ....................................................................................................36 
7.9. 
Concomitant Therapy .....................................................................................................36 
7.9.1. 
Prohibited Medications ...................................................................................................36 
7.9.2. 
Precautionary Medications..............................................................................................37 
7.10. 
Treatment After the End of the Study .............................................................................37 
8. 
Discontinuation/Withdrawal Criteria .........................................................................38 
8.1. 
Discontinuation of Study Treatment ...............................................................................38 
8.2. 
Withdrawal from the Study.............................................................................................38 
8.3. 
Lost to Follow-up............................................................................................................39 
9. 
Study Encounters ..........................................................................................................40 
9.1. 
Screening/Baseline Evaluation: Day 0/1 ........................................................................40 
9.2. 
Day 2 Through Day 13 ...................................................................................................41 
9.3. 
Days 2 (±1 day), and Days 4, 9, and 14 (±2 days) ..........................................................41 
9.4. 
Days 14 and 21 ...............................................................................................................41 
9.5. 
Day 28 .............................................................................................................................42 
10. 
Study Assessments and Procedures.............................................................................43 
10.1. 
Efficacy Assessments .....................................................................................................43 
10.1.1. Mid-nasal Swab ..............................................................................................................43 
10.1.2. Participant Survey ...........................................................................................................43 
10.2. 
Adverse Events ...............................................................................................................44 
10.2.1. Adverse Events ...............................................................................................................44 
10.2.2. Serious Adverse Events ..................................................................................................44 
10.2.3. Treatment-related AE and SAE ......................................................................................45 
10.3. 
Treatment of Overdose ...................................................................................................45 
10.4. 
Pregnancy........................................................................................................................45 
10.5. 
Safety Assessments .........................................................................................................45 
10.6. 
Dried Blood Spot Sub-study (Optional) .........................................................................45 
10.7. 
Biohazard Containment ..................................................................................................46 
11. 
Statistical Considerations .............................................................................................46 
11.1. 
Sample Size Determination ............................................................................................46 
11.1.1. LRTI and Hospitalization Endpoints ..............................................................................46 
11.1.2. Viral Shedding Endpoint.................................................................................................47 
11.2. 
Populations for Analyses ................................................................................................47 
11.3. 
Statistical Analyses .........................................................................................................48 

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11.3.1. Efficacy Analyses ...........................................................................................................48 
11.3.2. Secondary Endpoints ......................................................................................................49 
11.3.2.1. 
Safety Analyses ...........................................................................................................49 
11.3.2.2. 
Days of Hospitalization ............................................... Error! Bookmark not defined. 
11.3.2.3. 
Disease Severity ..........................................................................................................49 
11.3.2.4. 
Symptom Resolution ................................................... Error! Bookmark not defined. 
11.3.3. Pharmacokinetic Analysis ...............................................................................................49 
11.3.4. Exploratory Exposure-Response Analyses .....................................................................49 
11.3.5. Combined Study Analysis...............................................................................................49 
12. 
References ......................................................................................................................50 
13. 
Appendices .....................................................................................................................54 
Appendix 1: Abbreviations and Terms ..........................................................................................54 
Appendix 2: Protocol Structure .....................................................................................................56 
Appendix 3: Study Governance Considerations ............................................................................57 
Appendix 4: Site-Specific Protocol Addendum Template .............................................................60 
Appendix 5: Hydroxychloroquine Label .......................................................................................63 
Appendix 6: Azithromycin Label ..................................................................................................64 
Appendix 7: Lopinavir-ritonavir Label ..........................................................................................65 
Appendix 8: Physiologically Based Pharmacokinetic Model for 
Azithromycin Dose Regimen..........................................................................................66 
Appendix 9: Pharmacokinetic Sample Collection and Analysis ...................................................68 
Appendix 10: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis ............................................70 
Appendix 11: WHO Ordinal Scale for Clinical Improvement ......................................................71 
Appendix 12: The inFLUenza Patient-Reported Outcome instrument 
(Flu-PRO) – Modified for SARS-CoV-2........................................................................72 
 
List of Tables 
Table 1 
Sample Size per Arm Required to Detect a Relative Risk Reduction of 40% to 
60% Under Various Control Event and Dropout Rates ..... Error! Bookmark not 
defined. 
 
 

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1. 
Synopsis 
Narrow Title: 
Efficacy of Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: A 
Platform Trial 
Expanded Title (pending discussions of approach): 
Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient 
Adults: An Adaptive Randomized Platform Trial 
Short Title: 
Treatment for SARS-CoV-2 in High-Risk Adult Outpatients 
Rationale: 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes mild illness 
confined to the upper respiratory track in 80% of people but can cause severe lower respiratory 
tract infection (LRTI) in 20%, particularly among those in high-risk groups, defined by advanced 
age (>60 years) and presence of comorbidities (e.g., cardiopulmonary disease, renal disease, 
diabetes mellitus). Progression to LRTI appears to frequently result in hospitalization for 
supplemental oxygen therapy and may lead to need for ventilator respiratory support and 
ultimately death. Given the rapid spread of the SARS-CoV-2 pandemic, interventions that avert 
adverse patient outcomes and reduce the strain on the medical system are urgently needed. In 
addition, prolonged viral shedding has been noted after infection; therapeutic strategies that can 
effectively reduce viral shedding, and potentially onward transmission, have the potential to shift 
the trajectory of the pandemic. 
There are no FDA-approved therapeutic agents for any human coronavirus disease and many 
scientists and researchers have proposed potential agents based on in vitro and pre-clinical 
studies. These agents have potential benefits but also have inherent risks and limitations (e.g., 
scalability of supply). There is urgent need for controlled clinical studies in relevant patient 
populations to guide both policy makers and other clinical trialists on prioritized drugs, including 
a path toward future evaluations as data becomes available. This study intends to provide quick 
and informative data to assist in early decision-making and/or support combined analysis with 
other concurrently run studies. 
Hydroxychloroquine (HCQ) is currently approved for the suppressive treatment (for extrahepatic 
phase of malaria) and treatment of acute attacks of malaria due to several Plasmodium strains. It 
is also indicated for the treatment of discoid and systemic lupus erythematosus and rheumatoid 
arthritis. With the first Food and Drug Administration approval in 1955, safety and tolerability of 
HCQ are well described. In vitro, HCQ displays antiviral activity against coronaviruses, 
including SARS-CoV-2. Pharmacologic modeling based on observed drug concentrations and 
in vitro drug testing suggest that treatment at approved doses (200 to 800 mg daily) could 
achieve levels in respiratory tract tissues to inhibit virus replication and shedding, potentially 
reducing adverse outcomes of infection and onward transmission. Preliminary, uncontrolled 

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studies suggest that HCQ could be clinically beneficial in persons with hospitalized coronavirus 
disease (COVID-19) and reduce viral shedding. The first arm of this platform trial explored 
HCQ as a treatment for early COVID-19. 
Azithromycin is a broad-spectrum azalide antibiotic that was approved over 30 years for the 
treatment of a variety of bacterial infections, including pneumonia. Azithromycin has shown 
antiviral activity in vitro against Ebola, Zika, rhinovirus, and other respiratory viruses 
(Gautret 2020; Menzel 2016). The rationale for studying the combination of 
HCQ + azithromycin was early evidence of enhanced antiviral activity compared with HCQ 
alone in patients with COVID-19 disease in a small observational series reported by Gautret 
(2020). The second arm of this platform trial explored HCQ + azithromycin as a treatment for 
early COVID-19.  
High dose lopinavir-ritonavir (LPV/r), a combination medication that has been used to treat 
human immunodeficiency virus/acquired immunodeficiency syndrome, also has shown in vitro 
activity against SARS (Chu 2004; Chen 2004; Wu 2004). Compared to ribavirin as a historical 
control group, it has been previously shown that LPV/r (400 mg and 100 mg, respectively) can 
reduce the risks of adverse clinical outcomes such as acute respiratory distress syndrome and 
death as well as viral load among patients with SARS (Chen 2004; Schoenfeld 2009; 
Chan 2003). A recent randomized clinical trial of standard-dose LPV/r utilized in hospitalized 
patients was not effective in decreasing time to clinical improvement or decreasing ribonucleic 
acid levels in respiratory secretions (Cao 2020). However, it is hypothesized that utilization of 
higher dose LPV/r earlier in infection may have improved efficacy at preventing LRTI. The third 
arm of this platform trial will investigate LPV/r as a treatment for early COVID-19. 
This synopsis proposes a randomized platform trial for treatment of high-risk individuals in 
outpatient settings with SARS-CoV-2 infection, with primary outcomes focused on resolution of 
symptoms by Day 14 and reduction of upper respiratory viral shedding, defined as time to 
clearance (2 consecutive negative swabs). 
A flexible platform trial design will allow additional candidate agents for SARS-CoV-2 infection 
that are identified and prioritized for testing to be incorporated into this protocol as additional 
arms. The design of the trial and the statistical analysis plan will allow seamless integration of 
new interventions. Some study procedures may be adapted based on a unique safety profile of 
these new candidates, but the core study elements will be maintained. If an intervention is shown 
to be effective, this design would also allow replacement of the placebo group with the effective 
intervention as the comparator. 
Design: 
Randomized (participant-blinded, treating clinician-blinded, laboratory-blinded, pharmacist-
unblinded, and statistician-unblinded), multi-center, placebo-equivalent (ascorbic acid)-
controlled, and blinded study of lopinavir/ritonavir for the treatment of SARS-CoV-2 infection in 
high-risk adults not requiring hospital admission. Additional arms will be added should new 
potential agents be discovered or combination treatments be proposed.  In addition, arms may be 
dropped prior to completion if deemed futile or if there is a safety signal. 
Population: 

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Men and women 18 to 80 years of age who had their first positive PCR test for SARS-CoV-2 
within the past 72 hours and have COVID-19 symptoms (as per COVID-19 criteria). 
High-risk cohort: 
Eligible participants will be at increased risk of developing LRTI based on the established risk 
factors for severe COVID-19 disease (at least one of the following): 
i. 
Age ≥60 years 
ii. 
Presence of pulmonary disease, specifically moderate or severe persistent asthma, 
chronic obstructive pulmonary disease, pulmonary hypertension, emphysema 
iii. 
Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment 
iv. 
Hypertension, requiring at least 1 oral medication for treatment 
v. 
Immunocompromised status due to disease (e.g., those living with human 
immunodeficiency virus with a CD4 T-cell count of <200/mm3) 
vi. 
Immunocompromised status due to medication (e.g., persons taking 20 mg or more of 
prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, or 
cancer therapies) 
vii. 
Body mass index ≥35 kg/m2 (self-reported) 
Low-risk cohort: 
Eligible participants will be 18 to 59 years of age, inclusive, without any of the risk factors for 
developing severe COVID-19 disease (see high-risk cohort above). 
COVID-19 symptoms criteria are as follows:  At least TWO of the following symptoms: Fever 
(≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR  
At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing.  
Participants will be counseled about the preliminary in vitro data on LPV/r activity against 
SARS-CoV-2 and equipoise regarding efficacy in humans, given that there are only limited data 
at this time. 
Interventions: 
• Intervention A: HCQ (terminated) 
• Intervention B: HCQ + azithromycin (terminated) 
• Intervention C: LPV/r 
Treatment Regimens: 
• Treatment arm 3: LPV/r 800 mg-200 mg orally twice on Day 1, followed by 
400 mg-100 mg orally twice daily for an additional 9 days (Days 2 to 10)  
• Treatment arm 4: Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally 
twice daily for 9 days (Days 2 to 10) 

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Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
• To test the efficacy of LPV/r compared to 
placebo to resolve COVID-19 symptoms 
within 14 days. 
• COVID-19 symptoms are based on the 
following criteria:  
o At least TWO of the following 
symptoms: Fever (≥ 38ºC), chills, 
rigors, myalgia, headache, sore throat, 
new olfactory and taste disorder(s), 
OR  
o At least ONE of the following 
symptoms: cough, shortness of breath 
or difficulty breathing, OR 
o Severe respiratory illness with at least 
1 of the following:  
 Clinical or radiological evidence of 
pneumonia, OR 
 Acute respiratory distress 
syndrome (ARDS), OR 
 LRTI, defined by resting 
SpO2<93% sustained for 2 
readings 2 hours apart AND 
presence of subjective dyspnea or 
cough 
Death or COVID-19-related hospitalizations 
will count as a failure to resolve symptoms. 
• To test the efficacy of LPV/r compared to 
placebo to reduce SARS-CoV-2 viral 
shedding 
• Time to clearance of nasal SARS-CoV-2, 
defined as 2 consecutive negative swabs 
(swabs collected daily Day 1 through 
Day 14)  
Trial is statistically powered for this 
endpoint in both the high- and lower-risk 
populations, analyzed separately. 
Secondary 
• To test the safety of LPV/r compared 
to placebo for treatment of high-risk 
outpatients with SARS-CoV-2 
infection 
• Serious adverse events (including 
death and COVID-19-related 
hospitalization) and adverse events 
resulting in treatment discontinuation  

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• To test whether LPV/r has an effect on 
disease severity compared to placebo 
• Peak score on WHO Ordinal Scale for 
Clinical Improvement 
• Peak score on modified Flu-PRO 
within the first 14 days  
• To test whether LPV/r is associated 
with decreased viral shedding from 
self-collected nasal swabs over 14 
days compared to placebo 
• Proportion of days with SARS-CoV-2 
detected from mid-nasal swabs by 
PCR 
• Median quantity of SARS-CoV-2 
detected from mid-nasal swabs by 
PCR 
Exploratory 
• To assess pharmacokinetics and 
exposure-response relationship of 
LPV/r 
• LPV/r blood concentration in DBS 
COVID-19: coronavirus disease; DBS: dried blood spot; Flu-PRO: inFLUenza patient-reported outcome; LPV/r: 
lopinavir-ritonavir; LRTI: lower respiratory tract infection; SARS-CoV-2: severe acute respiratory syndrome 
coronavirus 2; SpO2: blood oxygen saturation level; WHO: World Health Organization. 
Sample Size: 
The study will enroll 173 participants per arm to achieve 80% statistical power at 2-sided type I 
error rate of 5% for a pairwise comparison against the control to detect a treatment effect of 
hazard ratio of 1.5 for the primary outcome(s) assuming control event rate of 60% for the 
primary outcome and 5% dropout rate. Additional controls will be added to allow for 
contemporaneous controls for the LPV/r arm.  Eligible participants will be randomized at a 1:1 
ratio LPV/r + and Ascorbic acid. If a second eligible patient is in the same household, both will 
be assigned to the same regimen. A blinded sample size re-assessment may be done to possibly 
increase the target sample size, conditional on the observed incidence rate and within household 
correlation. Should a new intervention be added, the randomization ratio may be adjusted to 
favor the new arm, ensuring that control arm participants are still enrolled concurrently with 
active arms; an empirical Bayesian information borrowing method may be used to incorporate 
past control arm data for the comparison of new intervention that is added later. 
Duration: 
Twenty-eight days of clinical follow-up per participant. 
Proposed Sites (up to 6): University of Washington, Tulane, Boston University, Cook County, 
and others to be discussed 

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2. 
Schedule of Activities 
Procedure 
Screening 
Self-quarantine 
 
EOS 
Treatment Period  
 
Day 0a 
Day 
1a 
Day 
2a 
Day  
3 
Day 
4a 
Days 
5 to 8 
Day  
9a 
Days 
10 to 13 
Day 
14a 
Day 
21 
Day 
28b 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
Sign HIPAA form 
X 
 
 
 
 
 
 
 
 
 
 
Past and current medical conditions, including 
known pregnancy and/or lactation status 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
 
 
 
 
 
 
 
 
 
 
Laboratory documentation of COVID-19 testing 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
Mid-nasal swab 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study therapy (LPV/r, ascorbic acid) 
 
## 
# 
# 
# 
# 
# 
#c 
 
 
 
Symptomatic relief medications as needed only 
(ondansetron, loperamide) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Daily Survey (including dosing and swab 
adherence, concomitant medications) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Modified Flu-PRO 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO Ordinal Scale for Clinical Improvement 
 
 
 
 
 
 
 
 
X 
X 
X 
Participant collected daily vitals (including 
temperature, pulse, SpO2, respiratory rate) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
QT monitoring* 
 
X 
X 
X 
X 
X 
X 
Xd 
 
 
 
Contact with study clinician or staff 
 
X 
X 
Xe 
X 
Xe 
X 
Xe 
X 
Xe 
X 
Exit Contact Survey (including concomitant 
medications, symptoms, etc.) 
 
 
 
 
 
 
 
 
 
 
X 
Adverse event review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
If in sub-study: dried blood spot sample for LPV/r 
concentration and anti-SARS-CoV-2 antibodies 
 
X 
1 to 5 samples (no more than 2 per day)  
after dosing start 
 
 
X 

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Procedure 
Screening 
Self-quarantine 
 
EOS 
Treatment Period  
 
Day 0a 
Day 
1a 
Day 
2a 
Day  
3 
Day 
4a 
Days 
5 to 8 
Day  
9a 
Days 
10 to 13 
Day 
14a 
Day 
21 
Day 
28b 
 
COVID-19: coronavirus disease; EOS: end of study; Flu-PRO: inFLUenza patient-reported outcome; HCQ: hydroxychloroquine; HIPAA: Health 
Insurance Portability and Accountability Act of 1996; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; SpO2: oxygen saturation; 
WHO: World Health Organization. 
Note: ## 800 mg-200 mg LPV/r twice a day or placebo (ascorbic acid 1 gm) twice a day.  
Note: # denotes 400 mg-100 mg LPV/r twice a day +placebo (ascorbic aid 500 mg) twice a day 
a Screening and Day 1, 2, 4, 9, and 14 evaluations will be conducted through a web-based screening tool, HIPAA-compliant video conference 
(Telehealth), telephone, or text messaging. Screening (Day 0) and Day 1 evaluations may occur on the same day. 
b For patients who are hospitalized on Day 28, the last visit will be ±3 days after discharge. The exit survey may also be conducted before day 28 if a 
participant terminates early and is willing.  
c Last day of study medication will be administered on Day 10 LPV/r, and ascorbic acid. 
d Last day of QT monitoring will be Day 11. 
e These evaluations will be as needed/requested by study participant. 
*May be omitted if not standard of care to monitor QTc for regimen 
 

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3. 
Introduction 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid + folic acid)-controlled, 
blinded platform trial for the treatment of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection in high-risk adults not requiring hospital admission. The trial will start 
with hydroxychloroquine (HCQ) (Intervention A), HCQ + azithromycin (Intervention B), and 
lopinavir-ritonavir (LPV/r) (Intervention C) as experimental interventions. Additional arms will 
be added as new agents or combinations are prioritized. In addition, if other agents are found to 
be effective, HCQ, HCQ + azithromycin, or LPV/r may become the control group against which 
new interventions are measured. Evaluations include safety and tolerability, SARS-CoV-2 viral 
shedding, and development of lower respiratory tract infection (LRTI). There will be 4 study 
arms (Arm 1: HCQ + placebo [folic acid], Arm 2: HCQ + azithromycin, Arm 3: LPV/r and Arm 
4: placebo [ascorbic acid +/- folic acid], ) enrolled to assess a daily dosing regimen administered 
for 10 days to prevent LRTI or decrease the time to symptom resolution and decrease viral 
shedding. 
Up to 173 eligible adults (18 to 80 years of age) per arm will be randomized (at the level of 
household) in a 1:1 ratio to receive one of the following therapies: 
• LPV/r 800 mg-200 mg orally twice on Day 1, followed by 400 mg-100 mg orally twice 
daily for an additional 9 days (Days 2 to 10)   
• Placebo: Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice 
daily for 9 days  
 LPV/r will not appear similar to ascorbic acid.   If there are more than 1 participant in the same 
household, all will be assigned to the same randomized group, preserving some degree of 
masking. 
During the study, participants will perform the following: 
• Collect mid-nasal swabs for viral detection for the co-primary trial endpoint 
• Complete daily physical assessments for symptoms of LRTI and measurement of 
temperature, respiratory rate, pulse, and oxygen saturation (SpO2), QT monitoring (as 
needed), respiratory rate  
• Complete up to 5 dried blood spots  
• Complete surveys that will include questions about symptoms from both the drug 
regimen and respiratory and systemic symptoms, review of concomitant medications, 
and other pertinent topics 
During the 28 study days, participants will take the medication, complete surveys, collect 
mid-nasal swab for viral quantification, and assess symptoms for progression to LRTI. Physical 
assessments will include daily temperature, SpO2, pulse, QT monitoring (as needed), dried blood 
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3.1. 
Background 
SARS-CoV-2 is a coronavirus novel to the human population discovered in December 2019; it is 
currently the cause of a global pandemic (Huang 2020; Zhu 2020; Chen 2020). The World 
Health Organization (WHO) named the novel coronavirus SARS-CoV-2 and the disease caused 
by the virus as COVID-19. 
As of 25 March 2020, nearly 500,000 persons were infected, with over 21,000 deaths reported 
from around the globe.  As of August 17, there were over 21.6 million confirmed cases, with 
nearly 775,000 deaths. Person-to-person transmission has occurred across the globe. Accurate 
reporting is limited by availability of diagnostic testing. WHO declared the COVID-19 pandemic 
a Public Health Emergency of International Concern on 30 January 2020 (WHO News 
Release Jan 2020), and the United States declared a national emergency on 13 March 2020 
(White House Press Release 2020). 
Most deaths and severe pneumonitis have occurred in the elderly or in persons with underlying 
pulmonary or cardiac comorbidities or diabetes. In healthy adults, including pregnant women, it 
can cause a febrile, self-limited pneumonia. Infection appears less symptomatic in children and 
younger adults (Cai 2020). Nevertheless, the burden of this pandemic to the global health and 
economic systems is expected to be substantial. No acquired immunity to this novel viral 
infection appears to exist in the human population globally, and no effective treatment or 
preventative agent is licensed at this time. 
As with many infectious epidemics, household contacts, first responders, caregivers, and medical 
personnel attending persons with COVID-19 are at high risk of infection. The incubation time 
requires 14 days of quarantine for exposed individuals not wearing personal protective 
equipment (Linton 2020), and on 03 March 2020, WHO declared a global shortage of personal 
protective equipment, leaving doctors, nurses, and other frontline workers dangerously 
ill-equipped to care for COVID-19 patients (WHO News Release Mar 2020). Extensive absences 
from the care network and health system will degrade the ability to care not only for those with 
COVID-19 but also for routine healthcare issues as well. At the height of local epidemic, the 
health care system becomes overburdened with patients with respiratory illness. To date, 
rigorous self-isolation and lockdown have been required to contain the SARS-CoV-2, leaving 
entire societies to abruptly stop normal life. Interventions are urgently needed to stop viral spread 
and to decrease the morbidity and mortality cause by the infection. The ability to stop viral 
replication to prevent transmission of the virus and to prevent disease progression, which is 
associated with decreased symptom duration , will be of benefit to the individual, and the health 
of the public. In addition, treating those at highest risk of disease progression  and hospitalization 
will have the greatest impact on the pandemic.  
3.2. 
Study Rationale 
3.2.1. 
COVID-19 and Antiviral Approaches 
SARS-CoV-2 is a novel betacoronavirus of zoonotic origin, similar to the coronaviruses severe 
acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome 
coronavirus (MERS-CoV). Based on current evidence, case fatality rate for SARS-CoV-2 is 
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(Chen 2020b). However, SARS-CoV-2 has potentially higher transmissibility (R0: 1.4 to 5.5) 
than both SARS-CoV (R0: 2 to 5) and MERS-CoV (R0: <1). 
Our understanding of the viral pathogenesis of SARS-CoV-2 remains limited. However, it 
appears that the virus cell entry depends on the binding of the viral spike (S) proteins to cellular 
receptors and on S protein priming by host cell proteases. SARS-CoV-2, like SARS-CoV, uses 
the same receptor angiotensin converting enzyme 2 (ACE2) on pulmonary epithelial cells for 
entry and the transmembrane serine protease 2 for S protein priming (Hoffmann 2020). The 
receptor binding domain of lineage B betacoronaviruses is a single, continuous domain that 
contains all of the structural information necessary to interact with the host receptor. Fusion is 
mediated at the cell membrane, delivering the viral nucleocapsid inside the cell for subsequent 
replication. ACE2 expression is found in the lung epithelial cells, vascular endothelium, renal 
tubular epithelium, and epithelia of the small intestine. Viral shedding has been localized 
primarily to respiratory droplets and fecal samples (Zhu 2020). 
Medications to treat and/or prevent SARS-CoV-2 need to inhibit aspects of the viral life cycle, 
ultimately blocking replication. Already-approved and available medications are ideal for 
immediate evaluation for SARS-CoV-2 infection treatment and prevention. Two potential targets 
for anti-SARS-CoV-2 medications are viral polymerases and proteases (Li 2019). Pilot clinical 
studies are already ongoing for SARS-CoV-2 using various repurposed antiviral medicines 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-
coronavirus-2019-ncov). Similarities between SARS-CoV-2 with SARS-CoV and MERS 
suggest that antivirals with in vitro efficacy against SARS-CoV and MERS may be promising 
agents as SARS-CoV-2 post-exposure prophylaxis (PEP) (Li 2019; Lee 2019). 
3.2.2. 
Antiviral Effects of Chloroquine 
Analogues Against COVID-19 
Chloroquine (CQ) was discovered in 1934 by Bayer and was used in 1945 as an antimalarial, 
which became one of the most prescribed drugs globally, prior to the emergence of widespread 
drug resistance in Plasmodium falciparum (Slater 1993). CQ was found to be effective against 
rheumatoid tenosynovitis in 1951 (Mackenzie 1970). HCQ was licensed in the United States in 
1955 as an antimalarial and as a drug for rheumatoid arthritis, and it was widely marketed for the 
latter due to a favorable safety profile with chronic use (Shippey 2018). The mechanisms of 
action for HCQ for treatment of rheumatoid arthritis and other autoimmune diseases are still not 
fully understood despite widespread use over the past 60 years (Schrezenmeier 2020). 
CQ and HCQ have been proposed as potential agents for treatment and prevention against other 
infectious agents beyond malaria (Rolain 2007; Savarino 2015). The mechanism of action differs 
according to the pathogen: against intracellular bacteria and fungi by alkalinizing vacuoles 
containing the microorganisms, restoring the activity of other antibiotics, and against viral 
replication through alkalization of acidic organelles, namely, endosomes, lysosomes, and Golgi 
vesicles. 
CQ is effective in vitro against SARS-CoV coronavirus in Vero E6 cells with a half-maximal 
effective concentration (EC50) of ~8 µM (Keyaerts 2004) and had shown evidence of prevention 
activity in vivo (Vincent 2005). Hence, these re-purposed drugs were obvious hits for testing 
against SARS-CoV-2. In vitro inhibition in Vero E6 cells against the novel coronavirus, SARS-

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CoV-2, has been published in recent weeks. Wang et al (2020) showed that the EC50 and EC90 
for CQ in Vero E6 cells are 1.13 and 6.90 µM, respectively. Yao et al (2020) showed that the 
EC50 for CQ treatment of infected cells at 48 hours was 5.47 µM, whereas HCQ appeared 
slightly more potent, with EC50 of 0.72 µM at 48 hours. These levels appear to be within the 
range of exposures that could be achieved with standard HCQ treatment, and likely prophylaxis, 
due to concentrations of the drug achieved in the lung tissue. No in vitro data in the lung 
epithelial cells or any animal model data are available. 
Multiple observational and small Investigator-initiated COVID-19 pneumonia treatment trials 
using CQ, HCQ, and variety of other medications are ongoing in China 
(https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-
coronavirus-2019-ncov). Gao et al (2020) reported anecdotal efficacy of CQ as treatment for 
COVID-19-associated pneumonia. 
3.2.3. 
Rationale for Drug Selection of HCQ 
The trial will test a daily regimen of HCQ for 10 days for treatment of SARS-CoV-2 (package 
insert, Appendix 5). Daily dosing has the highest likelihood to achieve sustained required drug 
levels for viral inhibition, as shown in the physiologically based pharmacokinetics (PBPK) 
modeling (Appendix 10). HCQ is commonly used daily in doses up to 600 mg of HCQ sulfate 
(465 mg base) per day for rheumatoid arthritis or systemic lupus erythematosus initially, with a 
usual maintenance dose of 200 mg (155 mg base) for maintenance therapy. HCQ and CQ are 
both commonly used in a weekly dosing schedule for malaria chemoprophylaxis. 
HCQ is associated with a better safety profile for daily and chronic use than CQ, including 
5 decades of experience with use in these dose ranges in adults and the elderly. It is on the WHO 
Essential Medicines List for use in rheumatic disorders and is widely prescribed as an 
anti-inflammatory for rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune 
syndromes. Based on the limited in vitro data available, HCQ appears to be slightly more potent 
than CQ against SARS-CoV-2 (Yao 2020). 
As the COVID-19 epidemic remains very fluid and new data are emerging from observational 
and clinical trials daily, this protocol is written to allow adaptation to incorporate additional 
medications beyond HCQ and HCQ + azithromycin. 
3.2.4. 
Rationale for Dosing Schedule of HCQ 
HCQ is a long-acting drug with a terminal half-life of approximately 40 days. It is well absorbed, 
moderately protein bound, and will accumulate in tissues including the lung, heart, liver, and 
kidneys. It is typically given with a loading dose of approximately 2-fold the standard dose to 
accelerate achieving steady-state drug concentrations (Furst 1999). Since the drug will be used in 
those with SARS-CoV-2 upper respiratory tract infection, it is desirable to quickly achieve 
adequate drug levels to decrease viral replication. 
A PBPK model was built (SIMCYP simulator version 18) using physical and chemical 
parameters of HCQ obtained from the literature (Collins 2018); pharmacokinetic (PK) 
parameters (liver intrinsic clearance, fa, ka) were determined from clinical data (Tett 2018). This 
PBPK model was used to simulate HCQ concentrations in plasma and lung fluid following 
5 proposed dosing regimens in order to select an optimal regimen for the Peking University 

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Third Hospital’s ongoing trial of HCQ in China. The combination of in vitro antiviral 
concentration-effect and predicted drug concentrations in this study were used to propose a 
loading dose of 400 mg HCQ twice on Day 1, and drug levels will remain above the EC50 for at 
least 14 days of treatment and potentially beyond Day 21. 
A second study (BYSY-DCTC-CPPO-HCQ-PBPKAR) was undertaken to simulate HCQ 
concentration-time profiles in plasma, whole blood, and lung. Since elderly patients have 
reduced glomerular filtration rate (GFR), simulations were conducted using a healthy Caucasian 
healthy population with renal injury (GFR 30 to 60 mL/min) and compared to a population with 
normal renal function to support the study design of therapeutic use of HCQ. 
This protocol will investigate a single dosage of HCQ. Participants will receive a loading dose of 
400 mg twice on Day 1, followed by 200 mg twice a day for 9 additional days. Subsequent 
investigations will be encouraged to undertake a more rigorous exposure-response assessment to 
define optimal dosing, including exploration of the lowest possible effective dose, and possible 
alternate dosing schedules (i.e., weekly instead of daily). 
3.2.5. 
Antiviral Effects of Azithromycin 
Against COVID-19 
Azithromycin is a broad-spectrum azalide antibiotic used to treat a number of bacterial 
infections, including pneumonia. Azithromycin has shown antiviral activity in vitro against Zika, 
Ebola, rhinoviruses, and other respiratory viruses (Gautret 2020; Menzel 2016). Although the 
mechanism of its antiviral activity is not clear, some findings suggest it may be associated with 
augmentation of interferon response (Menzel 2016). Alternatively, azithromycin may convey 
antiviral activity by increasing the pH of cell organelles such as endosomes and the trans-Golgi 
network (Poschet 2020). Changing the pH of intracellular vesicles may alter the glycosylation of 
ACE2, a key receptor for cell entry for SARS-CoV-2 (Belouzard 2012; Wrapp 2020). 
3.2.6. 
Rationale for Drug Selection of 
Azithromycin 
The trial will test a daily regimen of azithromycin in combination with HCQ in the treatment of 
SARS-CoV-2 (Zithromax package insert, Appendix 6). In the Gautret study (Gautret 2020), 
among 20 participants with confirmed COVID-19 who were treated with HCQ, 6 received 
azithromycin (500 mg on Day 1 followed by 250 mg/day on Days 2 to 5) to prevent bacterial 
pneumonia superinfection. On Day 6, all participants who were treated with the HCQ + 
azithromycin combination showed virologic cure as measured by PCR of nasopharyngeal 
samples compared with 57.1% of participants treated with HCQ alone. 
Azithromycin, which has been approved for use for >30 years, is associated with a favorable 
safety profile. It is on the WHO’s List of Essential Medicines, and WHO classifies it as critically 
important for human medicine. Azithromycin is widely available worldwide. Common short-
term drug toxicities include nausea, vomiting, diarrhea and upset stomach. 

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3.2.7. 
Rationale for Dose Selection of 
Azithromycin 
The dose of azithromycin selected for this study aligns with the Dosage and Administration 
recommendations in the United States prescribing information (USPI) for the treatment of 
community-acquired pneumonia. This regimen is 500 mg as a single dose on Day 1, followed by 
250 mg once daily on Days 2 through 5. Azithromycin does not undergo significant metabolism 
and does not complex with or induce cytochrome P450 (CYP), thus minimizing the potential for 
drug interactions. Because azithromycin has a long terminal half-life (79 hours with 500 mg oral 
dosing), once daily or single-dose treatments are possible (Ballow 1992).  
The dose regimen of 500 mg as a single dose on Day 1, followed by 250 mg once daily on 
Days 2 through 5 was used in the recently published study of HCQ and azithromycin in patients 
with COVID-19 (Gautret 2020). Using a PBPK model, azithromycin lung concentrations were 
simulated for this dose regimen to ensure that physiologically relevant lung exposure can be 
reached. Results are presented in Appendix 8. Based on the simulations, it appears that a dosing 
regimen of 500 mg for 1 day followed by 250 mg once daily for 4 days is able to attain 
concentrations of azithromycin in the lung that would approach the in vitro EC50 value reported 
for inhibition of SARS-CoV-2 by azithromycin (Touret 2020). 
3.2.8. 
Antiviral Effects of Lopinavir and 
Ritonavir Analogues Against COVID-
19 
LPV/r, also known as Kaletra, is a combination medication that has been used to treat human 
immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Lopinavir is a HIV type 1 
aspartate protease inhibitor that is usually “boosted” with ritonavir to increase the plasma 
half-life of lopinavir through the inhibition of CYP. Lopinavir has been shown to have in-vitro 
inhibitory activity against SARS-CoV (Chu 2004; Chen 2004; Wu 2004). Compared to ribavirin 
as a historical control group, it has been previously shown that LPV/r (400 mg and 100 mg, 
respectively) can reduce the risks of adverse clinical outcomes such as acute respiratory distress 
syndrome and death as well as viral load among patients with SARS (Chen 2004; 
Schoenfeld 2009; Chan 2003). Based on in vitro testing and previous clinical evaluation, LPV/r 
is an important treatment regimen that should be tested for SARS-CoV-2. Although a recent 
open-label clinical trial did not show efficacy of LPV/r to decrease days of hospitalization or 
viral shedding, this trial focused on patients who were already hospitalized, likely due to LRTI 
and used a suboptimal dosing strategy (Cao 2020). The proposed trial will treat participants 
when they still have upper respiratory tract infection, earlier in the illness, and will use a higher 
loading dose, which will allow the LPV/r to reach a plasma concentration that exceeds the EC50 
for SARS-CoV-2. 
3.2.9. 
Rationale for Drug Selection of LPV/r 
The trial will test a daily regimen of LPV/r for 10 days for treatment of SARS-CoV-2 (package 
insert, Appendix 7). Daily dosing after a large loading dose has the highest likelihood to achieve 
sustained required drug levels for viral inhibition. LPV/r is commonly used daily in regimens of 
combination antiretroviral therapy for the treatment of HIV infection. 

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LPV/r is associated with a favorable safety profile. Short-term drug toxicities include moderate 
nausea, diarrhea, and liver function test abnormalities. It is on the WHO Essential Medicines List 
for use in HIV infection, and is widely available throughout the world. 
3.2.10. 
Rationale for Dose Selection of LPV/r  
To obtain adequate levels to exceed the 50% inhibitory concentration for SARS-CoV-2, LPV/r 
will be dosed at 800 mg-200 mg twice daily on the first day. The dose will be decreased to 
400 mg-100 mg twice daily (United States Food and Drug Administration [FDA]-approved dose) 
for the remainder of the clinical trial. 
3.2.11. 
Rationale for Ascorbic Acid Control as 
a Comparator for HCQ and LPV/r 
In healthy adults, COVID-19 disease is likely to present as an upper respiratory viral infection, 
characterized by a febrile disease with cough and fatigue (Huang 2020; WHO Feb 2020). 
Symptom reporting may vary based on the participants’ perception as to whether they are taking 
HCQ or ascorbic acid (Barrett 2011), but the primary study endpoints are not affected. There is 
no rigorously proven therapy for individuals with outpatient COVID-19 disease, although 
multiple therapies are under investigation. 
Because there is no established therapy, use of a control is acceptable and ethical for both the 
participants’ health and safety as well as ensuring the most rigorous trial design to evaluate an 
intervention for COVID-19 disease caused by SARS-CoV-2. Participants will be blinded to their 
allocation to the extent possible. However, LPV/r will not appear similar to ascorbic acid. If >1 
individual from the same household is enrolled, all will be assigned to the same randomized 
group. 
The dose of ascorbic acid chosen for this protocol is safe. All participants, regardless of assigned 
group, will be able to take additional ascorbic acid (e.g., over the counter vitamins or through 
food) should they choose, as there is no known maximum daily safe dose of ascorbic acid. 
Clinical trial evidence has demonstrated that ascorbic acid, alone or in combination with other 
micronutrients, does not substantially reduce the risk of upper respiratory infections or severe 
consequences of infectious processes (Fujii 2020; Graat 2002); thus, ascorbic acid is not 
expected to have a prevention effect for SARS-CoV-19 and is considered a placebo-equivalent 
product for this study. 
3.2.12. 
Rationale for Folic Acid Control as a 
Comparator for Azithromycin 
Folic acid, also known as vitamin B9 is one of the B vitamins and commonly used as a dietary 
supplement. Specifically, folic acid is also used as a supplement during pregnancy to reduce the 
risk of neural tube defects in the baby. Folic acid is on the WHO’s List of Essential Medicines, 
widely available worldwide, and inexpensive. 
Folic acid has no known antiviral activity. The risk of toxicity from folic acid is low, because 
folic acid is water-soluble and excreted through urine. The 100% daily recommended for folic 
acid is 400 μg, and the upper intake level is established as 1000 μg/day. No health risks have 
been associated with high intake of folic acid from food sources. 

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As folic acid is not expected to have a preventative effect for SARS-CoV-19 it is considered an 
acceptable placebo-equivalent product for this study. 
3.3. 
Benefit/Risk Assessment 
COVID-19 disease can be unpredictable in its severity, but a 3.4% mortality rate has been 
observed among clinical pneumonia cases. The elderly (>60 years of age) and those with medical 
comorbidities (e.g., cardiopulmonary disease, renal disease, diabetes mellitus) are at highest risk 
of poor outcomes (Huang 2020; Zhu 2020; Chen 2020). Moreover, transmission in younger 
persons amplifies infection in communities, putting susceptible persons at risk. There is no 
proven drug for treatment of those with COVID-19 disease. HCQ and LPV/r have an excellent 
safety record at the proposed doses for many years and both agents have potent viral suppression 
in vitro. The safety profile of azithromycin at the proposed dose is similarly well characterized 
with safety considerations and monitoring guidance provided in the label. There is equipoise as 
to whether the in vitro efficacy of HCQ, HCQ + azithromycin, LPV/r, or any other drug or drug 
combination, will translate into efficacy to decrease symptom duration and decrease viral 
shedding. Thus, the potential benefit-to-risk ratio for testing HCQ, HCQ + azithromycin, and 
LPV/r as treatment is favorable in this population. 

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4. 
Objectives and Endpoints 
Initial clinical endpoints included progression to lower respiratory tract infection, hospitalization, 
and death.  The event rate for these endpoints was too low to achieve the study objective, and 
therefore the clinical endpoint was changed to symptom resolution within 14 days in Version 2.0. 
Objectives 
Endpoints 
Primary  
• To test the efficacy of LPV/r compared to 
placebo to resolve COVID-19 symptoms 
within 14 days. 
• COVID-19 symptoms are based on the 
following criteria:  
o At least TWO of the following 
symptoms: Fever (≥ 38ºC), chills, 
rigors, myalgia, headache, sore throat, 
new olfactory and taste disorder(s), 
OR  
o At least ONE of the following 
symptoms: cough, shortness of breath 
or difficulty breathing, OR 
o Severe respiratory illness with at least 
1 of the following:  
 Clinical or radiological evidence of 
pneumonia, OR 
 Acute respiratory distress 
syndrome (ARDS), OR 
 LRTI, defined by resting 
SpO2<93% sustained for 2 
readings 2 hours apart AND 
presence of subjective dyspnea or 
cough 
Death or COVID-19-related 
hospitalizations will count as a failure to 
resolve symptoms. 
• To test the efficacy of LPV/r compared to 
placebo to reduce SARS-CoV-2 viral 
shedding 
• Time to clearance of nasal SARS-CoV-2, 
defined as 2 consecutive negative swabs 
(swabs collected daily Day 1 through 
Day 14) 
Secondary 
• To test the safety of LPV/r compared to 
placebo for treatment of high-risk 
outpatients with SARS-CoV-2 
infection 
• Serious adverse events (including death 
and COVID-19-related 
hospitalization) and adverse events 
resulting in treatment discontinuation  

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• To test whether LPV/r has an effect on 
the duration of hospitalization among 
persons who become hospitalized with 
COVID-19 disease  
• Days of COVID-19-related 
hospitalization  
• To test whether LPV/r has an effect on 
disease severity compared to placebo 
• Peak score on WHO Ordinal Scale for 
Clinical Improvement 
• Peak score on modified Flu-PRO 
within the first 14 days 
• To test whether LPV/r is associated with 
decreased viral shedding from self-
collected nasal swabs over 14 days 
compared to placebo 
• Proportion of days with SARS-CoV-2 
detected from mid-nasal swabs by 
PCR 
• Median quantity of SARS-CoV-2 
detected from mid-nasal swabs by 
PCR 
Exploratory 
• To assess pharmacokinetics and 
exposure-response relationship of 
LPV/r 
• LPV/r blood concentration in DBS 
COVID-19: coronavirus disease; DBS: dried blood spot; Flu-PRO: inFLUenza patient-reported outcome; LPV/r: 
lopinavir-ritonavir; LRTI: lower respiratory tract infection; SARS-CoV-2: severe acute respiratory syndrome 
coronavirus 2; SpO2: blood oxygen saturation level; WHO: World Health Organization. 
 

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5. 
Study Design 
5.1. 
Overall Design 
The overarching goal of this study is to assess the effectiveness of interventions on the symptom 
duration, and length of viral shedding among adult outpatients with SARS-CoV-2 infection to 
inform public health control strategies. 
This is a randomized, multi-center, placebo-equivalent (ascorbic acid +/- folic acid)-controlled, 
blinded platform trial. Stratified randomization based on different trial sites will be used. The 
trial started with HCQ (Intervention A) and HCQ + azithromycin (Intervention B) to assess the 
efficacy on the prevention of LRTI progression. With this protocol amendment, HCQ and 
HCQ/azithromycin were stopped, and LPV/r (Intervention C) was added. The trial may allow for 
additional agents to be added and tested against placebo with standardized eligibility criteria, 
outcomes, and measurements. 
This study will enroll 173 eligible adults per arm (18 to 80 years of age) with high risk for 
disease progression or at low risk at baseline who are PCR-confirmed SARS-CoV-2 infection 
with symptoms compatible with COVID-19. Eligible participants will be enrolled and 
randomized in a 1:1 ratio to LPV/r or Vitamin C. Recruitment rate will be assessed on a weekly 
basis starting at the end of second week after the first eligible patient is recruited and 
randomized. Blinded sample size re-assessment will be done to increase the sample size target, 
should a lower control event rate (CER) and/or higher dropout rate than expected be observed. A 
decision for a possible interim analysis will be made during the trial based on the information on 
the observed recruitment rate, the CER, the dropout rate, and the final sample size target, if 
applicable. The decision for interim analysis will be made in a blinded manner (e.g., based on 
pooled number of events). The interim monitoring plan (written by the Study Statistician) will 
define monitoring bounds to maintain the 2-sided type I error rate at the desired 5% (e.g., 97.5% 
or higher probability of superiority over the control group). Should new experimental candidates 
be added during the trial, randomization ratios may be adapted to favor the new arms.  
It is anticipated that additional treatment modalities will be incorporated into this protocol, in an 
adaptive fashion. Those will be added through later protocol amendments, which will define 
additional sample size needs and any potential change to randomization (e.g., changing the 
randomization ratio, continuation/discontinuation of any of the existing arms, etc.). 
Participants will be counseled about the preliminary in vitro data on and LPV/r activity against 
SARS-CoV-2 and equipoise regarding efficacy in humans, given that there are only limited data 
from an uncontrolled study at this time. 
Participants may participate in a sub-study where they will be asked to provide a dried blood 
spot (DBS) sample for therapy concentration and pharmacokinetics of the medications as well as 
for SARS-CoV-2 antibody testing. 
An independent data and safety monitoring board (DSMB) will be convened for this study with 
expertise in COVID-19 or respiratory viruses and emerging epidemics as well as biostatistics. 
The purpose of the DSMB is to monitor the study for operational futility, social harms, and 
efficacy. The DSMB will also review the blinded sample size re-assessment plan and proposed 

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sample size changes and make recommendations on the randomization ratio, in case the new 
intervention arms are added. 
This multi-center study will be conducted in high COVID-19 disease incidence areas in the 
United States, with the potential to expand enrollment to international sites. 
5.2. 
Participant and Study Completion 
Up to 173 high and low-risk participants per arm will be randomly assigned to study treatment or 
control. This sample size target may increase based on the blinded sample size re-assessment. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the last scheduled procedure shown in the Schedule of Activities (SoA). 
This study will be considered completed when sufficient number of participants complete the 
study to enable appropriate evaluation of the primary endpoint. 

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6. 
Study Population 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
6.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply (173 
participants per arm): 
High-risk cohort (: 
1. Men or women 18 to 80 years of age, inclusive, at the time of signing the informed 
consent 
2. Willing and able to provide informed consent 
3. Laboratory confirmed SARS-CoV-2 infection, with first positive PCR test results within 
the past 72 hours 
4. COVID-19 symptoms, based on the following criteria: At least TWO of the following 
symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory 
and taste disorder(s), OR o At least ONE of the following symptoms: cough, shortness of 
breath or difficulty breathing 
5. Access to device and internet for Telehealth visits 
6. At increased risk of developing severe COVID-19 disease (at least one of the following) 
a. Age ≥60 years 
b. Presence of pulmonary disease, specifically moderate or severe persistent asthma, 
chronic obstructive pulmonary disease, pulmonary hypertension, emphysema 
c. Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for 
treatment 
d. Hypertension, requiring at least 1 oral medication for treatment 
e. Immunocompromised status due to disease (e.g., those living with HIV with a 
CD4 T-cell count of <200/mm3) 
f. Immunocompromised status due to medication (e.g., persons taking 20 mg or 
more of prednisone equivalents a day, anti-inflammatory monoclonal antibody 
therapies, or cancer therapies) 
g. Body mass index ≥35 (self-reported) 
Low-risk cohort: 
1. Men or women, 18 to 59 years of age, inclusive without any risk factors for developing 
severe COVID-19 disease (point 5 above) 
2. Willing and able to provide informed consent 
3. Laboratory confirmed SARS-CoV-2 infection, with first positive PCR test results within 
the past 72 hours 
4. COVID-19 symptoms, based on the following criteria: At least TWO of the following 
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and taste disorder(s), OR o At least ONE of the following symptoms: cough, shortness of 
breath or difficulty breathing 
5. Access to device and internet for Telehealth visits 
6.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Known hypersensitivity to HCQ or other 4-aminoquinoline compounds* 
2. Known hypersensitivity to azithromycin or other azalide or macrolide antibiotics* 
3. Known hypersensitivity to LPV/r 
4. Currently hospitalized due to COVID-19 and/or with discharge planning >24 hours out* 
5. Signs of respiratory distress prior to randomization, including respiratory rate >24 
6. Current medications include HCQ*, azithromycin*, or LPV/r 
7. Current medications include a protease inhibitor, ritonavir, or cobicistat 
8. Concomitant use of other anti-malarial treatment or chemoprophylaxis* 
9. History of retinopathy of any etiology* 
10. Psoriasis requiring immunosuppressive medications. Psoriasis managed with topical 
steroids may be permitted as per discretion of study clinician.* 
11. Porphyria* 
12. Chronic kidney disease (Stage IV or receiving dialysis) 
13. Known bone marrow disorders with significant neutropenia 
(polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K) 
14. Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen* 
15. Known cirrhosis 
16. Known personal or family history of long QT syndrome 
17. History of coronary artery disease with a history of graft or stent 
18. History of heart failure, Class 2 or greater using the New York Heart Association 
functional class 
19. Taking medications associated with prolonged QT and known risk of torsades de points 
(see Section 7.9.1).  These medications may include some antipsychotic and 
antidepressant medications. 
20. Taking warfarin (Coumadin or Jantoven) 
21. Taking medications contraindicated with the use of LPV/r, including medications 
metabolized by cytochrome P450 3A (CYP3A), which may accumulate in patients 
receiving LPV/r (see Section 7.9.1). These medications may include anticoagulants, 
anticonvulsants, rifampin, antifungals, and immunosuppressants.  
22. HIV infection with detectable plasma HIV ribonucleic acid (RNA) level or receiving 
protease inhibitors as part of combination antiretroviral therapy 
23. Known history of glucose-6-phosphate-dehydrogenase deficiency* 
24. History of myasthenia gravis* 
25. Unwilling to use nonhormonal contraception such as additional barrier method during 
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*Exclusion criteria related to HCQ or azithromycin, will not be included as these arms have 
been discontinued 
Note: Pregnant and lactating persons will be eligible for enrollment into this study. HCQ, 
azithromycin, and LPV/r have been shown to be safe in pregnant women. 
6.3. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) can be 
rescreened if there is a change in their eligibility. 
6.4. 
Recruitment 
Each site will establish local recruitment and screening methods that operationalize 
protocol-specified requirements for eligibility determination in a manner that is tailored to and 
most efficient for the local study setting and target study population. Each site will use a variety 
of recruitment approaches, including direct recruitment at clinics, referrals from other providers 
and SARS-CoV-2 testing sites and laboratories, and use of online and social networking websites 
and apps. Recruitment materials may educate participants about COVID-19, transmission within 
households, and epidemiology in the community. 
If additional participants are required to increase sample size or add additional treatment arms, 
the number will be communicated to approval bodies for authorization. 
6.5. 
Co-enrollment Guidelines 
Participants may be co-enrolled in other research studies, provided that these are observational 
studies only. Any other exception requires approval of the Principal Investigators; if a participant 
clinically worsens, such as requiring hospitalization, it is expected that an exception will be 
automatically granted and participation in treatment studies permitted. The study team should be 
consulted for co-enrollment in studies that do not meet this guidance or if there are questions 
about eligibility for co-enrollment. For any co-enrolled study, combined blood draws should not 
exceed current Red Cross phlebotomy guidance. 

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7. 
Treatments 
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.  
 
 
7.1. 
Treatments Administered 
Study 
Treatme
nt  
Hydroxychlo
ro- 
quine sulfate 
Ascorbic 
acid 
Lopinavir-
ritonavir 
Ascorbic 
acid 
Azithromy
cin 
Folic 
acid 
Ondansetro
n 
Loperamide 
Dosage 
Formulat
ion 
200 mg 
(155 mg 
base) tablets 
250 mg 
tablets 
200 mg-50 
mg tablets 
250 mg 
tablets 
250 mg 
tablets 
400 µg 
tablets 
4 mg tab 
2 mg tab 
Route of 
Administ
ration 
 
Oral 
Dosing 
Instructi
ons 
Take 2 tablets twice on 
Day 1 and 1 tablet twice a 
day for the subsequent 
9 days, for a total of 
10 days of treatment. 
Take at approximately the 
same time of the day with 
a meal or a glass of milk.  
Take 4 tablets every 12 
hours on Day 1, and 2 
tablets twice daily for 
the 9 subsequent days, 
for a total of 10 days of 
treatment. Take at 
approximately the 
same time each day 
with a meal.  
Take 2 tablets once 
on Day 1 and 1 tablet 
once a day for the 
subsequent 4 days, 
for a total of 5 days 
of treatment. Tablets 
can be taken with or 
without food. 
Take 1 
tablet as 
needed for 
nausea 
every 8 
hours.  Do 
not exceed 
8 pills per 
24 hour 
period. 
Take 2 tablets 
as needed for 
diarrhea.  Take 
1 additional pill 
with each 
episode of 
diarrhea.  Do 
not exceed 4 
pills per 24 
hour period. 
If a dose is missed, it should be taken as soon as possible. If it is less than 
4 hours before the next dose, the dose should be skipped. 
 
 
Packagin
g and 
Labeling 
The medication for home delivery will be dispensed in an otherwise-unmarked container with the study label. 
The container will be labeled with a unique identifier. The container will be packed in a standard box used for 
mail delivery of medications as needed. 
Manufac
turer 
Sandoz 
Cardinal 
Health 
Abbvie 
 
Greenston
e LLC 
NDC 
59762-
2198-3 
(blister 
pack) 
 
NDC 
59762-
2198-3 
(bottle) 
Leader 
(distrib
uted by 
Cardina
l 
Health) 
TBD 
TBD 

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7.2. 
Risks to the Participants 
7.2.1. 
Risks Associated Administration with 
HCQ 
With tens of millions of doses of HCQ administrated for malaria and autoimmune diseases, the 
side effect profile of HCQ is well described and the drug is generally well tolerated. With 
short-term administration (as opposed to chronic/year-long use in rheumatologic disease 
management), the major AEs are gastrointestinal (nausea, vomiting, dyspepsia, abdominal 
cramps, and diarrhea) and transient skin rashes. The gastrointestinal symptoms may vary by 
specific generic manufacturer of HCQ (Srinivasa 2017) and are best managed by taking the drug 
with food or a glass of milk (Appendix 5). A transient rash, most commonly morbilliform or 
psoriasiform, can develop in 10% of participants, often with a sustained loading dose, and is 
often managed by lowering the dose. To avoid this potential side effect, this protocol is using a 
short loading dose, not a sustained one. Uncommonly, idiosyncratic 
leukopenia/thrombocytopenia can occur and the drug should not be given to those with 
underlying bone marrow disorders. Lastly, hypoglycemia can occur and those taking insulin or 
glucose-lowering drugs are at risk; blood glucose should be monitored. 
The safety of HCQ for treatment of patients with COVID-19 disease is unknown. COVID-19 
may be associated with cardiac effects. HCQ may prolong QT, resulting in arrhythmias. 
Participants will be monitored for QT prolongation and counseled about this risk. 
Long-term manifestations of HCQ, including retinitis, renal and hepatic disease, and 
cardiomyopathy (Appendix 5), are not likely in short-term exposure. 
7.2.2. 
Risks Associated with Azithromycin 
The most common adverse reactions to azithromycin are diarrhea, nausea, abdominal pain, or 
vomiting (Zithromax USPI, Appendix 6). Severe side effects include serious allergic reactions, 
including, but not limited to, anaphylaxis, angioedema, and dermatologic reactions such as 
Stevens-Johnson syndrome. Abnormal liver function, hepatitis, cholestatic jaundice, hepatic 
necrosis, and hepatic failure have been reported, some of which have resulted in death. 
Azithromycin can cause abnormal changes in the cardiac electrophysiology that may lead to a 
potentially fatal irregular heart rhythm. It may increase the risk of death, especially in those with 
heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. 
The FDA warning indicated that people with pre-existing conditions are at particular risk, such 
as those with QT interval prolongation, proarrhythmic conditions, low blood levels of potassium 
or magnesium, a slower than normal heart rate, or those who use certain drugs to treat abnormal 
heart rhythms. Elderly patients may be more susceptible to development of torsades de pointes 
arrhythmias. 
7.2.3. 
QT Risks Associated with 
Coadministration of HCQ and 
Azithromycin 
Combination treatment with HCQ + azithromycin was associated with heart-rate corrected QT 
interval (QTc) prolongation in a study of 84 patients with SARS-CoV-2 (Chorin 2020). Maximal 
QTc prolongation was observed between Days 3 and 4 of treatment. QTc increase from baseline 

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was >40 ms in 30% of the patients and 11% exhibited severely prolonged QTc, defined as a 
maximum increase to >500 ms. Multivariate analysis showed that the development of acute renal 
failure rather than baseline QTc was a significant predictor of severe QTc prolongation in these 
patients. 
7.2.4. 
Risks Associated with LPV/r 
The safety and tolerability of LPV/r has been well characterized through clinical trials and 
postmarketing experience since first authorization for use in 2001 for the approved HIV 
indication with over 7 million patient years of exposure. The LPV/r prescribing information 
(Appendix 7) describes the known safety profile of LPV/r. Based on clinical trials and 
postmarketing experience, the most frequently reported adverse drug reactions among patients 
receiving LPV/r alone or in combination with other antiretroviral agents 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, hepatotoxicity and 
toxicity in preterm neonates of LPV/r oral solution. In addition, in the HIV population, immune 
reconstitution inflammatory syndrome manifesting as autoimmune disorders (such as Grave's 
disease) has been reported. Important potential risks include PR prolongation at therapeutic 
dosing, and QT prolongation with supratherapeutic doses. LPV/r 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 
coadministered 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 LPV/r 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 LPV/r. LPV/r should be used with caution in such 
patients. In addition, QT prolongation with supratherapeutic doses and when LPV/r is 
coadministered with drugs known to prolong the QT interval has been reported. Because LPV/r 
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 LPV/r may compromise 
the absorption and efficacy (due to decreased compliance) of LPV/r or other concurrent drugs. 
Serious persistent vomiting and/or diarrhea with LPV/r use might also compromise renal 
function. The safety of LPV/r for treatment of patients with COVID-19 disease is unknown. 
COVID-19 may be associated with cardiac effects. LPV/r may prolong QT at supratherapeutic 
doses and prolong PR at therapeutic doses, resulting in arrhythmias.  
7.2.5. 
Risks Associated with COVID-19 
Diagnosis 
Enrollment in this protocol will not impact the public health department’s advice for 
self-quarantine. Enrollment may improve morale during quarantine for COVID-19 infection. 

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COVID-19 infection may be associated with anxiety, and the ability to monitor for disease 
progression and interact with study clinicians may allay anxiety. 
7.3. 
Strategies to Minimize Risk 
7.3.1. 
Dose Selection 
The recommended dose of HCQ for chronic use in lupus erythematosus is 200 to 400 mg daily, a 
dose that is safely taken for years including among elderly patients (≥65 years). The selection of 
the time-limited dosing for this study is likely to be safe with transient adverse events (AEs) 
(gastrointestinal symptoms and rashes) that are self-remitting. 
The recommended dose of azithromycin is 500 mg as a single dose on Day 1, followed by 
250 mg once daily on Days 2 through 5. This dose has been safely used for several years for 
treatment of a wide variety of bacterial infections, including pneumonia. 
The recommended dose of LPV/r is 400 mg-100 mg twice daily, a dose that has been utilized for 
several years for treatment of HIV infection as part of combination antiretroviral therapy. To 
rapidly obtain steady state in this trial, the medication will be dosed at a higher amount (double) 
on the first day of administration.  The loading dose may be associated with GI side effects 
(nausea, vomiting, and diarrhea). 
7.3.2. 
 
Management of Participants to 
Limit Risks of SARS-CoV-2 
Transmission 
To limit the transmission of SARS-CoV-2, participants will receive visits via secure Telehealth 
in order to limit the movement of persons with potential SARS-CoV-2 and leave clinical space 
free for ill patients requiring care. Also, to limit exposure in waiting rooms and pharmacies, 
clinical specimens will be self-collected and medications will be delivered to homes. This will 
also eliminate exposure of study personnel to SARS-CoV-2. 
7.4. 
Dose Modification and Toxicity Management 
If a study therapy dose is missed, it should be taken as soon as possible. If it is less than 4 hours 
before the next dose, the dose should be skipped. 
Modification for toxicities is discussed below. Only toxicities related to study medications 
provided through the study will be considered in the toxicity management section. 
LPV/R is known to cause GI side effects, specifically nausea, vomiting, abdominal pain, and 
diarrhea.  Since participants will have difficulty obtaining medications for symptomatic relief 
due to these symptoms during the  COVID-19 quarantine period, medications to control these 
symptoms will be given to each participant.  Symptomatic medication will be included in 
separate medication vials and will clearly labeled for participants.  Ondansetron 4 mg tabs (#10) 
and loperamide 2 mg tabs (#10) will be provided to each participant.    
Grade 1 or 2 
Participants who develop Grade 1 or 2 toxicity (per Division of Acquired Immunodeficiency 
Syndrome [DAIDS] AE Grading Table; see: https://rsc.tech-res.com/docs/default-

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source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-
adverse-events-corrected-v-2-1.pdf) that is considered by the site Investigator to be related to the 
study medication may continue study treatment at the discretion of the site Investigator with 
close follow up. If a participant chooses to discontinue study treatment, the site should notify the 
study protocol team within 7 days. These participants will remain on study, off study treatment, 
and have all evaluations performed. 
Grade 3 
• Participants who develop a Grade 3 symptomatic toxicity thought by the site Investigator 
to be related to study drug should have study product withheld, and the site should 
consult with the Core Protocol team. The participant should be reevaluated every 2 days 
until the AE returns to Grade ≤2, at which time study drug may be reintroduced at the 
discretion of the site Investigator in consultation with the protocol team. 
• Participants experiencing Grade 3 toxicity requiring permanent discontinuation of study 
product should be followed up weekly until resolution of the toxicity. Participants will 
have premature study treatment discontinuation evaluations performed. These 
participants will remain on study, off study treatment, and have all evaluations performed 
per the SoA. 
Grade 4 
• Participants who develop a Grade 4 symptomatic toxicity will have study product 
permanently discontinued, and the site should notify the Principal Investigator within 
72 hours. 
• Participants experiencing Grade 4 toxicity requiring permanent discontinuation of study 
product should be followed up weekly until resolution of the AE or return to baseline. 
These participants will remain on study, off study treatment, and have all evaluations 
performed per the SoA. 
Specific Management of Toxicities Related to Study-provided Drugs 
HCQ 
Gastrointestinal disturbance 
Gastrointestinal disturbance (nausea, vomiting, dyspepsia, abdominal cramps, and diarrhea) is a 
common known possible side effect of HCQ. Taking with food or milk may improve tolerability. 
Visual disturbances 
Suspected visual changes should be evaluated for possible etiologies—if an HCQ-associated 
visual disturbance is suspected, HCQ should be stopped. 
Allergic reactions 
HCQ should be discontinued permanently if a serious allergic reaction is suspected. These 
participants will remain on study, off study treatment, and have all evaluations performed per the 
standard operating procedure(s). 
QT prolongation 

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HCQ is associated with QT prolongation. QT will be assessed during the study using a portable 
monitor that can transmit electrocardiograms (ECGs) to measure the QTc to a central location, 
which will be monitored. Participants will be counseled about this risk. 
Hypoglycemia 
HCQ can be associated with hypoglycemia, particularly among patients with diabetes mellitus 
who are also taking insulin or sulfonylureas. Participants will be counseled about this risk. 
Azithromycin 
Gastrointestinal disturbance 
Gastrointestinal adverse reactions (nausea, vomiting, abdominal pain, and diarrhea) are common 
side effect of azithromycin. Most gastrointestinal side effects do not require treatment 
discontinuation and participants may receive treatment for symptoms (e.g., antiemetics). 
Allergic reaction 
Serious allergic reactions, including, but not limited to anaphylaxis, angioedema, and 
dermatologic reactions such as Stevens-Johnson syndrome have been reported with azithromycin 
treatment. Azithromycin should be discontinued immediately in the event of a hypersensitivity 
reaction. 
QT prolongation 
Azithromycin is associated with QT prolongation. QT will be assessed during the study using a 
portable monitor that can transmit ECGs to measure the QTc to a central location, which will be 
monitored. Participants will be counseled about this risk. 
LPV/r 
QT prolongation 
LPV/r may be associated with QT prolongation. Participants will be counseled about this risk. 
 
Gastrointestinal disturbance 
Nausea, vomiting, and diarrhea are common known possible side effects of LPV/r. Taking with 
food may improve tolerability.  Participants will be counseled extensively about this risk. 
Ondansetron 4 mg tabs (#10) as needed for nausea and vomiting  and loperamide 2 mg tabs 
(#10) as needed for diarrhea will be provided to each participant.  A small supply will be given 
to participants for at least 2 days of symptom relief.  It is anticipated that if symptoms are not 
controlled with the available medications, that participants may not be able to tolerate study 
medication. Loperamide is a well tolerated medication available over the counter.  Risks include 
constipation, abdominal cramps.  In rare cases, allergic reaction, fatigue/drowsiness, or toxic 
megacolon may occur.   Up to 16 mg can be used per day.  With higher than recommended 
doses, there is risk of QT prolongation.  Participants will be instructed not to take more than 4 
tablets (8 mg) of of loperamide per day.  Those participants who take more than the 
recommended dosage to control diarrhea will have study medication held to reduce the risk of 
QT prolongation. 
 

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Ondansetron may be associated with headache, fatigue, and malaise.  Constipation may also 
occur.  Allergic reaction/hypersensitivity may also occur.  Participants will be instructed not to 
take more than 12 mg per day of ondansetron.  Those participants who take more than the 
recommended dose  to control symptoms will have study medication held to reduce the risk of 
QT prolongation. 
     
7.5. 
Method of Treatment Assignment 
Participants will be randomized in a 1:1 ratio to placebo (ascorbic acid), or LPV/r, at the level of 
the household (all eligible participants in 1 household will receive the same intervention). The 
randomization plan will be overseen by the Study Statistician. The randomization code and 
resulting allocation list will be generated and overseen by the Study Statistician. The list will be 
blocked and stratified by site and risk level. 
7.6. 
Blinding 
7.6.1. 
Patient Blinding 
This is a blinded study. However, the medications are not identical-appearing and dosing is 
different for the active agents so blinding will operate in different ways across those involved in 
the study, preserving blinding for the participants, those who directly interact with them, and 
measurement of the study endpoints: 
• Participants will be blinded. The bottle of medication they receive will not identify the 
treatment allocation and only the number and frequency of pills to be taken. If 
>1 participant per household is randomized, all will receive the same treatment. 
• Treating clinicians will be blinded, as the study medication will be dispensed directly to 
participants. 
• Laboratory testing for viral shedding will be blinded, as laboratory staff will not be 
informed of randomized assignment. It should be noted that the viral shedding endpoint 
of the trial is an objective assessment, unlikely altered by unmasking, should it occur. 
• Study pharmacy staff will be unblinded, as they will prepare the study medication. 
• The study statistician will be unblinded for analysis purposes. 
Eligible participants will receive one of the following therapies: 
• Placebo: Ascorbic acid 1 gm orally twice on Day 1 followed by 500 mg orally twice daily 
for 9 days (Days 2 to 10) 
• LPV/r 800 mg-200 mg orally twice on Day 1, followed by 400 mg-100 mg orally twice 
daily for an additional 9 days (Days 2 to 10)  
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be 
bitter and ascorbic acid will be sour. However, LPV/r will not appear similar to ascorbic acid. 
Azithromycin and folic acid have the same dosing schedule but are different in shape. Because 
participants in 1 household will all receive the same assignment and study clinicians will not see 
the study medication, the blind will be maintained. 

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The participants will be blinded to their randomization group once assigned. At enrollment, the 
unblinded Study Pharmacist will use the randomization code revealed at the point of 
randomization to provide the participant with their group assignment and dispense the allocated 
study medication in a bottle marked with the study label. The medication and medication 
information, mid-nasal swabs sufficient to complete the study procedures, DBS sampling kit, if 
within the sub-study, and study instructions will be delivered to the participant. 
7.7. 
Preparation/Handling/Storage/Accountability 
Drugs should be stored at room temperature, as per package insert. Records must be maintained 
that document receipt, release for dosing, disposal, or return to the Sponsor. 
7.8. 
Treatment Compliance 
The participant will be contacted to ensure that they received the box of study supplies, were 
able to collect the first mid-nasal swab and store it appropriately, and took their first day of 
medication. Participants will be asked to complete a survey that includes information regarding 
treatment administration. Medication errors, including under-dosing, will be recorded in the 
survey. In a sub-study, HCQ, azithromycin, and LPV/r concentrations via a DBS will also be 
evaluated. 
Consultation via Telehealth, text messaging, or telephone will be available to provide support to 
the participant to complete study procedures. 
7.9. 
Concomitant Therapy 
Participants will be asked about concomitant medications at the screening/baseline evaluation 
visit. During the study, participants will be asked to complete surveys (Daily Survey and Exit 
Contact Survey) that include information regarding any medication or vaccine (including 
over-the-counter or prescription medicines, vitamins, and/or herbal supplements) that the 
participant receives during the study. At each contact, the Investigator should question the 
participant about any medication taken.  
7.9.1. 
Prohibited Medications 
Medications listed as “Known Risk of Torsades de Pointe” on the website Credible Meds 
(CredibleMeds.org) will be prohibited with interventions known to prolong the QT interval 
(including HCQ, azithromycin, and LPV/r). These medications include: quinolone antibiotics 
(e.g., ciprofloxacin, levofloxacin, and moxifloxacin); macrolide antibiotics (e.g., erythromycin 
and clarithromycin); methadone; and antiarrhythmic drugs such as Class I (e.g., quinidine, 
procainamide, and disopromide), Class III (e.g., dofelitide, ibutilide, and sotalol), and 
amiodarone. Other prohibited medications include cisapride, cilastozol, cimetidine, fluconazole, 
terfenadine, antipsychotic medications (chlorpromazine, halperidol, and thioridazine), donepezil, 
oxaliplatin, and the antidepressants citalopram and escitalopram. 
Prohibited medications for concomitant administration with HCQ include digoxin, cyclosporin, 
tamoxifen, anticoagulants (e.g., warfarin), some anticonvulsants, and rifampin. Refer to 
Appendix 5 for all medications prohibited for coadministration with HCQ. 

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Prohibited medications for concomitant administration with azithromycin include warfarin. Refer 
to Appendix 6 for all medications prohibited for coadministration with azithromycin. 
Prohibited medications for concomitant administration with LPV/r include drugs that are highly 
dependent on CYP3A for clearance and for which elevated plasma concentrations are associated 
with serious and/or life-threatening reactions (e.g., alfuzosin, ranolazine, and simvastatin) and 
drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma 
concentrations may be associated with the potential for loss of virologic response (e.g., 
apalutamide, rifampin, and St. John’s Wort). Refer to Appendix 7 for all medications prohibited 
for coadministration with LPV/r. 
7.9.2. 
Precautionary Medications 
Use of medications classified as precautionary is not study prohibitory but will be discussed with 
the study clinician and the participant. These medications include androgens, antidiabetic agents, 
phenothiazines, artemether, beta-blockers, cardiac glycosides, aminoquinolines, dapsone, herbs, 
lumefantrine, maitake, mefloquine, monoamine oxidase inhibitors, nelfinavir, pegvisomant, 
prothionamide, and selective serotonin reuptake inhibitors. Careful monitoring is needed during 
concomitant use of azithromycin with colchicine or phenytoin. Medications listed as “Possible 
Risk of Torsades de Pointe” and “Conditional Risk of Torsades de Pointe” on the website 
Credible Meds (CredibleMeds.org) will be permitted as per discretion of study clinicians and 
after discussion with the study participant. 
7.10. Treatment After the End of the Study 
No additional treatment will be provided at the end of the study. 

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8. 
Discontinuation/Withdrawal Criteria 
8.1. 
Discontinuation of Study Treatment 
Study treatment will be discontinued for the following reasons: 
• Hospitalization  
• Requirement for prohibited concomitant medications or other contraindication to study 
product 
• Occurrence of an AE requiring discontinuation of study product, including prolonged QT 
• Request by participant to terminate study treatment 
• Clinical reasons believed to be life-threatening by the physician, even if not addressed in 
Section 7.2 
Participants who stop study product should continue study participation off study product with 
continued evaluations as per the SoA. The reason for study product discontinuation should be 
recorded. 
Hospitalized participants will be followed through hospitalization and the last visit will be within 
3 days of discharge. 
8.2. 
Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time for the following reasons: 
o At the request of the primary care provider if he/she thinks the study is no longer in 
the best interest of the participant 
o Participant is judged by the Investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously interfere with 
the validity of the study results 
o At the discretion of the Institutional Review Board/Ethics Committee or government 
agencies as part of their duties, Investigator, or industry supporter 
• If the participant withdraws consent for disclosure of future information, the Sponsor 
may retain and continue to use any data collected before such withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
• See SoA for data to be collected at the time of study discontinuation and follow-up and 
for any further evaluations that need to be completed. 

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8.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if he/she is unable to be contacted by the study 
site. 
The following actions must be taken if a participant fails to comply with required study 
procedures: 
• The site must attempt to contact the participant as soon as possible and counsel the 
participant on the importance of maintaining the assigned procedure schedule and 
ascertain whether or not the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 

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9. 
Study Encounters 
The current COVID-19 pandemic has placed a significant burden on the healthcare system. For 
this study, specimen and data collection will be conducted to minimize impact of non-ill 
participants within the healthcare system. If the participant is assessed as eligible, contact 
between study participants and study personnel will occur via a Health Insurance Portability and 
Accountability Act (HIPAA)-compliant video conference (Telehealth). Optionally, contact with 
the study clinician or staff after Day 1 may be conducted by telephone. 
Participants will be instructed to seek clinical care should they manifest any signs or symptoms 
of LRTI requiring medical intervention and notify their physician about trial participation. 
9.1. 
Screening/Baseline Evaluation: Day 0/1 
Participants will be assessed for study eligibility through a screening conducted through a 
web-based screening tool, HIPAA-compliant video conference (Telehealth), telephone, or text 
messaging. 
Day 0 evaluations are as follows: 
• Informed consent 
• Collection of demographic information 
• Sign HIPAA form 
• Collection of past and current medical conditions, including known pregnancy and/or 
lactation status 
• Collection of concomitant medication information 
• Collection of information (including laboratory documentation of COVID-19 testing) 
• Check of inclusion and exclusion criteria 
Eligible participants will be randomized. Participants will receive a monitoring kit via courier, 
which will include thermometer and SpO2 device.They will be instructed on how to self-assess 
respiratory rate. In addition, they will receive a swab kit via courier or mail, which includes a 
study instruction booklet, swabs, plastic tubes for swab collection, a return box with affixed 
Category B UN3373 label, as required by International Air Transport Association (IATA) 
guidelines (UN3373 Medical Packaging 2020), and a pre-paid return shipping label.  
The participant will do the following on Day 1: 
• Collect mid-nasal swab for PCR 
• Complete Daily Survey (online, telephone, or text messaging). This survey will include 
confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, AEs, and symptoms review and objective measures 
including SpO2, respiratory rate, temperature, pulse, and ECG*. In addition, the modified 
inFLUenza patient-reported outcome (Flu-PRO) survey will be completed.  
• Take study therapy (LPV/r or placebo [ascorbic acid]), as assigned 
• May collect DBS sample for analysis of HCQ, azithromycin, and LPV/r concentrations. 

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Instructions for skin puncture and DBS sample preparation are provided in Appendix 9. A study 
team member will be available via Telehealth, telephone, or text messaging to provide support 
for completion of this study procedure. 
Screening (Day 0) and Day 1 procedures can occur on the same day. 
The SARS-CoV-2 positive test results will be confirmed through laboratory records or through 
detailed description of testing as described by participant.  
9.2. 
Day 2 Through Day 13 
The participant will do the following every day from Day 2 through Day 13, inclusive: 
• Collect mid-nasal swab for PCR 
• Take study therapy until Day 10 (inclusive) for LPV/r, or ascorbic acid (as assigned) 
• Complete Daily Survey (online, telephone, or text messaging). This Survey will include 
confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, AEs, and symptoms review and objective measures 
including SpO2, respiratory rate, temperature, pulse, and ECG. ECG measurements may 
be recorded on Days 2 through 11 only*. In addition, the modified Flu-PRO survey will 
be completed. 
• If in DBS sub-study, collect DBS samples for analysis of HCQ, azithromycin, or LPV/r 
concentrations at any time during this period (1 to 5 times) after study drug dosing has 
commenced.  
• *EKG monitoring may not be necessary if HCQ/AZ are not used. 
A study team member will be available via Telehealth, text messaging, or telephone to provide 
support for completion of study procedures. The courier will collect the swabs at minimum 
within 1 or 2 days of Day 7 and Day 13 and potentially as frequently as daily. 
9.3. 
Days 2 (±1 day), and Days 4, 9, and 14 (±2 days) 
Contact with study clinician or staff will be conducted via telemedicine (Telehealth) or 
telephone. Participants will be clinically assessed for signs and symptoms of respiratory distress 
and will have in person assessment of AEs. As needed, additional contact with the study 
clinician or staff will be conducted at the request of the participant (e.g., if developing 
concerning symptoms or an adverse event) or if needed to clarify study procedures or follow-up 
symptoms. 
9.4. 
Days 14 and 21 
The participant will do the following on Days 14 and 21: 
• Collect mid-nasal swab for PCR 
• Complete Daily Survey (online, telephone, or text messaging). This survey will include 
confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, AEs, and symptoms review and objective measures 
including SpO2, temperature, and pulse. In addition, the modified Flu-PRO and WHO 
Ordinal Scale for Clinical Improvement surveys will be completed. 

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The courier will collect the swabs of Day 14 and Day 21 with the Day 28 swabs. 
9.5. 
Day 28 
The participant will do the following on Day 28: 
• Collect mid-nasal swab for PCR 
• Complete the Exit Contact Survey (online, telephone, or text messaging). This survey 
will include confirmation of adherence to study therapy dosing and daily swab collection, 
concomitant medication review, AEs, and symptoms review and objective measures 
including SpO2, temperature, and pulse. In addition, the modified Flu-PRO and WHO 
Ordinal Scale for Clinical Improvement surveys will be completed. 
• If in DBS sub-study, collect DBS sample for analysis of HCQ, azithromycin, or LPV/r 
concentrations as well as detection of anti-SARS-CoV-2 antibodies. 
For participants who are hospitalized on Day 28, the Day 28 procedures will be performed within 
3 days after discharge from the hospital. 
A study team member will be available via Telehealth, text messaging, or telephone to provide 
support for completion of study procedures. 
The courier will collect the swabs at minimum within 1 or 2 days of Day 28. 
Clinical outcomes will be confirmed through the electronic health record, if possible. 
Participant Reimbursement 
Participants will be reimbursed on Day 28 or at the post discharge visit. No reimbursement will 
be provided for unscheduled Telehealth visits requested by the participants for support with 
study procedures. 

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10. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA. 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue study 
treatment. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All baseline evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing of the informed consent form may be utilized for screening or baseline 
purposes provided that the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA. 
• Blood samples will only be collected as a part of a sub-study. The maximum amount of blood 
collected from each participant over the duration of the study, including any extra 
assessments that may be required, will not exceed 10 mL. 
10.1. Efficacy Assessments 
10.1.1. 
Mid-nasal Swab 
Participants will collect daily mid-nasal swabs for on Days 1 to 14, 21, and 28 for viral detection. 
Participants will receive a swab kit either via courier or mail, which includes a study instruction 
booklet, swabs, plastic tubes for swab collection, a return box with affixed Category B UN3373 
label, as required by IATA guidelines (UN3373 Medical Packaging 2020), and a pre-paid return 
shipping label. Participants are instructed to place their self-collected nasal swabs directly into 
the plastic tube that is pre-labeled with a unique barcode. Next, participants are instructed to 
place the plastic tube containing the self-collected nasal swab into a specimen bag, pre-packaged 
with an absorbent sheet, and then place the specimen bag into the provided return shipping box 
or pouch. Swab kits may contain either viral transport media, 0.9% saline, or phosphate-buffered 
saline, which have been shown to be equivalent for storage of SARS-CoV-2 samples based on 
validated assays (Rodino 2020). Previous testing has demonstrated that respiratory viral RNA is 
stable in room temperature for up to 1 week. 
The used swabs will be collected by the courier or returned via the postal service or shipping 
service, such as FedEx. 
Swabs will be subjected to RNA amplification and tested for SARS-CoV-2. 
10.1.2. 
Participant Survey 
Participants will be asked to complete surveys (Daily Surveys and Exit Contact Survey) that will 
include questions about symptoms from both the drug regimen and respiratory and systemic 

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symptom, review of concomitant medications, and other pertinent topics. A modified self-
reported Flu-Pro instrument will be completed each day through Day 14 and on Day 21 and 
Day 28 to assess degree of illness (Yu 2020) (Appendix 12). 
10.2. Adverse Events 
Participants will be asked to complete surveys (Daily Surveys and Exit Contact Survey) that 
include information on any symptoms that they are experiencing. In addition, AE review by a 
staff member (via telephone, Telehealth, or text messaging) will be performed. 
All AEs must be recorded on the electronic case report forms (eCRFs) if any of the following 
criteria have been met: 
• All AEs meeting SAE definition 
• All AEs leading to discontinuation of study medication 
• All AEs judged by the site Investigator to be associated with study medication 
10.2.1. 
Adverse Events 
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
subject administered a pharmaceutical product, which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of an investigational product, whether or not considered related to the product. 
AEs may include the onset of new illness and the exacerbation of pre-existing medical 
conditions. An AE can include an undesirable medical condition occurring at any time, including 
baseline or washout periods, even if no study treatment has been administered. 
10.2.2. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the participant or may require 
intervention to prevent one of the other outcomes listed in the definition above 
All AEs that are recorded must have their severity graded. To grade AEs, sites should refer to the 
DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found on the DAIDS 
Regulatory Support Center website at https://rsc.tech-res.com/docs/default-
source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-and-pediatric-
adverse-events-corrected-v-2-1.pdf. 

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10.2.3. 
Treatment-related AE and SAE 
A treatment-related adverse event is defined as any new AE that begins, or any preexisting 
condition that worsens in severity, after at least 1 dose of study treatment has been administered 
until the end of study  (i.e,. Day 28) and is considered by the Investigator to be related to the 
study medication. 
All AEs and SAEs should have attribution recorded as treatment- or not treatment-related, in the 
judgment of the site Investigator. 
10.3. Treatment of Overdose 
Overdose of HCQ, azithromycin, or LPV/r should be managed according to the labeling 
information (see Appendix 5, Appendix 6, and Appendix 7, respectively). Study drug overdose, 
including misuse or abuse of the product and medication errors, should be reported in the eCRF 
in the clinician notes. 
Ascorbic acid and folic acid exhibit low toxicity; risks from overdose are expected to be 
minimal. 
10.4. Pregnancy 
Pregnancies occurring in participants enrolled in this study must be reported and followed to 
outcome. Pregnancy alone is not regarded as an AE unless there is a possibility that the study 
drug may have interfered with the effectiveness of a contraceptive medication. Elective abortions 
without complications should not be considered AEs unless they were therapeutic abortions. 
Hospitalization for normal delivery of a healthy newborn should not be considered an SAE. 
Pregnancy is not considered an SAE unless there is an associated serious outcome. Spontaneous 
abortions should always be reported as SAEs. 
10.5. Safety Assessments 
Safety will be assessed via participant Surveys, as shown in the SoA. 
Participants will be asked to complete surveys (Daily Surveys and Exit Contact Survey) that 
include questions about their health, healthcare seeking, symptoms, illness within their 
household, contact, and mobility. Qualifying events will be recorded on the eCRF and reported 
as AEs, as described in Section 10.2. 
10.6. Dried Blood Spot Sub-study (Optional) 
All participants will be offered enrollment into the DBS sub-study.  For those study sites not 
wishing to participate in the DBS sub-study, this will not be considered a protocol deviation. 
Participants will receive instructions for DBS self-collection in writing, with telephone, 
Telehealth, and text messaging options as support. Once cards have been dried, they will be 
collected by the study courier and returned to the laboratory. 
The aim of the DBS sub-study is to evaluate HCQ, azithromycin, and LPV/r drug concentrations 
as an adherence measure and the PK of HCQ, azithromycin, and LPV/r. If serological assays for 
SARS-CoV-2 are available, DBS may be tested for SARS-CoV-2 antibodies. 

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Pharmacokinetics 
The exposure-response relationship of HCQ, azithromycin, or LPV/r of patients treated for 
SARS-CoV-2 has not been established. Population PK analyses can be used to further inform 
dose selection in other populations and support concentration-response investigations with 
efficacy and safety outcomes. 
To accomplish this, sparse PK sampling techniques can be employed. This would involve 
collection of whole blood at 1 to 5 times after dosing has commenced. The time of collection 
post-dose can be random. 
Given the long half-lives of HCQ and azithromycin, samples for several weeks after the last dose 
are also informative to the population PK model development. 
The basic requirements for PK sampling are as follows: 
1. Accurate record of time of the dose prior to the blood sampling (dd:mm:yy; hh:mm) 
2. Accurate recording of time of blood sampling (dd:mm:yy; hh:mm) for each blood 
sampling 
3. Whole blood can be obtained by venipuncture or capillary blood by skin puncture using a 
lancet 
4. Approximately 100 µL of blood is then applied to filter paper as outlined in Appendix 9 
Anti-SARS-CoV-2 Antibody Testing 
DBS sample for serology will be collected at Day 28 and tested for SARS-CoV-2 antibodies 
provided that an appropriate test is available. 
10.7. Biohazard Containment 
As the transmission of SARS-CoV-2 and other respiratory droplet pathogens can occur through 
contact with respiratory droplets and contaminated surfaces, precautions will be employed by all 
personnel in the handling of all specimens for this study, as currently recommended by the 
Centers for Disease Control and Prevention and the National Institutes of Health. 
All dangerous goods and materials, including diagnostic specimens and infectious substances, 
must be transported using packaging mandated by Code of Federal Regulations 42 Part 72. 
Please refer to instructions detailed in the IATA Dangerous Goods Regulations. 
11. 
Statistical Considerations 
11.1. Sample Size Determination 
The overall size of the study is driven by the clinical endpoint, resolution of COVID-19 
symptoms. 
11.1.1. 
COVID-19 Endpoints 
Overall sample size will depend on the number of events observed. To detect at least a 1.5-fold 
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and four interim monitoring analyses with stopping for futility and efficacy based on the 
O’Brien-Fleming bounds and 80% power, the trial is designed to achieve 99 events per pairwise 
comparison for the symptom resolution endpoints.  To achieve this, 173 participants will be 
enrolled per arm. 
As the initial sample size target, 210 per arm was chosen for each experimental group (HCQ, 
HCQ + azithromycin), assuming a control arm rate of approximately 30% and 5% dropout rate.   
HR 
(active/control) 
Events/arm 
N per arm 
Median 
control arm 
(days) 
Median 
active arm 
(days)* 
1.4 
142 
247 
10 
7 
1.5 
99 
173 
10 
7 
1.6 
75 
129 
10 
6 
1.7 
59 
103 
10 
6 
1.8 
49 
85 
10 
6 
1.9 
41 
71 
10 
5 
2,0 
36 
63 
10 
5 
*Under constant baseline hazard assumption 
11.1.2. 
Viral Shedding Endpoint 
Assuming the median time to cessation of viral shedding is 10 days and a constant baseline 
hazard for cessation of shedding, approximately 62% of participants would no longer experience 
viral shedding at 14 days under the null hypothesis of no intervention effect. Assuming 420 
participants per pairwise comparison, 90% statistical power, 1-sided type I error rate of 2.5% for 
efficacy, we can detect at least a 37% increase in the rate of cessation of viral shedding. Under an 
extreme example of having only half that sample, 210, we could detect an increase of 54% or 
higher.  
 
11.2. Populations for Analyses 
For analysis purposes, the following populations are defined and will be described in greater 
detail in the trial Statistical Analysis Plan: 

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Population 
Description 
Intention to Treat (ITT) 
All enrolled participants 
Modified ITT 
All enrolled participants who do not have LRTI at Baseline: 
high-risk group for the primary clinical endpoint; high- and low-
risk groups (separately) for the primary virologic endpoint. 
PK evaluable 
Participants from the DBS sub-study with at least 1 interpretable 
PK sample. 
DBS: dried blood spot; PK: pharmacokinetic; PCR: polymerase chain reaction; SARS-CoV-2: severe acute 
respiratory syndrome coronavirus 2. 
11.3. Statistical Analyses 
The Statistical Analysis Plan will be developed and finalized before database lock and will 
describe the participant populations to be included in the analyses, the detailed analytical plans 
with endpoints and procedures for accounting for missing, unused, and spurious data. An Interim 
Monitoring Plan will also be developed to describe approaches for re-estimation of sample size 
and any planned interim analyses. This section presents a brief summary of the planned 
statistical analyses of the primary and secondary endpoints (these are listed in Section 4). 
11.3.1. 
Efficacy Analyses 
Demographic characteristics (age, sex, race) of each study group will be tabulated. 
The mean age (plus range and standard deviation) by sex of the enrolled participants, as a whole 
and per group, will be calculated. 
Primary analyses: The primary analyses will be conducted on the intend-to-treat population 
overall and by cohort (high-risk and low-risk). Participants randomized to each active treatment 
will be compared to participants randomized to placebo (ascorbic acid). If appropriate, the 
primary analysis will make use of all participants randomized to placebo, whether 
contemporaneously enrolled or not, using an Empirical Bayesian information borrowing method 
(described below). Due to anticipated heterogeneity in risk of disease progression, pre-specified 
baseline variables, including age, BMI, and days of symptoms at time of enrollment will be 
included in the model to increase precision. 
Both primary endpoints will be analyzed using a Cox proportional hazards model with robust 
standard errors, adjusted for within household correlation. 
As-treated analysis: The primary analyses will be repeated, replacing randomization arm by 
actual treatment to account for possible off-label use of and noncompliance to the investigational 
products. 
Subgroup analyses: All subgroup analyses will be pre-specified in the Statistical Analysis Plan. 
Any further subgroup analyses will be considered ad hoc. 
Missing Data 

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Due to the design of the study and retention activities, measurable outcomes are expected for all 
participants. However, in the unlikely event of a missing test result, the missing data will be 
imputed. 
11.3.2. 
Secondary Endpoints 
All secondary endpoints will be assessed in the Intention-to-Treat population overall and by 
cohort. 
11.3.2.1. Safety Analyses 
All safety analyses will be performed on the Intention-to-Treat population. AEs will be 
compared by study group. 
11.3.2.2. Disease Severity 
Disease severity, as measured by the WHO Ordinal Scale for Clinical Improvement 
(Appendix 11), will be compared between the groups using a proportional odds model. 
Disease severity over the first 14 days and at Days 21 and 28 will also be measured by the 
modified Flu-PRO survey (Appendix 12). Results will be analyzed as for the WHO Ordinal 
Scale for Clinical Improvement. 
Progression and regression of disease severity will be modeled using multistate models. 
11.3.3. 
Pharmacokinetic Analysis 
Sparse PK from DBS will be analyzed using standard population PK analysis methodologies 
using standard software such as NONMEM® version 7.4 or Phoenix NLME version 8.2. 
11.3.4. 
Exploratory Exposure-Response 
Analyses 
PK-evaluable participants will have post-hoc individual concentration profiles and exposure 
estimates determined for exploratory exposure-response analyses against primary and secondary 
efficacy and safety endpoints. Exploratory PK/pharmacodynamic analyses will be performed as 
the data allow. 
11.3.5. 
Combined Study Analysis 
This protocol is being published as a model protocol for other institutions to consider as they 
undertake studying treatments to prevent progression of COVID-19 among outpatients with 
SARS-CoV-2 infection. It is hoped that individual participant data from similar studies can be 
pooled into a combined study analysis. De-identified data from the present study will be made 
available for these purposes in accordance with the funder’s open access policy 
(https://www.gatesfoundation.org/how-we-work/general-information/open-access-policy). 
 

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Tett SE, Cutler DJ, Day RO, Brown KF. Bioavailability of hydroxychloroquine tablets in healthy 
volunteers. Br J Clin Pharmacol. 1989;27(6): 771-779. 
Touret F, Gilles M, Barral K, NougairédeA, Decroly E, de Lamballerie X, Coutard B. In vitro 
screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 
replication. 2020 bioRxiv preprint doi:https://doi.org/10.1101/2020.04.03.023846. 
UN3373 Medical Packaging. Biological Substance Category B. Available at: 
https://www.un3373.com/category-biological-substances/category-b. Updated 2018 Jun. 
Accessed 2020 Mar 01. 
Vincent MJ, Bergferon E, Benjannet S, et al. Chloroquine is a potent inhibitor of SARS 
coronavirus infection and spread. Virol J. 2005 Aug;2:69-78. 
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 Mar;30(3):269-271.  
White House Press Release. https://www.whitehouse.gov/presidential-actions/proclamation-
declaring-national-emergency-concerning-novel-coronavirus-disease-covid-19-outbreak. 
2020 Mar 13. 
WHO News Release. Shortage of personal protective equipment endangering health workers 
worldwide. 2020 Mar 03. 
WHO News Release. Statement on the second meeting of the International Health Regulations 
(2005) Emergency Committee regarding the outbreak of novel coronavirus (2019-nCoV). 2020 
Jan 30. 
Wrapp D, Wand N, Corbett KS, et al. Cryo-EM structure of the 2019-nCoV spike in the 
prefusion conformation. Science. 2020 Mar 13;367(6483):1260-1263. 
Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing design 
of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2). Clin Inf Dis. 2020 Mar. pii: ciaa237. 
Yu J, Powers JH, Vallo D, et al. Evaluation of efficacy endpoints for a Phase IIb study of a 
respiratory syncytial virus vaccine in older adults using patient-reported outcomes with 
laboratory confirmation. Value Health. 2020 Feb;23(2):227-235. 
Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China, 
2019. N Engl J Med. 2020 Feb;382(8):727-733. 
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 10012-10017. 

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WHO. Report of the WHO-China joint mission on coronavirus disease 2019 (COVID-19). 
2020 Feb 16-24. 

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13. 
Appendices 
Appendix 1: Abbreviations and Terms 
Term 
Definition 
ACE2 
Angiotensin converting enzyme 2 
AE 
Adverse event 
CER 
Control event rate 
COVID-19 
Coronavirus disease 
CQ 
Chloroquine 
CYP 
Cytochrome P450 
CYP3A 
Cytochrome P450 3A 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DBS 
Dried blood spot 
DSMB 
Data and safety monitoring board 
EC50 
Half-maximal effective concentration 
ECG 
Electrocardiogram 
eCRFs 
Electronic case report forms 
Eligible 
Qualified for enrollment into the study based upon adherence to 
inclusion/exclusion criteria 
FDA 
Food and Drug Administration 
Flu-PRO 
InFLUenza patient-reported outcome 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCQ 
Hydroxychloroquine 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
IATA 
International Air Transport Association 
ICF 
Informed consent form 
Index case 
Term used throughout the protocol to denote the person with confirmed or 
suspected SARS-CoV-2 infection to whom the study participant was exposed 
IRB 
Institutional Review Board 
LPV/r 
Lopinavir-ritonavir 
LRTI 
Lower respiratory tract infection 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
Participant(s) 
Term used throughout the protocol to denote the enrolled individual(s) 
PBPK 
Physiologically based pharmacokinetics 
PCR 
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PEP 
Post-exposure prophylaxis 
PK 
Pharmacokinetic(s) 
QTc 
Heart-rate corrected QT interval 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SARS-CoV 
Severe acute respiratory syndrome coronavirus 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SoA 
Schedule of Activities 
SpO2 
Oxygen saturation 
USPI 
United States prescribing information 
WHO 
World Health Organization 
WIRB 
Western Institutional Review Board 
 

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Appendix 2: Protocol Structure 
The protocol for this trial will be structured to be modular. Given the perpetual nature of this 
trial, there may be modifications and/or additions to the main protocol. Each modification and/or 
addition to the main protocol will be subject to the data and safety monitoring board who will 
receive recommendation from other study committees (see Appendix 3). 
The main protocol will contain all the background and rationale for this trial and all generic 
information to the trial, the research approach, the trial design and conduct, and the overall trial 
governance, and ethical considerations. Other appendices for study governance, site-specific 
protocol addendum template, hydroxychloroquine (HCQ) label, azithromycin label, lopinavir-
ritonavir label, pharmacokinetic modelling, and pharmacokinetic sample collection and analysis 
are provided below. The Intervention-Specific Appendices (e.g., HCQ label appendix) will 
contain the information about the interventions. There will be a specific appendix for each of the 
intervention arm with features of the given intervention strategy and how it will be delivered, and 
any additional endpoints and data collection that are not covered in the Main Protocol. 
 

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Appendix 3: Study Governance Considerations 
Investigators and Institutional Affiliations 
The following Investigators and Institutional Affiliations were established at the time of protocol 
authoring. Designees may be provided, as appropriate. Other institutions may utilize this model 
protocol with permission from the Principal Investigator. 
Name 
Role  
Institution 
Contact Information 
Dr. Christine 
Johnston, MD, 
MPH 
Principal 
Investigator 
University of 
Washington 
Phone: +1 206 520 4318 
Email: cjohnsto@uw.edu 
University of Washington Coordinating Center 
Dr. Elizabeth R. 
Brown, ScD 
Study 
Statistician 
Fred 
Hutchinson 
Cancer 
Research Center 
Phone: +1 206 667-1731 
Email: erbrown@fredhutch.org  
Dr. Jared Baeten, 
MD, PhD 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 520-3808 
Email: jbaeten@uw.edu 
Dr. Connie Celum, 
MD, MPH 
Co-
Investigator 
University of 
Washington 
Phone: +1 206 520-3800 
Email: ccelum@uw.edu 
Dr. Ruanne 
Barnabas, MD, PhD 
Co-
investigator 
University of 
Washington 
Phone: +1 206 520 3813 
Email: rbarnaba@uw.edu 
Dr. Joshua Schiffer, 
MD 
Co-
investigator 
Fred 
Hutchinson 
Cancer 
Research Center 
Phone: +1 206 667 7359 
Email: jschiffe@fredhutch.org 
Committees Structure 
The Trial Steering Committee will take the overall responsibility for the trial design and conduct. 
All committees will act in accordance to the International Clinical Harmonization Guidelines for 
Good Clinical Practice (GCP) Principles. 
Study Team Monitoring 
The study team will monitor the conduct of the study through monthly summary reports of arms 
of accrual and baseline characteristics and quarterly reports of data pooled over treatment arms 
of data completeness, specimen collection, and adverse events (AEs). The study team will review 
individual participant-level safety data frequently to assess the relation of all reported AEs to 
study treatment. On a weekly basis, the study team will review by-arm summaries of premature 
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Independent Monitor 
Study conduct will be monitored by an independent monitor. Monitors will visit participating 
clinical research sites, or schedule equivalent virtual visits, to review the individual participant 
records, including consent forms, electronic case report forms, supporting data, laboratory 
specimen records, and endpoints through laboratory and medical records (physicians’ progress 
notes, nurses’ notes, individuals’ hospital charts), to ensure protection of study participants, 
compliance with the protocol, and accuracy and completeness of records. The monitors also will 
inspect the sites’ regulatory files to ensure that regulatory requirements are being followed and 
the sites’ pharmacies to review product storage and management. 
Data and Safety Monitoring Board 
An independent data and safety monitoring board (DSMB) will be convened for this study with 
expertise in coronavirus disease (COVID-19) or respiratory viruses, antiviral therapies and 
shedding, and emerging epidemics and a biostatistician. The purpose of the DSMB is to monitor 
the study for operational futility, social harms, and efficacy. The DSMB will evaluate the 
progress of the project, including periodic assessments of accrual, retention, safety, performance 
and variation of the project sites, and other factors that can affect project implementation. 
The DSMB will review and approve modifications to the overall enrollment target based on the 
event rate. Due to the anticipated rapid speed of enrollment and the short duration of the study, it 
is unlikely that pre-specified stopping rules for efficacy and futility in terms of the efficacy of 
hydroxychloroquine (HCQ), HCQ + azithromycin, or lopinavir-ritonavir will be reached before 
all participants are enrolled. The DSMB will review severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) endpoints. 
The DSMB will conduct interim reviews (if specified) when adequate data have been accrued 
and convene by teleconference. Open reports containing accrual and retention rates, participant 
characteristics, and serious adverse events will be sent to the protocol team and DSMB members 
the week prior to the DSMB meeting. Only the DSMB members and the unblinded 
biostatistician will receive password-protected closed reports of SARS-CoV-2 endpoints by 
randomization arm. 
Regulatory and Ethical Considerations 
The study will be conducted according to GCP, the Belmont Report, and the Declaration of 
Helsinki. The study protocol, site-specific informed consent forms (ICFs), participant education 
and recruitment materials, and other requested documents—including any subsequent 
modifications—will be reviewed and approved by Western Institutional Review Board (WIRB), 
as the single IRB of record, responsible for oversight of research conducted at the study sites. 
Subsequent to initial review and approval, the WIRB will review the study at least annually. 
Informed Consent Process 
The principles of informed consent in the current edition of the Declaration of Helsinki will be 
implemented in each clinical study before any protocol-specified procedures or interventions are 
carried out. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form will be given to 
the participant, and this fact will be documented in the participant’s record. 

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A participant who is rescreened is not required to sign another ICF; eligibility for the study must 
be re-checked prior to enrollment. 
Study Records 
Each study site will establish a standard operating procedure for confidentiality protection. Each 
site will ensure that study records including administrative documentation and regulatory 
documentation as well as documentation related to each participant enrolled in the study, 
including ICFs, locator forms, case report forms, notations of all contacts with the participant, 
and all other source documents are stored in a secure manner. 
Confidentiality 
Participants’ study information will not be released without their written permission, except as 
necessary for oversight by: 
- 
The protocol Principal Investigators or designees 
- 
Study funders 
- 
WIRB 
- 
University of Washington IRB 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will be 
identified by coded number only to maintain participant confidentiality. The exceptions are 
SARS-CoV-2 testing results, which are subject to local and state reporting which is name-based. 
Local public health may contact participants diagnosed with SARS-CoV-2 for the purpose of 
surveillance and contact notification. Participants will be informed prior to SARS-CoV-2 testing 
that results are reportable and may lead to contact by local public health if results are positive for 
infection. 
All records will be kept locked. After initial acquisition of data, all computer entry and 
networking programs will be done with coded numbers only. Clinical information will not be 
released without written permission of the participant, except as necessary for monitoring by the 
IRB, Office for Human Research Protections, other local, United States, and international 
regulatory entities as part of their duties or the industry supporters or designees. 
 

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Appendix 4: Site-Specific Protocol Addendum Template 
PURPOSE: The use of this site-specific protocol addendum is recommended with a multi-site 
study. 
The purpose of this site-specific protocol addendum is to obtain information describing the local 
site-specific elements for conduct of the Core Protocol. The descriptions should focus on who, 
what, and where of the local study activities. 
INSTRUCTIONS: 
1. Add the Name of the study site to the Title of the Protocol in the header of the document. 
2. Please complete each section below. If general description language already appears in 
the Core Protocol, which adequately describes the local activity at the study site, a 
notation can be inserted in the given section that reads, “As described in the Core 
Protocol.” 
3. Please identify the completed addendum document using a version number and date. 
4. Please note: the site-specific protocol addendum will require review and approval by the 
local Institutional Review Board (IRB)/Ethics Committee (EC) of record for the study 
site. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Site Information: 
Name of Institution/Company: 
Address: 
 
Study Site Information for the Site Investigator: 
Name of Site Investigator: 
Title: 
Institution/Affiliation: 
Address: 
Telephone Number: 
Cell/Other Number: 
Fax Number: 
 
Study Site Number: 
 
Assurance Information: 
United States Department of Health and Human Services Office for Human Research Protections 
Assurance Federal Wide Assurance number: 

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Expiration Date: 
 
IRB/Ethics Committee Information: 
Name of Human Subjects Protection oversight office for study site: 
Name and number of reviewing IRB/EC: 
Telephone Number at Office: 
Fax Number at Office: 
If Available, Point of Contact at IRB/EC: 
Name:  
Telephone Number: 
 
Local Site-specific Information: 
1. Identify key study personnel (include name, title, address, point of contact information). 
2. Describe the key study personnel roles and responsibilities. 
3. Describe the local recruiting procedures and strategies. Provide copy of any site-specific 
recruitment material. Identification of personnel responsible for completing tasks. 
4. Describe the local consenting process. Provide a copy of the site-specific consent form(s). 
If an Ombudsman is named for the study site, provide name, title, and point of contact 
information. 
5. Identify local study collaborations at the site such as pharmacy, laboratories, and other 
institutional departments. 
6. Describe the local specimen/sampling procedures in place. Include acquisition, 
disposition, storage, and unique coding. If samples will be kept for future use, describe 
procedures and the security measures for short-term and long-term management. Provide 
name of repository. 
7. Describe the plan for on-site management of study records and data, and participant study 
records. Explain procedures and security measures in place for short- and long-term 
management. Declare who will have access to data. 
8. Describe the local measures in place to promote privacy and confidentiality. 
9. Describe the local procedures in place for provision of care for the participant regarding 
research-related injuries. 
10. Identify who the participant can contact locally should the participant have any questions 
regarding the research. Identify who the participant can contact should the participant 
have questions regarding their rights as a study participant. Include the points of contact 
information (name, title, and telephone number). 
11. Describe the procedures in place to address Health Insurance Portability and 
Accountability Act requirements. If a separate authorization form will be used at the 

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study site, provide a copy or ensure appropriate language has been included in the 
consent document(s). 
12. Describe any unique site-specific study procedures or supplemental activities. 
13. Declare any unique study population/cultural influences, socioeconomic conditions, etc. 
14. Declare any other site-specific reporting obligations and procedures. Name any additional 
oversight boards or committees. 
15. Define abbreviations that may apply to the specific study site. 
 
 
 

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Appendix 5: Hydroxychloroquine Label 
Generic hydroxychloroquine label (current as of June 2018) is available online at 
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b82bbda6-64f2-4426-b4ec-
254eeea895ae and provided below. 
 

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Appendix 6: Azithromycin Label 
The Azithromycin label is available online at 
http://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=511 and provided below. 
 

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Appendix 7: Lopinavir-ritonavir Label 
Kaletra (Lopinavir-ritonavir), US Prescribing Information, AbbVie, December 2019 is available 
online at https://rsc.niaid.nih.gov/sites/default/files/Lopinavir-
Ritonanir%20%28Kaletrata%29%20PI%20dated%20December%202019.pdf and provided 
below. 
 

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Appendix 8: Physiologically Based Pharmacokinetic Model for Azithromycin 
Dose Regimen 
A physiologically based pharmacokinetic (PBPK) model for azithromycin was developed 
previously and verified against clinical data (Johnson et al., 2016). With the exception of the B:P 
ratio, which was set at 2.28, the input parameters for the azithromycin model remained the same. 
This updated model was then used to predict exposures in plasma and lung after administration 
of 500 mg for 1 day and 250 mg QD for 4 days, a dosage regimen that was used by Gautret et al. 
(2020) to prevent bacterial super-infection in patients receiving hydroxyl-chloroquine as 
treatment for SARS-CoV-2. Based on physicochemical data, the predicted lung to tissue ratio 
(Kp) was 16.33, which was lower than the observed ratio of 50.5 (Lucchi et al., 2008). Both 
predicted and observed ratios were used in simulations (100 subjects aged 20 – 50 years; 50% 
female) of plasma and lung concentration-time profiles which were then compared against 
in vitro values of 2.12 (EC50) and 8.65 µM (EC90) reported for inhibition of SARS-CoV-2 by 
azithromycin (Touret et al., 2020) (Figure 1). It should be noted that the unbound fraction in 
plasma (fu) was set at 0.69 and the predicted fu in lung tissue was 0.82. Thus, unbound and total 
concentrations were similar in both plasma and lung. 
 
Figure 1. Predicted concentration-time profiles for azithromycin in the lung based on Kp values 
of 16.33 and 50 in the lung. 
Based on the simulations shown, it appears that the dosing regimen of 500 mg for 1 day followed 
by 250 mg QD for 4 days, is able to attain concentrations of azithromycin in lung that would 
approach the in vitro EC50 value determined for azithromycin.   
 

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Gautret et al. (2020) Hydroxychloroquine and azithromycin as a treatment of COVID-19: results 
of an open-label non-randomised clinical trial. International Journal of Antimicrobial Agents – In 
Press 17 March 2020: – DOI : 10.1016/j.ijantimicag.2020.10594. 
Johnson TN, Jamei M and Rowland-Yeo K (2016). How does in vivo biliary elimination of drugs 
change with age? Evidence from in vitro and clinical data using a systems pharmacology approach. 
Drug Metab Dispos; 44:1090-1098. 
Lucchi M, Damle B, Fang A et al., (2008). Pharmacokinetics of azithromycin in serum, bronchial 
washings, alveolar macrophages and lung tissue following a single oral dose of extended or 
immediate release formulations of azithromycin. Journal of Antimicrobial Chemotherapy; 61: 
884–891. 
Touret F, Gilles M, Barral K, NougairédeA, Decroly E, de Lamballerie X, Coutard B. In vitro 
screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 
replication. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.03.023846. 
 

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Appendix 9: Pharmacokinetic Sample Collection and Analysis 
Collection of Blood 
Skin puncture 
1. Put on a pair of disposable gloves. 
2. Before skin puncture, the participant should warm his/her hands. The finger is massaged 
anterogradely to enrich the blood flow toward the puncture site. 
3. Clean the skin of the palmar side of the tip of the distal phalanx of the third or fourth 
finger of the nonwriting hand with a suitable disinfectant, for example, 70% isopropyl 
alcohol. Puncture the skin by a single-use safety lancet. The finger should be held in such 
a position that the gravity facilitates the collection of blood from the fingertip. 
4. When collection of capillary blood by skin puncture is complete, place a bandage on the 
fingertip. 
Venipuncture 
To be conducted by trained personnel per standard procedures. 
Preparation of Blood Spots 
Preparation from blood collected by skin puncture 
1. Wipe off the first drop of blood with a gauze pad because it may contain excess tissue 
fluids. Massage the finger again to increase blood flow at the puncture site. Transfer the 
following drop to one of the circles of a filter card without touching the surface directly 
with the fingertip. Allow the blood to be soaked into the texture of the filter by capillary 
forces only. 
2. Let the next large drop of capillary blood form on the fingertip and collect it in the next 
circle. Continue this procedure until all necessary circles are filled or blood flow stops. 
3. Do not squeeze or “milk” the finger excessively if the blood flow is not sufficient to fill 
all the required circles of the filter card. If blood flow stops, place a bandage on the 
fingertip. Perform a second skin puncture on another finger if more blood is needed for 
the examination. 
4. For blood obtained by venipuncture, use syringe to apply approximately 100 µL of blood 
on the filter paper. 
Drying of Blood Spots 
To dry the blood spots, put the filter cards on a clean paper towel and let them dry, preferably 
overnight (but for at least 4 hours), at room temperature in the absence of any external source of 
heat. When the drying process is complete, the blood spots have a uniformly dark brownish color 
and no red areas are visible anymore. 

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Storage and Transportation of Dried Blood Spots 
NOTE: Processing of the blood spots can be interrupted after drying. The filter cards can now be 
stored. 
1. For storage, put the filter paper card in a single, gas-impermeable zipper bag, containing 
1 to 2 desiccant sachets to protect the specimens from moisture. Optionally, add a 
humidity indicator card. 
2. Transfer this bag to a freezer as soon as possible. If freezers are not available under field 
conditions, storage at -4°C or even at ambient temperature is feasible for up to 14 days. 
3. Transport frozen dried blood spots specimens on dry ice. For filter cards initially kept at 
ambient temperature, use a triple packaging system, which consists of the zipper bag(s) 
as the inner container(s) as well as an inner and an outer envelope. No content markings 
are required on the outer envelope for shipment by regular mail, but the international 
biohazard symbol must be affixed to the primary inner container. 
4. Exclude the filter cards from further processing if the desiccant packs and/or the 
additional humidity indicator card changes to a pink color. 
On the filter paper, the participant should record the following: 
1. Date of collection 
Samples that appear to be collected according to the schedule of activities, which have the 
required amount of blood for a 5- to 6-mm punch and have the minimal required information 
(1 through 3 above), will be processed for hydroxychloroquine (and metabolite) and 
azithromycin concentration. 

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Appendix 10: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis 
 

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Appendix 11: WHO Ordinal Scale for Clinical Improvement 
WHO COVID-19 Core Protocol 
SOLIDARITY Trial 
Version 10.0, March 22, 2020 
 
 

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Appendix 12: The inFLUenza Patient-Reported Outcome instrument 
(Flu-PRO) – Modified for SARS-CoV-2 
 
DAILY SURVEY (D1-14, D21, D28) 
inFLUenza patient-reported outcome (Flu-PRO): 32 items validated, can score across domains. 
 
***FYI: This takes about 5 minutes to complete 
 
How are you feeling today? 
FLU-PRO 
 
Not at all 
A little bit 
Somewhat 
Quite a bit  
Very much 
Nose 
  Runny or dripping 
  Congestion or stuffy 
  Sneezing 
  Sinus pressure 
  Lack of smell 
Throat 
  Sore throat 
  Scratchy or itchy throat 
  Difficulty swallowing 
  Lack of taste 
Eyes 
  Teary or watery eyes 
  Sore or painful eyes 
  Eyes sensitive to light 
Chest/Respiratory 
  Trouble breathing 
  Chest congestion 
  Chest tightness 
  Dry or hacking cough 
  Wet or loose cough 

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  Sputum (coughing up sputum or phlegm) 
  Wheezing 
Gastrointestinal 
  Felt nauseous 
  Stomach ache 
  Vomit 
  Diarrhea 
Body/Systemic 
  Felt Dizzy 
  Head congestion 
  Headache 
  Lack of appetite 
  Sleeping more than usual 
  Body aches or pains 
  Weak or tired 
  Chills of shivering 
  Felt cold 
  Felt hot 
  Sweating 
 
How are you feeling today? 
0 no symptoms 1 Mild  
2 Moderate 
3 Severe 
4 Very severe 
Please rate interference in daily activities due to illness: 
1 Not at all  
2 A little bit 
3 Somewhat  
4 Quite a bit  
5 Very much 
How is your general health? 
1 Poor  
2 Fair  
3 Good  
4 Very good  
5 Excellent 
Have you returned to your usual health today?  
Yes/no 
Have you returned to your usual activities today? 
Yes/no 
 
TAKE MEDS, TAKE SWAB (Copy post-exposure prophylaxis) 
Take your vitals: 

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• 
Oxygen level 
• 
Pulse 
• 
Temperature 
• 
Respiratory rate 
• 
Electrocardiogram monitor 
 
PM Time: 
• 
Take meds 
• 
Take vitals 
• 
Oxygen level 
• 
Pulse 
• 
Temperature 
• 
Respiratory rate 
Anxious mood  
Not at all  
mild 
moderate 
severe  
very severe 
 
 
Yu J, Powers JH, Vallo D, et al. Evaluation of efficacy endpoints for a Phase IIb study of a 
respiratory syncytial virus vaccine in older adults using patient-reported outcomes with 
laboratory confirmation. Value Health. 2020 Feb;23(2):227-235.