Conditions: COVID-19 SARS-CoV-2
Keywords: Outpatient Treatment COVID-19
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 289
Healthy volunteers: yes

Brief summary:
This is a randomized trial for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in high-risk adults not requiring hospital admission.The overarching goal of this study is to assess the effectiveness of interventions on the incidence of lower respiratory tract infection (LRTI) progression among high-risk adult outpatients with SARS-CoV-2 infection to inform public health control strategies.

Detailed description:
This is a randomized, multi-center, placebo-equivalent (ascorbic acid + folic acid)-controlled, blinded platform trial. Eligible participants will be enrolled and randomized to Hydrocychloroquine (HCQ) + placebo (folic acid), HCQ + azithromycin, lopinavir-ritonavir (LPV/r) or placebo (ascorbic acid + folic acid). Initially, this study will enroll up to 495 eligible adults ( with high risk for Lower respiratory tract infection (LRTI) progression at baseline who are PCR-confirmed SARS-CoV-2 infection (165 per arm). An additional cohort of 135 eligible adults without risk factors for LRTI progression at baseline who are PCR-confirmed SARS-CoV-2 infection will be enrolled for the co-primary virologic outcome. 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. 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.

Arms:
arm 1: Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days (Days 2 to 5) arm 2: HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days \[Days 2 to 5\]) arm 3: HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed by 250 mg orally once daily for an additional 4 days (Days 2 to 5). arm 4: 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) arm 5: Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days

Interventions: intervention 1: Ascorbic Acid intervention 2: Hydroxychloroquine Sulfate intervention 3: Azithromycin intervention 4: Folic Acid intervention 5: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Intervention descriptions: intervention 1: Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy intervention 2: Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy intervention 3: Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy intervention 4: Eligible participants in a household will receive folic acid and an additional intervention drug intervention 5: Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy

Protocol document:
ICF_005.pdf: 
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: 
 
17 August 2020 
 


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INFORMED CONSENT FORM 
 
 
TITLE: 
Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk 
Outpatient Adults:  An Adaptive Randomized Platform Trial 
 
 
 
LOPINAVIR/RITONAVIR ARM 
 
PROTOCOL NO.: 
UW-ICRC Protocol #55 
 
WIRB® Protocol #20200801 
 
SPONSOR: 
University of Washington 
 
INVESTIGATOR: 
Name 
 
Address 
 
City, State  Zip 
 
Country 
 
STUDY-RELATED 
PHONE NUMBER(S): 
Phone Number 
 
Phone Number (24 hours) 
 
[24 hour number is required] 
 
 
We are asking you to be in a research study.  This study is being conducted by [Site Name] and the University of 
Washington Virology Research Clinic, which is based in Seattle, Washington. This form describes the study procedures and 
gives you information to decide whether you wish to be in the study. Being in the study is entirely your choice (voluntary).  
 
What should I do?  
 
1. Read this form, or have it read to you. 
2. Make sure the study doctor or study staff explains the study to you. 
3. Ask questions (e.g., time commitment, unfamiliar words, specific procedures, etc.) 
4. Take time to consider this, and talk about it with your family and friends.  
 
The first part of this consent form gives you a summary of this study.  
 
The second part of this consent form gives you more details about the study procedures and any risks to you. 
 
PURPOSE OF THE STUDY 
 
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus that causes coronavirus disease (COVID-19).  
The purpose of this study is to understand if taking lopinavir/ritonavir (LPV/r) may be used to help treat people infected 
with early SARS-CoV-2 infection. Currently, there are no FDA-approved treatment drugs for SARS-CoV-2 infection or 
COVID-19.  
 
LPV/r is an investigational antiviral medication that has been used to control HIV infection. The FDA first approved the 
LPV/r in 2000 and safety and tolerability are well described. It is currently not known if LPV/r is an effective treatment for 
COVID-19. 
 


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This study will show us whether early treatment of SARS-CoV-2 infection is effective at preventing more severe illness.  
We will study these medications in people who are well enough to be treated in their homes.  We will study the medication 
in people who are at increased risk for developing complications of SARS-CoV-2 infection, and also people who do not 
have identified risk factors for more severe infection. 
 
If you choose to be in the study, you will be assigned by chance (chance is like flipping a coin) to either LPV/r or vitamin 
C. You will take a double dose of LPV/r or vitamin C by mouth twice daily for one day, followed by a single dose by 
mouth twice daily for 9 days, for a total of 10 days of treatment. 
 
Pregnant and lactating persons will be eligible for enrollment into this study. LPV/r has been shown to be safe in pregnant 
women.  Participants taking hormonal contraceptives to prevent pregnancy will be educated that they will need to use a 
backup form of birth control during the study period. 
 
STUDY PROCEDURES 
 
We are testing LPV/r in adults who have had a laboratory confirmed SARS-CoV-2 infection within the past 72 hours and 
have symptoms of COVID-19. We are inviting you to participate because you have been referred by your healthcare 
provider or have been self-referred. Here is what the study involves:  
 
• 
You will be contacted by our research team and asked to join this study. You will be in this study for approximately 
28 days and no in-person visits are necessary – every interaction will occur via telephone, telehealth, internet, or 
mail. If you are selected for a substudy you will complete extra sample collections throughout the study and 28 
days after your first visit.  
• 
We will ask you to complete a brief enrollment survey about medical history, current & past symptoms, date of 
COVID-19 diagnosis, current use of medicines, and demographics. These questions will be asked either by 
telephone or answering questions in an online survey.  
• 
We will ask you to sign Health Insurance Portability and Accountability Act (HIPAA) forms so we may access 
your COVID-19 related medical records.   
• 
You will complete a short survey about your current health for 14 days.  We will ask you to meet with study staff 
via telehealth roughly every 3-4 days during the study.  You will have the option to request to meet with study staff 
via telehealth more frequently. We will ask you to check your temperature, oxygen saturation, pulse, and 
respiratory rate twice a day.  We may also ask you to check your heart rhythm using a device.  We will provide all 
supplies to you to do these assessments.  The procedures will take about 30 minutes each day.   
• 
You will be asked to self-test for your current COVID-19 status by swabbing the inside of your nose with a special 
swab called a nasal swab. We will ask you to repeat this procedure with a new swab daily while in the study. Once 
you have swabbed the inside of your nose, you will put your swab in a special tube for storage. 
• 
You may also be asked to prick your finger to collect drops of blood called dried blood spots on a special card. We 
may ask you to collect these blood spots at enrollment, partway through the study, and at the end of the study.  
• 
We will provide you with all the supplies you need to collect your samples. The supplies will arrive in a couriered 
package, and we will give you envelopes and postage to either mail them back or a courier will come collect them. 
• 
To test for novel coronavirus, the swabs will be sent to the University of Washington.  Your results may not be 
available for weeks after the study is completed.  When your results are available, we will provide them to you.  
These swabs are not part of routine clinical care. 
 
This study does not replace or affect any care you might receive from your doctor.  
 


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RISKS, STRESS, OR DISCOMFORT 
 
Because there are always some risks to taking part in a research study, we have listed some of the most likely risks of 
participation in this study here: 
 
Possible Risks related to LPV/r treatment  
 
• 
Nausea 
• 
Occasional dizziness 
• 
Diarrhea 
• 
Abdominal pain 
 
There are also rare but serious risks of LPV/r treatment, like: 
 
• 
Serious allergic reaction  
• 
Liver problems 
• 
Pancreatitis 
• 
Heart rhythm problems 
• 
Life-threatening drug interactions 
 
We may provide you medications to provide symptomatic relief from diarrhea (loperamide) or nausea (ondansetron) related 
to study medication.   
 
Possible Risks related to Nasal Swabs or Fingerprick: 
 
• 
Swabbing your nose may cause mild discomfort, watery eyes, or sneezing. 
• 
Drawing a few drops of blood from your finger for the dry blood test may cause temporary discomfort from the 
needle stick, bruising, and infection. 
 
Some questions we might ask you are sensitive and may make you feel uncomfortable. You do not have to answer any 
question you do not want to. There is a risk that your privacy could be breached. We will do everything we can to make 
sure that this does not happen. 
 
BENEFITS OF THE STUDY 
 
Possible Benefits: 
If you are in the group that receives LPV/r, and if it proves to reduce your chances of developing severe COVID-19 disease 
or shortens the duration of your disease. 
 
If you are in the group that receives vitamin C, this may help to support your immune system but you will not receive study 
drugs.   
 
You may benefit from participating in the study, but this cannot be guaranteed. 
 
Your Other Options: 
There are currently no approved drugs to treat COVID-19. However, your clinician may choose to prescribe you drugs 
including LPV/r to treat COVID-19 if they think the drugs may help, even though no drugs yet are known to help or FDA-
approved. You do not have to participate in this study.  
 


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Your other choices may include: 
 
• 
Taking part in another study. 
• 
Working with your doctor to manage your COVID-19 outside of a study. 
 
You may want to talk to your doctor about your choices before agreeing to participate in this study.  
 
SOURCE OF FUNDING 
 
The [Site Name] and/or the University of Washington is receiving financial support from the Bill & Melinda Gates 
Foundation. 
 
DETAILED STUDY INFORMATION 
 
The following is a more complete description of this study. Please read this description carefully. You can ask any 
questions you want to help you decide whether to join the study. If you join this study, we will offer you a copy of this form 
to keep for future reference. 
 
Research studies include only people who choose to take part. Please take your time to make your decision about 
participating. You may discuss your decision with your family and friends and with your health care team. If you have any 
questions, you may ask your study doctor. If you decline to participate your doctor will still give you care for your COVID-
19 diagnosis.  
 
Why am I being asked to participate? 
You are being asked to take part in this study because you are an adult who has had a laboratory confirmed SARS-CoV-2 
infection result within the past 72 hours with symptoms of COVID-19 disease.  
 
Why is this study being done? 
The purpose of this study is to understand if the medication used to treat HIV infection called LPV/r can reduce the length 
and/or severity of COVID-19 disease. The study will also look at whether the drugs are safe for patients with COVID-19.  
While LPV/r are approved by the Food and Drug Administration (FDA), using the drugs to treat COVID-19 is 
investigational and is not approved by the FDA. 
 
The manufacturer of the drugs that are being used in this study are not involved with the conduct of this study. AbbeVie, 
the maker of LPV/r, has donated the medication for this study.  The study will provide the assigned drug at no cost to the 
research participant. 
 
How many people will take part in this study? 
About 346 people will take part in this study.  
 
What will happen if I take part in this research study? 
If you are eligible to be in the study and you choose to take part, then you will need the following tests and procedures: 
 
• 
You will be asked to complete surveys by telephone, web, or video chat. 
o You will be asked to attend telehealth visits with the study staff. 
o You will be asked a series of questions about your health, including your current COVID-19 symptoms, 
including shortness of breath, fever, and cough.   
o You will be asked if you have any symptoms that can be associated with taking LPV/r. 
o You will also be asked other questions about your medical history, current vitals, current & past symptoms, 
date of COVID-19 diagnosis, current use of medicines, and demographics. 


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• 
You will self-test to monitor your COVID-19 nasal shedding. This will be done by swabbing the inside of your 
nose.  
• 
You may be asked to collect a few drops of blood by pricking your finger and collecting it on a piece of filter paper 
we provide you. This blood will be used to test for the level of drug or COVID-19 antibodies in your blood, 
infection fighting cells, or inflammatory markers. If other tests directly related to COVID-19 are developed, we 
may use the blood to understand your immune response using those tests. 
• 
We will ask you to check your temperature, oxygen saturation, pulse, and respiratory rate twice a day.  We may 
also ask you to check your heart rhythm using a device.  We will provide all supplies to you to do these 
assessments and will teach you how to use them.  The procedures will take about 30 minutes each day.  
• 
You will receive an email daily with a link to a survey to document when you take the treatment (LPV/r or vitamin 
C). The survey will ask how you are feeling, and if you have collected a nasal swab. We would like you to 
complete this once a day for the 14 days you are enrolled in the study, and on Day 21 and Day 28.  
• 
You will be asked to complete a final brief survey by telephone or internet at completion of the study. Some of 
these questions may include how you are feeling, if you thought you were taking LPV/r or vitamin C, and your 
thoughts on participating in the study.  
 
You will be "randomized" into one of the study groups described below. Randomization means that you are put into a group 
by chance, like flipping a coin. A computer program will place you in one of the groups. You will have an equal or 50% 
chance (one in two) of being placed in the LPV/r treatment group vs. the vitamin group. You and your doctor will not know 
which group you are assigned to. The study pharmacist will know your group assignment & will disclose the information at 
the end of the study, or if there is a medical emergency and it is required to do so.  
 
You will be provided with a supply of pills.  You will take a double dose by mouth twice daily for one day. Then, you 
will take a single dose by mouth twice daily for the next 9 days, for a total of 10 days of treatment.  You will be provided 
with dosing directions when you receive the medications. 
 
• 
If you are assigned to the group receiving LPV/r, you will be taking 800 mg-200 mg LPV/r twice daily on day one, 
and then 400 mg-100 mg of LPV/r twice daily for the next 9 days.   
 
• 
If you are assigned to the group receiving the vitamin C pill, you will be taking 1,000 mg of vitamin C twice daily 
on day one, and then 500 mg of vitamin C twice daily for the next 9 days.   
 
Timing of study visits and procedures: 
 
• 
The initial enrollment survey will take approximately 15 minutes. 
• 
The initial enrollment visit with the study staff will take approximately 45 minutes, to up to 2 hours. 
• 
The follow up visit (days 2, 4 and 9, and 14) with the study staff will take approximately 20 minutes. 
• 
The daily follow up survey (days 2-14) will take you approximately 15 minutes.  
• 
The follow-up survey at day 21 and 28 will take approximately 10 minutes. 
• 
If you are in the sub study, you will be asked to collect a dried blood spot on day 1 and day 28, and on other days as 
study staff requests. You will not be asked to collect a dried blood spot more than 5 times during the study.  Each 
collection will take approximately 10 minutes.  
 
Study location: All study procedures will be at your own home.   
 
Nasal swabs for SARS-CoV-2, the virus that causes COVID-19: The study will ask you to swab the inside of your nose 
every day from day 1 until day 14, and then collect a swab on day 21 and day 28. The study staff will teach you how to do 
this.  Swabbing will take approximately 5 minutes. 
 


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Results of testing done for research only will not be available to you or your providers, just to the researchers in the study. 
You will be able to contact the study to find out your results, if you wish. We will report your test results to your local 
health department if required to do so by law.  
 
Dried blood spot: If you are in the sub study, a self-test dry blood spot test sample will be drawn by pricking one of your 
fingers with a lancet. You will be asked to collect your blood on day 1 and day 28, and on other days as your doctor 
requests.  You will not be asked to collect a dried blood spot more than 5 times during the study. 
 
How long will I be in the study?  Everyone will be in the study for 28 days.   
 
Can I stop being in the study? 
Yes. You can decide to stop at any time. Tell the study team if you are thinking about stopping or if you decide to stop. 
They will tell you how to stop your participation safely.   
 
If you are admitted to the hospital, you should discontinue your study-provided medication.  You may stop collecting nasal 
swabs and doing the daily survey. We will keep in touch with you during your hospitalization, and will request a survey 3 
days after hospital discharge. 
 
It is important to tell the study team if you are thinking about stopping so any risks from LPV/r can be evaluated, and the 
study team can discuss what follow-up care and testing could be most helpful for you. 
 
The study team may stop you from taking part in this study at any time if we believe it is in your best interest, if you do not 
follow the study rules, or if the study is stopped. 
 
What side effects or risks can I expect from the treatment? 
Everyone taking part in the study will be watched carefully for any side effects. However, doctors don't know all the side 
effects that may happen. Side effects may be mild or very serious. Many side effects go away soon after you stop taking the 
LPV/r. In some rare cases, side effects can be serious, long lasting, or may never go away. 
 
You should talk to your study doctor about any side-effects you experience while taking part in the study. 
 
For participants assigned to the LPV/r treatment group, risks and side effects include: 
 
Likely 
• 
Nausea 
• 
Occasional dizziness 
• 
Diarrhea 
• 
Abdominal pain 
 
Less likely 
• 
Serious allergic reaction  
• 
Liver problems 
 
Rare but serious 
• 
Pancreatitis 
• 
Heart rhythm problems 
• 
Life-threatening drug interactions 
 
We may provide you medications to provide symptomatic relief from diarrhea (loperamide) or nausea (ondansetron) related 
to study medication.   
 


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Randomization risks: You will be assigned to receive LPV/r or vitamin C, and the group to which you are assigned may 
prove to be less effective or to have more side effects than the other study treatment or other available treatments. 
 
Dry Blood Spot: Drawing a dry blood test may cause temporary discomfort from the needle stick, bruising, and rarely, 
infection. 
 
Privacy and confidentiality risks: We will make every effort to protect your confidentiality during the study. However, it 
is possible that others may learn that you are part of this study and they may know you have COVID-19. The most common 
risks we know about are family or friends worrying, getting upset or angry, or knowing that you are infected and treating 
you unfairly as a result. 
 
You should feel free to discuss participation in this study with friends and family. 
 
We will report your test results to local health departments when legally required to do so.   
 
Although every reasonable effort has been taken, confidentiality during online communication procedures cannot be 
guaranteed and it is possible that additional information beyond that collected for research purposes may be viewed by 
others not associated with this study for unauthorized purposes. 
 
You will be required to use your email address to gain access to the heart rhythm monitoring site. 
 
Unknown Risks: Although LPV/r is well studied and widely used, LPV/r for COVID-19 treatment may have side effects 
that no one knows about yet. The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study. 
 
For more information about risks and side effects, ask your study team. 
 
Are there benefits to taking part in the study? 
If you are in the group that receives one of the treatments (LPV/r) and if it proves to reduce the severity of duration of 
COVID-19 without causing side effects that you cannot tolerate, you may benefit from participating in the study, but this 
cannot be guaranteed. 
 
If you are in the group that does not receive LPV/r, you may have the same or fewer side effects associated with the other 
groups, but this cannot be guaranteed. 
 
What other choices do I have if I do not take part in this study? 
Your other choices may include: 
 
• 
Taking part in another study. 
• 
Working with your health care provider to manage your COVID-19 outside of a study. 
 
How will my specimens and information be used? 
Researchers will use your specimens and information to conduct this study. Once the study is done using your specimens 
and information, we may share them with other researchers so they can use them for other studies in the future. We will not 
share your name or any other personal information that would let the researchers know who you are.  
 
Research results: There may be times when researchers using your information or specimens may learn new information. 
The researchers may or may not share these results with you, depending on a number of factors. 
 


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How will information about me be kept confidential? 
Participation in research involves some loss of privacy. We will do our best to make sure that information about you is kept 
confidential, but we cannot guarantee total privacy. The results of tests may become part of your study record and may be 
communicated to the local health department if required. All other information collected as part of this study will be part of 
your study record only and will not include your name or other identifying information. All study records will be stored in a 
locked location or under password protection on study computers. 
 
Only study staff will have access to your study record. If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used. 
 
Your personal information may be given out if required by law. 
 
Your study records may be viewed by the study team and representatives of: 
 
• 
International Clinical Research Center 
• 
The University of Washington 
• 
Office for Human Research Protections 
• 
The Institutional Review Board (IRB) 
• 
The U.S. Food and Drug Administration 
• 
[Site Name] 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law.  This Web 
site will not include information that can identify you.  At most, the Web site will include a summary of the results.  You 
can search this Web site at any time. 
 
Are there any costs to me for taking part in this study? 
There are no costs to you. Any procedures done only for research will not be charged to you or your insurer. 
 
The study will provide the drug of your assigned treatment group to you at no cost. 
 
Will I be paid for taking part in this study? 
If you complete all parts of the study, you will be paid $400. You will receive $300 on day 14 if you completed the surveys, 
nasal swabs. You will receive $100 on day 28 if you complete the additional nasal swabs and blood spot.   
 
What happens if I am injured because I took part in this study? 
If you think you have a medical problem or illness related to this research, contact [Name] right away. They will treat you 
or refer you for treatment. It is important that you tell study doctors if you feel that you have been injured because of taking 
part in this study. Study doctors at each site are: 
 
[Name] 
 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions, concerns, or complaints you have about this study, or if you feel you 
have experienced a research-related injury; see contact information above. If you wish to ask questions about the study or 
your rights as a research participant to someone other than the researchers, or if you wish to voice any problems, questions, 
complaints or concerns you may have about the study, please contact the Institutional Review Board (IRB) at 800-562-
4789, Help@wirb.com. 
 
What are my rights if I take part in this study? 
Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you take part 
in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you or 


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Beca use  f ut ure st u dies t hat y o u  ma y  be eli gi ble f or ma y  bec o me a vaila ble, we  are as ki n g n o w if y o u  w o ul d li ke t o lear n 
a b o ut t hese st u dies. Y o u  ca n still be a part  of  t he mai n  st u d y e ve n if y o u  sa y " n o" t o t his. 
 
I a gree  t hat I ma y  be c o ntacte d i n t he f ut ure t o see if I a m i ntereste d i n partici pati n g  i n f urt her researc h. 
 
 Yes          N o  
 
 
 
 
Si g nat ure of s u bject  
Date  
 
 


IRB Approved Template 
MUST BE APPROVED  
FOR SITES BEFORE USE  
AS MODIFIED 
Sep 03, 2020 
 
COVID-19 Treatment, protocol version 2.1, August 17, 2020 
 
10
**For Sites in California** 
AUTHORIZATION TO USE AND DISCLOSE INFORMATION FOR RESEARCH 
PURPOSES  
 
What information may be used and given to others? 
The study doctor will get your personal and medical information.  For example:  
• Past and present medical records 
• Research records 
• Records about phone calls made as part of this research 
• Records about your study visits. 
 
Who may use and give out information about you? 
The study doctor and the study staff.  [They may also share the research information with [enter 
SMO company name], an agent for the study doctor. delete if the site does not have an SMO] 
 
Who might get this information? 
The sponsor of this research.  “Sponsor” means any persons or companies that are: 
• working for or with the sponsor, or  
• owned by the sponsor. 
 
Your information may be given to:  
• The U.S. Food and Drug Administration (FDA), 
• Department of Health and Human Services (DHHS) agencies, 
• Governmental agencies in other countries,  
• The institution where the research is being done, 
• Governmental agencies to whom certain diseases (reportable diseases) must be reported, and 
• Institutional Review Board (IRB)  
 
Why will this information be used and/or given to others? 
• to do the research,  
• to study the results, and  
• to make sure that the research was done right.   
 
If the results of this study are made public, information that identifies you will not be used. 
 
What if I decide not to give permission to use and give out my health information? 
Then you will not be able to be in this research study. 
 


IRB Approved Template 
MUST BE APPROVED  
FOR SITES BEFORE USE  
AS MODIFIED 
Sep 03, 2020 
 
COVID-19 Treatment, protocol version 2.1, August 17, 2020 
 
11
May I review or copy my information? 
Yes, but only after the research is over.  
 
May I withdraw or revoke (cancel) my permission? 
This permission will be good until December 31, 2060. 
 
You may withdraw or take away your permission to use and disclose your health information at 
any time.  You do this by sending written notice to the study doctor.  If you withdraw your 
permission, you will not be able to stay in this study. 
 
When you withdraw your permission, no new health information identifying you will be gathered 
after that date.  Information that has already been gathered may still be used and given to others.   
 
Is my health information protected after it has been given to others? 
There is a risk that your information will be given to others without your permission. 
 
Authorization: 
I have been given the information about the use and disclosure of my health information for this 
research study.  My questions have been answered. 
 
I authorize the use and disclosure of my health information to the parties listed in the 
authorization section of this consent for the purposes described above. 
 
AUTHORIZATION SIGNATURE: 
 
 
 
 
 
 
Signature of Subject 
 
Date 

Prot_003.pdf: 
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 
 


CONFIDENTIAL 
Treatment for SARS-CoV-2 in High-risk Adult Outpatients 
Version 2.1 
 
1 
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. 


CONFIDENTIAL 
Treatment for SARS-CoV-2 in High-risk Adult Outpatients 
Version 2.1 
 
2 
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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Treatment for SARS-CoV-2 in High-risk Adult Outpatients 
Version 2.1 
 
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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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7 
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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8 
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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9 
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 
spot and respiratory rate. 


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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 
about 3%, which is significantly lower than that of SARS-CoV (10%) and MERS-CoV (40%) 


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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 
symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory 


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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). 
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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 
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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 
increased risk of the COVID-19 symptom resolution rate under a null hypothesis of no reduction 


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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 
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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. 
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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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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 
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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. 
 

Prot_002.pdf: 
 
 
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 1.4; 11 April 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, 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 
B. Azithromycin 
C. Ascorbic acid (control) 
D. 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 
Protocol Registry Number: 
To be determined 
Regulatory Agency Identifying Number(s): 
Not applicable 
Sponsor Name and Legal Registered Address: 
University of Washington 
Roosevelt Way NE, Seattle, WA 98115 
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 
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............................................................................................................................6 
2. 
Schedule of Activities ....................................................................................................11 
3. 
Introduction ...................................................................................................................13 
3.1. 
Background .....................................................................................................................14 
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 ..................................15 
3.2.3. 
Rationale for Drug Selection of HCQ .............................................................................16 
3.2.4. 
Rationale for Dosing Schedule of HCQ..........................................................................16 
3.2.5. 
Antiviral Effects of Azithromycin Against COVID-19 ..................................................17 
3.2.6. 
Rationale for Drug Selection of Azithromycin ...............................................................17 
3.2.7. 
Rationale for Dose Selection of Azithromycin ...............................................................18 
3.2.8. 
Rationale for Ascorbic Acid Control as a Comparator for HCQ ....................................18 
3.2.9. 
Rationale for Folic Acid Control as a Comparator for 
Azithromycin ..................................................................................................................19 
3.3. 
Benefit/Risk Assessment ................................................................................................19 
4. 
Objectives and Endpoints ............................................................................................20 
5. 
Study Design ..................................................................................................................22 
5.1. 
Overall Design ................................................................................................................22 
5.2. 
Participant and Study Completion ..................................................................................23 
6. 
Study Population ...........................................................................................................24 
6.1. 
Inclusion Criteria ............................................................................................................24 
6.2. 
Exclusion Criteria ...........................................................................................................24 
6.3. 
Screen Failures ................................................................................................................25 
6.4. 
Recruitment .....................................................................................................................25 
6.5. 
Co-enrollment Guidelines ...............................................................................................26 
7. 
Treatments .....................................................................................................................27 
7.1. 
Treatments Administered ................................................................................................27 
7.2. 
Risks to the Participants ..................................................................................................27 
7.2.1. 
Risks Associated Administration with HCQ ..................................................................27 
7.2.2. 
Risks Associated with Azithromycin ..............................................................................28 
7.2.3. 
QT Risks Associated with Coadministration of HCQ and 
Azithromycin ..................................................................................................................28 
7.2.4. 
Risks Associated with COVID-19 Diagnosis .................................................................28 
7.3. 
Strategies to Minimize Risk ............................................................................................29 
7.3.1. 
Dose Selection ................................................................................................................29 
7.3.2. 
Management of Participants to Limit Risks of SARS-CoV-2 
Transmission ...................................................................................................................29 
7.4. 
Dose Modification and Toxicity Management ...............................................................29 
7.5. 
Method of Treatment Assignment ..................................................................................31 


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7.6. 
Blinding ..........................................................................................................................31 
7.6.1. 
Patient Blinding ..............................................................................................................31 
7.7. 
Preparation/Handling/Storage/Accountability ................................................................32 
7.8. 
Treatment Compliance ....................................................................................................32 
7.9. 
Concomitant Therapy .....................................................................................................32 
7.9.1. 
Prohibited Medications ...................................................................................................32 
7.9.2. 
Precautionary Medications..............................................................................................33 
7.10. 
Treatment After the End of the Study .............................................................................33 
8. 
Discontinuation/Withdrawal Criteria .........................................................................34 
8.1. 
Discontinuation of Study Treatment ...............................................................................34 
8.2. 
Withdrawal from the Study.............................................................................................34 
8.3. 
Lost to Follow-up............................................................................................................35 
9. 
Study Encounters ..........................................................................................................36 
9.1. 
Screening/Baseline Evaluation: Day 0/1 ........................................................................36 
9.2. 
Day 2 Through Day 13 ...................................................................................................37 
9.3. 
Days 2, 4, 9, and 14 (±1 day) ..........................................................................................37 
9.4. 
Days 14 and 21 ...............................................................................................................37 
9.5. 
Day 28 .............................................................................................................................38 
10. 
Study Assessments and Procedures.............................................................................39 
10.1. 
Efficacy Assessments .....................................................................................................39 
10.1.1. Mid-nasal Swab ..............................................................................................................39 
10.1.2. Participant Survey ...........................................................................................................39 
10.2. 
Adverse Events ...............................................................................................................40 
10.2.1. Adverse Events ...............................................................................................................40 
10.2.2. Serious Adverse Events ..................................................................................................40 
10.2.3. Treatment-related AE and SAE ......................................................................................41 
10.3. 
Treatment of Overdose ...................................................................................................41 
10.4. 
Pregnancy........................................................................................................................41 
10.5. 
Safety Assessments .........................................................................................................41 
10.6. 
Dried Blood Spot Sub-study (Optional) .........................................................................41 
10.7. 
Biohazard Containment ..................................................................................................42 
11. 
Statistical Considerations .............................................................................................42 
11.1. 
Sample Size Determination ............................................................................................42 
11.2. 
Populations for Analyses ................................................................................................44 
11.3. 
Statistical Analyses .........................................................................................................44 
11.3.1. Efficacy Analyses ...........................................................................................................45 
11.3.2. Secondary Endpoints ......................................................................................................46 
11.3.2.1. 
Safety Analyses ...........................................................................................................46 
11.3.2.2. 
Hospitalization ............................................................................................................46 
11.3.2.3. 
Disease Severity ..........................................................................................................46 
11.3.2.4. 
Symptom Resolution ...................................................................................................46 
11.3.3. Pharmacokinetic Analysis ...............................................................................................46 
11.3.4. Exploratory Exposure-Response Analyses .....................................................................47 


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11.3.5. Combined Study Analysis...............................................................................................47 
12. 
References ......................................................................................................................48 
13. 
Appendices .....................................................................................................................51 
Appendix 1: Abbreviations and Terms ..........................................................................................51 
Appendix 2: Protocol Structure .....................................................................................................53 
Appendix 3: Study Governance Considerations ............................................................................54 
Appendix 4: Site-Specific Protocol Addendum Template .............................................................57 
Appendix 5: Hydroxychloroquine Label .......................................................................................60 
Appendix 6: Azithromycin Label ..................................................................................................61 
Appendix 7: Physiologically Based Pharmacokinetic Model for 
Azithromycin Dose Regimen..........................................................................................62 
Appendix 8: Pharmacokinetic Sample Collection and Analysis ...................................................63 
Appendix 9: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis ............................................65 
Appendix 10: The inFLUenza Patient-Reported Outcome instrument 
(Flu-PRO) – Modified for SARS-CoV-2........................................................................66 
Appendix 11: WHO Ordinal Scale for Clinical Improvement ......................................................69 
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 ...................................... 43 
Table 2 
Expected Recruitment and Number of Measurable Clinical Outcomes for the 
First 6 to 8 Weeks of Trial ...................................................................................... 43 
 


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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 licensed 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. To date, no rigorous treatment studies of 
outpatient SARS-CoV-2 infection have been reported. 
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 [1, 2]. 
Most recently, the combination of HCQ + azithromycin showed possible evidence of enhanced 
antiviral activity compared with HCQ alone in patients with COVID19 disease in a small 
observational series reported by Gautret et al (2020) [1]. 
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 progression 
to LRTI, defined by blood oxygen saturation level (SpO2) <93% sustained for 2 readings 2 hours 
apart AND presence of subjective dyspnea or cough, cumulative incidence of hospitalization or 
mortality at Day 28, 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 + folic 
acid)-controlled, and blinded study of HCQ and HCQ + azithromycin 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. 
Population: 
Men and women 18 to 80 years of age who test positive for SARS-CoV-2 within the past 
72 hours. 
High-risk cohort (total of 495 participants, 165 per arm): 
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 


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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 ≥30 kg/m2 (self reported) 
Low-risk cohort (total of 135 participants, 45 per arm): 
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). 
Participants will be counseled about the preliminary in vitro data on HCQ and HCQ + 
azithromycin 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. 
Intervention: 
• Intervention A: HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice 
daily for an additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on 
Day 1, followed by 400 µg orally once daily for an additional 4 days [Days 2 to 5]). 
• Intervention B: HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice 
daily for an additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on 
Day 1, followed by 250 mg orally once daily for an additional 4 days (Days 2 to 5). 
• Placebo: Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice 
daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once 
daily for an additional 4 days (Days 2 to 5). 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary  
• To test the efficacy of HCQ or HCQ + 
azithromycin compared to placebo to 
prevent progression to LRTI, among 
persons with SARS-CoV-2 infection 
who are at high risk of progression 
• To test the efficacy of HCQ or HCQ + 
azithromycin compared to placebo to 
reduce SARS-CoV-2 viral shedding  
• LRTI, defined by resting SpO2<93% 
sustained for 2 readings 2 hours apart 
AND presence of subjective dyspnea 
or cough  
The trial is statistically powered for 
this endpoint in the high-risk 
population. 
• Cumulative incidence of 
hospitalization or mortality, measured 
at Day 28 
The trial is statistically powered for 


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this endpoint in the high-risk 
population. 
• 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 HCQ or HCQ + 
azithromycin compared to placebo for 
treatment of high-risk outpatients with 
SARS-CoV-2 infection 
• Serious adverse events (including 
death and hospitalization) and adverse 
events resulting in treatment 
discontinuation  
• To test whether HCQ or HCQ + 
azithromycin has an effect on the 
duration of hospitalization among 
persons who become hospitalized with 
COVID-19 disease  
• Days of hospitalization 
 
• To test whether HCQ or HCQ + 
azithromycin 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 HCQ or HCQ + 
azithromycin decreases the resolution 
rate for symptomatic SARS-CoV-2 
infection/COVID-19 disease compared 
to placebo 
• Proportion of days with fever after 
randomization 
• Proportion of days with respiratory 
symptoms after randomization 
• Proportion of days with SpO2<93% for 
>1 hour/day without supplemental 
oxygen after randomization 
• To test whether HCQ or HCQ + 
azithromycin 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 


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• To assess pharmacokinetics and 
exposure-response relationship of 
HCQ 
• To assess pharmacokinetics and 
exposure-response relationship of 
HCQ + azithromycin 
• HCQ blood concentration in DBS 
• Azithromycin blood concentration in 
DBS  
COVID-19: coronavirus disease; DBS: dried blood spot; Flu-PRO: inFLUenza patient-reported outcome; 
HCQ: hydroxychloroquine; 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 initially enroll 495 high-risk participants (165 per arm) to achieve 90% statistical 
power at 2-sided type I error rate of 5% for a pairwise comparison against the control to detect a 
treatment effect of relative risk reduction of 50% for the primary outcome(s) assuming control 
event rate of 30% for the primary outcome and 5% dropout rate. A smaller cohort of 
135 participants (45 per arm) aged 18 to 59 years and without risk factors for progression to 
LRTI will be enrolled for the co-primary virologic outcome. Eligible participants will be 
randomized at an equal allocation ratio to study treatment (HCQ + placebo [folic acid], HCQ + 
azithromycin, or placebo [ascorbic acid + folic 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. With an expected recruitment rate of approximately 83 to 
124 patients per week, it can be expected that 53 to 79 patients from the control group will be 
observed for clinical outcome in the high-risk group in the fourth week. Should a new 
intervention be added, allocation ratio will 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 will 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. 
Enrollment over 4 weeks: Recruitment rate of 83 to 124 patients per week. 
Completion in 6 weeks from first patient in (without sample size re-assessment). 
Proposed Sites (up to 6): University of Washington, University of Maryland, SUNY, Tulane, 
NYU, 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 (HCQ, azithromycin, ascorbic acid, 
folic acid) 
 
## 
# 
# 
# 
#c 
# 
#d 
 
 
 
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, QT monitoring, 
respiratory rate) 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
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 HCQ 
and azithromycin concentration and anti-SARS-
CoV-2 antibodies 
 
X 
1 to 5 samples (no more than 1 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: ## denotes either 400 mg HCQ twice a day + placebo (800 µg folic acid) once a day, 400 mg HCQ twice a day + 500 mg azithromycin once a 
day, or placebo (500 mg ascorbic acid twice a day + 800 µg folic acid once a day) (depending on treatment arm assignment).  
Note: # denotes either 200 mg HCQ twice a day + placebo (400 µg folic acid) once a day, 200 mg HCQ twice a day + 250 mg azithromycin once a 
day, or placebo (250 mg ascorbic acid twice a day + 400 µg folic acid once a day) (depending on treatment arm assignment). 
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. 
c Last day of study medication will be administered on Day 5 for azithromycin and folic acid. 
d Last day of study medication will be administered on Day 10 for HCQ and ascorbic acid. 
e These evaluations will be as needed/requested by study participant. 
 


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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) and HCQ + azithromycin (Intervention B) 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 or HCQ + azithromycin 
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). Initially, there will be 3 study arms (Arm 1: HCQ + placebo 
[folic acid], Arm 2: HCQ + azithromycin, Arm 3: placebo [ascorbic acid + folic acid]) enrolled 
to assess a daily dosing regimen administered for 10 days to prevent LRTI and decrease viral 
shedding. 
Up to 165 eligible high-risk adults (18 to 80 years of age) per arm will be randomized (at the 
level of household) in a 1:1:1 ratio to receive one of the following therapies: 
• HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an 
additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, 
followed by 400 µg orally once daily for an additional 4 days [Days 2 to 5]) 
• HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an 
additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed 
by 250 mg orally once daily for an additional 4 days (Days 2 to 5) 
• Placebo: Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice 
daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once 
daily for an additional 4 days (Days 2 to 5) 
A second group of 135 adults (18 to 59 years of age) without risk factors for progression to LRTI 
per arm will be randomized in a 1:1:1 ratio to the same interventions. 
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be 
bitter and ascorbic acid will be sour. Azithromycin will not appear similar to folic 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, 
respiratory rate 
• Complete surveys that will include questions about symptoms from both the drug 
regimen and respiratory and systemic symptoms, review of concomitant medications, 
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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, and respiratory rate. 
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 [3,4,5]. 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. Person-to-person transmission has occurred in China, across temperate 
Asia, Europe, and North America, with sporadic cases in Africa and person-to-person 
transmission in the southern hemisphere. 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 [6], and the United States declared a national 
emergency on 13 March 2020 [7]. 
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 [8]. 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 [9], 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 [10]. 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 LRTI, which is associated with need for hospitalization and possibly mechanical 
ventilatory support, will be of benefit to the individual, the hospital system, and the health of the 
public. In addition, treating those at highest risk of progression to LRTI and hospitalization will 
have the greatest impact on the pandemic. Including a cohort without risk factors for LRTI for 
the co-primary virologic outcome will provide additional data to inform whether the intervention 
is likely to have a public health benefit by reducing transmission in situations where self-
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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 
about 3%, which is significantly lower than that of SARS-CoV (10%) and MERS-CoV (40%) 
[11]. However, SARS-CoV-2 has potentially higher transmissibility (R0: 1.4 to 5.5) than both 
SARS-CoV (R0: 2-5) 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 [12]. 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 [4]. 
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 [13]. 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) [13,14]. 
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 [15]. CQ was found to be effective against rheumatoid 
tenosynovitis in 1951 [16]. 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 [17]. 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 [18]. 
CQ and HCQ have been proposed as potential agents for treatment and prevention against other 
infectious agents beyond malaria [19,20]. The mechanism of action differs according to the 
pathogen: against intracellular bacteria and fungi by alkalinizing vacuoles containing the 


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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 [21] and had shown evidence of prevention activity in 
vivo [22]. 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-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 [23]. 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 [24]. 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 reported anecdotal efficacy of CQ as treatment for 
COVID-19-associated pneumonia [25]. 
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 9). 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 [24]. 
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 [26]. Since the drug will be used in those 


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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 [27]; pharmacokinetic (PK) parameters (liver 
intrinsic clearance, fa, ka) were determined from clinical data [28]. 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 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 [1, 2]. Although the mechanism of its antiviral 
activity is not clear, some findings suggest it may be associated with augmentation of interferon 
response [2]. Alternatively, azithromycin may convey antiviral activity by increasing the pH of 
cell organelles such as endosomes and the trans-Golgi network [29]. Changing the pH of 
intracellular vesicles may alter the glycosylation of ACE2, a key receptor for cell entry for 
SARS-CoV-2 [30,31]. 
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 [1], 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 


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important for human medicine. Azithromycin is widely available worldwide. Common short-
term drug toxicities include nausea, vomiting, diarrhea and upset stomach. 
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 cytochromes P450, 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 [32].  
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 [1]. 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 7. 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 [33]. 
3.2.8. 
Rationale for Ascorbic Acid Control as a Comparator for HCQ 
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 [3,34]. Symptom reporting may vary 
based on the participants’ perception as to whether they are taking HCQ or ascorbic acid [35], 
but the primary study endpoints of LRTI and viral shedding 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, particularly for the comparison of ascorbic acid and HCQ. Both 
of those medications have a taste, tablets will not be labeled as either HCQ or ascorbic acid, and 
an ascorbic acid tablet that is comparable in size and shape to HCQ will be used. 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 [36,37]; thus, ascorbic acid is not expected to have a 
prevention effect for SARS-CoV-19 and is considered a placebo-equivalent product for this 
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3.2.9. 
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 
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 [3,4,5]. 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 has 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 and 
azithromycin, or any other drug or drug combination, will translate into efficacy to prevent 
LRTI. Thus, the potential benefit-to-risk ratio for testing HCQ and HCQ + azithromycin as 
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4. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary  
• To test the efficacy of HCQ or HCQ + 
azithromycin compared to placebo to 
prevent progression to LRTI, among 
persons with SARS-CoV-2 infection 
who are at high risk of progression 
• To test the efficacy of HCQ or HCQ + 
azithromycin compared to placebo to 
reduce SARS-CoV-2 viral shedding  
• LRTI, defined by resting SpO2<93%, 
sustained for 2 readings 2 hours apart 
AND presence of subjective dyspnea 
or cough  
The trial is statistically powered for 
this endpoint in the high-risk 
population. 
• Cumulative incidence of hospitalization 
or mortality, measured at Day 28 
The trial is statistically powered for 
this endpoint in the high-risk 
population. 
• 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 HCQ or HCQ + 
azithromycin compared to placebo for 
treatment of high-risk outpatients with 
SARS-CoV-2 infection 
• Serious adverse events (including death 
and hospitalization) and adverse 
events resulting in treatment 
discontinuation  
• To test whether HCQ or HCQ + 
azithromycin has an effect on the 
duration of hospitalization among 
persons who become hospitalized with 
COVID-19 disease  
• Days of hospitalization  
• To test whether HCQ or HCQ + 
azithromycin has an effect on disease 
severity compared to placebo 
• Peak score on WHO Ordinal Scale for 
Clinical Improvement 
• Peak score on modified Flu-PRO 
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• To test whether HCQ or HCQ + 
azithromycin decreases the resolution 
rate for symptomatic SARS-CoV-2 
infection/COVID-19 disease compared 
to placebo 
• Proportion of days with fever after 
randomization 
• Proportion of days with respiratory 
symptoms after randomization 
• Proportion of days with SpO2<93% for 
>1 hour/day without supplemental 
oxygen after randomization 
• To test whether HCQ or HCQ + 
azithromycin 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 
HCQ 
• To assess pharmacokinetics and 
exposure-response relationship of 
HCQ + azithromycin 
• HCQ blood concentration in DBS 
• Azithromycin blood concentration in 
DBS  
COVID-19: coronavirus disease; DBS: dried blood spot; Flu-PRO: inFLUenza patient-reported outcome; 
HCQ: hydroxychloroquine; 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 incidence 
of LRTI progression among high-risk 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 will start with HCQ (Intervention A) and HCQ + azithromycin (Intervention B) to assess the 
efficacy on the prevention of LRTI progression. The trial may allow for agents to be added and 
tested against placebo with standardized eligibility criteria, outcomes, and measurements. 
Initially, this study will enroll up to 495 eligible adults (18 to 80 years of age) with high risk for 
LRTI progression at baseline who are PCR-confirmed SARS-CoV-2 infection (165 per arm). An 
additional cohort of 135 eligible adults (18 to 59 years of age) without risk factors for LRTI 
progression at baseline who are PCR-confirmed SARS-CoV-2 infection will be enrolled for the 
co-primary virologic outcome (45 per arm). Eligible participants will be enrolled and 
randomized in a 1:1:1 ratio to HCQ + placebo (folic acid), HCQ + azithromycin, or placebo 
(ascorbic acid + folic acid). 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, allocation ratios will be adapted to favor the new arms. For instance, if another 
experimental intervention (i.e., Intervention C) is added when HCQ, HCQ + azithromycin, and 
control arm are all actively recruiting, higher allocation ratio in favor of Intervention C will be 
adopted (e.g. 2:1:1:1). 
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 HCQ and HCQ + 
azithromycin 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. 


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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 
sample size changes and make recommendations on the allocation 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 
As an initial target, up to 165 high-risk participants and 45 low-risk participants per arm will be 
randomly assigned to study treatment or control. This sample size target will likely 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: 
High-risk cohort (total of 495 participants, 165 per arm): 
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 test results within past 72 hours 
4. Access to device and internet for Telehealth visits 
5. 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 human 
immunodeficiency virus 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 ≥30 (self-reported) 
Low-risk cohort (total of 135 participants, 45 per arm): 
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 test results within past 72 hours 
4. 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. Currently hospitalized 
4. Signs of respiratory distress prior to randomization, including respiratory rate >24 
5. Current medications include HCQ 


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6. Concomitant use of other anti-malarial treatment or chemoprophylaxis 
7. History of retinopathy of any etiology 
8. Psoriasis 
9. Porphyria 
10. Chronic kidney disease (Stage IV or receiving dialysis) 
11. Known bone marrow disorders with significant neutropenia 
(polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K) 
12. Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen 
13. Known cirrhosis 
14. Known personal or family history of long QT syndrome 
15. History of coronary artery disease with a history of graft or stent 
16. History of heart failure, Class 2 or greater using the New York Heart Association 
functional class 
17. Taking medications associated with prolonged QT such as antipsychotic medications or 
antidepressants (e.g., citalopram, venlafaxine, and bupropion) and unable to stop during 
the trial 
18. Taking warfarin (Coumadin or Jantoven) 
19. Known history of glucose-6-phosphate-dehydrogenase deficiency 
20. History of myasthenia gravis 
Note: Pregnant and lactating persons will be eligible for enrollment into this study. Both 
HCQ and azithromycin 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 will educate participants about COVID-19, transmission within 
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The proposed sites have established track records of high-quality clinical research integrated into 
clinical care settings; annual retention rates in clinical trials conducted in these sites exceed 80% 
to 90%. The sites have large COVID-19 epidemics with regulation limiting contact to reduce 
infectious spread. 
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 Treatment 
Name 
Hydroxychloroquine 
sulfate 
Ascorbic acid 
Azithromycin 
Folic acid 
Dosage 
Formulation 
200 mg (155 mg 
base) tablets 
250 mg tablets 
250 mg tablets 
400 µg tablets 
Route of 
Administration 
Oral 
Dosing 
Instructions 
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. 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. 
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. 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. 
Packaging 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. 
Manufacturer 
Sandoz 
Cardinal Health 
Greenstone LLC 
NDC 59762-2198-3 
(blister pack) 
 
NDC 59762-2198-3 
(bottle) 
Leader 
(distributed by 
Cardinal Health) 
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 [38] 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 


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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 Food and Drug Administration 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 [39]. Maximal QTc 
prolongation was observed between Days 3 and 4 of treatment. QTc increase from baseline 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 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. 
COVID-19 infection may be associated with anxiety, and the ability to monitor for LRTI and 
interact with study clinicians may allay anxiety. 


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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. 
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. 
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-
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 


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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 
HCQ is associated with QT prolongation. QT will be assessed during the study using a portable 
monitor that can transmit arrhythmias 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). 


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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 arrhythmias to a central location which will be monitored. 
Participants will be counseled about this risk. 
7.5. 
Method of Treatment Assignment 
Participants will be randomized in a 1:1:1 ratio to HCQ + folic acid, HCQ + azithromycin, or 
ascorbic acid + folic acid 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 2 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: 
• HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an 
additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, 
followed by 400 µg orally once daily for an additional 4 days [Days 2 to 5]) 


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• HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an 
additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed 
by 250 mg orally once daily for an additional 4 days (Days 2 to 5) 
• Placebo: Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice 
daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once 
daily for an additional 4 days (Days 2 to 5) 
HCQ and ascorbic acid will appear similar, and taste will be partially masked as HCQ can be 
bitter and ascorbic acid will be sour. 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. 
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 and azithromycin 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 
Prohibited medications for concomitant administration with HCQ include digoxin, cyclosporin, 
amiodarone, cimetidine, and tamoxifen, anticoagulants (e.g., warfarin), anticonvulsants, 


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rifampin, antifungals, immunosuppressants, antipsychotic medications, and antidepressants 
(citalopram, venlafaxine, and bupropion). Refer to Appendix 5 for medications prohibited for 
coadministration with HCQ. 
Prohibited medications for concomitant administration with azithromycin include quinolone 
antibiotics (e.g., levofloxacin, moxifloxacin), macrolide antibiotics (e.g., erythromycin, 
clarithromycin), and antiarrhythmic drugs such as Class I (e.g., quinidine, procainamide, 
disopromide) and Class III (e.g., dofelitide, ibutilide, sotalol). Refer to Appendix 6 for 
medications prohibited for coadministration with azithromycin. 
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, 
escitalopram, herbs, lumefantrine, maitake, mefloquine, monoamine oxidase inhibitors, 
nelfinavir, pegvisomant, prothionamide, quinolones, salicylates, and selective serotonin reuptake 
inhibitors, and warfarin. Careful monitoring is needed during concomitant use of azithromycin 
with digoxin, colchicine, or phenytoin. 
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 (at the discretion of the inpatient provider, hospitalized participants may 
continue to receive study treatment if maintained on the originally randomized treatment 
regimen) 
• 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 regarding exposure to the index case (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, SpO2 device, and QT monitor. 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 Quick Start Instruction Card, swabs, plastic tubes for swab collection, a return box 
with affixed Category B UN3373 label, as required by International Air Transport Association 
(IATA) guidelines [40], 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 QT. In addition, the modified 
inFLUenza patient-reported outcome (Flu-PRO) survey will be completed.  
• Take study therapy (HCQ + placebo [folic acid], HCQ + azithromycin, or placebo 
(ascorbic acid + folic acid), as assigned 


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• If in DBS sub-study, collect DBS sample for analysis of HCQ and azithromycin 
concentrations. 
Instructions for skin puncture and DBS sample preparation are provided in Appendix 8. 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. 
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 5 (inclusive) for azithromycin or folic acid (as assigned) 
and until Day 10 (inclusive) for HCQ 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 QT. In addition, the modified 
Flu-PRO survey will be completed. 
• If in DBS sub-study, collect DBS samples for analysis of HCQ and azithromycin 
concentrations at any time during this period (1 to 5 times) after study drug dosing has 
commenced. No more than 1 sample per day should be collected. 
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, 4, 9, and 14 (±1 day) 
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 


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including SpO2, temperature, pulse, and QT. In addition, the modified Flu-PRO and 
WHO Ordinal Scale for Clinical Improvement surveys will be completed. 
The courier will collect the swabs at minimum within 1 or 2 days of Day 14 and Day 21. 
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, pulse, and QT. 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 and azithromycin 
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 to participants for referral of their close contacts. No reimbursement will be 
provided for unscheduled Telehealth visits requested by the participants for support with study 
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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 Quick Start 
Instruction Card, swabs, plastic tubes for swab collection, a return box with affixed Category B 
UN3373 label, as required by IATA guidelines [40], 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. 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 
[41]. Previous testing has demonstrated that respiratory viral ribonucleic acid (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. 
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 Survey 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 [42] (Appendix 10). 
10.2. 
Adverse Events 
Participants will be asked to complete surveys (Daily Survey 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 30 days after the end of study visit (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 or azithromycin should be managed according to the labeling information (see 
Appendix 5 and Appendix 6). 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 Survey 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) 
Up to 200 participants will be enrolled in the DBS sub-study. DBS will be requested, but not 
required, of all participants. 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 
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The aim of the DBS sub-study is to evaluate HCQ and azithromycin drug concentrations as an 
adherence measure and the PK of HCQ or azithromycin. If serological assays for SARS-CoV-2 
are available, DBS may be tested for SARS-CoV-2 antibodies. 
Pharmacokinetics 
The exposure-response relationship of HCQ and azithromycin of 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; however, no more than 1 sample per day should be collected. 
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 8 
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 sample size required to show a 50% treatment efficacy (i.e., relative risk reduction of 50%) 
is entirely dependent on the CER. Sample size calculations used an estimated 30% CER. 


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The table below shows the sample size required at various treatment effects, CER, and dropout 
rates for operating characteristics of 90% statistical power and 2-sided type I error rate of 5%. 
Power may be lower depending on CER and dropout rate (Table 1). As the initial sample size 
target, 165 per arm was chosen for each experimental group (HCQ and HCQ + azithromycin) to 
achieve 90% power with 0.05 two-sided type I error for a pairwise comparison against the 
control (ascorbic acid and folic acid) to detect at least 50% treatment efficacy in reducing the 
progression to LRTI (primary endpoint) assuming a CER of 30% and 5% dropout rate. 
Table 1 
Sample Size per Arm Required to Detect a Relative Risk Reduction of 40% 
to 60% Under Various Control Event and Dropout Rates 
RRR 
Dropout Rate=0% 
Dropout Rate=5% 
Dropout Rate=20% 
CER=10% 
CER=20% 
CER=30% 
CER=10% 
CER=20% 
CER=30% 
CER=10% 
CER=20% 
CER=30% 
40% 
962 
437 
261 
1013 
460 
275 
1202 
546 
327 
50% 
578 
263 
158 
609 
277 
165 
723 
329 
198 
60% 
375 
171 
103 
395 
180 
108 
469 
214 
128 
CER: Control event rate; RRR: Relative risk reduction. 
Sample size calculation was done with the desired operating characteristics of 90% statistical power and 5% type I error rate (2-sided). 
As illustrated in the table above, the statistical power will depend heavily on the observed CER. 
Given the uncertainty of the target population, the final target sample size will be re-estimated 
using the observed CER and dropout rate in the control group as a blinded sample size re-
assessment. As it is difficult to predict the enrollment rate, the recruitment rate will be assessed 
on a weekly basis starting at the end of second week. It is expected that the enrollment rate will 
be fast, and to enroll the initial target size of 495 participants (165 per three groups), it will take 
4 to 6 weeks, resulting in an approximate recruitment rate of approximately 83 to 
124 participants per week. At the end of fourth week, it can be expected that 53 to 79 participants 
from the control group have been followed-up with their clinical follow-up providing reasonable 
estimates on CER and dropout rate (Table 2). 
Table 2 
Expected Recruitment and Number of Measurable Clinical Outcomes for the 
First 6 to 8 Weeks of Trial 
Time 
Recruitment Rate of  
83 Participants/Week 
Recruitment Rate of  
124 Participants/Week 
Number of Enrolled 
Total Participants 
Number of Total 
Measurable 
Outcomes 
Number of Enrolled 
Total Participants 
Number of Total 
Measurable 
Outcomes 
End of Week 1 
83 
0 
124 
0 


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End of Week 2 
166 
0 
248 
0 
End of Week 3 
249 
79 
372 
118 
End of Week 4 
332 
158 
495 
236 
End of Week 5 
415 
237 
495 
354 
End of Week 6 
495 
316 
495 
471 
End of Week 7 
495 
395 
-- 
-- 
End of Week 8 
495 
471 
-- 
-- 
The number of enrolled participants at the end of each week was calculated with the recruitment rate assumptions 
of 83 and 124 participants per week. The number of total measurable outcome was calculated based on 
14 days of clinical follow-up required for each participant and under the assumption of 5% dropout rate. 
The procedure for the blinded sample size re-assessment will be described in an Interim 
Monitoring Plan approved by the DSMB. In brief, the study statistician will assess the CER and 
dropout rate and re-calculate the sample size required to achieve 90% statistical power at 5% 
2-sided type I error rate to detect a treatment effect size of 50% relative risk reduction. This will 
be done with proper firewall to maintain blinding of the information on the re-calculated sample 
size. If study findings indicate that a study arm should be dropped and additional arms added, the 
sample size required will be calculated based on accumulated data. 
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: 
Population 
Description 
Intention to Treat (ITT) 
All enrolled participants: 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 


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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 + folic acid). 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. 
LRTI will be analyzed using logistic regression stratified by site. 
Sensitivity 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. 
Empirical Bayesian information borrowing method 
In the case that a new experimental treatment is added into this platform trial, there will already 
be data already collected from patients who are enrolled prior (past data). To incorporate the past 
control data with the concurrent control data from patients who are concurrently enrolled, 
empirical Bayesian information borrowing method will be used [43]. Instead of using concurrent 
data only, combining past data with the concurrent data can potentially be advantageous in terms 
of statistical power and lower number of participants that are needed to be randomized to the 
control arm. This is particularly important for possible improved ethics and feasibility for the 
context of conducting a platform trial for SARS-CoV-2. Additionally, in the case that relevant 
external trial data become available, this empirical information borrowing method may be used. 
The DSMB, which will contain clinical experts, will make on whether to include or ignore the 
external trial data. The Study Statistician will assess the similarities of the external trial(s) to this 
clinical trial in terms of eligibility criteria, trial location, data collection procedures, and the 
reliability and comprehensiveness of the available dataset. If deemed appropriate, the empirical 
Bayesian information borrowing method will be used to determine the degree of the information 
that can be “borrowed” from the external dataset and be used for the statistical comparison. 
As there are multiple randomized clinical trials that are either ongoing or being planned right 
now for SARS-CoV-2 with potentially relevant interventions, it is important to plan for an 
approach, such as this empirical Bayesian borrowing method, that can potentially incorporate 
these external data with the internal data. An important feature of this method is the avoidance of 


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use of any subjective or informative prior distributions that may become a point of dispute in 
certain schools of thought. To our knowledge, there are currently 2 published clinical trials with 
potentially relevant interventions as the ones that are proposed for this adaptive platform trial [1, 
44]. In the Chinese trial registry, there are more than 300 interventional trials that have been 
registered for SARS-CoV-2. It is very likely that external data source will become available 
during the trial. 
The full technical details on the empirical Bayesian information borrowing method will be 
described in the Statistical Analysis Plan. 
Missing Data 
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. Hospitalization 
Hospitalization rates between the groups will be compared using logistic regression stratified by 
site. Number of days hospitalized will be described graphically and by median and interquartile 
rage. 
11.3.2.3. 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 10). Results will be analyzed as for the WHO Ordinal 
Scale for Clinical Improvement. 
11.3.2.4. Symptom Resolution 
Days with fever after randomization, respiratory symptoms after randomization, and Sp02<93% 
after randomization will be modeled using Poisson regression stratified by site with an offset for 
number of days of observation. 
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. 


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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 development of LRTI 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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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 
DAIDS 
Division of Acquired Immunodeficiency Syndrome 
DBS 
Dried blood spot 
DSMB 
Data and safety monitoring board 
EC50 
Half-maximal effective concentration 
eCRFs 
Electronic case report forms 
Eligible 
Qualified for enrollment into the study based upon adherence to 
inclusion/exclusion criteria 
Flu-PRO 
InFLUenza patient-reported outcome 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HCQ 
Hydroxychloroquine 
HIPAA 
Health Insurance Portability and Accountability Act 
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 
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 
Polymerase chain reaction 
PEP 
Post-exposure prophylaxis 
PK 
Pharmacokinetic(s) 
QTc 
Heart-rate corrected QT interval 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 


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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, 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 
study discontinuations and premature study treatment discontinuations (and reasons) and AEs. 


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Independent Monitor 
Study conduct will be monitored by an independent monitor. Monitors will visit participating 
clinical research sites 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 
HCQ or HCQ + azithromycin 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. 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: 
 


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Assurance Information: 
United States Department of Health and Human Services Office for Human Research Protections 
Assurance Federal Wide Assurance number: 
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 


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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 
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: 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. 
 
Appendix 8: 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. 


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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. 
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. His/her name and date of birth 
2. Date and time of sample 
3. Date and time of last dose 
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 9: Physiologically Based Pharmacokinetic Modeling of 
Hydroxychloroquine Used for Post-exposure Prophylaxis 
 
 


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Appendix 10: 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 
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  Wet or loose cough 
  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) 


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Take your vitals: 
• 
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. 


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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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SAP_007.pdf: 
Confidential 
COVID-19 Tx Statistical Analysis Plan 
All proprietary rights reserved 
Page 1 of 14 
STATISTICAL ANALYSIS PLAN 
Efficacy of Hydroxychloroquine and Hydroxychloroquine + Azithromycin for Early 
Treatment of SARS-CoV-2 Infection for Prevention of COVID-19 Disease  
Protocol Registry Number: NCT04354428
Effective Date: 24/01/2022 
Version: 1.1


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STATISTICAL ANALYSIS PLAN 
Protocol Name: 
Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among 
High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial  
Author(s): 
Elizabeth R. Brown, ScD 
Version: 
1.1 
Author(s): 
Elizabeth R. Brown, ScD 
Protocol Statistician 
Signature 
Date: 
DD/MM/YYYY 
24/01/2022


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Page 3 of 14 
TABLE OF CONTENTS 
1.
INTRODUCTION ......................................................................................................................... 4
1.1. GENERAL DESIGN CONSIDERATIONS 
...................................................................................................... 4 
1.2. STUDY OBJECTIVES AND ENDPOINTS 
...................................................................................................... 4 
1.3. UPDATED OBJECTIVES AND ENDPOINTS 
.................................................................................................. 5 
1.4. RANDOMIZATION 
............................................................................................................................... 5 
1.5. SAMPLE SIZE AND POWER 
................................................................................................................... 6 
1.5.1. LRTI and Hospitalization Endpoints 
........................................................................................ 6 
1.5.2. Viral Shedding Endpoint 
......................................................................................................... 6 
2.
GENERAL DATA ANALYSIS CONSIDERATIONS 
............................................................................. 6
2.1. BASELINE DATA 
................................................................................................................................. 6 
2.2. ANALYSIS COHORTS AND DATA SETS 
..................................................................................................... 7 
3.
TRIAL PARTICIPANT DISPOSITION .............................................................................................. 8
3.1. DISPOSITION OF PARTICIPANTS 
............................................................................................................. 8 
3.2. TREATMENT EXPOSURE 
....................................................................................................................... 8 
4.  EFFICACY/EFFECTIVENESS ANALYSES ......................................................................................... 9
4.1. EFFICACY ANALYSES 
............................................................................................................................ 9 
4.1.1. LRTI objective ......................................................................................................................... 9 
4.1.2. Hospitalization/Death objective 
........................................................................................... 
10 
4.1.3. Duration of Shedding Objective 
............................................................................................ 
10 
5.
INTERIM MONITORING 
............................................................................................................ 
10
6.
SAFETY ANALYSES 
.................................................................................................................... 
11
6.1. QT PROLONGATION 
......................................................................................................................... 
11 
6.2. ADVERSE EVENTS AND DEATHS .......................................................................................................... 
11 
7.
NON-SAFETY SECONDARY ENDPOINTS 
..................................................................................... 
11
7.1. HOSPITALIZATION ............................................................................................................................ 
11 
7.2. DISEASE SEVERITY ............................................................................................................................ 
12 
7.3. SYMPTOM RESOLUTION 
.................................................................................................................... 
12 
7.4. MAGNITUDE OF VIRAL SHEDDING 
........................................................................................................ 
13 
8.
FOLLOW-UP SUMMARIES ........................................................................................................ 
14
9.
REFERENCES ............................................................................................................................ 
14
10.
CHANGE HISTORY 
.................................................................................................................... 
14


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LIST OF ABBREVIATIONS AND ACRONYMS 
A list of abbreviations used in the SAP. 
Term/Abbreviation 
Definition 
HCQ 
Hydroxychloroquine 
HCQ+A 
hydroxychloroquine + azithromycin 
LRTI 
Lower respiratory tract infection 
WHO 
World Health Organization 
1.INTRODUCTION
This version of the SAP focuses on the three arms first implemented in the protocol. 
1.1. G
ENERAL DESIGN CONSIDERATIONS 
1.2. S
TUDY OBJECTIVES AND ENDPOINTS 
The protocol was written early in the pandemic when there was not adequate information about 
typical  disease  course.  Between  
then  and  
the  writing  of  
this  document,  our  understanding  of 
COVID-19 disease progression has changed, resulting in changes to some of the objectives and 
endpoints. Most notably, the trial was stopped early for operational futility on the primary clinical 
objectives. These changes are noted in the table below. 
Table 1 Original objectives and endpoints as written in the protocol 
Objectives 
Endpoints 
Primary 
To test the efficacy of HCQ and HCQ + 
azithromycin compared to placebo to 
prevent progression to LRTI, among 
persons with SARS-CoV-2 infection who are 
at high risk of progression 
LRTI, defined by resting SpO2<93%, sustained 
for 2 readings 2 hours apart AND presence of 
subjective dyspnea or cough  
To test the efficacy of HCQ and HCQ + 
azithromycin compared to placebo to 
prevent hospitalization and death measured 
at Day 28 among participants who are at 
high risk of progression 
Cumulative incidence of hospitalization or 
mortality, measured at Day 28 
To test the efficacy of HCQ and HCQ + 
azithromycin 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 
1.To test the safety of HCQ and HCQ +
azithromycin compared to placebo for
Serious adverse events (including death and 
hospitalization) and adverse events resulting in 
treatment discontinuation  


 
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treatment of high-risk outpatients with 
SARS-CoV-2 infection 
2. To test whether HCQ and HCQ + 
azithromycin has an effect on the 
duration of hospitalization among 
persons who become hospitalized with 
COVID-19 disease  
Days of hospitalization 
 
3. To test whether HCQ and HCQ + 
azithromycin 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   
4. To test whether HCQ and HCQ + 
azithromycin decreases the resolution 
rate for symptomatic SARS-CoV-2 
infection/COVID-19 disease compared 
to placebo 
• Proportion of days with fever after 
randomization 
• Proportion of days with respiratory 
symptoms after randomization 
• Proportion of days with SpO2<93% without 
supplemental oxygen after randomization 
5. To test whether HCQ and HCQ + 
azithromycin 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 
• Quantity of SARS-CoV-2 detected from 
mid-nasal swabs by PCR 
1.3. 
UPDATED OBJECTIVES AND ENDPOINTS 
The  
trial  was  stopped  early  due  
to  operational  
futility  
the  meet  
the  
first  
two  primary  objectives 
(development  of  LRTI  and  hospitalization/death).  In light  of  this  several  of  the  secondary 
endpoints have been updated as follows. 
• Because  of  
the  very  
few  number  of  hospitalizations,  
the Secondary Objective 2 will  no 
longer be evaluated. 
• The endpoint for Secondary Objective 3 will be the Flu-PRO score evaluated daily over 
14  days instead  of  only  the  maximum  value.  Appropriate  statistical  methods  will  be 
detailed in Section 7.2. 
• The  CDC  definition  of  COVID-19  will  now  define  
the  endpoint  
for Secondary Objective 
(SO) 4. The endpoints currently presented in Table 1 for SO 4 will be summarized over 
time as described in Section 7.2. 
1.4. 
RANDOMIZATION 
Due  
to  
the  adaptive  design  of  
the  study,  we  
implemented  
randomization to  12  dummy  codes, 
stratified by site and risk cohort. Participants are randomized to 1 of 12 dummy codes that are 
mapped to active and control arms using an allocation ratio appropriate to the current design of 
the  study.   Participants   were  randomized  1:1:1  for  the   Hydroxychloroquine  and 
Hydroxychloroquine + Azithromycin efficacy study.  


 
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1.5. 
SAMPLE SIZE AND POWER 
When the protocol was written, we assumed that the trial would enroll quickly and therefore end 
a short time after starting, making 
interim analyses unattainable. Unfortunately, that has not been 
the case due to changes in the epidemic and controversy surrounding hydroxychloroquine. This 
SAP makes minor changes to the study design to allow for multiple interim looks at efficacy and 
futility  and  therefore  includes  minor  changes  to  enrollment  targets.  The  new  sample  size 
calculations are described here. All sample size calculations are based on 4 
interim analyses with 
one final analysis and stopping rules for efficacy and futility. 
1.5.1. 
LRTI and Hospitalization Endpoints 
Overall  sample  size  will  depend  on  the  number  of  events  observed.  To  detect at  
least  50% 
treatment  efficacy  in  reducing LRTI  or  hospitalization/death under  a  null  hypothesis  of  no 
reduction,  
four  
interim  monitoring  analyses  with  stopping  
for  
futility  and  efficacy  based  on  
the 
O’Brien-Fleming bounds and 90% power, the trial is designed to achieve 93 events per pairwise 
comparison for the LRTI and hospitalization endpoints. For two active arms and one control arm, 
the total number of events required for each endpoint is 124. 
As the initial sample size target, 165 per arm was chosen for each experimental group (HCQ, 
HCQ + azithromycin), assuming a control arm rate of approximately 30% and 5% dropout rate. 
1.5.2. 
Viral Shedding Endpoint 
Assuming  
the  median  
time  
to  cessation  of  viral  shedding  
is  10  days,  with  a  constant  baseline 
hazard  
for  cessation  of  shedding,  90%  statistical  power, 1-sided  
type  
I  error  rate  of 2.5% for 
efficacy and early stopping for futility, the design (including interim analyses) can detect 60% or 
greater 
increase 
in the rate of shedding cessation in the 
combined high- and 
low-risk cohorts with 
200 viral clearance events per pairwise comparison. 
2. GENERAL DATA ANALYSIS CONSIDERATIONS 
Descriptive statistics that will be used to summarize continuous variables are as follows: mean 
and standard deviation, median and interquartile range, quartiles, range, and number of missing 
data  values.  If  applicable,  continuous  data  that  are  skewed  will  be  transformed  to  meet 
assumptions of normality. For categorical variables, descriptive statistics that will be used 
include 
the  following:  frequencies,  relative  frequencies,  and  the  number  of  missing  data  values. 
Descriptive  analyses  summarizing  baseline  and  
follow-up  data will  be  stratified  by  site  and/or 
country.  Line,  scatter  and  box  plots  will  be  used,  as  appropriate,  for  longitudinal  data 
representations.  An  alpha  level  of  0.05  will  be  used  for  all  statistical  tests  unless  otherwise 
specified. 
2.1. 
BASELINE DATA 
The following baseline variables will be described: age, sex, presence of known COVID-19 risk 
factors (includes all factors that categorize participants into the high-risk category), race/ethnicity 
and time since onset of symptoms. 


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Baseline variables will be summarized overall and within high and low risk strata by treatment 
arm. Because  of  the  potential  for  imbalance  between  arms  due  to  household-based 
randomization, statistical testing across arms will be performed using gee adjusted by risk strata 
with  exchangeable correlation  within  household.  
If  
there  appears  
to  be  
imbalance  across  
the 
arms, (p<0.10), the variable will be adjusted for in primary analyses. 
2.2. A
NALYSIS COHORTS AND DATA SETS 
This section describes the cohorts and corresponding datasets for the primary, secondary and 
exploratory  analyses described  
in  
this  document.  
In  
the  definitions  below,  cohort  
refers  
to  
the 
study  participants  
included  
in  a  dataset;  whereas  
the  datasets  
further  specify  which  visits  are 
included from the specified cohort. All data sets 
include the baseline variables specified 
in Section 
2.1 and are included as guidance, recognizing that in practice, what is listed as a single data set 
may actually require sets of data sets (for example repeated vs single time point outcomes for 
secondary outcomes) depending on the analysis.  
Intention to Treat (ITT) Cohort: The ITT Cohort includes all participants enrolled into the study. 
Modified Intention to Treat (mITT) Cohort: The mITT Cohort includes all participants enrolled 
into the study who completed the day 1 (enrollment) questionnaire. 
Viral Shedding (VS) Data Set This data set will include all participants in the cohort with 
all data required for primary and secondary viral shedding endpoints. 
Hydroxychloroquine (HCQ) Secondary Efficacy Data Set This data set will include all 
participants in the cohort randomized to hydroxychloroquine or contemporaneous control 
and secondary endpoints. 
Hydroxychloroquine + azithromycin (HCQ+A) Secondary Efficacy Data Set This data 
set  will  include  all  participants in  the  cohort  randomized  to  the  combination 
hydroxychloroquine/azithromycin  arm  or  its  contemporaneous  control  and  secondary 
endpoints. 
Hydroxychloroquine (HCQ) Safety Data Set This data set will include all participants in 
the cohort randomized to hydroxychloroquine or contemporaneous control and secondary 
outcomes. 
Hydroxychloroquine  +  azithromycin  (HCQ+A)  Safety  Data  Set This  data  set  will 
include   all   participants in   the   cohort   randomized   to   the   combination 
hydroxychloroquine/azithromycin  arm  or  its  contemporaneous  control  and  safety 
outcomes. 
Hospitalized Data Set This data set will include all participants who reported a COVID-
19-related hospitalization within the planned 28 days of follow-up. 
Modified Intention to Treat (ITT) High Risk (HR) Cohort: The ITT HR Cohort includes all mITT 
cohort participants enrolled into the study’s high risk cohort. 
Hydroxychloroquine (HCQ) Efficacy Data Set This data set will include all participants 
in the cohort randomized to hydroxychloroquine or contemporaneous control. 
Hydroxychloroquine + azithromycin (HCQ+A) Efficacy  Data  Set This  data  set  will 
include   all   participants in   the   cohort   randomized   to   the   combination 
hydroxychloroquine/azithromycin arm or its contemporaneous control. 


 
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Intention to Treat (ITT) Low Risk (LR) Cohort: The ITT LR Cohort 
includes all contacts enrolled 
into  the  study’s  low  risk  cohort  (persons  age  18-59  without  risk  factors  for  severe  disease, 
including pulmonary disease, DM1 or DM2, HTN, immunocompromising condition, or BMI>30)). 
Modified Intention to Treat (mITT) LRTI Cohort: The mITT LRTI cohort includes ITT HR Cohort 
participants who did not meet the criteria for the primary LRTI endpoint on day 1. The following 
data sets are created from participants in this cohort. 
Hydroxychloroquine (HCQ) LRTI Efficacy  Data  Set This  data  set  will include  all 
participants in the cohort randomized to hydroxychloroquine or contemporaneous control. 
Hydroxychloroquine + azithromycin (HCQ+A) LRTI Efficacy Data Set This data set 
will  include  all  participants in  the  cohort randomized  to  the  combination 
hydroxychloroquine/azithromycin arm or its contemporaneous control. 
Modified  
Intention  to  Treat  (mITT) Disease  Resolution Cohort: This  cohort  
includes mITT  
Cohort participants who meet the COVID-19 disease criteria on day 1 (Section 7.3). The following 
data sets are created from participants in this cohort. 
Hydroxychloroquine (HCQ) Disease Resolution Data Set This data set will include all 
participants 
in the cohort randomized to hydroxychloroquine or contemporaneous control. 
Hydroxychloroquine + azithromycin (HCQ+A) Disease Resolution Data Set This data 
set  will  include  all  participants in  the  cohort  randomized  to  the  combination 
hydroxychloroquine/azithromycin arm or its contemporaneous control. 
Modified Intention to Treat (mITT) Viral Shedding Cohort: This cohort includes mITT  Cohort 
participants who do not meet the definition for clearance of viral shedding at baseline (day 1 and 
day 2 negative swabs). The following data sets are created from participants in this cohort. 
Hydroxychloroquine (HCQ) Viral Shedding (VS) Data Set This data set will include all 
participants 
in the cohort randomized to hydroxychloroquine or contemporaneous control. 
Hydroxychloroquine + azithromycin (HCQ+A) Viral Shedding (VS) Data Set This data 
set  will  include  all  participants in  the  cohort  randomized  to  the  combination 
hydroxychloroquine/azithromycin arm or its contemporaneous control. 
3. TRIAL PARTICIPANT DISPOSITION 
3.1. 
DISPOSITION OF PARTICIPANTS 
All of  the participants  who screened  for  and entered  the  study will  be  accounted  for in  a 
CONSORT flow diagram stratified by cohort (high vs. low risk) including the following measures:  
The  numbers  of  participants  screened,  screened  out  (with  reasons  for  exclusion),  enrolled, 
randomized, allocated to each study arm (with reasons for not receiving assigned intervention), 
reasons for discontinuation from follow-up (e.g., lost to follow-up, adverse event, noncompliance, 
etc.), and the number of participants with available data for each endpoint.   
3.2. 
TREATMENT EXPOSURE 
Self-reported pill taking will be reported by prescribed dosing day stratified by arm and overall. 
The summary measures will be number of doses taken and number of doses taken divided by 


 
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number prescribed. The number and proportion of compliant participants will be reported by day 
and overall time. 
4. EFFICACY/EFFECTIVENESS ANALYSES  
4.1. 
EFFICACY ANALYSES 
All  efficacy  analyses  will  be  adjusted  for  age,  sex at  birth and  time from  symptom  onset to 
enrollment. These adjustments will be additive unless otherwise specified. 
All analyses will account for the household clustering using robust standard errors as available. If 
not available, bootstrap methods will be used.  
For time to event analyses, baseline (time 0) will be day of the enrollment visit. 
Endpoints  will  be  summarized  as  number  of  participants:  hospitalized  without  prior  LRTI, 
hospitalized  with  prior LRTI,  died  without  prior  LRTI,  died  with  prior  LRTI,  who  meet  LRTI 
definition.  These  will  be  shown  as  counts  and  percentages  overall  and  by  cohorts  defined  
in 
Section 2.2 within further breakdown by arm. 
4.1.1. LRTI objective 
Objective: To test the efficacy of HCQ and HCQ + azithromycin compared to placebo to prevent 
progression  to  LRTI,  among  persons  with  SARS-CoV-2  infection  who  are  at  high  risk  of 
progression. 
Outcome: LRTI,  defined  by  resting  SpO2<93%,  sustained  
for  2  readings  2  hours  apart  AND 
presence of subjective dyspnea or cough within the first 14 days of follow-up. 
Cohorts: mITT LRTI Cohort  
Data Sets: HCQ LRTI Efficacy Data Set, HCQ+A LRTI Efficacy Data Set 
Definition of Endpoint: A participant will be defied as having the endpoint 
if they have two resting 
SpO2  
readings less than  93%  
two  hours apart but  not  more  
than  48  hours  apart AND  
report 
subjective dyspnea (defined as a response of “somewhat or higher” on the “trouble breathing” 
question on flupro) or cough (defined as “somewhat or higher” as self-reported wet or dry cough) 
within 24 hours of the time the SpO2 is reported during in the first fourteen days of follow-up. The 
event time will be recorded as the day of the first SpO2 reading less than 93% with the presence 
of subjective dyspnea or cough. Participants who do not reach this endpoint will be censored at 
the last time that the endpoint was ascertained not to be present. Hospitalization or death due to 
COVID-19 may be a competing risk. Per FDA guidance, participants who are hospitalized or die 
due to COVID-19 will have an event time that is the first of LRTI, hospitalization or death. 
Analysis Details:  
Kaplan-Meier  cumulative  
incidence  curves  will  be  estimated  and  plotted  
for  each  
intervention 
including 95% confidence intervals accounting for household cluster.  
Cox proportional hazards models stratified by site and adjusted for baseline covariates identified 
above will be used to estimate the efficacy as 1 minus the hazard ratio. Due to potential clustering 
induced by the household design, robust standard errors will be estimated for the hazard ratio. 
The overall efficacy will be tested using a p-value ascertained from the Wald statistic based on 


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the robust standard error. 95% confidence intervals will also be calculated based on the robust 
standard error. If there are too few endpoints to fit a Cox model then the proportion of participants 
meeting the endpoint 
in the first 14 days will be reported. Each active arm will be compared to the 
control arm separately using Fisher’s Exact test. 
4.1.2. Hospitalization/Death objective 
Objective: To test the efficacy of HCQ, HCQ + azithromycin, or LPV/r compared to placebo to 
prevent hospitalization and death measured at Day 28 among participants who are at high risk of 
progression 
Outcome: COVID-19 related hospitalization or death at or before day 28 or follow-up 
Cohort: mITT High Risk Cohort 
Data sets: HCQ Efficacy Data Set, HCQ+A Efficacy Data Set 
Definition  of  Endpoint: A  participant  will  be  defined  as  having  the  endpoint  if  they  were 
hospitalized or died due to COVID-19 as determined by the adjudication committee before day 
28.  
Analysis Details: 
The proportion of participants with a hospitalization or death before the end of planned follow-up 
will be reported. Each active arm will be compared to the control arm separately using Fisher’s 
Exact test. 
4.1.3. Duration of Shedding Objective 
Objective: To separately estimate and test the efficacy of HCQ and HCQ + azithromycin placebo 
to reduce SARS-CoV-2 viral shedding in high and low risk participants combined. 
Outcome: Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs 
(swabs collected daily Day 1 through Day 14). 
Cohort: mITT Viral Shedding Cohort 
Data sets: HCQ VS Data Set, HCQ+A VS Data Set 
Endpoint: The endpoint time will be set as the day of the first negative swab. Hospitalization and 
death  are  also  competing  risks  for  this  outcome;  however,  clearance  is  a  positive  outcome 
whereas hospitalization and death are negative outcomes that may impede our ability to detect 
clearance. Participants who are hospitalized or die will have their event time censored at day 14. 
Other participants who do not have 2 consecutive negative tests will be censored on the day of 
their last positive test. 
Analysis details: 
Same as Section 4.1.1. 
5.INTERIM MONITORING
A Data Monitoring Committee (DMC) will be convened to monitor the progress of the study. This 
will include study outcomes as well as futility and efficacy on the LRTI endpoint. 


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On July 23, 2020, the DSMB met and enrollment into the trial was stopped on July 28, 2020 for 
operational futility. No interim analyses were performed.  
6.SAFETY ANALYSES
All safety analyses will be performed on the ITT cohort with outcomes presented by randomization 
arm reported overall and stratified by high and low risk.  
6.1. 
QT PROLONGATION 
To investigate whether the interventions lead to QT prolongation as measured by Corrected QT 
interval  (QTc),  we  will  create  boxplots  of  QTc by study  day and  arm.  To test  for  an  overall 
difference  between  arms,  we  will  fit  linear  mixed  effects  models  of  QTc post  randomization 
through day 14 with random intercepts and time slopes. Randomization arm will be a main effect 
with additional main effect adjustments for time, age, sex, site and cohort. 
6.2. A
DVERSE EVENTS AND DEATHS 
Serious adverse events (SAEs, including hospitalization and death), reportable adverse events 
leading  to treatment discontinuation  (RAEs),  and  cardiac  v.  non-cardiac  events will  be 
summarized in frequency tables (including both the number of each SAE/RAE and the number of 
distinct participants ever reporting each SAE/RAE) by severity and randomization arm, for each 
of the low and high risk cohorts, and overall.  
7.NON-SAFETY SECONDARY ENDPOINTS
7.1. H
OSPITALIZATION 
Objective: To  test  whether  HCQ or HCQ  +  azithromycin has  an  effect  on  the  duration  of 
hospitalization  among  persons  who  become  hospitalized  with  COVID-19  disease compared  
to 
control. 
Outcome: Days of hospitalization 
Cohort: ITT Cohort 
Data sets: Hospitalized Data Set 
Endpoint: Number of days from admission to discharge (this may be informatively censored by 
death) 
Analysis details:  
Because  of  very  
low  
incidence  of  hospitalization  
in  
this  study,  only  
the minimum,  median  and 
maximum of days of hospitalization will be reported by arm. 


 
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7.2. 
DISEASE SEVERITY 
Objective: To  test  whether  HCQ or HCQ  +  azithromycin  has  an  effect  on  disease  severity 
compared to placebo 
Outcomes: Disease severity is measured using two scales: the WHO Ordinal Scale for Clinical 
Improvement and The Modified Flu-PRO 
Cohort: ITT Cohort 
Data sets:  
Endpoints: This  analysis  will  have  two  endpoints:  1)  the  WHO  Ordinal  Scale  for  Clinical 
Improvement  measured  on  days  14,  21  and  28  and  2)  
the score  
from  
the  modified  Flu-PRO 
measured daily on the first 14 days 
in the study, excluding the baseline (day 1). The modified Flu-
PRO  score  
is  calculated  as  
the  mean  score  across  
the  Flu-PRO  questionnaire (sum  numeric 
value over all symptoms and divided by number of symptoms[1]). 
Analysis  details: The  distribution  of  scores  will  be  described  by  arm  at  each  visit  
including 
minimum, maximum, median and IQR. Boxplots of the Flu-PRO score will be presented by visit 
and arm and further stratified by risk cohort.  
Testing: Because the maximum observed value may have undesirable statistical properties, we 
will perform  hypothesis  
testing  on  all  
the observed  data over  
the  
first  14  days. Mixed  effects 
models with random slopes and intercepts will be used to model the mean Flu-PRO score over 
time  with  a  main  effect  of  
randomization.  The  
interaction  between  
randomization  and  
time  will 
also be included to explore the potential effect of randomization on the change in Flu-PRO score 
over time. Testing between arms will be based on the coefficients from the main treatment effect 
and the interaction term using Wald tests. These tests will detect average differences between 
the  arms  in  Flu-PRO  scores. Recognizing  that  linear  models  may  not  well  fit  the  Flu-PRO 
trajectories, an exploratory model using B-splines will also be fit. 
7.3. 
SYMPTOM RESOLUTION 
Objective: To  test  whether  HCQ or HCQ  +  azithromycin  decreases the  resolution  rate  for 
symptomatic SARS-CoV-2 infection/COVID-19 disease compared to placebo 
Outcome: Symptomatic  SARS-CoV-2  infection/COVID-19  disease is  defined 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  
• At least ONE of the following symptoms: cough, shortness of breath or difficulty 
breathing, OR 
• Severe respiratory illness with at least 1 of the following:  
o Clinical or radiological evidence of pneumonia, OR 
o Acute respiratory distress syndrome (ARDS) 
 
A participant will be defined as having reached the endpoint if they have two consecutive visits 
that do not meet the definition above. The time of the endpoint will be the midpoint between the 
last symptomatic day before reaching the endpoint and the first non-symptomatic day defining the 
endpoint. Participants who do not have the endpoint will be censored at the last time they were 


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known to be symptomatic. Death and hospitalization will be counted in the endpoint by assigning 
their follow-up to be censored at day 14. 
Cohort: mITT Disease Resolution Cohort 
Data sets: HCQ Disease Resolution Data Set, HCQ+A Disease Resolution Data Set 
Endpoint: Resolution of COVID-19 symptoms for 2 or more days. 
Stratification variables: Indicator of more than 4 days since onset of symptoms (as measured 
at enrollment visit)  
Analysis  details: Kaplan-Meier  cumulative  
incidence  curves  will  be  estimated  and  plotted  
for 
each intervention including 95% confidence intervals accounting for household cluster. Curves 
will also be plotted by arm and stratification variable. 
Cox proportional hazards models stratified by high/low risk and adjusted for baseline covariates 
identified above will be used to estimate the efficacy as 1 minus the hazard ratio. Due to potential 
clustering  
induced  by  the  household  design,  robust  standard  errors  will  be  estimated  for  the 
hazard ratio. The overall efficacy will be tested using a p-value ascertained from the Wald statistic 
based on the robust standard error. 95% confidence 
intervals will also be calculated based on the 
robust standard error. 
7.4. M
AGNITUDE OF VIRAL SHEDDING 
Objective: To  test  whether  HCQ or HCQ  +  azithromycin  
is  associated  with  decreased  viral 
shedding from self-collected nasal swabs over 14 days compared to placebo 
Outcomes: Quantity of SARS-CoV-2 detected from mid-nasal swabs by PCR as measured by 
cycle threshold (Ct)  
Cohort: mITT Cohort 
Data sets: VS Data Set 
Analysis  details: Generalized  
linear  mixed  effects  models  with  
random  
intercepts  and slopes 
(time) will be used to model the quantity of SARS-CoV-2 over time. Because of the high number 
of samples where Ct was above the upper limit (eg >40) and not recorded, we will do analyses 
with Ct dichotomized as follows: 
• Ct>40 on both targets vs Ct<=40 on either target
• Concordant results vs discordant or negative
• Ct<24 on either target as this may be an 
indicator of greater propensity to be 
infectious[2].
Fixed effects will 
include randomization arm, B-spline coefficients for time, an 
interaction between 
arm and time, cohort, age, and other baseline covariates indicated for the primary analysis. Time 
will be the time since enrollment visit to collection of the sample. 


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8.FOLLOW-UP SUMMARIES
Additional  descriptive  analyses  will  be  performed  on  the  following  variables as  recorded  on 
participant surveys over time: Temperature, O2 saturation, heart rate and respiratory rate. These 
analyses will 
include boxplots by visit and arm, further broken out by risk cohort and table reporting 
mean, median and IQR by visit and arm stratified by risk cohort. 
9.REFERENCES
1.
Powers, J.H., 3rd, et al., Reliability, Validity, and Responsiveness of InFLUenza Patient-
Reported  Outcome  (FLU-PRO(c))  Scores  
in  
Influenza-Positive  Patients. Value  Health,
2018. 21(2): p. 210-218.
2.
Bullard, J., et al., Predicting infectious SARS-CoV-2 from diagnostic samples. Clin Infect
Dis, 2020.
10. CHANGE HISTORY
Major changes after Version 1.0 will be recorded here. 
Version 
Affected 
Section(s) 
Activity Description 
Number Effective 
Date 
1.1          24/01/2022   Title Page               Corrected Protocol Registry Number

ICF_004.pdf: 
Pr ot o c ol  Titl e: 
Effi c a c y  o f N o v el  A g e nt s  f or Tr e at m e n t o f S A R S -C o V -
2 I nf e cti o n A m o n g Hi g h- Ri s k  O ut p ati e n t A d ult s : A n  
A d a pti v e R a n d o mi z e d Pl atf o r m Tri al 
N C T  N um b er:  
N C T 0 4 3 5 4 4 2 8  
D o c u m e nt  D at e: 
1 5  A pril  2 0 2 0 


I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A pr 1 5, 2 0 2 0 
 
C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
1  
I N F O R M E D C O N S E N T  F O R M  
 
 
TI T L E : 
Efficac y   of N o vel  A ge nts   f or Treat me nt   of S A R S -C o V - 2  I nfecti o n  A m o n g Hi g h -Ris k  
O ut patie nt A d ults:   A n  A da pti ve  Ra n d o mize d Platf or m  Trial  
 
P R O T O C O L  N O .: 
U W -I C R C Pr ot oc ol # 5 5 
 
WI R B
®  Pr ot oc ol # 2 0 2 0 0 8 0 1 
 
S P O N S O R : 
U ni versit y  of Wa s hi n gt o n 
 
I N V E S TI G A T O R: 
Na me  
 
A d dress 
 
Cit y, State  Zi p  
 
C o u ntr y 
 
S T U D Y -R E L A T E D  
P H O N E  N U M B E R( S):  
P h o ne N u m ber 
 
P h o ne N u m ber ( 2 4 h o urs) 
 
[ 2 4 h o ur n u m ber is re q uire d] 
 
 
We  are as ki n g y o u  t o be i n a researc h st u d y.  T his  st u d y is bei n g c o n d ucte d b y [Site Na me ] a n d t he U ni versit y  of 
Was hi n gt o n  Vir ol o g y,  w hic h  is base d  i n Seattle,  Was hi n gt o n. T his  f or m descri bes  t he st u d y pr oce d ures  a n d gi ves  y o u  
i nf or mati o n t o deci de  w het her y o u  wis h  t o be  i n t he st u d y. Bei n g  i n t he st u d y is e ntirel y y o ur c h oice ( v ol u ntar y).  
 
W h at s h o ul d I d o ?   
1.  Rea d  t his f or m, or ha ve  it rea d t o y o u. 
2.  Ma ke  s ure t he st u d y d oct or or st u d y staff e x plai ns t he st u d y t o y o u. 
3.  As k  q uesti o ns (e. g., ti me c o m mit me nt, u nfa miliar w or ds,  s pecific pr oce d ures,  etc.) 
4.  T a ke  ti me t o c o nsi der  t his, a n d tal k a b o ut it wit h  y o ur fa mil y a n d frie n ds.  
 
T he first part  of t his c o nse nt  f or m gi ves  y o u  a s u m m ar y of  t his st u d y.  
 
T he sec o n d part  of t his c o nse nt  f or m gi ves  y o u  m ore  details  a b o ut t he st u d y pr oce d ures a n d a n y ris ks t o y o u. 
 
P U R P O S E  O F  T H E  S T U D Y  
 
Se vere  ac ute res pirat or y s y n dr o me c or o na vir us 2 ( S A R S-C o V - 2) is t he vir us  t hat ca uses  c or o na vir us disease  ( C O VI D- 1 9).  
T he p ur p ose of t his st u d y is t o u n dersta n d  if ta ki n g h y dr o x yc hl or o q ui ne ( H C Q) O R  H C Q  pl us azit hr o m yci n ma y  be use d  t o 
hel p treat pe o ple i nfecte d wit h  earl y S A R S -C o V - 2 i nfecti o n. C urre ntl y,  t here are n o  F D A -a p pr o ve d treat me nt dr u gs f or 
S A R S -C o V - 2 i nfecti o n or  C O VI D - 1 9.  
 
H C Q  is c urre ntl y a p pr o ve d  t o treat malaria  a n d a ut oi m m u ne  diseases.  T he  F D A  first a p pr o ve d  H C Q  i n 1 9 5 5.  O verall,  it is 
safe a n d well  t olerate d. We  d o n’t k n o w if H C Q  is a n effecti ve treat me nt f or C O VI D - 1 9.  
 
Azit hr o m yci n  is a n a nti bi otic use d  t o treat p ne u m o nia a n d si n us i nfecti o ns. We  d o n’t k n o w if azit hr o m yci n i n c o m bi nati o n 
wit h  H C Q  is a n effecti ve  treat me nt f or C O VI D - 1 9. 
 


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M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A pr 1 5, 2 0 2 0 
 
C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
2  
T his  st u d y will  sh o w  us w het her  earl y treat me nt of S A R S -C o V - 2 i nfecti o n is effecti ve at pre ve nti n g m ore  se vere ill ness.  
We  will  st u d y t hese me dicati o ns  i n pe o ple w h o  are well  e n o u g h t o be treate d i n t heir h o mes.  We  will  st u d y t he me dicati o n  
i n pe o ple w h o  are at i ncrease d ris k f or de vel o pi n g c o m plicati o ns of S A R S -C o V - 2 i nfecti o n, a n d als o pe o ple w h o  d o n ot 
ha ve  i de ntifie d ris k fact ors f or m ore  se vere i nfecti o n. 
 
If y o u  c h o ose t o be i n t he st u d y, y o u  will  be assi g ne d b y  c ha nce  (c ha nce is li ke fli p pi n g a c oi n) t o eit her ta ke H C Q  + f olic 
aci d, H C Q - + azit hr o m yci n, or vita mi n  C + f olic aci d. Y o u  will  ta ke a d o u ble d ose  b y H C Q  or vita mi n  C b y m o ut h t wice 
dail y  f or o ne  da y,  f oll o we d b y a si n gle d ose  b y m o ut h t wice dail y  f or 9 da ys,  f or a t otal of  1 0 da ys  of treat me nt.  Y o u  will  
take  a d o u ble d ose of azit hr o m yci n  or f olic aci d o n  da y o ne, f oll o we d b y o nce dail y  f or 4 da ys.  
 
Pre g na nt a n d lactati n g pers o ns will  be  eli gi ble f or e nr oll me nt i nt o t his st u d y. B ot h  H C Q  a n d azit hr o m yci n  ha ve  bee n  s h o w n 
t o be safe i n pre g na nt w o me n. 
 
S T U D Y  P R O C E D U R E S  
 
We  are testi n g H C Q  a n d H C Q +azit hr o m yci n  i n a d ults w h o  ha ve  ha d a la b orat or y c o nfir me d S A R S -C o V - 2 i nfecti o n wit hi n  
t he past  7 2 h o urs. We  are i n viti n g y o u  t o partici pate  beca use  y o u  ha ve  bee n  referre d b y y o ur healt hcare  pr o vi der or  ha ve  
bee n  self-referre d. Here  is w hat  t he st u d y i n v ol ves:  
 
•  
Y o u  will  be c o ntacte d b y o ur  researc h tea m a n d as ke d t o j oi n t his st u d y. Y o u  will  be i n t his st u d y f or a p pr o xi matel y 
2 8 da ys  a n d n o i n- pers o n visits  are necessar y  – e ver y i nteracti o n will  occ ur  via  tele p h o ne, tele healt h, i nter net, or 
mail.  If y o u  are selecte d f or a s u bst u d y y o u  will  c o m plete e xtra sa m ple c ollecti o ns t hr o u g h o ut t he st u d y a n d 2 8  
da ys  after  y o ur first visit.   
•  
We  will  as k y o u  t o c o m plete a brief  e nr oll me nt s ur ve y a b o ut me dical  hist or y,  c urre nt & past  s y m pt o ms, date of 
C O VI D - 1 9 dia g n osis, c urre nt use  of me dici nes,  a n d de m o gra p hics. T hese  q uesti o ns will  be  as ke d eit her b y 
tele p h o ne or a ns weri n g q uesti o ns i n a n o nli ne s ur ve y.  
•  
We  will  as k y o u  t o si g n Healt h  I ns ura nce P orta bilit y  a n d Acc o u nta bilit y  Act  ( HI P A A) f or ms s o we  ma y  access  
y o ur C O VI D - 1 9 relate d me dical  rec or ds.   
•  
Y o u  will  c o m plete a s h ort s ur ve y a b o ut y o ur c urre nt  healt h  f or 1 4 da ys.   We  will  as k y o u  t o meet  wit h  st u d y staff 
via  tele healt h r o u g hl y e ver y 3- 4 da ys  d uri n g t he st u d y.  Y o u  will  ha ve  t he o pti o n t o re q uest t o meet  wit h  st u d y staff 
via  tele healt h m ore  fre q ue ntl y. We  will  as k y o u  t o c hec k y o ur te m perat ure, o x y ge n  sat urati o n, p ulse,  a n d 
res pirat or y rate t wice a da y.   We  will  als o as k y o u  t o c hec k y o ur heart  r h yt h m usi n g  a de vice.   We  will  pr o vi de  all 
s u p plies t o y o u  t o d o t hese assess me nts.   T he  pr oce d ures will  ta ke a b o ut 3 0 mi n utes eac h da y.    
•  
Y o u  w ill be as ke d t o self-test f or y o ur c urre nt  C O VI D - 1 9 stat us b y s wa b bi n g t he i nsi de of y o ur n ose  wit h  a s pecial 
s wa b calle d a nasal  s wa b. We  will  as k y o u  t o re peat t his pr oce d ure wit h  a ne w  s wa b dail y  w hile  i n t he st u d y. O nce  
y o u  ha ve  s wa b be d t he i nsi de of y o ur n ose,  y o u  will  p ut  y o ur s wa b i n a s pecial t u be f or st ora ge. 
•  
Y o u  ma y  als o be as ke d t o pric k  y o ur fi n ger t o c ollect dr o ps of  bl o o d calle d drie d  bl o o d s p ots o n a s pecial car d. We  
ma y  as k y o u  t o c ollect  t hese bl o o d s p ots at e nr oll me nt, part wa y  t hr o u g h t he st u d y, a n d at t he e n d of t he st u d y.  
•  
We  will  pr o vi de  y o u  wit h  all of  t he s u p plies y o u  nee d  t o c ollect y o ur sa m ples. T he s u p plies will  arri ve i n a 
c o uriere d pac ka ge,  a n d we  will  gi ve  y o u  e n vel o pes a n d p osta ge t o eit her mail  t he m bac k  or a c o urier will  c o me 
c ollect  t he m. 
•  
T o  test f or n o vel  c or o na vir us, t he s wa bs will  be  se nt t o t he U ni versit y  of Was hi n gt o n.   Y o ur res ults ma y  n ot be 
a vaila ble  f or wee ks  after t he st u d y is c o m plete d.  W he n  y o ur res ults are a vaila ble, we  will  pr o vi de t he m t o y o u.  
T hese  s wa bs are n ot part  of r o uti ne cli nical  care. 
 
T hi s st u d y d oes n ot re place or affect  a n y care y o u  mi g ht recei ve fr o m y o ur d oct or.  
 


I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A pr 1 5, 2 0 2 0 
 
C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
3  
RI S K S,  S T R E S S,  O R  DI S C O M F O R T  
 
Beca use  t here are al wa ys  s o me ris ks t o ta ki n g part i n a researc h st u d y, we  ha ve  liste d s o me of t he m ost  li kel y ris ks of  
partici pati o n i n t his st u d y here:  
 
P ossi ble  Ris ks  rel ate d t o H C Q  tre at me nt  
 
•  
Na usea  
•  
Diarr hea  
•  
S ki n  pi g me ntati o n  
 
T here  are  als o  r are b ut  seri o us ris ks of  H C Q  tre at me nt, li ke: 
 
•  
Seri o us  aller gic reacti o n, i ncl u di n g a se vere s ki n ras h 
•  
Reti n o pat h y  
•  
Ne ur o pat h y  
•  
S keletal  m y o pat h y 
•  
Car di o m y o pat h y 
•  
Heart  r h yt h m pr o ble ms 
•  
L o w  bl o o d s u gar ( h y p o gl yce mia), es peciall y f or t h ose ta ki n g a nti dia betes  me d icati o ns. 
 
P ossi ble  Ris ks  rel ate d t o azit hr o m yci n tre at me nt  
 
•  
Na usea  
•  
Occasi o nal  dizzi ness  
•  
Diarr hea  
•  
A b d o mi nal pai n  
•  
V o miti n g  
 
T here  are  als o  r are b ut  seri o us ris ks of  azit hr o m yci n tre at me nt, li ke: 
 
•  
Seri o us  aller gic reacti o n  
•  
Heart  r h yt h m pr o ble ms 
•  
Dr u g  i nteracti o ns 
 
Ris k  of  o ver d ose:  T here  are ris ks t o ta ki n g t o o m uc h  H C Q.  T he a m o u nt of  H C Q  prescri be d  i n t his st u d y is safe.  H o we ver,  
if y o u  partici pate  i n t his cli nical  trial, d o n ot  ta ke H C Q  pr o vi de d b y y o ur healt h  care pr o vi der or ot her  s o urces.   
 
If y o u  have  diabetes a n d y o u  are ta ki n g i ns uli n, y o u  ma y  nee d  t o decrease  y o ur i ns uli n d osa ges  w hile  o n t his st u d y.  If y o u  
are ta ki n g oral  dia betes me dicati o ns or  i ns uli n, y o u  ma y  nee d  t o i ncrease y o ur m o nit ori n g of bl o o d s u gar a n d y o ur 
a ware ness  of l o w bl o o d s u gar.  If t his is n ot p ossi ble, t his st u d y ma y  n ot be safe f or y o u.   
 
T he ris k of heart  r h yt h m c ha n ges  ma y  be i ncrease d wit h  t he c o m bi nati o n of  azit hr o m yci n a n d h y dr o x yc hl or o q ui ne.  T here  
is a ris k of heart  r h yt h m a b n or malities w hic h  ma y  lea d t o seri o us c o nse q ue nces  a n d e ve n deat h. We  will  m o nit or y o ur heart  
r h yt h m d uri n g t he st u d y t o ma ke  t he st u d y as safe as p ossi ble.    
 


I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A pr 1 5, 2 0 2 0 
 
C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
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P ossi ble  Ris ks  rel ate d t o N as al S w a bs  or Fi n ger pric k:  
 
•  
S wa b bi n g y o ur n ose ma y  ca use  mil d  disc o mf ort, water y  e yes, or s neezi n g. 
•  
Dra wi n g  a fe w dr o ps of bl o o d fr o m y o ur fi n ger f or t he dr y bl o o d test ma y  ca use te m p orar y disc o mf ort fr o m t he 
nee dle stic k, br uisi n g, a n d i nfecti o n. 
 
S o me  q uesti o ns we  mi g ht  as k y o u  are se nsiti ve a n d ma y  ma ke  y o u  feel u nc o mf orta ble. Y o u  d o n ot  ha ve  t o a ns wer  a n y 
q uesti o n y o u  d o n ot wa nt  t o. T here  is a ris k t hat y o ur pri vac y  c o ul d be breac he d.  We  will  d o e ver yt hi n g we  ca n t o ma ke  
s ure t hat t his d oes n ot ha p pe n. 
 
B E N E FI T S  O F  T H E  S T U D Y  
 
P ossi ble  Be nefits:  
If y o u  are i n t he gr o u p t hat recei ves H C Q,  a n d if it pr o ves  t o re d uce y o ur c ha nces  of de vel o pi n g se vere C O VI D - 1 9 disease  
or s h orte ns t he d urati o n of  y o ur disease.  
 
If y o u  are i n t he gr o u p t hat recei ves H C Q +azit hr o m yci n,  a n d if it pr o ves  t o re d uce y o ur c ha nces  of  de vel o pi n g  se vere 
C O VI D - 1 9 disease  or  s h orte ns t he d urati o n of y o ur disease.  
 
If y o u  are i n t he gr o u p t hat recei ves vita mi n  C, t his ma y  hel p t o s u p p ort y o ur i m m u ne s yste m b ut y o u  will  n ot  recei ve eit her 
of t he st u d y dr u gs.   
 
Y o u  ma y  be nefit fr o m partici pati n g  i n t he st u d y, b ut t his ca n n ot be g uara ntee d.  
 
Y o ur  Ot he r O pti o ns:  
T here  are c urre ntl y n o a p pr o ve d dr u gs t o treat C O VI D - 1 9. H o we ver,  y o ur cli nicia n ma y  c h o ose t o prescri be y o u  dr u gs 
i ncl u di n g H C Q  & H C Q/azit hr o m yci n  t o treat C O VI D - 1 9 if t he y t hi n k t he dr u gs ma y  hel p, e ve n t h o u g h n o dr u gs  yet  are 
k n o w n t o hel p or F D A -a p pr o ve d. Y o u  d o n ot  ha ve  t o partici pate  i n t his st u d y.  
 
Y o ur ot her c h oices  ma y  i ncl u de: 
•  
T a ki n g  part  i n a n ot her st u d y. 
•  
W or ki n g wit h  y o ur d oct or t o ma na ge  y o ur C O VI D - 1 9 o utsi de of  a st u d y. 
 
Y o u  ma y  wa nt  t o tal k t o y o ur  d oct or a b o ut y o ur c h oices bef ore a greei n g t o partici pate  i n t his st u d y.  
 
S O U R C E  O F  F U N DI N G  
 
T he [Site  Na me ] a n d/ or   t he U ni versit y  of  Was hi n gt o n  is recei vi n g  fi na ncial  s u p p ort fr o m  t he Bill   &  Meli n da Gates  
F o u n dati o n. 
 
D E T AI L E D  S T U D Y  I N F O R M A TI O N 
 
T he f oll o wi n g is a m ore  c o m plete  descri pti o n of t his st u d y. Please  rea d t his descri pti o n caref ull y. Y o u  ca n as k a n y 
q uesti o ns y o u  wa nt  t o hel p  y o u  deci de w het her  t o j oi n t he st u d y. If y o u  j oi n t his st u d y, we  will  offer  y o u  a c o p y of t his f or m 
t o kee p  f or f ut ure refere nce. 
 
Resea rc h st u dies i ncl u de o nl y  pe o ple w h o  c h o ose t o ta ke part. Please  ta ke y o ur ti me t o ma ke  y o ur decisi o n a b o ut 
partici pati n g. Y o u  ma y  disc uss y o ur decisi o n wit h  y o ur fa mil y a n d frie n ds a n d wit h  y o ur healt h  care tea m. If y o u  ha ve  a n y 
q uesti o ns, y o u  ma y  as k y o ur  st u d y d oct or. If y o u  decli ne  t o partici pate  y o ur d oct or will  still gi ve  y o u  care f or y o ur C O VI D -
1 9 dia g n osis.  
 


I R B A p pr o v e d Te m plate 
M U S T  B E  A P P R O V E D  
F O R  SI T E S  B E F O R E  U S E  
A S M O DI FI E D  
A pr 1 5, 2 0 2 0 
 
C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
5  
W h y  a m I bei n g  as ke d  t o p artici p ate ?  
Y o u  are bei n g as ke d t o ta ke part  i n t his st u d y beca use  y o u  are a n a d ult w h o  has  ha d  a la b orat or y c o nfir me d S A R S -C o V - 2 
i nfecti o n res ult wit hi n  t he past  7 2  h o urs.  
 
W h y  is t his st u d y bei n g  d o ne ?  
T he p ur p ose of t his st u d y is t o u n dersta n d  if t he malaria  a n d a ut oi m m u nit y me dicati o n  calle d h y dr o x yc hl or o q ui ne ( H C Q) 
O R  t he c o m bi nati o n of H C Q  wit h  t he a nti bi otic calle d azit hr o m yci n, can re d uce t he le n gt h a n d/ or se verit y of C O VI D - 1 9 
disease.  T he  st u d y will  als o l o o k at w het her  t he dr u gs  are safe f or patie nts  wit h  C O VI D - 1 9.  W hile  H C Q  a n d azit hr o m yci n 
are a p pr o ve d b y t he F o o d a n d Dr u g  A d mi nistrati o n  ( F D A), usi n g t he dr u gs t o treat C O VI D - 1 9 is i n vesti gati o nal a n d is n ot  
a p pr o ve d b y t he F D A.  
 
T he ma n ufact urer of  t he dr u gs t hat are bei n g use d  i n t his st u d y are n ot  i n v ol ve d i n t his st u d y. T he  st u d y will  pr o vi de t he 
assi g ne d dr u g at n o  c ost  t o t he researc h partici pa nt.  
 
H o w  m a n y  pe o ple  will  t a ke p art  i n t his st u d y ? 
A b o ut 6 3 0 pe o ple will  ta ke part i n t his st u d y.  
 
W h at will  h a p pe n  if I t a ke p art  i n t his rese arc h st u d y ? 
If y o u  are eli gi ble t o be i n t he st u d y a n d y o u  c h o ose t o ta ke part,  t he n y o u  will  nee d  t he f oll o wi n g tests a n d pr oce d ures: 
 
•  
Y o u  will be as ke d t o c o m plete s ur ve ys b y tele p h o ne, we b,  or vi de o  c hat. 
o  Y o u  will  be as ke d t o atte n d tele healt h visits  wit h  t he st u dy staff. 
o  Y o u  will  be as ke d a series of q uesti o ns a b o ut y o ur healt h,  i ncl u di n g y o ur c urre nt  C O VI D - 1 9 s y m pt o ms, 
i ncl u di n g s h ort ness of breat h, fe ver, a n d c o u g h.   
o  Y o u  will  be as ke d if y o u  ha ve  a n y s y m pt o ms t hat ca n be  ass ociate d wit h  ta ki n g H C Q  or azit hr o m yci n. 
o  Y o u  will  als o be  as ke d ot her  q uesti o ns a b o ut y o ur me dical  hist or y,  c urre nt  vitals,  c urre nt  & past  s y m pt o ms, 
date of C O VI D - 1 9 dia g n osis, c urre nt  use  of  me dici nes,  a n d de m o gra p hics. 
•  
Y o u  will  self-test t o m o nit or y o ur C O VI D - 1 9 nasal  s he d di n g. T his  will  be d o ne b y s wa b bi n g t he i nsi de of  y o ur 
n ose.  
•  
Y o u  ma y  be as ke d t o c ollect  a fe w dr o ps of  bl o o d b y pric ki n g y o ur fi n ger a n d c ollecti ng it o n a piece  of filter pa per  
we  pr o vi de y o u. T his  bl o o d will  be use d  t o test f or t he le vel of dr u g  or C O VI D - 1 9 a nti b o dies i n y o ur bl o o d, 
i nfecti o n fi g hti n g cells, or  i nfla m mat or y mar kers.  If ot her tests directl y  relate d t o C O VI D - 1 9 are de vel o pe d  we  ma y  
use t he bl o o d t o u n dersta n d y o ur i m m u ne res p o nse usi n g  t h ose tests. 
•  
We  w ill as k y o u  t o c hec k y o ur te m perat ure, o x y ge n  sat urati o n, p ulse, a n d res pirat or y rate t wice a da y.   We  will  als o 
as k y o u  t o c hec k y o ur heart  r h yt h m usi n g a de vice.   We  will  pr o vi de all s u p plies t o y o u  t o d o t hese assess me nts  a n d 
will  teac h y o u  h o w t o use  t he m.  T he pr oce d ures will  ta ke a b o ut 3 0  mi n utes eac h da y.   
•  
Y o u  will  recei ve a n e mail dail y  wit h  a li n k t o a s ur ve y t o d oc u me nt w he n  y o u  ta ke t he treat me nt (eit her H C Q +f olic  
aci d, H C Q +a zit hr o m yci n, or vita mi n  C +f olic  aci d). T he  s ur ve y will  as k h o w y o u  are feeli n g, a n d if y o u  ha ve  
c ollecte d a nasal  s wa b. We  w o ul d li ke y o u  t o c o m plete t his o nce a da y  f or t he 1 4 da ys  y o u  are e nr olle d i n t he st u d y, 
a n d o n Da y  2 1 a n d Da y  2 8.  
•  
Y o u  will  be as ked t o c o m plete a fi nal brief  s ur ve y b y t ele p h o ne or  i nter net at c o m pleti o n of t he st u d y. S o me  of 
t hese q uesti o ns ma y  i ncl u de h o w y o u  are feeli n g, if y o u  t h o u g ht y o u  were  ta ki n g H C Q,  azit hr o m yci n, or vita mi n  C,  
a n d y o ur t h o u g hts o n partici pati n g  i n t he st u d y.  
 
Y o u  will  be "ra n d o mize d" i nt o o ne  of t he st u d y gr o u ps descri be d  bel o w. Ra n d o mizati o n mea ns  t hat y o u  are p ut  i nt o a gr o u p  
b y c ha nce, li ke fli p pi n g a c oi n. A c o m p uter pr o gra m will  place  y o u  i n o ne of t he gr o u ps. Y o u  will  ha ve  a n e q ual  or  3 3. 3 3 % 
c ha nce ( one  i n t hree) of  bei n g place d  i n t he H C Q  treat me nt gr o u p vs.  H C Q +azit hr o m yci n  treat me nt gr o u p vs.  t he vita mi n  
gr o u p. Y o u  a n d y o ur d oct or will  n ot k n o w w hic h  gr o u p y o u  are assi g ne d t o. T he  st u d y p har macist  will  k n o w y o ur gr o u p 
assi g n me nt  & will  discl ose  t he i nf or mati o n at t he e n d of  t he st u d y, or if t here is a me dical  e mer ge nc y a n d it is re q uire d t o 
d o s o.  
 


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C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
6  
Y o u will  be  pr o vi de d  wit h  a s u p pl y of  pills.   Y o u  will  ta ke a d o u ble d ose  b y m o ut h  t wice dail y  f or o ne da y.  T he n,  y o u  
will  ta ke a si n gle d ose b y m o ut h t wice dail y  f or t he ne xt  9 da ys,  f or a t otal of 1 0 da ys  of treat me nt.  Y o u  will  be  pr o vi de d 
wit h  d osi n g directi o ns w he n  y o u  recei ve t he me dicati o ns.  
 
•  
If y o u are  assi g ne d  t o t he gr o u p recei vi n g H C Q,  y o u  will  be ta ki n g 4 0 0 m g  H C Q  t wice dail y  o n da y o ne, a n d 
t he n 2 0 0 m g of H C Q  t wice dail y  f or t he ne xt  9 da ys.  Y o u  will  ta ke f olic aci d 8 0 0 mc g dail y  o n da y o ne, a n d f olic 
aci d 4 0 0 mc g dail y  o n da y 2- 5. 
 
•  
If y o u are  assi g ne d  t o t he gr o u p recei vi n g H C Q/ azit hr o m yci n,  y o u  will  be ta ki n g 4 0 0 m g  H C Q   t wice dail y  o n 
da y o ne, a n d t he n 2 0 0 m g  of  H C Q  t wice dail y  f or t he ne xt  9 da ys.  Y o u  will  ta ke azit hr o m yci n 5 0 0 m g  dail y  o n da y 
o ne, a n d azit hr o m yci n  2 5 0 m g dail y  o n da y 2- 5. 
 
•  
If y o u are  assi g ne d  t o t he gr o u p recei vi n g t he vit a mi n C pill,  y o u  will  be  ta ki n g 5 0 0 m g  of vita mi n  C t wice dail y  
o n da y o ne, a n d t he n 2 5 0 m g  of vita mi n  C t wice dail y  f or t he ne xt  9 da ys.  Y o u  will  ta ke f olic aci d 8 0 0 mc g dail y  o n 
da y o ne, a n d f olic aci d 4 0 0 mc g dail y  o n da y 2- 5. 
 
Ti mi n g  of  st u d y visits  a n d  pr oce d ures:  
 
•  
T he i nitial e nr oll me nt s ur ve y will  ta ke a p pr o xi matel y 1 5  mi n utes. 
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T he i nitial e nr oll me nt visit  wit h  t he st u d y staff will  ta ke a p pr o xi matel y 4 5 mi n utes, t o u p t o 2 h o urs. 
•  
T he f oll o w u p  visit  ( da ys 2, 4 a n d 9, a n d 1 4) wit h  t he st u d y staff will  ta ke a p pr o xi matel y 2 0 mi n utes. 
•  
T he dail y  f oll o w u p s ur ve y ( da ys 2- 1 4) will  ta ke y o u  a p pr o xi matel y 1 5 mi n utes.  
•  
T he f oll o w- u p s ur ve y at da y  2 1 a n d 2 8 will  ta ke a p pr o xi matel y 1 0 mi n utes. 
•  
If y o u  are i n t he s u b st u d y, y o u  will  be  as ke d t o c ollect a drie d  bl o o d s p ot o n da y  1 a n d da y 2 8, a n d o n ot her  da ys  as 
st u d y staff re q uests. Y o u  will  n ot  be as ke d t o c ollect a drie d  bl o o d s p ot m ore  t ha n 5 ti mes d uri n g t he st u d y.  Eac h  
c ollecti o n will  ta ke a p pr o xi matel y 1 0 mi n utes.  
 
St u d y  l oc ati o n: All  st u d y pr oce d ures will  be  at y o ur o w n  h o me.   
 
N as al s w a bs f or S A R S -C o V - 2, t he vir us t h at c a uses  C O VI D -1 9:  T he st u d y will  as k y o u  t o s wa b t he i nsi de of y o ur n ose 
e ver y da y fr o m da y 1 u ntil da y 1 4, a n d t he n c ollect a s wa b o n da y 2 1 a n d da y 2 8. T he st u d y staff will  teac h y o u  h o w t o d o 
t his.  S wa b bi n g will  ta ke a p pr o xi matel y 5 mi n utes. 
 
R es ults of  testi n g d o ne f or researc h o nl y  will  n ot  be a vaila ble  t o y o u  or y o ur pr o vi ders,  j ust t o t he researc hers i n t he st u d y. 
Y o u  will  be a ble t o c o ntact  t he st u d y t o fi n d o ut  y o ur res ults, if y o u  wis h.  We  will  re p ort y o ur test res ults t o y o ur l ocal 
healt h de part me nt if re q uire d t o d o s o b y la w.  
 
Dri e d bl o o d s p ot: If y o u  are i n t he s u b st u d y, a self-test dr y bl o o d s p ot test sa m ple will  be dra w n  b y pric ki n g o ne of y o ur 
fi n gers wit h  a la ncet. Y o u  will  be as ke d t o c ollect  y o ur bl o o d o n da y  1 a n d da y 2 8,  a n d o n ot her  da ys  as y o ur d oct or 
re q uests.  Y o u  will  n ot be as ke d t o c ollect  a drie d  bl o o d s p ot m ore  t ha n 5 ti mes d uri n g t he st u d y. 
 
H o w  l o n g will  I be  i n t he st u d y ?  E ver y o ne  will  be  i n t he st u d y f or 2 8 da ys.  If y o u  are i n t he s u b st u d y, y o u  will  als o ha ve  
a n a d diti o nal drie d  bl o o d s p ot c ollecti o n a 2 8 da ys.   
 
C a n  I st o p bei n g  i n t he st u d y ? 
Yes.  Y o u  ca n deci de t o st o p at a n y ti me. T ell  t he st u d y tea m if y o u  are t hi n ki n g a b o ut st o p pi n g or if y o u  deci de t o st o p. 
T he y will  tell y o u  h o w t o st o p y o ur partici pati o n  safel y.   
 
If y o u  are a d mitte d t o t he h os pital, y o ur d oct or will  deci de  if y o u  s h o ul d c o nti n ue o n t he st u d y me dicati o n.   Y o u  ma y  st o p 
c ollecti n g nasal  s wa bs a n d d oi n g t he dail y  s ur ve y. We  will  kee p  i n t o uc h wit h  y o u  d uri n g y o ur h os pitalizati o n, a n d will  
req uest a s ur ve y 3 da ys  after  h os pital disc har ge.  


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C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
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It is i m p orta nt t o tell t he st u d y tea m if y o u  are t hi n ki n g a b o ut st o p pi n g s o a n y ris ks fr o m t he H C Q  or H C Q +azit hr o m yci n  
ca n be e val uate d, a n d t he st u d y tea m ca n disc uss  w hat  f oll o w- u p care a n d testi n g c o ul d be  m ost  hel pf ul f or y o u. 
 
T he st u d y tea m ma y  st o p y o u  fr o m ta ki n g part i n t his st u d y at a n y ti me if we  belie ve  it is i n y o ur best  i nterest, if y o u  d o n ot  
f oll o w t he st u d y r ules, or  if t he st u d y is st o p pe d. 
 
W h at si de effects  or  ris ks c a n I e x pect  f r o m t he tre at me nt ? 
E ver y o ne  ta ki n g part i n t he st u d y will  be watc he d  caref ull y f or a n y si de effects. H o we ver,  d oct ors d o n't k n o w all t he si de 
effects  t hat ma y  ha p pe n. Si de  effects  ma y  be mil d  or ver y  seri o us. Ma n y  si de effects g o  a wa y s o o n after y o u  st o p ta ki n g t he 
H C Q  or H C Q +azit hr o m yci n. I n s o me rare cases, si de effects ca n be seri o us, l o n g lasti n g, or ma y  ne ver  g o  a wa y. 
 
Y o u  s h o ul d tal k t o y o ur st u d y d oct or a b o ut a n y si de-effects  y o u  e x perie nce  w hile  ta ki n g part i n t he st u d y. 
 
F or  partici pa nts  assi g ne d  t o t he H C Q treat me nt gr o u p, ris ks a n d si de effects  i ncl u de: 
 
Li kel y  
 
•  
Na usea  
•  
Diarr hea  
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S ki n  pi g me ntati o n  
 
Less  li kel y 
 
•  
Seri o us  aller gic reacti o n, i ncl u di n g a se vere s ki n ras h 
•  
Reti n o pat h y  
 
R are  b ut  seri o us 
 
•  
Seri o us  aller gic reacti o n, w hic h  ma y  i ncl u de tr o u ble breat hi n g,  hi ves,  a n d i n v ol ve me nt of s ki n a n d ot her  or ga ns  i n 
t he b o d y 
•  
Seri o us  s ki n reacti o n 
•  
Ne ur o pat h y  
•  
S keletal  m y o pat h y 
•  
Car di o m y o pat h y  
•  
Heart  r h yt h m pr o ble ms 
 
H C Q  ca n be ass ociate d  wit h  l o w bl o o d s u gar.  If y o u  ha ve  dia betes  a n d are ta ki n g i ns uli n, y o u  ma y  nee d  t o decrease  y o ur 
i ns uli n d osa ges  w hile  o n t his st u d y.  If y o u  are ta ki n g oral dia betes me dicati o ns or  i ns uli n, y o u  ma y  nee d  t o i ncrease y o ur 
m o nit ori n g of bl o o d s u gar a n d y o ur a ware ness  of  l o w bl o o d s u gar.  If t his is n ot p ossi ble,  t his st u d y ma y  n ot be safe f or 
y o u.   
 
F or  partici pa nts  assi g ne d  t o t he treat me nt gr o u p i ncl u di n g azit hr o m yci n, ris ks a n d si de effects  i ncl u de: 
 
Li kel y  
•  
Na usea  
•  
Diarr hea  
•  
V o miti n g  
•  
Occasi o nal  dizzi ness  
•  
A b d o mi nal pai n  
 


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C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
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Less  li kel y 
•  
Seri o us  aller gic reacti o n  
 
R are  b ut  seri o us 
•  
Heart  r h yt h m pr o ble ms 
•  
Life -t hreate ni n g dr u g i nteracti o ns 
 
T he ris k of heart  r h yt h m c ha n ges  ma y  be i ncrease d wit h  t he c o m bi nati o n of  azit hr o m yci n a n d h y dr o x yc hl or o q ui ne.  We  
will  m o nit or y o ur heart  r h yt h m d uri n g t he st u d y t o ma ke  t he st u d y as safe as p ossi ble.  T her e is a ris k of heart  r h yt h m 
a b n or malities w hic h  i n rare cases ca n lea d t o seri o us c o nse q ue nces.   F or  partici pa nts  assi g ne d t o t he vita mi n  C gr o u p, ris ks 
a n d si de effects  i ncl u de na usea,  diarr hea,  a n d st o mac h cra m ps. 
 
R a n d o miz ati o n ris ks:  Y o u  will  be assi g ne d  t o recei ve H C Q +f olic  aci d, H C Q +azit hr o m yci n, or vita mi n  C +f olic  aci d, a n d 
t he gr o u p t o w hic h  y o u  are assi g ne d  ma y  pr o ve t o be less effecti ve or t o ha ve  m ore  si de effects  t ha n t he ot her  st u d y 
treat me nt or  ot her a vaila ble treat me nts. 
 
Dr y  Bl o o d S p ot:  Dra w i n g a dr y bl o o d test ma y  ca use te m p orar y disc o mf ort fr o m t he nee dle stic k, br uisi n g,  a n d rarel y, 
i nfecti o n. 
 
P ri v ac y  a n d  c o nfi de nti alit y  ris ks:  We  will  ma ke  e ver y eff ort  t o pr otect  y o ur c o nfi de ntialit y d uri n g t he st u d y. H o we ver,  it 
is p ossi ble t hat ot hers  ma y  lear n t hat y o u  are part  of  t his st u d y a n d t he y ma y  k n o w y o u  ha ve  C O VI D - 1 9. T he m ost  c o m m o n 
ris ks we  k n o w a b o ut are fa mil y or frie n ds w orr yi n g,  getti n g u pset or  a n gr y, or k n o wi n g t hat y o u  are i nfecte d a n d treati n g 
y o u  u nfairl y as a res ult. 
 
Y o u  sh o u l d feel free t o disc uss  partici pati o n  i n t his st u d y wit h  frie n ds a n d fa mil y. 
 
We  will  re p ort y o ur test res ults t o l ocal healt h  de part me nts w he n  le gall y re q uire d t o d o s o.   
 
Alt h o u g h e ver y reas o na ble eff ort has bee n  ta ke n, c o nfi de ntialit y d uri n g o nli ne c o m m u nicati o n pr oce d ures  ca n n ot be  
g uara ntee d  a n d it is p ossi ble t hat a d diti o nal  i nf or mati o n be y o n d t hat c ollecte d f or researc h p ur p oses ma y  be vie we d  b y 
ot hers n ot  ass ociate d  wit h  t his st u d y f or u na ut h orize d p ur p oses. 
 
Y o u  will  be re q uire d t o use y o ur e mail a d dr ess t o gai n  access  t o t he heart  r h yt h m m o nit ori n g site. 
 
U n k n o w n  Ris ks:  Alt h o u g h  H C Q  a n d azit hr o m yci n  are well  st u die d a n d wi del y  use d, use of H C Q  a n d azit hr o m yci n f or 
C O VI D - 1 9 treat me nt ma y  ha ve  si de effects  t hat n o o ne  k n o ws a b o ut yet.  T he researc hers wi ll let y o u  k n o w if t he y lear n 
a n yt hi n g t hat mi g ht  ma ke  y o u c ha n ge y o ur mi n d  a b o ut partici pati n g  i n t he st u d y. 
 
F or  m ore  i nf or mati o n a b o ut ris ks a n d si de effects, as k y o ur st u d y tea m. 
 
Are  t here be nefits  t o t a ki n g p art  i n t he st u d y ? 
If y o u  are i n t he gr o u p t hat recei ves H C Q,  a n d if it pr o ves  t o re d uce t he se verit y of  d urati o n of  C O VI D - 1 9 wit h o ut ca usi n g 
si de effects  t hat y o u  ca n n ot t olerate, y o u  ma y  be nefit fr o m partici pati n g  i n t he st u d y, b ut t his ca n n ot be g uara ntee d.  
 
If y o u  are i n t he gr o u p t hat recei ves H C Q +azit hr o m yci n,  a n d if it pr o ves  t o re d uce t he se verit y of d urati o n of C O VI D - 1 9 
wit h o ut ca usi n g si de effects t hat y o u  ca n n ot t olerate, y o u  ma y  be nefit fr o m partici pati n g  i n t he st u d y, b ut t his ca n n ot be 
g uara ntee d. 
 


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C O VI D -1 9 Treat me nt, pr ot oc ol versi o n 1. 4 1 1 A pril  2 0 2 0  
 
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If y o u  are i n t he gr o u p t hat d oes n ot  recei ve H C Q,  y o u  ma y  ha ve  t he sa me or fe wer si de effects  ass ociate d wit h  H C Q  
c o m pare d  t o t h ose w h o  d o  ta ke H C Q,  b ut t his ca n n ot be  g uara ntee d.  
 
If y o u  are i n t he gr o u p t hat d oes n ot  recei ve H C Q +azit hr o m yci n, y o u  ma y  ha ve  t he sa me or fe wer si de effects ass ociate d 
wit h  H C Q +azit hr o m yci n  c o m pare d t o t h ose w h o  d o ta ke H C Q +azit hr o m yci n, b ut t his ca n n ot be g uara ntee d. 
 
W h at ot her  c h oices  d o  I h a ve if I d o  n ot  t a ke p art  i n t his st u d y ? 
Y o ur ot her c h oices  ma y  i ncl u de: 
 
•  
T a ki n g  part  i n a n ot her st u d y. 
•  
W or ki n g wit h  y o ur healt h  care pr o vi der  t o ma na ge  y o ur C O VI D - 1 9 o utsi de of a st u d y. 
 
H o w  will  m y  s peci me ns a n d  i nf or m ati o n be  use d ?  
Researc hers  will  use  y o ur s peci me ns a n d i nf or mati o n t o c o n d uct t his st u d y. O nce  t he st u d y is d o ne usi n g  y o ur  s peci me ns 
a n d i nf or mati o n, we  ma y  s hare t he m wit h  ot her  researc hers s o t he y ca n use t he m f or ot her  st u dies i n t he f ut ure. We  will  n ot  
s hare y o ur na me  or a n y ot her  pers o nal i nf or mati o n t hat w o ul d let t he researc hers k n o w w h o  y o u  are.  
 
Rese arc h  res ults:  T here  ma y  be ti mes w he n  researc hers usi n g y o ur i nf or mati o n or  s peci me ns ma y  lear n ne w i nf or mati o n. 
T he researc hers ma y  or ma y  n ot s hare t hese res ults wit h  y o u, de pe n di n g o n a n u m ber of  fact ors. 
 
H o w  w ill i nf or m ati o n a b o ut  me  be  ke pt  c o nfi de nti al ?  
Partici pati o n  i n researc h i n v ol ves s o me l oss of pri vac y.  We  will  d o o ur  best  t o ma ke  s ure t hat i nf or mati o n a b o ut y o u  is ke pt  
c o nfi de ntial, b ut we  ca n n ot g uara ntee t otal pri vac y.  T he  res ults of  tests ma y  bec o me part of y o ur st u d y rec or d a n d ma y  be 
c o m m u nicate d  t o t he l ocal healt h  de part me nt if re q uired. All  ot her  i nf or mati o n c ollecte d as part  of t his st u d y will  be part  of 
y o ur st u d y rec or d o nl y a n d will  n ot i ncl u de y o ur na me  or ot her i de ntif yi n g i nf or mati o n. All  st u d y rec or ds will  be st ore d i n a 
l oc ke d l ocati o n or u n der pass w or d pr otecti o n  o n st u d y c o m p uters. 
 
O nl y  st u d y staff will  ha ve  access  t o y o ur st u d y rec or d. If i nf or mati o n fr o m t his st u d y is p u blis he d or  prese nte d  at scie ntific 
meeti n gs,  y o ur na me  a n d ot her pers o nal  i nf or mati o n will  n ot  be  use d. 
 
Y o ur pers o nal i nf or mati o n ma y  be gi ve n  o ut if re q uire d b y la w. 
 
Y o ur st u d y rec or ds ma y  be vie we d  b y t he st u d y tea m a n d re prese ntati ves of:  
 
•  
I nter nati o nal Cli nical  Researc h  Ce nter  
•  
T he U ni versit y  of Was hi n gt o n 
•  
Office  f or H u ma n  Researc h  Pr otecti o ns  
•  
Wester n  I nstit uti o nal Re vie w  B oar d ®  ( WI R B® ) 
•  
T he U. S.  Fo o d a nd Dr u g  A d mi nistrati o n  
•  
[Site Na me ] 
 
A descri pti o n  of t his cli nical  trial will  be a vaila ble  o n  htt ps:// w w w. Cli nical Trials. g o v,  as re q uire d b y U. S.  La w.   T his  We b  
site will  n ot  i ncl u de i nf or mati o n t hat ca n i de ntif y y o u.  At  m ost,  t he We b  site will  i ncl u de a su m mar y  of t he res ults.  Y o u  
ca n searc h t his We b  site at a n y ti me. 
 
Are  t here a n y  c osts  t o me  f or t a ki n g p art  i n t his st u d y ? 
T here  are n o c osts t o y o u. A n y  pr oce d ures d o ne o nl y  f or researc h will  n ot  be c har ge d t o y o u  or y o ur i ns urer. 
 
T he st u d y will  pr o vi de t he dr u g of y o ur assi g ne d  treat me nt gr o u p t o y o u  at n o  c ost. 
 


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Will  I be  p ai d  f or t a ki n g p art  i n t his st u d y ? 
If y o u  c o m plete all parts  of  t he st u d y, y o u  will  be pai d  $ 2 0 0. Y o u  will  recei ve $ 2 0 0 o n da y 1 4 if y o u  c o m plete d t he s ur ve ys, 
nasal  s wa bs a n d bl o o d s p ot. S u b  st u d y partici pa nts  will  recei ve $ 1 0 0 o n  da y 2 8 if t he y c o m plete t he a d diti o nal nasal  s wa bs 
a n d bl o o d s p ot. N ot  e ver y o ne  will  be as ke d t o c o m plete a bl o o d s p ot. 
 
W h at h a p pe ns  if I a m i nj ure d bec a use  I t o o k p art  i n t his st u d y ? 
 
If y o u  t hi n k y o u  ha ve a me dical  pr o ble m or ill ness relate d t o t his researc h, c o ntact [Na me ] ri g ht a wa y. T he y will  treat y o u  
or refer y o u  f or treat me nt. It is i m p orta nt t hat y o u  tell st u d y d oct ors if y o u  feel t hat y o u  ha ve  bee n  i nj ure d beca use  of  ta ki n g 
part i n t his st u d y. St u d y d oct ors at eac h site are: 
 
[Na me ] 
 
W h o  c a n a ns wer  m y  q uesti o ns  a b o ut  t he st u d y ? 
Y o u  ca n tal k t o y o ur st u d y d oct or a b o ut a n y q uesti o ns, c o ncer ns, or c o m plai nts  y o u  ha ve  a b o ut t his st u d y – see c o ntact  
i nf or mati o n a b o ve. If y o u  wis h  t o as k q uesti o ns a b o ut t he st u d y or y o ur ri g hts as a researc h partici pa nt  t o s o me o ne ot her 
t ha n t he researc hers, or  if y o u  wis h  t o v oice  a n y pr o ble ms, q uesti o ns, c o m plai nts or  c o ncer ns  y o u  ma y  ha ve  a b o ut t he st u d y, 
please  c o ntact t he Wester n  I nstit uti o nal Re vie w  B oar d ®  ( WI R B® ) at 8 0 0- 5 6 2- 4 7 8 9, Hel p @ wir b.c o m. 
 
W h at  are  m y  ri g hts  if I t a ke p art  i n t his st u d y ? 
T a ki n g  part  i n t his st u d y is y o ur c h oice. Y o u  ma y  c h o ose eit her t o ta ke part  or n ot t o ta ke part  i n t he st u d y. If y o u  ta ke part 
i n t his st u d y, y o u  ma y  lea ve t he st u d y at a n y ti me. N o  matter  w hat  decisi o n  y o u  ma ke,  t here will  be  n o pe nalt y  t o y o u  or 
l oss be nefits t o w hic h  y o u  are ot her wise  e ntitle d. Y o u will  n ot l ose a n y of y o ur re g ular be nefits.  Lea vi n g  t he st u d y will  n ot  
affect  y o ur me dical  care.  
 
D uri n g t he st u d y, we  will  tell y o u  a b o ut a n y ne w i nf or mati o n or c ha n ges i n t he st u d y t hat ma y  affect  y o ur healt h  or 
willi n g ness  t o c o nti n ue i n t he st u d y. 
 
I n case of i nj ur y res ulti n g fr o m t his st u d y, y o u  d o n ot l ose a n y of y o ur le gal ri g hts t o see k pa y me nt b y si g ni n g t his f or m. 
 
S u bj ect’s  st ate me nt 
T his  st u d y has bee n  e x plai ne d t o me.   I v ol u nteer t o ta ke part  i n t his researc h.  I ha ve  ha d a c ha nce t o as k q uesti o ns.  If I 
ha ve  q uesti o ns later a b o ut t he researc h, or if I ha ve  bee n  har me d  b y partici pati n g  i n t his st u d y, I ca n c o ntact o n e of t he 
researc hers liste d o n  t he first pa ge  of  t his c o nse nt f or m.  If I ha ve  q uesti o ns a b o ut m y  ri g hts as a researc h s u bject, I ca n call 
WI R B ® at 8 0 0- 5 6 2- 4 7 8 9. I gi ve  per missi o n  t o t he researc hers t o use  m y  me dical  rec or ds as descri be d  i n t his c o nse nt  f or m.  
 
 
 
 
Pri nte d  na me  of s u bject 
Si g nat ure of s u bject 
Date  
 
 
 
 
Pri nte d  na me  of pers o n o btai ni n g  c o nse nt    Si g nat ure of  pers o n o btai ni n g  c o nse nt 
Date  
 
C o pies t o: 
Researc her  
 
S u bj ect  


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O pti o n al  C o nse nt  
 
F ut ure  St u dies  
Beca use  f ut ure st u dies t hat y o u  ma y  be eli gi ble f or ma y  bec o me a vaila ble, we  are as ki n g n o w if y o u  w o ul d li ke t o lear n 
a b o ut t hese st u dies. Y o u  ca n still be a part  of  t he mai n  st u d y e ve n if y o u  sa y " n o" t o t his. 
 
I a gree  t hat I ma y  be c o ntacte d i n t he f ut ure t o see if I a m i ntereste d i n partici p ati n g i n f urt her researc h. 
 
   Yes            N o  
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Si g nat ure of s u bject                                                 Date  
 
 


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* * F or Sites i n C alif or ni a * *  
A U T H O RI Z A TI O N T O U S E A N D DI S C L O S E I N F O R M A TI O N F O R R E S E A R C H 
P U R P O S E S   
 
W h at i nf or m ati o n m a y be use d a n d gi ve n t o ot hers ?  
T he st u d y d oct or will get y o ur pers o nal a n d me dical i nf or mati o n.  F or e xa m ple:  
•  Past a n d prese nt me dical rec or ds  
•  Researc h rec or ds  
•  Rec or ds a b o ut p h o ne calls ma de as part of t his resea rc h 
•  Rec or ds a b o ut y o ur st u d y visits.  
 
W h o m a y use a n d gi ve o ut i nf or m ati o n a b o ut y o u ?  
T he st u d y d oct or a n d t he st u d y staff.  [T he y ma y als o s hare t he researc h i nf or mati o n wit h  [e nter 
S M O c o m pa n y na me] , a n a ge nt f or t he st u d y d oct or. delete if t he site d oes  n ot ha ve a n S M O]  
 
W h o mi g ht get t his i nf or m ati o n ?  
T he s p o ns or of t his researc h.  “ S p o ns or” mea ns a n y pers o ns or c o m pa nies t hat are:  
•  w or ki n g f or or wit h t he s p o ns or, or  
•  o w ne d b y t he s p o ns or.  
 
Y o ur i nf or m ati o n m a y  be gi ve n t o:  
•  T he U. S. F o o d a n d Dr u g A d mi n istrati o n ( F D A), 
•  De part me nt of Healt h a n d H u ma n Ser vices ( D H H S) a ge ncies,  
•  G o ver n me ntal a ge ncies i n ot her c o u ntries,  
•  T he i nstit uti o n w here t he researc h is bei n g d o ne,  
•  G o ver n me ntal a ge ncies t o w h o m certai n diseases (re p orta ble diseases) m ust be re p orte d, a n d 
•  I nstit uti o nal Re vie w B oar d (I R B)  
 
W h y will t his i nf or m ati o n be use d a n d/ or gi ve n t o ot hers ?  
•  t o d o t he researc h,  
•  t o st u d y t he res ults, a n d  
•  t o ma ke s ure t hat t he researc h was d o ne ri g ht.   
 
If t he res ults of t his st u d y are ma de p u blic, i nf or mati o n t hat i de ntifies y o u will n ot be use d. 
 
W h at if I deci de n ot t o gi ve per missi o n t o use a n d gi ve o ut m y he alt h i nf or m ati o n ?  
T he n y o u will n ot be a ble t o be i n t his researc h st u d y.  
 


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M a y I re vie w or c o p y m y i nf or m ati o n ?  
Yes, b ut o nl y after t he researc h is o ver.  
 
M a y I wit h dr a w or re v o ke (c a ncel) m y per missi o n ?  
T his per missi o n will be g o o d u ntil Dece m ber 3 1, 2 0 6 0 . 
 
Y o u ma y wit h dra w or ta ke a wa y y o ur per missi o n t o use a n d discl ose y o ur healt h i nf or mati o n at 
a n y ti me.  Y o u d o t his b y se n di n g writte n n otice t o t he st u d y d oct or.  If y o u wit h dra w y o ur 
per missi o n, y o u will n ot be a ble t o sta y i n t his st u d y.  
 
W he n y o u wit h dra w y o ur per missi o n, n o ne w healt h i nf or mati o n i de ntif yi n g y o u will be gat here d 
after t hat date.  I nf or mati o n t hat has alrea d y bee n gat here d ma y still be  use d a n d gi ve n t o ot hers.   
 
Is m y he alt h i nf or m ati o n pr otecte d after it h as bee n gi ve n t o ot hers ? 
T here is a ris k t hat y o ur i nf or mati o n will be gi ve n t o ot hers wit h o ut y o ur per missi o n.  
 
A ut h oriz ati o n:  
I ha ve bee n gi ve n t he i nf or mati o n a b o ut t he use a n d discl os ure of m y healt h i nf or mati o n f or t his 
researc h st u d y.  M y q uesti o ns ha ve bee n a ns were d. 
 
I a ut h orize t he use a n d discl os ure of m y he alt h i nf or mati o n t o t he parties liste d i n t he 
a ut h orizati o n secti o n of t his c o nse nt f or t he p ur p oses descri be d a b o ve.  
 
A U T H O RI Z A TI O N SI G N A T U R E:  
 
 
 
  
 
 
Si g n at ure of S u bject  
 
D ate