Clinical trial NCT04358068
Conditions: COVID-19 SARS-CoV 2
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2020-05-13; Completion date: 2020-07-08
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Detailed description:
This Phase IIB study was designed to evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Participants were randomized 1:1 to receive active or placebo study treatment. The target sample size was 2000 participants, with approximately 1000 in each arm. Stratification was by "high" versus "low" risk of progression to severe COVID-19, where "high risk" was defined as a person age ≥60 years or having at least one of several specified comorbidities.

Participants were prescribed study treatment for 7 days and were to be followed for an additional 24 weeks. Assessments on a subset of participants were planned to include blood collection, self-collected nasal swabs, and nasopharyngeal swabs.

On June 23, 2020, sites were informed that the study was closing to follow-up due to slow enrollment and lack of community enthusiasm. Follow-up through week 24 was not completed for any participant. Participants were asked to complete the Day 20 visit and then were discontinued from the study. Due to the early termination, enrollment into the specimen collection subset did not occur, and results associated with those specimens are not available. Due to the small number of participants enrolled, some statistical tests were not able to be performed and only descriptive results are provided.

Arms: arm 1: Hydroxychloroquine 400 mg (administered as two 200 mg capsules) orally twice daily for 2 doses starting on Day 0, followed by 200 mg (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS:

Azithromycin 500 mg (administered as two 250 mg capsules) orally as a single dose on Day 0, followed by 250 mg (administered as one 250 mg capsule) orally once daily for 4 doses (4 days). arm 2: Placebo for Hydroxychloroquine (administered as two matching placebo capsules) orally twice daily for 2 doses starting on Day 0, followed by Placebo for HCQ (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS:

Placebo for Azithromycin (administered as two matching placebo capsules) orally as a single dose on Day 0, followed by Placebo for Azithromycin (administered as one matching placebo capsule) orally once daily for 4 doses (4 days).
Interventions: intervention 1: Hydroxychloroquine (HCQ) intervention 2: Azithromycin (Azithro) intervention 3: Placebo for Hydroxychloroquine intervention 4: Placebo for Azithromycin
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally intervention 4: Administered orally

Protocol documents:
ICF_000.pdf: 
National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
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Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
INFORMED CONSENT FORM 
AND AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH 
INFORMATION 
 
 
Sponsor / Study Title: 
  
National Institute of Allergy and Infectious Diseases / 
“A Randomized, Double-blind, Placebo-controlled 
Trial to Evaluate the Efficacy of Hydroxychloroquine 
and Azithromycin to Prevent Hospitalization or Death 
in Persons with COVID-19” 
 
Protocol Number: 
 
A5395 Final Version 2.0 April 24, 2020 
 
Principal Investigator: 
(Study Doctor) 
 
 
 
Telephone: 
 
 
 
Address: 
 
 
 
 
    
 
 
 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate the ability of hydroxychloroquine 
(HCQ) and azithromycin (Azithro) compared to placebo to prevent 
hospitalization or death in persons with COVID-19. 
 
STUDY 
TREATMENT  
There will be study treatment provided and required in this study. It is not 
known whether this study treatment will help your COVID-19 or not. You 
will be randomized to either Group A or Group B. Randomized means 
that your assignment will be random, like rolling dice. In this study, you 
will have a 50/50 chance of receiving either hydroxychloroquine and 
Azithro or Placebos. You and the study doctor will not know what group 
you are in, and therefore, will not know which study treatment you are 
taking (this is also referred to as “double-blinded”). You will take 
hydroxychloroquine/Placebo two (200 mg each) capsules by mouth 
twice a day on the first day, followed by one 200 mg capsule twice a 
day for 6 days. Hydroxychloroquine/Placebo should be taken with food 
or milk. You will also take Azithro/Placebo two (250 mg each) capsules by 
mouth once on the first day and then one capsule (250 mg) every day for 
4 additional days.   


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NUMBER OF  
 
PARTICIPANTS 
There will be 2 study treatment groups of 1000 people, for a total of 2000 
participants. 
 
 
LENGTH OF  
STUDY 
The study will last for about 6 months (7 days on study treatment) 
 
REQUIRED  
ACTIVITIES 
 
Sample collections 
 
You will report your symptoms and temperature (if you have a 
thermometer at home) and how often you took study drugs and at what 
time throughout the study. 
 
Some study sites will be collecting additional samples. If your study site is 
participating in this portion of the study, you will be asked to sign and date 
a separate consent form that provides more detail about these activities. 
At the start of the study you may have some blood collected from a vein 
in your arm, perform a self-collect nose swab, and, in addition, have study 
staff do a nasopharyngeal swab of your nose. You will have both types of 
nose swabs at Day 6 and 20 and blood collected again at Days 6 and 20. 
All blood will be stored. 
 
Even if your study site is participating in the additional sample collection, 
you do not have to take part in this portion. You can still be in the main 
part of the study and receive study treatment even if you decide not to 
provide additional samples.   
 
   
RISKS  
 
The following are possible: 
• 
Hydroxychloroquine side effects  
o Nausea 
o Diarrhea 
o Vomiting 
o Headache 
o Tiredness 
o Stomach (abdominal) pain 
o Muscle weakness 
 
• 
Possible hydroxychloroquine side effects that are uncommon but 
potentially serious: 
o Serious (including fatal) allergic and skin reaction  
o Fast heart rate or pulse 
o Prolongation of QT interval (heart takes longer than normal to 
recharge between beats) and cases of “torsades de pointes” 
(dangerous fast heart beats) 
o Ventricular tachycardia or fibrillation, a condition of the heart that 
can cause a fast heart rate and increase the risk of stroke and 
heart attack 


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o Hypoglycemia (blood sugar is low) 
o Blurry vision 
o Muscle pain 
o Death 
 
• 
Azithro side effects 
o Diarrhea 
o Nausea 
o Abdominal pain 
o Vomiting 
 
• 
Possible Azithro side effects that are uncommon but potentially 
serious: 
o Serious (including fatal) allergic and skin reaction  
o Pseudomembranous colitis (swelling or inflammation of the large 
intestine due to overgrowth of Clostridium difficile) 
o New onset of myasthenia gravis (long-term neuromuscular 
disease that leads to skeletal muscle weakness) 
o Exacerbation of myasthenia gravis (weakness in skeletal muscles) 
o Ventricular arrhythmias (occurs more frequently in people with 
heart disease) 
o Severe, and sometimes fatal, hepatotoxicity (liver damage) 
o Prolongation of QT interval (heart takes longer than normal to 
recharge between beats) and cases of “torsades de pointes” 
(heart beats faster than usual) 
o Clostridium difficile (bacteria)-associated diarrhea 
o Death 
 
BENEFITS 
If you take part in this study, there may be a direct benefit to you, but no 
guarantee can be made. It is also possible that you may receive no 
benefit from being in this study. Information learned from this study may 
help others who have SARS-CoV-2 infection. 
 
OTHER CHOICES  
Instead of being in this study, you have the option of:  
 
• 
Treatment with prescription drugs available to you by your medical 
provider. 
• 
Treatment with experimental drugs, if you qualify, treatment with “off-
label” treatment with hydroxychloroquine and/or azithromycin if prescribed 
by your medical provider. 
• 
No treatment. 
 


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This form is for use in a research study that may involve subjects who may or may not have the 
capacity to consent to take part in the study.  When the subject cannot legally consent to take 
part, pronouns “you” and “your” should be read as referring to the subject rather than the person 
(legally authorized representative) who is signing and dating this form for the subject. In cases 
where the subject’s representative gives consent, the subject should be informed about the 
study to the extent possible given his/her understanding. During the course of the study, if the 
subject regains the capacity to consent, informed consent will be obtained from the subject and 
the subject offered the ability to leave the study if desired. 
 
INTRODUCTION  
 
You are being asked to take part in this research study because you have been diagnosed with 
SARS-CoV-2 (a new virus that can cause severe pneumonia and death) and have symptoms of 
this infection, commonly known as COVID-19. This study is sponsored by the National Institutes 
of Health (NIH). The study doctor listed on page one of this form is in charge of this study at this 
site. Before you decide if you want to be a part of this study, we want you to know about the 
study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
SARS-CoV-2 is a new virus that has caused a widespread outbreak of an illness called COVID-
19. In most people it causes a mild to moderate upper respiratory infection, like a “cold”. In 
others, this virus can cause a pneumonia, which can be serious and life-threatening.  
There is no proven therapy for COVID-19. 
 
The investigators of this study would like to know if the medication hydroxychloroquine (HCQ) 
combined with azithromycin (Azithro) can protect people from becoming sick enough from 
SARS-CoV-2 infection to require hospitalization or from dying. This study will gather data on the 
effectiveness of hydroxychloroquine and Azithro to prevent hospitalization and death in adults 
with SARS-CoV-2 infection when compared to Placebo (sugar capsule). Another purpose of this 
study is to see if hydroxychloroquine and Azithro is safe for people who are infected with 
SARS-CoV-2 and have symptoms consistent with COVID-19. 
 
Hydroxychloroquine is currently approved by the Food and Drug Administration (FDA) for 
prevention and treatment of malaria infection and treatment of disease in individuals with 
rheumatoid arthritis, porphyria cutanea tarda (blood disorder that affects the skin), and lupus (an 
autoimmune disease). Azithromycin is currently FDA approved for treating bacterial infections. 
Hydroxychloroquine and Azithro have not previously been tested in a randomized controlled 
trial (where people are assigned randomly to study treatment and compared to people not 
taking study treatment) to see if they can prevent severe disease from SARS-CoV-2 infection. 
 
If you are an employee or relative of an employee of this research center, you are under no 
obligation to participate in this study.  You/your family member may withdraw from the study at 
any time and for any reason, and neither you/your family member’s decision to participate in the 
study, nor any decision on your/their part to withdraw, will have any effect on your/your family 
member’s performance appraisal or employment at this clinical research center.   


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You/your family member may refuse to participate, or you/your family member may withdraw 
from the study at any time without penalty or anyone blaming you.  
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
If you decide to take part in this study, you will be screened to determine if you qualify for the 
study.  
 
There is some information that we collect on everyone who is screened for an AIDS Clinical 
Trials Group (ACTG) study. As part of the screening, some demographic (such as, age, 
sex/gender, race), clinical (such as disease condition, diagnosis), and laboratory (such as, 
inflammation and SARS-CoV-2 levels) information will be collected from you. We also collect 
information on whether you use (or have used) IV drugs or smoke marijuana or have smoked 
tobacco or other nicotine products. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that researchers can determine whether there are patterns and/or common reasons 
why people do not join a study.  
 
Study Visits 
The schedule of visits and study procedures are explained in Attachment B. 
 
You will most likely be screened over the phone, but you also could be screened in person. If 
you qualify for the study, you will have an in-person entry visit to get your study treatment for the 
duration of the study, or a remote (i.e., by telephone or video) visit in which your study treatment 
for the duration of the study will be mailed or delivered to you. The screening and entry visit may 
occur on the same day. You will be randomized to receive either hydroxychloroquine and 
Azithro (Group A) or Placebos (Group B). Randomized means that your assignment will be 
random, like rolling dice. In this study, you will have a 50/50 chance of receiving either 
hydroxychloroquine and Azithro or Placebos. You and the study doctor will not know what 
study group you are in. 
 
 
If you are in Group A, you will take two hydroxychloroquine capsules (200 mg each) by 
mouth twice a day on the first day, followed by one 200 mg capsule twice a day for 6 
days. Hydroxychloroquine should be taken with food or milk. You will also take two Azithro 
capsules (250 mg each) by mouth once on the first day and then one capsule (250 mg) every 
day for 4 additional days.  
 
If you are in Group B, you will take two Placebo hydroxychloroquine capsules (200 mg each) 
by mouth twice a day on the first day, followed by one 200 mg capsule twice a day for 6 
days. Placebo hydroxychloroquine should be taken with food or milk. You will also take two 
Placebo Azithro capsules (250 mg each) by mouth once on the first day and then one capsule 
(250 mg each) every day for 4 additional days. Study staff will counsel you on how to take 
these study drugs. Both study groups are important to the study to answer the study questions. 
 
After entry, you will be followed-up by telephone or video a few times. These phone calls will 
take between 30 and 60 minutes to complete. During the study, you will take your temperature if 
you have a thermometer at home and complete a symptom diary.  
 


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If you need medical help at any time during the study, please contact the study staff right away. 
 
Screening Visit (in-person or remote) 
You will be asked for your medical and medication history. You will be asked about your 
symptoms. 
 
Study Entry (in-person or remote) 
Following the screening visit (if not combined with the entry visit), if you qualify for the study, 
you will be asked for your medical and medication history again, be given your study treatment 
and be given a Study Diary packet and complete the Study Diary for that day (if remote visit, 
these items will be mailed or delivered to you). You will be asked to provide contact information 
for people close to you in case study staff cannot reach you during the study. We would like you 
to tell these contacts that you are in the study, so they know they may receive a call from study 
staff. You will also be asked to provide your health care provider’s contact information along 
with the name(s) of the hospital you would likely go to if you get really sick (see consent below 
under “WHAT IF THE SITE CAN NO LONGER REACH ME DURING THE STUDY?”). You will 
also be asked to provide your home address. You will take your study treatment on this day. If 
you have an in-person visit, study staff will observe you taking the study treatment. If you have a 
remote visit, you will need to tell study staff when you have taken the study drug. 
 
Follow-up Visits 
You will be contacted by phone by study staff on Days 2, 4, 6, 9, 13, and 17, and at 3 and 6 
months after you enter the study. During the study, you will complete a symptom diary. You will 
also be asked questions about how you are taking the study treatment and health care that you 
have accessed. Site staff will also ask you to update your secondary contact information. These 
visits will take between 30 and 60 minutes.  
 
You will have an in-person visit or remote visit on Day 20 to see how you are feeling and for 
you to turn in your Study Diary. If your Day 20 visit is not done in person, you will be called by 
study staff to do the visit over the phone or by video. Arrangements will be made for you to send 
the symptom diary to the clinic. This visit will take between 30 and 60 minutes. 
 
 
 
If you cannot be reached, the study staff will contact your alternative contacts or your health 
care provider. If you become hospitalized, the study staff will ask your contacts for information 
about you being in the hospital. The study staff will also ask your contacts about death, should 
that occur (see consent below under “WHAT IF THE SITE CAN NO LONGER REACH ME 
DURING THE STUDY?”). 
 
Early discontinuation 
If at any point in the study you want to stop study treatment or stop participating in the study, 
you must contact the site immediately and will be asked to come to the clinic for an extra 
visit. 
 
1. Stopping the study treatment early 
You or your doctor may decide to stop the study treatment that you began at entry.  
 
If you must stop taking the study treatment early, you will continue the study and complete 
the study visits as described in this form.  
 


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2. Leaving the study early 
You or your doctor may decide that you will no longer stay in the study or you are notified 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study.  
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
Up to 2000 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 6 months (7 days on treatment).  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled.  
• 
Continuing the study treatment may be harmful to you. 
• 
Your primary care provider requests that you stop participating in the study. 
• 
You do not take your first dose of study treatment when you start the study. 
 
The study doctor may also need to take you off the study drug without your permission if: 
• 
You are taking other medications that should not be taken with the study drug. 
 
If you must stop taking the study treatments before the study is over, the study doctor will ask 
you to continue to be part of the study and return for study visits and procedures.  
 
 
WHAT HAPPENS IF I DECIDE TO PERMANENTLY STOP TAKING STUDY DRUGS? 
 
If you must permanently stop taking study-provided hydroxychloroquine and Azithro or 
Placebo before your study participation is over, the study staff will discuss other options that 
may be of benefit to you. 
 
 
WHAT HAPPENS WHEN I FINISH THE ONE WEEK STUDY DRUGS? 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with the hydroxychloroquine and Azithro you received on the study. If continuing 
to take these or similar drugs/agents would be of benefit to you, the study staff will discuss how 
you may be able to obtain them.  
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
There are risks to taking part in any research study. The effectiveness of the study treatments is 
not known. One risk is that the study treatments may not stop you from becoming sicker, being 
hospitalized or dying from SARS-CoV-2.  


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Another risk is that the study treatments used in this study may have side effects, some of which 
are listed below. Additionally, the study drugs tested in the study may have unknown side-effects 
in persons with SARS-CoV-2 infection. In a research study, all of the risks or side effects may 
not be known before you start the study. You need to tell your study doctor or a member of the 
study team immediately if you experience any side effects.  
 
Please note that these lists do not include all the side effects seen with the study drugs. These 
lists include the more serious or common side effects with a known or possible relationship to 
the study drugs. If you have questions concerning the additional side effects, please ask the 
medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
given with the study treatment. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study. Medications that are high risk include:  
• 
“Off-label” prescription for hydroxychloroquine, chloroquine, and/or azithromycin 
• 
Cardiac medications 
o Antiarrhythmic drugs: quinidine [Quinidex Extentabs, Quinaglute, Quinalan, 
Cardioquin], procainamide [Pronestyl], disopyramide [Norpace, Norpace CR], 
dofetilide [Tikosyn], ibutilide [Corvert], and sotalol [Betapace, Betapace 
AF, Sorine, Sotylize] 
o Loop diuretics: furosemide [Furocot, Lasix], bumetanide [Bumex], torsemide 
[Demadex], ethacrynic acid [Edecrin] 
• 
Non-cardiac medications 
o Diphenhydramine [Benadryl, Banophen, Allermax, Genahist, Sominex, Unisom, 
ZzzQuil] 
o Antiepileptic medications: Carbamazepine (Tegretol, Carbegen), Eslicarbazepine 
(Aptiom), Ethosuximide, Felbamate (Felbatol), Gabapentin (Neurontin), Lamotrigine 
(Lamictal), Levetiracetam (Desitrend, Keppra), Oxcarbazepine (Trileptal), 
Phenobarbital, Phenytoin (Dilantin, Epanutin), Piracetam (Nootropil), Pregabalin 
(Alzain, Axalid, Lyrica, Rewisca), Rufinamide (Inovelon), Stiripentol (Diacomit), 
Tiagabine (Gabitril), Topiramate (Topamax), Sodium Valproate (Epilim, Episenta, 
Epival), Valproic Acid (Convulex, Depakote, Depakene), Zonisamide (Zonegran) 
o Antipsychotic and antidepressant agents: Neuroleptic (haloperidol [Haldol], 
droperidol [Inapsine], thioridazine [Mellaril, Mellaril-S], chlorpromazine [Thorazine, 
Ormazine]); Atypical antipsychotics (ziprasidone [Geodon], risperidone [Risperdal M-
Tab, RisperiDONE M-Tab], zimeldine [Normud, Zelmid], citalopram [CeleXA]); 
Antidepressants (amitriptyline [Elavil, Vanatrip], desipramine [Norpramin], imipramine 
[Tofranil and Tofranil-PM], maprotiline [Ludiomil], doxepin [Silenor, SINEquan], 
fluoxetine [PROzac, PROzac Weekly, Rapiflux, Sarafem, Selfemra], escitalopram 
[Lexapro], citalopram [CeleXA]) 
o Antibiotics: Quinolone (levofloxacin [Levaquin], moxifloxacin [Moxeza, Vigamox]); 
Macrolide (erythromycin [EES 200, EES 400, EES Granules, Eryc, Eryped, Eyrped 
200, Eyrped 400, Ery-Tab, Erythrocin, Erythrocin Stearate, IIosone, PCE, PCE 
Dispertab], clarithromycin [Biaxin, Biaxin Filmtab, Biaxin XL])  
o Antimalarials (quinine [Qualaquin, Quinamm, Quiphile], halofantrine [Halfan])  
o Antiprotozoal (pentamidine [Pentam]) 
o Antifungal (azole group [Vfend, Sporanox, Noxafil, Diflucan, Nizoral, Mycelex Troche, 
Cresemba, Onmel, Oravig, Tolsura])  


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o Antimotility agents (antidiarrheals) 
o Methadone [Diskets Dispersible, Dolophine, Methadone HCl Intensol, Methadose] 
Please contact the study doctor or nurse before starting any of these medications while on the 
study. Also, you must tell the study doctor or nurse before enrolling in any other clinical trials 
while on this study. 
 
If you enroll in this trial and are randomized to receive active hydroxychloroquine and 
azithromycin drugs, and you also receive “off-label” prescription for hydroxychloroquine, 
chloroquine, and/or azithromycin, then there is a risk of over-dosing. It is possible to have 
serious side effects with risk for death. It is important that you do not take hydroxychloroquine 
or Azithro from sources outside of the study, like from your primary doctor. If you do take one or 
both of these drugs from sources outside the study, please let the study staff know right away.  
There is also a risk that these drugs have no benefit for COVID-19, and thus drug exposure 
would carry more risk than placebo. 
 
Commonly reported side effects of hydroxychloroquine are: 
• 
Nausea 
• 
Diarrhea 
• 
Vomiting 
• 
Headache 
• 
Tiredness 
• 
Stomach (abdominal) pain 
• 
Muscle weakness 
 
Less common, but potentially severe and potentially life-threatening side effects of 
hydroxychloroquine in volunteers were:  
• 
Allergic reactions and rash 
• 
Tachycardia (fast heart rate or pulse) 
• 
Prolongation of QT interval (heart takes longer than normal to recharge between beats) and 
cases of “torsades de pointes” (dangerously fast heart beats) 
• 
Ventricular tachycardia or fibrillation, a condition of the heart that can cause a fast heart rate 
and increase the risk of stroke and heart attack 
• 
Hypoglycemia (blood sugar is low) 
• 
Blurry vision 
• 
Muscle pain 
• 
Death 
 
If you have psoriasis and are randomized to receive hydroxychloroquine, you may experience 
a psoriasis flare. 
 
Side Effects of Azithro 
• 
Diarrhea 
• 
Nausea 
• 
Abdominal pain 
• 
Vomiting 
• 
Pseudomembranous colitis (swelling or inflammation of the large intestine due to overgrowth 
of Clostridium difficile) 


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• 
New onset of myasthenia gravis (long-term neuromuscular disease that leads to skeletal 
muscle weakness) 
• 
Exacerbation of myasthenia gravis (weakness in skeletal muscles) 
• 
Ventricular arrhythmias (occurs more frequently in people with heart disease) 
 
The following severe and potentially life-threatening side effects have been reported: 
• 
Serious (including fatal) allergic and skin reaction 
• 
Severe, and sometimes fatal, hepatotoxicity (liver damage) 
• 
Prolongation of QT interval (heart takes longer than normal to recharge between beats) and 
cases of “torsades de pointes” (dangerously fast heart beats) 
• 
Clostridium difficile (bacteria)-associated diarrhea 
• 
Death 
 
As with all drugs, you could have an allergic reaction such as a rash or hives. Allergic reactions 
can be dangerous; if you develop an allergic reaction, you will be given medication (similar to 
Benadryl) to counter the reaction and be taken off study drug. 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING? 
 
Pregnancy 
The safety of hydroxychloroquine during pregnancy is not fully established. However, 
pregnant women with lupus and arthritis are recommended to continue hydroxychloroquine 
throughout pregnancy. Studies have shown that taking hydroxychloroquine during pregnancy 
does not harm the fetus. It should be noted that hydroxychloroquine at the dose used in this 
study has not been used before during pregnancy and may involve risks.  
 
In animal studies, no evidence of harm to the fetus due to Azithro was found. When given as 
malaria prevention during pregnancy, Azithro was not shown to harm the fetus.  
 
The study treatment may involve risks to you (or to the embryo or fetus, if you or your partner 
become pregnant), which are currently unforeseen. Let your study doctor know immediately if 
you become pregnant. If you become pregnant while on the study, the study staff would like to 
obtain information from you about the outcome of the pregnancy (even if it is after your 
participation in the study ends). 
 
If you are pregnant, please discuss study participation with your OB/GYN provider. 
 
Breastfeeding 
Hydroxychloroquine is excreted in human breast milk. When given at the dose used in this 
study the relative amount of hydroxychloroquine in breast milk is considered safe for infants.  
Azithro is excreted in human milk, but considered safe to use during breastfeeding.  
 
It is unknown if SARS-CoV-2 is excreted in human breast milk. If you would like to breastfeed 
during this study, please talk to your OB/GYN provider. 
 
 
 
 
 


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ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
No direct benefits should be expected from participating in this study. If you take part in this 
study, there may be a direct benefit to you, but no guarantee can be made. It is also possible 
that you may receive no benefit from being in this study. Information learned from this study 
may help others who have SARS-CoV-2 infection. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• 
Treatment with prescription drugs available to you by your medical provider. 
• 
Treatment with experimental drugs, if you qualify, treatment with “off-label” treatment 
with hydroxychloroquine and/or azithromycin if prescribed by your medical provider. 
• 
No treatment. 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices.  
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use.  
Information, documents, or biospecimens protected by this Certificate cannot be disclosed to 
anyone else who is not connected with the research except, if there is a federal, state, or local 
law that requires disclosure (see below); if you have consented to the disclosure, including for 
your medical treatment; or if it is used for other scientific research, as allowed by federal 
regulations protecting research subjects.  
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 12 of 18   
 
 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 
A description of this clinical trial will be available on 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.  
 
 
WHAT IF THE SITE CAN NO LONGER REACH ME DURING THE STUDY? 
  
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained from you at screening and updated at each visit. If you are still unable 
to be reached, we will attempt to obtain information about you from your designated contacts, 
clinic records, or by contacting your health care providers (if you agree).  
 
Contacting Your Health Care Providers 
With your permission, for which you would need to sign a waiver, study staff may contact your 
health care providers or hospitals where you might receive care to determine if you have been 
hospitalized or died while in the study, and the cause of death. Will you allow us to contact your 
health care provider(s) or hospitals to obtain this information?  
 
________ YES ________ NO _______Initials 
 
If you said Yes, please list the names of your health care provider and the hospitals you would 
likely be admitted to, below: 
 
 
 
 
 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for study-related visits or procedures. If you require medical care as 
a result of taking study drugs, it is possible that your insurance company will not pay for these 
costs because you are taking part in a research study.  You are more likely to require medical 
care as a result of having COVID-19. Costs related to acute care/hospitalization will not be 
covered by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
You will be paid $25 at the completion of each visit. If you do not complete the study, for any 
reason, you will be paid for each study visit you do complete. 
 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 13 of 18   
 
 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
A new public health declaration, called the Public Readiness and Emergency Preparedness 
Declaration (PREP), was issued by the Department of Health and Human Services on March 
10, 2020.  This declaration limits the legal rights of a subject participating in a COVID-19 clinical 
study that uses a drug, device or vaccine designed to treat, diagnose, cure or prevent COVID-
19. This includes the study drug Hydroxychloroquine and Azithromycin used in this study.  
Subjects using Hydroxychloroquine and Azithromycin in this study will have limits on their right 
to sue the manufacturers, the study sponsor, healthcare providers and others for significant 
injuries and adverse reactions. 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies and will not result in any penalty or loss of benefits to which you are otherwise 
entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study, please contact the study doctor at the 
telephone number listed on the first page of this consent document. If you seek emergency 
care, or hospitalization is required, alert the treating physician that you are participating in this 
research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research subjects. If you have any questions about your rights as a research subject, 
and/or concerns or complaints regarding this research study, contact: 
 
• 
By mail: 
 
 
 
• 
or call toll free:    
 
• 
or by email:          
 
 
Please reference the following number when contacting the Study Subject Adviser: 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 14 of 18   
 
 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name and date below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) 
Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 15 of 18   
 
Roger Bedimo, MD 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and study staff will use 
and share health data about you to conduct the study. Health data may 
include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records 
kept by your doctor or other health care workers.  
 
For this study, the study staff may share health data about you with 
authorized users. Authorized users may include: 
• Representatives of the National Institute of Allergy and Infectious 
Diseases. 
• Representatives of the AIDS Clinical Trials Group. 
• Representatives of University of California, Los Angeles (UCLA). 
• Representatives of Teva Pharmaceuticals Industries Ltd. (the industry 
sponsor). 
• Representatives of Advarra IRB (an Institutional Review Board that 
reviews this study). 
• The Food and Drug Administration (FDA) and other US federal and 
state agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, 
and STDs) must be reported. 
• Governmental agencies of other countries. 
• Outside individuals and companies, such as laboratories and data 
storage companies, that work with the researchers and sponsor and 
need to access your information to conduct this study. 
• Other research doctors and medical centers participating in this 
study, if applicable.  
• A data safety monitoring board which oversees this study, if 
applicable. 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 16 of 18   
 
Roger Bedimo, MD 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
Your health data will be used to conduct and oversee the research, 
including for instance: 
• To see if the study drugs work and are safe. 
• To compare the study drugs to other drugs. 
• For other research activities related to the study drugs. 
 
Once your health data has been shared with authorized users, it may no 
longer be protected by federal privacy law and could possibly be used or 
disclosed in ways other than those listed here.  
 
Your permission to use and share health data about you will end in 50 
years unless you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data 
about you at any time by writing to the study doctor at the address listed on 
the first page of this form. If you do this, you will not be able to stay in this 
study. No new health data that identifies you will be gathered after your 
written request is received. However, health data about you that has 
already been gathered may still be used and given to others as described 
in this form.  
 
Your right to access your health data in the study records will be 
suspended during the study to keep from changing the study results. When 
the study is over, you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part 
in the study. 
 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 17 of 18   
 
 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have 
been answered. I voluntarily agree to allow study staff to collect, use and 
share my health data as specified in this form. I will receive a signed and 
dated copy of this form for my records. I am not giving up any of my legal 
rights by signing and dating this form.  
 
__________________________________ 
Printed Name of Subject 
 
 
__________________________________ 
 
 
__________ 
Signature of Subject 
 
 
 
 
 
Date 
 
 
__________________________________ 
 
 
Printed Name of Legally Authorized Representative   
 
 
__________________________________ 
 
 
__________ 
Signature of Legally Authorized Representative  
 
Date  
 
 
____________________________________________________________ 
Authority of Legally Authorized Representative to act on behalf of Subject 
 
 
__________________________________ 
Printed Name of the Person Obtaining the Authorization 
 
 
__________________________________ 
 
 
__________ 
Signature of the Person Obtaining the 
 
 
 
Date 
Authorization 
 
 
 
 


National Institute of Allergy and Infectious Diseases/ Protocol Number A5395 
Page 18 of 18   
 
 
Advarra IRB Approved Version 1 May 2020 
Revised 1 May 2020 
 
WITNESS SIGNATURE FOR SUBJECTS WHO CANNOT READ  
The study subject has indicated that he/she is unable to read. This 
Authorization document has been read to the subject by a member of the 
study staff, discussed with the subject by a member of the study staff, and 
the subject has been given an opportunity to ask questions of the study 
staff.   
 
 
____________________________________ 
Printed Name of Impartial Witness  
 
 
____________________________________  
 
__________ 
Signature of Impartial Witness  
 
 
 
 
Date  
 

Prot_002.pdf: 
 
A5395 
 
 
A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of 
Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons 
with COVID-19 
 
 
A Multicenter Trial of the AIDS Clinical Trials Group (ACTG) 
 
 
 
 
Sponsored by: 
National Institute of Allergy 
and Infectious Diseases 
 
 
Industry Support Provided by:  
Teva Pharmaceuticals Industries Ltd. 
 
IND# 149235 
 
 
 
 
 
 
 
Protocol Chair: 
Davey Smith, MD 
 
Protocol Vice Chairs: 
Kara Chew, MD, MS 
 
Eric Daar, MD 
 
David Wohl, MD 
 
DAIDS Clinical Representative: 
Leyi Lin, MD 
 
 
Clinical Trials Specialists: 
 Christina Vernon, MPH, PMP 
 
Chanelle Wimbish, BS 
 
 
FINAL Version 2.0 
April 24, 2020 
 


 
 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
A5395 
 
A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of 
Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons with 
COVID-19 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable US Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
 
 
 
 
Signed: ___________________________________ Date: _____________ 
 Name/Title 
 
 
 


 
 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
 
 
TABLE OF CONTENTS 
 
 
Page 
 
SIGNATURE PAGE .................................................................................................................... 2 
SITES PARTICIPATING IN THE STUDY .................................................................................... 5 
PROTOCOL TEAM ROSTER ..................................................................................................... 6 
STUDY MANAGEMENT ............................................................................................................. 9 
GLOSSARY OF PROTOCOL-SPECIFIC TERMS ..................................................................... 11 
SCHEMA .................................................................................................................................. 13 
1.0 
HYPOTHESIS AND STUDY OBJECTIVES ................................................................... 14 
1.1 
Hypothesis ......................................................................................................... 14 
1.2 
Primary Objective ............................................................................................... 14 
1.3 
Secondary Objectives ........................................................................................ 14 
1.4 
Exploratory Objectives ....................................................................................... 14 
2.0 
INTRODUCTION ........................................................................................................... 15 
2.1 
Background ........................................................................................................ 15 
2.2 
Rationale ........................................................................................................... 21 
3.0 
STUDY DESIGN ........................................................................................................... 27 
4.0  
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................ 30 
4.1 
Inclusion Criteria ................................................................................................ 30 
4.2 
Exclusion Criteria ............................................................................................... 30 
4.3 
Study Enrollment Procedures............................................................................. 32 
4.4 
Co-enrollment Guidelines ................................................................................... 33 
5.0 
STUDY TREATMENT ................................................................................................... 33 
5.1 
Regimens, Administration, and Duration ............................................................ 33 
5.2 
Study Product Formulation and Preparation ....................................................... 33 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability .............................. 34 
5.4 
Concomitant Medications ................................................................................... 35 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ........................................................... 36 
6.1 
Schedule of Evaluations (SOE) .......................................................................... 36 
6.2 
Timing of Evaluations ......................................................................................... 38 
6.3 
Instructions for Evaluations ................................................................................ 40 
7.0 
ADVERSE EVENTS AND STUDY MONITORING ......................................................... 46 
7.1 
Definition of Adverse Events .............................................................................. 46 
7.2 
Adverse Event Collection Requirements for This Protocol ................................. 47 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS ........................................ 47 
7.4 
Study Monitoring ................................................................................................ 49 


 
 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
 
 
CONTENTS (Cont’d) 
Page 
 
8.0 
CLINICAL MANAGEMENT ISSUES .............................................................................. 49 
8.1 
Toxicity .............................................................................................................. 49 
8.2 
Management of Side Effects of HCQ [78] .......................................................... 49 
8.3 
Management of Side Effects of Azithro [79] ....................................................... 50 
8.4 
Pregnancy.......................................................................................................... 51 
8.5 
Breastfeeding ..................................................................................................... 51 
9.0 
CRITERIA FOR DISCONTINUATION ........................................................................... 51 
9.1 
Permanent and Premature Treatment Discontinuation ....................................... 51 
9.2 
Premature Study Discontinuation ....................................................................... 52 
10.0 
STATISTICAL CONSIDERATIONS ............................................................................... 52 
11.0 
PHARMACOLOGY PLAN .............................................................................................. 61 
11.1 
Pharmacology Objectives .................................................................................. 61 
11.2 
Pharmacology Study Design .............................................................................. 61 
11.3 
Pharmacological Data Analysis and Modeling Plan ............................................ 62 
11.4 
Anticipated Outcomes ........................................................................................ 62 
12.0 
DATA COLLECTION AND MONITORING ..................................................................... 63 
12.1 
Reporting Protocol Deviations ............................................................................ 63 
12.2 
Records to Be Kept ............................................................................................ 63 
12.3 
Role of Data Management ................................................................................. 63 
12.4 
Clinical Site Monitoring and Record Availability .................................................. 63 
13.0 
PARTICIPANTS ............................................................................................................ 64 
13.1 
Institutional Review Board (IRB) Review and Informed Consent ........................ 64 
13.2 
Participant Confidentiality ................................................................................... 64 
13.3 
Study Discontinuation ........................................................................................ 64 
14.0 
PUBLICATION OF RESEARCH FINDINGS .................................................................. 64 
15.0 
BIOHAZARD CONTAINMENT ...................................................................................... 65 
16.0 
REFERENCES .............................................................................................................. 66 
APPENDIX I: SAMPLE INFORMED CONSENT ....................................................................... 72 
ATTACHMENT A: CONSENT TO PARTICIPATE IN OPTIONAL INTENSIVE 
SAMPLING STUDY ....................................................................................................... 88 
ATTACHMENT B: EXPLANATION OF STUDY VISITS AND EVALUATIONS .......................... 89 
ATTACHMENT C: CONSENT FOR USE OF EXTRA SAMPLES .............................................. 93 
 


 
5 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
 
 
SITES PARTICIPATING IN THE STUDY 
 
A5395 is a multicenter study that will be initially limited to and conducted at US ACTG Clinical 
Research Sites (CRSs) based on the local incidence of COVID-19. A list of eligible CRSs will be 
maintained on the Site tab on the protocol specific web page (PSWP) on the ACTG Member 
website and will include additional sites outside of the ACTG, if added at a later time. 
 
 
 
 
 


 
6 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
 
 
PROTOCOL TEAM ROSTER 
 
Chair 
Davey Smith, MD 
University of California, San Diego  
Antiviral Research Center, 220 Dickinson St. 
San Diego, CA 92103 
Phone: 619-543-7449 
Fax: 619-298-0177 
E-mail: d13smith@health.ucsd.edu 
 
Vice Chairs 
Kara W. Chew, MD, MS  
UCLA Center for Clinical AIDS Research 
and Education (CARE) Infectious Diseases 
11075 Santa Monica Boulevard Suite 100  
Los Angeles, CA 90025  
Phone: 310-825-0796  
Fax: 310-477-7657  
E-mail: kchew@mednet.ucla.edu  
 
Eric Daar, MD 
Harbor University of California  
Los Angeles Center CRS 
CDCRC Building, 2051124 West Carson St. 
Torrance, CA 90502 
Phone: 424-201-3000 
Fax: 310-533-0447 
E-mail: edaar@labiomed.org 
 
David Alain Wohl, MD 
Chapel Hill CRS 
Suite 2100, Bioinformatics Building 
130 Mason Farm Road 
Chapel Hill, NC 27514 
Phone: 919-843-2723 
Fax: 919-966-8928 
E-mail: wohl@med.unc.edu 
 
DAIDS Clinical Representative  
Leyi Lin, MD 
DAIDS/NIAID/NIH/HIVRB 
5601 Fishers LaneMSC 9830, Room 9E47 
Rockville, MD 20852 
Phone: 301-761-6232 
E-mail: leyi.lin@nih.gov
Clinical Trials Specialists 
Christina Vernon, MPH, PMP 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3341 
Fax: 301-628-3302 
E-mail: Christina.Vernon@dlhcorp.com 
 
Chanelle Wimbish, BS 
ACTG Network Coordinating Center 
Social & Scientific Systems, a DLH Company  
8757 Georgia Avenue, 12th Floor 
Silver Spring, MD  20910-3714 
Phone: 301-628-3367 
Fax: 301-628-3302 
E-mail: Chanelle.Wimbish@dlhcorp.com 
 
Statisticians 
Michael Hughes, PhD 
Statistical and Data Analysis Center 
Harvard T.H. Chan School of Public Health 
Building 2, Room 439A 
655 Huntington Avenue 
Boston MA 02115-6017 
Phone: 617-432-3161 
Fax: 617-432-2832 
E-mail: mhughes@sdac.harvard.edu 
 
Carlee Moser, PhD 
Center for Biostatistics in AIDS Research 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 513 
Boston, MA 02115 
Phone: 617-432-2526 
Fax: 617-432-2829 
E-mail: cmoser@sdac.harvard.edu 


 
7 
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FINAL Version 2.0 
 
TEAM ROSTER (Cont'd) 
04/24/20 
 
Statisticians (Cont'd) 
Justin Ritz, MS 
Center for Biostatistics in AIDS Research 
Harvard T.H. Chan School of Public Health 
FXB Building, Room 510 
Boston MA 02115 
Phone: 617-432-3034 
Fax: 617-432-3163 
E-mail: jritz@sdac.harvard.edu 
 
Data Manager 
Sara Sieczkarski, PhD 
ACTG Data Management Center 
Frontier Science & Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: 716-834-0900 
E-mail: sieczka@frontierscience.org 
 
DAIDS Pharmacists 
Justine Beck, PharmD 
NIAID/NIH/DHHS/PAB 
5601 Fishers Lane, Room 9D39 
Bethesda, MD 20852 
Phone: 301-761-5288 
Fax: 240-627-3112 
E-mail: justine.beck@nih.gov  
 
Shawn Chiambah, PhD 
NIAID/NIH/DHHS/PAB 
5601 Fishers Lane, Room 9A26 
Rockville, MD 20852 
Phone: 301-761-7336 
E-mail: shawn.chiambah@nih.gov 
 
Virologist  
Robert W. Coombs, MD, PhD 
University of Washington  
AIDS Clinical Trials Unit CRS 
Retrovirology Lab Research and Training 
Building, 7th Floor 
325 9th Avenue 
Seattle, WA 98104-2420 
Phone: 206-897-5205 
Fax: 206-897-5203 
E-mail: bcoombs@u.washington.edu
Pharmacologist  
Rada Savic, PhD 
UCSF School of Pharmacy and Medicine 
Dept. of Bioengineering &Therapeutic Sciences 
University of California San Francisco,1700 4th St, 
San Francisco, CA 94158 
Phone: 415-502-0640 
Fax: 415-502-4361 
E-mail: rada.savic@ucsf.edu 
 
Investigators  
Judith Currier, MD, MSc  
Clinical AIDS Research and Education 
(CARE) Center CRS  
11075 Santa Monica Boulevard, Suite 100  
Los Angeles CA 90025  
Phone:  310-825-6689 
Fax:  310-477-7657 
E-mail: jscurrier@mednet.ucla.edu 
 
Gregory Deye, MD 
DMID/NIAID/NIH 
5601 Fishers Lane 
MSC 9830, Room 8A39 
Rockville, MD 20852 
E-mail: gregory.deye@nih.gov 
 
Joseph Eron, MD 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 210  
Chapel Hill, NC 27599-7215 
Phone: 919-843-2722 
Fax: 919-966-6714 
E-mail: jeron@med.unc.edu 
 
Field Representative 
Sadia Shaik, MD 
Harbor University of California Los Angeles 
Center CRS 
CDCRC Building 
1124 West Carson Street 
Torrance CA 90502-2052 
Phone: 310-222-5291 
Fax: 310-782-2964 
E-mail: sshaik@labiomed.org 


 
8 
A5395 
 
 
FINAL Version 2.0 
 
TEAM ROSTER (Cont'd) 
04/24/20 
 
Laboratory Technologists 
Joan Dragavon, MLM 
University of Washington 
AIDS Clinical Trials Unit 
Retrovirology Laboratory 
Ninth & Jefferson Building, Room 342.7 
908 Jefferson Street 
Seattle, WA 98104 
Phone: 206-897-5210 
E-mail: dragavon@uw.edu 
 
Amy James Loftis, BS 
University of North Carolina Global HIV 
Prevention and Treatment CTU 
Bioinformatics Building 
130 Mason Farm Road, Suite 2144  
Chapel Hill, NC 27599-7215 
Phone: 919-966-5462 
E-mail: amy_james@med.unc.edu 
 
Community Scientific Subcommittee (CSS) 
Representative 
Angel L. Hernandez, BA 
Puerto Rico AIDS Clinical Trials Unit CRS 
Barrio Saltos 
Road 566 Int Road 593, KM 0.2 
Orocovis, Puerto Rico 00720 
Phone: 787-919-6145 
E-mail: angelhdz2863@gmail.com 
 
Laboratory Data Manager 
Kevin Knowles, PhD, MA 
Frontier Science & Technology Research 
Foundation, Inc.  4033 Maple Road 
Amherst, NY 14226 
Phone:  716-834-0900 Ext. 7238 
E-mail: knowles@frontierscience.org 
 
Laboratory Specialist 
William Murtaugh, MPH 
ACTG Laboratory Center 
IMPAACT Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Boulevard, Suite 200 
Los Angeles, CA 90025 
Phone: 310-794-9894 
E-mail: wmurtaugh@milabcentral.org 
 


 
9 
A5395 
 
 
FINAL Version 2.0 
 
 
04/24/20 
 
STUDY MANAGEMENT 
 
All general questions concerning this protocol should be sent to actg.teamA5395@fstrf.org via 
e-mail. The appropriate team member will respond with a "cc" to actg.teamA5395@fstrf.org. A 
response should generally be received within 24 hours (Monday through Friday). 
 
Protocol E-mail Group 
Sites should contact the User Support Group at the Data Management Center (DMC) as soon 
as possible to have the relevant personnel at the site added to the actg.protA5395 e-mail group. 
Include the protocol number in the e-mail subject line.  
• 
Send an e-mail message to actg.user.support@fstrf.org.  
 
Clinical Management:  
For questions concerning entry criteria, toxicity management, concomitant medications, and co-
enrollment, contact the Clinical Management Committee (CMC). Send an e-mail message to 
actg.cmcA5395@fstrf.org. Include the protocol number, patient identification number (PID), and 
a brief relevant history. 
 
Laboratory 
For questions specifically related to virologic or pharmacologic laboratory tests, contact the 
Protocol Virologist or Pharmacologist.  
• 
Send an e-mail message to actg.teamA5395@fstrf.org (ATTENTION: Robert Coombs or 
Rada Savic). 
 
Data Management 
• 
For nonclinical questions about transfers, inclusion/exclusion criteria, electronic case report 
forms (eCRFs), randomization/registration, and other data management issues, contact the 
data manager. Completion guidelines for eCRFs and participant-completed CRFs can be 
downloaded from the FSTRF website at www.frontierscience.org. 
• 
For transfers, reference the Study Participant Transfer SOP-119, and contact Sara 
Sieczkarski directly.  
• 
For other questions, send an e-mail message to actg.teamA5395@fstrf.org (ATTENTION: 
Sara Sieczkarski).  
• 
Include the protocol number, PID, and a detailed question. 
 
Randomization/Participant Registration  
For randomization/participant registration questions or problems and study identification number 
SID lists:  
• 
Send an e-mail message to rando.support@fstrf.org or call the DMC Randomization Desk at 
716-834-0900, extension 7301.  
 
DMC Portal and Medidata Rave Problems  
Contact DMC User Support. 
• 
Send an e-mail message to actg.user.support@fstrf.org or call 716-834-0900 x7302. 
 


 
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Protocol Document Questions 
For questions concerning the protocol document, contact the Clinical Trials Specialists.  
• 
Send an e-mail message to actg.teamA5395@fstrf.org (ATTENTION: Christina Vernon and 
Chanelle Wimbish). 
 
Copies of the Protocol 
To request a hard copy of the protocol, send an e-mail message to ACTGNCC@dlhcorp.com. 
Electronic copies can be downloaded from the ACTG website at https://www.actgnetwork.org. 
 
Product Package Inserts and/or Investigator Brochures 
To request copies of product package inserts or investigator brochures, contact the DAIDS 
Regulatory Support Center (RSC) at RIC@tech-res.com or call 301-897-1708. 
 
Protocol Registration 
For protocol registration questions, send an e-mail message to Protocol@tech-res.com or call 
301-897-1707.  
 
Protocol Activation 
For questions related to protocol activation at US sites contact the Clinical Trials Specialists.  
• 
Send an e-mail message to actg.teamA5395@fstrf.org (ATTENTION: Christina Vernon and 
Chanelle Wimbish). 
 
Study Product 
For questions or problems regarding study product, dose, supplies, records, and returns, call 
Justine Beck or Shawn Chiambah, Protocol Pharmacists, at 301-496-8213.  
 
Study Drug Orders 
Call the Clinical Research Products Management Center (CRPMC) at 301-294-0741. 
 
IND (Investigational New Drug) Number or Questions  
For any questions related to the IND submission, contact the DAIDS RSC at Regulatory@tech-
res.com or call 301-897-1706. 
 
Expedited Adverse Event (EAE) Reporting/Questions  
Contact DAIDS through the RSC Safety Office at DAIDSRSCSafetyOffice@tech-res.com or call 
1-800-537-9979 or 301-897-1709; or fax 1-800-275-7619 or 301-897-1710.  
 
Telephone Calls 
Sites are responsible for documenting telephone calls made to A5395 team members.  
• 
Send an e-mail message to actg.teamA5395@fstrf.org. 
 
Protocol-Specific Web Page 
Additional information about management of the protocol can be found on the protocol-specific 
web page (PSWP). 


 
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GLOSSARY OF PROTOCOL-SPECIFIC TERMS 
 
AE  
adverse event  
ARDS 
acute respiratory distress syndrome 
Azithro 
azithromycin 
CFR  
Code of Federal Regulations  
CI  
confidence interval  
CLIA  
Clinical Laboratory Improvement Amendments  
COPD 
chronic obstructive pulmonary disease  
COVID-19 
Coronavirus Disease 2019 
CQMP 
Clinical Quality Management Plan  
CrCl  
creatinine clearance 
CVD 
cardiovascular disease 
DHHS  
Department of Health and Human Services  
DMID  
Division of Microbiology and Infectious Diseases 
DRESS 
drug reaction with eosinophilia and systemic symptoms  
DSMB 
Data and Safety Monitoring Board 
EC 
Ethics Committee  
eCRF 
electronic Case Report Form  
FDA 
Food and Drug Administration  
EKG 
electrocardiogram  
GCP 
Good Clinical Practice  
GI  
gastrointestinal 
HCQ 
hydroxychloroquine 
HTN 
hypertension 
IB  
Investigator Brochure  
ICF  
informed consent form  
ICU 
intensive care unit 
IND  
Investigational New Drug Application  
IRB  
Institutional Review Board  
IV  
intravenous  
MERS 
Middle East Respiratory Syndrome  
NIAID 
National Institute of Allergy and Infectious Diseases  
NIH  
National Institutes of Health  
OHRP 
Office for Human Research Protections  


 
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PHI  
Protected Health Information  
PI  
Principal Investigator  
SAE  
serious adverse event  
SAP   
Statistical Analysis Plan  
 
SARS-CoV-2  Severe Acute Respiratory Syndrome coronavirus 2  
SDCC  
Statistical and Data Coordinating Center  
SOP  
Standard Operating Procedure  
SUSAR  
Suspected Unexpected Serious Adverse Reaction  
TdP  
torsades de pointes 
WHO 
World Health Organization


 
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SCHEMA 
 
 
A5395 
 
A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of 
Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons with 
COVID-19 
 
 
DESIGN 
This is a phase IIB, double-blind, placebo-controlled, randomized trial, 
designed to compare the efficacy of hydroxychloroquine (HCQ) plus 
azithromycin (Azithro) versus placebo to prevent hospitalization and 
death in symptomatic adult outpatients with COVID-19 caused by SARS-
CoV-2 infection. 
 
 
DURATION 
24 weeks. Treatment will be for 7 days with 23 weeks of follow-up.  
 
 
SAMPLE SIZE 
2000 participants who start study treatment; approximately 1000 
participants in each of two treatment arms (A and B). Participants who are 
randomized but do not start study treatment will be replaced. A subset 
(200 participants who start treatment) will follow an additional sampling 
evaluation schedule. 
 
 
POPULATION 
Symptomatic, outpatient, adults (≥18 years) with SARS-CoV-2 infection 
 
 
STRATIFICATION  
Stratification will be by “high” versus “low” risk of progression to severe 
COVID-19, where “high risk” is defined as a person age ≥60 years or 
having at least one of several specified comorbidities. 
 
 
REGIMEN  
Participants will be randomized 1:1 to receive active/placebo study 
treatment as follows: HCQ/Placebo 400 mg orally twice a day on Day 0 
followed by 200 mg orally twice a day for 6 days, and Azithro/Placebo 
500 mg once on Day 0, followed by 250 mg daily for 4 days. 
 
 


 
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1.0 
HYPOTHESIS AND STUDY OBJECTIVES 
 
1.1 
Hypothesis 
 
1.1.1 Hydroxychloroquine (HCQ) and Azithromycin (Azithro) will prevent hospitalization 
and death in persons with symptomatic SARS-CoV-2 infection. 
 
1.2 
Primary Objective 
 
1.2.1 To determine if HCQ and Azithro will prevent the composite endpoint of either 
hospitalization or death by 21 days after study entry. Hospitalization is defined as 
≥24 hours of acute care. 
 
1.3 
Secondary Objectives 
 
1.3.1 To determine safety of HCQ and Azithro including 1) adverse events (AEs) 
leading to early discontinuation of treatment with HCQ and Azithro and 2) cardiac 
AEs. 
 
1.3.2 To determine if HCQ and Azithro reduce the frequency of detection and levels of 
SARS-CoV-2 RNA in site-collected nasopharyngeal (NP) swabs and self-
collected nasal swabs in subset of participants. 
 
1.3.3 To determine if HCQ and Azithro change the severity and duration of self-
reported symptom experience of COVID-19. 
 
1.3.4 To determine if HCQ and Azithro will prevent the composite endpoint of either 
hospitalization or death by 24 weeks after study entry. Hospitalization is defined 
as ≥24 hours of acute care.   
 
1.4 
Exploratory Objectives 
 
1.4.1 To explore if outpatient HCQ and Azithro change the hospital course once a 
participant requires hospitalization. 
 
1.4.2 To identify pretreatment hematology, chemistry, and inflammatory biomarkers 
that are associated with outcomes. 
 
1.4.3 To explore differences in outcomes between HCQ and Azithro versus placebo 
treatment groups among subgroups of the population, notably by sex, 
race/ethnicity, and risk groups defined by age and comorbidities.   
 
1.4.4 To explore possible predictors of outcomes across the study population, notably 
sex, race/ethnicity, and risk groups defined by age and comorbidities. 
 
 


 
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1.4.5 To determine the comparability between site-collected NP swabs and self-
collected nasal swabs for the detection of SARS-CoV-2 shedding. 
 
 
2.0 
INTRODUCTION 
 
2.1 
Background 
 
Threat 
A novel pneumonia caused by a previously unknown betacoronavirus emerged in 
Wuhan, China, in December 2019. The virus is closely related to the severe acute 
respiratory syndrome coronavirus (SARS-CoV-1), which led to an outbreak in 2003, and 
has been named SARS-CoV-2. The human disease caused by SARS-CoV-2 is called 
COVID-19.  
During the current SARS-CoV-2 outbreak, the incidence of known cases has rapidly 
increased such that, on January 5, 2020, there were 59 confirmed cases, 278 cases on 
January 20, 2118 cases on January 26, and more than 80,000 cases and 2700 deaths 
as of February 25, 2020, according to various international health reporting agencies. As 
a result, on January 30, 2020, the International Health Regulations Emergency 
Committee of the World Health Organization (WHO) declared the COVID-19 outbreak a 
Public Health Emergency of International Concern. On January 31, 2020, the US 
Department of Health and Human Services declared a public health emergency in the 
United States. As of April 22, 2020, there are 2,594,724 cases of COVID-19, including 
826,248 cases in the United States (US), resulting in a total of 179,778 deaths globally. 
Despite quarantine measures, SARS-CoV-2 continues to spread [1]. Outbreak 
forecasting and modeling suggest that these numbers will continue to rise [2]. 
 
Global efforts to evaluate novel antivirals and therapeutic interventions to treat COVID-
19 have intensified. There is currently no vaccine to prevent SARS-CoV-2 infection or 
therapeutic agent to treat COVID-19. Therefore, there is an urgent public health need for 
rapid development of novel interventions. 
Virology 
Coronaviruses (CoVs) are positive-sense, single-stranded, enveloped RNA viruses, 
many of which are commonly found in humans and cause mild symptoms. Over the past 
two decades, emerging pathogenic CoVs capable of causing life-threatening disease in 
humans and animals have been identified, namely, SARS-CoV-1 in 2002-2003 and 
Middle East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. 
Disease Course 
Once infection occurs, the clinical course is variable. Best current data suggest that 
fewer than 2.5% of infected persons will show symptoms within “2.2 days (CI, 1.8 to 2.9 
days) of exposure, and symptom onset will occur within 11.5 days (CI, 8.2 to 15.6 days) 
for 97.5% of infected persons” [3]. In most (~80%) cases, COVID-19 presents as a mild-
to-moderately severe, self-limited acute respiratory illness with fever, cough, and 
shortness of breath. It remains unclear exactly what the rate of progression of COVID-19 
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distress syndrome (ARDS), kidney failure, and death. It is clear that older age, male sex, 
and comorbidities including diabetes and hypertension increase the risk for worse 
outcomes (Figure 2.1-1) [4-6]. In a recent meta-analysis, the main clinical symptoms 
were fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), expectoration (28.2%), 
and dyspnea (21.9%). Minor symptoms included headache or dizziness (12.1%), 
diarrhea (4.8%), and nausea and vomiting (3.9%) [7]. Laboratory examinations showed 
that lymphocytopenia (64.5%), increase of C-reactive protein (CRP) (44.3%), increase of 
lactate dehydrogenase (LDH) (28.3%), and leukocytopenia (29.4%) were more common 
in those with COVID-19 [4, 8]. 
 
 
Figure 2.1-1:  Timeline of COVID Disease Progression after Hospitalization. 
Onset refers to onset of symptoms. 
 
Shedding 
Viral infections jump from host to host through a variety of pathways. CoVs do this 
through respiratory droplets. Understanding this shedding is important to understanding 
epidemic spread and how shedding relates to disease progression. Best evidence 
available now suggests that viral shedding, especially in upper respiratory secretions, is 
detectable around 2 days before symptoms develop and continues throughout the 
symptomatic phase. This shedding can be quite high during active disease and can 
continue for up to 37 days, with a quarter of persons still shedding at 3 weeks, as 
detected by nasopharyngeal swabs [4]. 
Biomarkers 
The literature also points to a systemic inflammatory response that predicts disease 
progression and death. Having a biomarker panel that can predict such progression 
early would be helpful in making clinical decisions and triaging clinical care [4]. In 
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IL7, IL10, granulocyte colony stimulating factor (GCSF), interferon gamma-induced 
protein (IP)10, monocyte chemoattractant protein 1 (MCP1), macrophage inflammatory 
protein 1-alpha (MIP1A), and tumor necrosis factor-alpha (TNFα) than hospitalized 
patients not requiring ICU admission [5]. Nothing is currently known about which 
inflammatory biomarkers during early infection might predict increased risk for 
hospitalization.  
 
Biomedical Interventions 
There are no approved treatments for COVID-19. Some agents have shown activity 
against other betacoronaviruses, such as lopinavir/ritonavir, chlorpromazine, 
nitazoxanide, gemcitabine, and dasatinib [9], and two agents have shown in vitro activity 
against the virus, including chloroquine and the adenosine analog remdesivir [10]. There 
is no clinically proven antiviral treatment for SARS-CoV-2 infection, although a clinical 
trial of remdesivir [11] is underway in China [12], and the US for severe pulmonary 
disease, and anecdotal evidence has been published about HCQ and Azithro [13]. 
Chloroquine and its less toxic derivative HCQ (first FDA approved in 1955 for the 
treatment of malaria) have garnered substantial interest as off-label treatment for 
COVID-19. They are alkalinizing lysosomatropic drugs that accumulate in lysosomes 
[14]. Both drugs block viral infection by increasing endosomal pH, which is required for 
viral particles to fuse with a cell. Chloroquine also interferes with glycosylation of cellular 
receptors of CoV, including SARS-CoV 
[15]. In vitro data in Vero E6 cells have 
demonstrated that chloroquine functions 
at both entry and at post-entry stages of 
the SARS-CoV-2 infection, unlike 
remdesivir [10]. Further in vitro data 
showed that there is an exposure-
response relationship for HCQ (Figure 
2.1-2). Both drugs also modulate the 
immune response, and have long been 
used to treat autoimmune diseases such 
as rheumatoid arthritis, porphyria cutanea 
tarda, and lupus [14]. Such immune 
modulation may also help in thwarting 
ARDS [16]. 
HCQ Pharmacology 
HCQ and chloroquine have similar 
pharmacokinetics, with rapid 
gastrointestinal absorption and elimination 
by the kidneys. Both are also metabolized by the cytochrome P450 enzymes (CYP2D6, 
2C8, 3A4, and 3A5). HCQ is metabolized to desethylhydroxy-chloroquine, 
desethylchloroquine, and bidesethylhydroxychloroquine by the liver and excreted by the 
kidneys, with desethylhydroxychloroquine being most common [17, 18a]. The absorption 
half-life is 3 to 4 hours and the terminal half-life ranges from 40 to 50 days. Based on 
modeling of HCQ pharmacokinetics and its antiviral effects, Dr. Rada Savic at UCSF 
found that higher doses of HCQ would be associated with progressive loss of detection 
Figure 2.1-2: In vitro Activity of Remdesivir, 
Hydroxychloroquine, and Chloroquine [10] 


 
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of SARS-CoV-2 in the nasopharynx over 6 days of dosing (Figure 2.1-3), in a dose-
dependent manner [18b]. However, higher doses are also associated with longer QT 
interval prolongations; thus, in order to balance the potential risks and benefits for 
treatment in the outpatient setting, treatment in this trial will include a loading dose of 
800 mg divided into two 400 mg doses taken 12 hours apart starting at enrollment, 
followed by 200 mg twice daily for 6 days (12 doses), with a total dose of 3200 mg of 
HCQ during the study.   
 
Figure 2.1-3: Estimated Efficacy (% of PCR-negative samples) and QTc 
Prolongation for Various Hydroxychloroquine Regimens 
 
HCQ Interactions 
HCQ does not have significant interactions with most other medications, but may 
enhance liver toxicity of select drugs, for example, aurothioglucose, cimetidine, or 
digoxin. It can also increase the blood plasma concentrations of penicillamine, which 
may contribute to the development of side effects from penicillamine, and decrease the 
levels of ampicillin and praziquantel. It can also enhance hypoglycemic effects of insulin 
and oral hypoglycemic agents.  
Azithro Pharmacology 
Azithro was first approved for clinical use in 1988 [19]. It is currently FDA approved for 
use in mild to moderate bacterial infections including sinusitis, community acquired 
pneumonia, urethritis/cervicitis, pharyngitis, and acute bacterial exacerbations of chronic 
obstructive pulmonary disease. It is the first of the azalide class of antimicrobials, which 
does not undergo significant metabolism and does not complex with or induce 
cytochromes P450 (CYPs), therefore decreasing the potential for drug interactions [19, 
20]. Azithro has been found to have a long terminal half-life of 50 hours with 500 mg IV 
dosing and 79 hours with 500 mg oral dosing, making once a day or single dose 
treatments possible [21]. It is also known to have a large volume of distribution and 
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intracellular concentrations in immune cells [22]. The co-administration of meals along 
with Azithro has no impact on bioavailability [23]. 
Azithro Interactions 
In pre-clinical studies, Azithro has been shown to increase QT intervals, but without 
inducing torsades de pointes (TdP) [24]. Given QT prolongation may occur, concurrent 
Azithro administration is not recommended with high-risk QT-prolonging agents, such as 
fexinidazole and pimozide. Other QT-prolonging agents such as antipsychotics or class 
IC antiarrhythmics should be used with caution with monitoring of QTc interval. In 
addition, Azithro as a P-glycoprotein (P-gp) inhibitor should be avoided in concurrent use 
of colchicine, topotecan, rimegepant, pazopanib, or vincristine, as it may increase the 
serum concentration of these drugs [25]. There is conflicting evidence on the effect of 
Azithro on warfarin drug metabolism. In general, it appears that there is a modest 
decrease in warfarin clearance and thus a possible increase in anticoagulant effect [26]. 
Patients should continue to have international normalized ratio monitored when Azithro 
is used with warfarin. In addition, there is potential risk of increased rhabdomyolysis with 
concurrent use of statins, and patients should be monitored on such therapy [27]. 
HCQ and Azithro Interactions  
There are no pharmacologic drug-drug interactions between Azithro and chloroquine, 
and thus none are expected between Azithro and HCQ, including in pregnant women 
[28, 29]. 
 
Potential Risks of HCQ and Azithro 
HCQ and Azithro have each been used widely for many years, for the independent 
indications described previously. Potential risks are described further in this section 
below. 
 
HCQ 
Common side effects of HCQ include headache, emesis, diarrhea, vision changes, and 
muscle weakness. Severe side effects are mainly limited to allergic reactions and eye 
toxicity, “chloroquine retinopathy” [30], and cardiac toxicity. “Chloroquine retinopathy” is 
a relatively serious toxicity associated with HCQ use among people taking HCQ for 
greater than 5 years [31]. Further, rapid-onset retinopathy has been reported in persons 
being treated with erlotinib and high-dose HCQ (1000 mg daily) for non-small cell lung 
cancer [32]. Generally, people taking 400 mg of HCQ or less per day or for short periods 
have a negligible risk of retinopathy, as macular toxicity is related to total cumulative 
dose [22]. The dose and durations proposed in this trial are unlikely to cause retinopathy 
[31]. 
 
HCQ can prolong the QT interval, and ventricular arrhythmias and TdP have been 
reported, but usually after prolonged administration [33], particularly in patients with 
lupus and other comorbidities such as end-stage renal disease [34-37]. In general, 
drug-induced TdP and life-threatening ventricular arrhythmias from HCQ are very rare 
and typically only observed when doses of 5 g or more are taken [14, 33, 38]. HCQ is a 
derivative of chloroquine, and the relationship between chloroquine and QT prolongation 
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interval. When chloroquine was administered to healthy adults (regimen 600 mg + 600 
mg + 300 mg on Days 1, 2, and 3, respectively) the average increase in QTc interval 
was 28 ms (18-38 ms; 95% CI) with no cardiac AEs reported [39]. While chloroquine and 
HCQ are different compounds, animal toxicity studies indicate HCQ is two to three times 
less toxic across different species [40]. 
Further, the WHO states, “[d]rug-induced TdP and life-threatening ventricular tachy-
arrhythmias are very rare events, and there are no simple screening tests to identify 
people at risk.” Also from WHO, “[d]espite hundreds of millions of doses administered in 
the treatment of malaria, there have been no reports of sudden unexplained death 
associated with quinine, chloroquine or amodiaquine, although each drug causes 
QT/QTc interval prolongation” [38]. 
Azithro 
Common side effects associated with both oral and IV administration of Azithro include 
nausea and vomiting, likely due to increased gastric motility [19]. Severe side effects 
include pseudomembranous colitis, exacerbation of myasthenia gravis, Stevens-
Johnson syndrome/toxic epidermal necrolysis, and drug reaction with eosinophilia and 
systemic symptoms (DRESS) [41, 42]. In addition, there is an increased rate of cancer 
relapse for hematopoietic stem cell transplant patients with acute lymphocytic leukemia 
(ALL), acute myelocytic leukemia or bronchiolitis obliterans who received long-term 
Azithro therapy (greater than 2 years) [43]. However, patients taking Azithro for short 
periods have a negligible risk of this complication. Azithro crosses the placenta and is 
found in low concentrations in breast milk, but is considered safe to use in pregnancy 
[44].  
 
Prolongation of QT with Azithro treatment has been seen in pre-clinical studies, but 
clinical studies of long term treatment with Azithro have not observed this effect [45]. 
Additionally, in the preclinical studies that demonstrated QT prolongation with Azithro, 
the QT prolongation did not lead to TdP, the clinical outcome of concern [24]. 
Furthermore, in clinical studies of long-term treatment (median of 9 months) with Azithro 
in patients with non-tuberculous mycobacterial infection, no significant change in QTc 
intervals and no cardiovascular events were observed during the treatment period [45].  
 
COVID-19 
There are some concerning reports that COVID-19 is associated with cardiac disease. In 
particular, a recent study in China found that persons with underlying cardiovascular 
disease are at high risk for severe disease and death [46]. It is unclear if cardiac 
morbidity is worse in the setting of COVID-19 with other pneumonia-causing pathogens 
[47], and unknown if the risks of short course HCQ and Azithro differ in the context of 
COVID-19. 
Assessment of Potential Risks and Benefits 
Although there are limited clinical data of HCQ plus Azithro use, there are preclinical 
data on using chloroquine plus Azithro in a rapid-pacing model in an anesthetized 
guinea pig model, which has been shown to be predictive of concentration-dependent 
onset of TdP [48]. This study evaluated increasing doses of azithromycin dehydrate and 
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The investigators reported no biologically significant effect on mean alternans. In fact, 
when combined, Azithro reduced the magnitude of alternans observed with chloroquine 
alone. This preclinical data is supported by clinical studies using chloroquine with 
Azithro. The Kimani et al. study evaluated malaria prevention during pregnancy where 
1445 women received 3 days of chloroquine plus Azithro that was repeated at 4-8 week 
intervals during the second and third trimesters of pregnancy. Although QT intervals 
were not assessed at baseline or throughout the study, there were no reported cardiac 
AEs [29]. Sagara et al. conducted two randomized, comparative, non-inferiority studies 
in Africa where patients with malaria received Azithro 1000 mg (n=227) or Azithro 500 
mg (n=9) with chloroquine 600 mg, all once daily for 3 days [49]. While QT interval was 
not measured at the beginning or during the study, there were no cardiac AEs noted. 
While subjective adverse events of dizziness and palpitations were reported, they 
occurred no more frequently than seen in the mefloquine control arm. The azithromycin 
label reports that, in comparison to chloroquine alone, the maximum mean (95% 
upper confidence bound) increases in QTcF are 5 (10) ms, 7 (12) ms, and 9 (14) 
ms, with the co-administration of 500 mg, 1000 mg, and 1500 mg azithromycin, 
respectively. 
 
Given that the proposed study will exclude those taking concomitant medications with 
high risk of prolonging QT (section 5.4.1), we do not feel that electrocardiograms (EKGs) 
at study entry or during treatment are needed. We believe that exclusions on the basis 
of baseline QTc are unlikely to add significantly to overall safety, above and beyond 
the planned exclusion of participants with higher risk for drug-induced ventricular 
arrhythmias and cardiac events based upon relevant personal or family cardiac history, 
high risk clinical history including severe renal and liver disease, and those who are 
taking additional QTc prolonging agents. Further, in the midst of a global pandemic, the 
risk-benefit assessment must consider a wide range of participants, study staff and 
resource utilization-related issues. In this case, the condition of TdP is expected to be 
very rare and the performance of EKGs would require the use of personal protective 
equipment (PPE), for which supplies must be carefully preserved as the current 
pandemic escalates, and the risk of additional direct contact between staff and highly 
infectious study participants. As a result, we feel that the potential benefit of HCQ plus 
Azithro treatment for a disease with an overall case fatality rate of up to 3% (and based 
on preliminary estimates in the US, 3-11% among persons aged 65-84 years) outweighs 
the very small risk of a treatment-related cardiac AE, and therefore do not feel that EKGs 
at study screening or during treatment would be justified [50, 51].  
 
2.2 
Rationale 
 
At present, there is no specific antiviral therapy for COVID-19. Few treatment studies 
have been conducted because most human CoV strains cause self-limited disease, and 
care is supportive. After SARS-CoV-1 was identified in 2002-2003 and caused a large 
global outbreak, there was an increased interest in the development of specific 
therapeutic agents. SARS-CoV-1 patients were treated with corticosteroids, type 1 IFN 
agents, convalescent plasma, ribavirin, and lopinavir or ritonavir; except for ribavirin, 
many of these agents have in vitro pre-clinical data that support their efficacy [52-67]. 
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entry proteins, proteases, polymerases, and methyltransferases have been tested; 
however, none of them has been shown to be efficacious in clinical trials [68-70]. 
 
Given the lack of specific antiviral therapy for SARS-CoV-2 infection, and the known 
safety profiles and ready availability of HCQ and Azithro as potential antiviral agents, 
this regimen warranted further consideration. This, along with some promise 
observed in pre-clinical and small clinical studies, resulted in designing this 
randomized, placebo-controlled trial to evaluate the efficacy and safety of HCQ and 
Azithro in persons who have active SARS-CoV-2 infection and mild to moderate COVID-
19 symptoms.  
 
Why HCQ and Azithro for COVID-19?  
Mechanism: Since a putative antiviral mechanism for HCQ is alkalinizing of lysosomes 
[14, 15], there is good reasoning that Azithro can potentiate this activity because it also 
increases the pH of lysosomes, and has been documented to potentiate this effect with 
chloroquine. Given the extensive data from malaria studies, these drugs can be safely 
used together with no drug-drug interactions [29, 49] (see below).  
 
French experience: There is a recent uncontrolled study by Gautret et al. that evaluated 
HCQ and Azithro for SARS-CoV-2 shedding. It was a 20-person single-arm study with 
SARS-CoV-2 infection in a hospital setting. The study evaluated 600 mg of HCQ daily, 
and Azithro was added to the HCQ treatment based on clinical status. Untreated 
patients from another center and cases refusing the protocol were included as negative 
controls. Presence and absence of virus at Day 6-post inclusion was the study end point. 
The authors showed that HCQ may be effective in reducing viral loads (Figure 2.2-1). 
Specifically, HCQ reduced the proportion of persons with SARS-CoV-2 infection with 
polymerase chain reaction (PCR)-positive samples by 75% in the 6-day period, and 
when it was combined with Azithro, it improved the treatment efficacy to 95% [13]. 
 
The same authors recently published on-line their experience with 80 patients, 6 of 
whom were in the original published cohort, admitted to their inpatient ward with 
documented SARS-CoV-2 infection [13, 71]. None of these individuals were originally 
admitted to the ICU, with 54% having evidence of lower respiratory tract infection and 
5% being asymptomatic, and only 15% requiring supplemental oxygen at presentation. 
The authors reported that one died on their unit and one was transferred to an intensive 
care unit. They reported that 83% were nasopharyngeal swab PCR negative on Day 7 
and 93% by Day 8. They further noted that 97.5% were culture negative by Day 5 of 
follow-up. 
 
However, there are a number of limitations of the smaller study: 1) it was not 
randomized, 2) a therapeutic effect in the first 2 days of treatment is unusual as drug 
levels are unlikely to have achieved therapeutic levels, 3) the small number of 
participants, 4) the dropout rate in the treatment arm and exclusion from the analysis of 
a death and 3 ICU admissions, 5) the reliance on clearance of SARS-CoV-2 detected by 
NP swab as the primary outcome given the natural history, even in severe disease, is 
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persons receiving HCQ and Azithro, compared to the persons receiving HCQ alone. A 
secondary analysis of the data from this non-randomized trial was conducted and 
concluded that the data “show modest to no impact of HCQ treatment, with more 
significant effects from the HCQ-AZ combination, potentially suggesting a role for co-
infections in COVID-19 pathogenesis. The trial of Gautret and colleagues, with 
consideration of the effect sizes, and p-values from multiple models, does not provide 
sufficient evidence to support wide-scale rollout of HCQ monotherapy for the treatment 
of COVID-19; larger randomized studies should be considered. However, these data do 
suggest further study of HCQ-Azithro combination therapy should be prioritized “as 
rapidly as possible” [72]. 
 
  
 
 Figure 2.2-1: Clinical Course during HCQ and Azithromycin Treatment 
 
The second larger study substantially increases the number of enrolled individuals, but 
also lacks a control group. It also enrolled a group with relatively mild disease, which is 
consistent with the population we plan to enroll and perhaps provides support for our 
strategy to use this regimen to prevent hospitalization in this subset of infected 
individuals. 
Chinese experience: Reported clinical studies with these agents for COVID-19, apart 
from the Gautret studies, have been limited to chloroquine or HCQ and not Azithro or the 
combination. An initial report of clinical trials testing the safety and efficacy of 
chloroquine for the treatment of COVID-19 pneumonia across 10 hospitals in China 
noted that preliminary results from 100 patients suggested superiority of chloroquine 
phosphate to control treatment (control treatment unspecified), in outcomes including 
“inhibiting the exacerbation of pneumonia, improving lung imaging findings, promoting a 
virus-negative conversion, and shortening the disease course.” Further details are not 
available.  Per this report, these initial findings have led to the recommendation that 
chloroquine phosphate be included in national Chinese guidelines for the management 
of COVID-19 [73]. 
 


 
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An additional study of HCQ treatment in 30 “common” COVID-19 patients (reportedly 
with relatively mild disease) was published, with only the abstract available in English 
[74a]. In this study participants were randomized 1:1 to HCQ 400 mg po daily plus usual 
therapies vs usual therapies alone. All participants received inhaled interferon-alpha, 
and the majority in both arms (80% of the HCQ arm, 67% of the control arm) received 
umifenovir, and two participants in the control arm also received lopinavir and ritonavir. 
No difference in endpoints of PCR-negative Day 7 pharyngeal swabs, time to 
undetectable viral load, radiographic progression, and days to resolution of fever were 
observed. This small study was highly confounded by concomitant therapies and, thus 
the conclusions that can be made about the efficacy (or lack of efficacy) of HCQ are 
limited.  
 
Future: Additional national and international trials of HCQ are underway or planned, 
largely in hospitalized patients, including a WHO trial (SOLIDARITY) comparing five 
treatment arms: chloroquine/HCQ, remdesivir, LPV/r, LPV/r plus interferon-beta, or 
standard of care; a European trial (DISCOVERY), with the same treatment arms as the 
WHO trial, but with HCQ only and not chloroquine or HCQ; an RCT of LPV/r versus 
HCQ in patients with mild disease (NCT04307693); an RCT of HCQ versus no HCQ in 
patients with mild or moderate disease, or asymptomatic (NCT04323631); HCQ versus 
placebo for COVID-19-related ARDS (NCT04315896); an RCT of various combinations 
of HIV protease inhibitors, oseltamivir, favipiravir, and HCQ (NCT04303299); a non-
randomized trial of LPV/r versus HCQ versus baricitinib (janus kinase inhibitor) versus 
sarilumab (anti-IL-6 receptor antibody) (NCT04321993) for moderate to severe COVID-
19 in hospitalized patients; a trial of remdesivir versus HCQ versus standard of care 
(NCT04321616); a randomized open-label trial of remdesivir, LPV/r, interferon beta, 
HCQ, or standard of care in hospitalized patients (NCT04315948); and multiple post-
exposure prophylaxis trials of HCQ. Two unblinded studies of HCQ plus Azithro versus 
HCQ for COVID-19 pneumonia and hospitalized patients are planned in Brazil 
(NCT04321278, NCT04322123). Both of these trials are planning doses of HCQ 400 mg 
po BID and Azithro 500 mg po daily, one given for 10 days and one for 7 days.  
 
Summary: The combination of HCQ and Azithro deserves further evaluation in a 
rigorous clinical trial in the outpatient setting. If we evaluate HCQ alone and find that it is 
no better than Placebo, then we have not answered the question if HCQ and Azithro is 
effective for COVID-19. Given the biologic rationale of potentiating raising lysosome pH 
[14, 15], then we would be left without a clear answer. However, if the proposed study 
shows that HCQ and Azithro is not better than Placebo alone, then we can be relatively 
confident that neither had an effect.  
 
Further, the use of HCQ and Azithro can be implemented at scale through one 
outpatient visit or remote non-face-to-face visit at study entry. This will minimize contact 
between study participants and study staff to reduce use of PPE and potential risk of 
SARS-CoV-2 transmission. 
 
Mitigation of Risk from HCQ and Azithro 
HCQ can prolong the QT interval, and ventricular arrhythmias and TdP have been 
reported, but usually after prolonged administration [33], particularly in patients with 


 
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lupus and other comorbidities such as end stage renal disease [34-37]. In fact, drug-
induced TdP and other life-threatening ventricular arrhythmias from HCQ are very rare 
and typically only observed at high doses given for long periods of time [14, 33, 38]. 
HCQ is a derivative of chloroquine, and the same molecule in both drugs causes the 
QTc prolongation; therefore, the use of chloroquine in malaria studies helps guide our 
reasoning with HCQ. When chloroquine was administered to healthy adults (regimen 
600 mg + 600 mg + 300 mg on Days 1, 2, and 3, respectively) the average increase in 
QTc interval was 28 ms (18-38 ms; 95% CI) with no cardiac AEs reported [39].  
 
The combination of short-course chloroquine and Azithro has been observed to 
be well tolerated in malaria trials. In particular, Kimani et al studied malaria prevention 
during pregnancy where 1445 women received 3 days of chloroquine plus Azithro that 
was repeated at 4-8 week intervals during the second and third trimester of pregnancy. 
Although QT intervals were not assessed at baseline or throughout the study, there were 
no reported cardiac AEs [29], which would be the main danger signal for TdP in such a 
study. Further, Sagara et al. conducted two randomized, comparative, non-inferiority 
studies in Africa where patients with malaria received Azithro 1000 mg (n=227) or 
Azithro 500 mg (n=9) with chloroquine 600 mg base, all once daily for 3 days and there 
were no treatment-related cardiac events [49]. Given the extensive experience in 
malaria prophylaxis and treatment, it is clear that any QT prolongation by either drug is 
not likely to be clinically relevant. In fact, the WHO explicitly states “Despite hundreds of 
millions of doses administered in the treatment of malaria, there have been no reports of 
sudden unexplained death associated with quinine, chloroquine or amodiaquine, 
although each drug causes QT/QTc interval prolongation” [38]. 
 
Despite the low risk of clinically relevant QT prolongation, the proposed study design 
incorporates a number of measures to further reduce the risk. These include the 
exclusion of people who take other agents known to prolong QTc, have a personal or 
family history of Long QT syndrome, a history of ventricular arrhythmias, known 
structural or ischemic heart disease, or severe kidney or liver disease. 
 
The use of mobile devices that can perform ECG and measure vital signs has been 
discussed extensively by the study team and team leads have discussed the capabilities 
of select devices with their manufacturers or researchers who have used them. Based 
on these discussions, we have chosen to not include such monitoring for safety 
purposes for several reasons. Foremost, real-time monitoring for the large number of 
participants who will be enrolled at any one time will likely be unmanageable, and our 
older participants may have a harder time with such devices. Therefore, such monitoring 
is unlikely to lead to an immediate intervention. In addition, given the short duration of 
treatment and the long half-life of HCQ and Azithro, discontinuation of these drugs 
following detection of QTc prolongation, even if feasible, may have limited impact. 
 
To help mitigate the risk of HCQ and Azithro causing TdP, we have followed the 
guidance from Simpson et al. [74b], which states, “minimizing exposure/contact: It 
may be reasonable to forego ECG screening to allow patients to remain in 
quarantine if no high-risk features exist (history of long QT syndrome, 
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history of prolonged QTc on any ECG, history of abnormal renal function and/or 
electrolytes).” Therefore, we will exclude potential participants with underlying 
conditions associated with TdP, including: history of ventricular arrhythmia or on 
antiarrhythmics, personal or family history of long QT syndrome, history of 
hypomagnesemia or hypokalemia, history of structural or ischemic cardiac 
disease, use of antiepileptic or loop diuretic drugs, or use of drugs that can also 
prolong the QT interval. We will also have the close monitoring by the DSMB that 
can assist in quickly identifying safety issues with HCQ. 
Overall, HCQ and Azithro are FDA-approved drugs that have the potential to decrease 
disease progression in early COVID-19 illness. HCQ shown anti-SARS-CoV-2 activity in 
vitro and there is a clear mechanistic pathway for Azithro to enhance HCQ activity. The 
combination has preliminary, though limited, non-randomized in vivo studies, as 
described above, to suggest candidacy as treatment for COVID-19. Rigorous clinical 
trials must be conducted to ascertain effectiveness and safety. These agents may be 
more likely to have an effect early in the course of SARS-CoV-2 infection and an 
intervention that decreases or prevent hospitalization would have substantial clinical, 
public health and economic impact. The proposed study is a multicenter, randomized, 
placebo-controlled study. As designed, it will be able to acquire rigorous data about the 
safety and efficacy of HCQ and Azithro compared to placebo for COVID-19 that will lead 
to generalizable evidence.  
 
Justification for Dose 
Doses of HCQ and Azithro are based on the pharmacokinetics of each drug, historical 
population pharmacokinetics models’ PK-QTc relationship, in vitro concentration-
response relationship for HCQ, clinical PKPD model from persons treated for COVID-19 
in the Gautret et al. study, the natural course of viral infection in humans and, finally, 
clinical trial simulations for efficacy and safety using all available pharmacological data 
[10, 71, 75-77]. Further, this trial has been designed to approximate outpatient 
clinical practice. For outpatients with mild-to-moderate COVID-19 receiving HCQ 
and Azithro, an EKG would not be standard (nor would blood work). This, again, 
reflects a balance between the value of assessment and the risk of infection to 
healthcare workers (and study staff) in the setting of active and acute COVID-19. 
Thus, we have opted for a “no touch” research protocol for outpatient 
participants, and, in close discussions with the FDA and heeding their guidance, 
we have chosen doses of HCQ and Azithro that are commonly used in the 
outpatient setting with no laboratory or EKG monitoring. 
 
Justification for the Control Arm 
In light of the heterogeneity of disease progression in those with COVID-19, it is 
extremely important that this study include a control group. To this end, this trial will have 
a double-blinded placebo control arm to best determine the efficacy and safety of HCQ 
and Azithro in the outpatient setting for persons with COVID-19.  
 
Justification for Placebo Controlled Design 
There is public interest in several putative therapeutic agents for COVID-19. However, 
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above-mentioned non-randomized trial of HCQ with and without Azithro signals a 
possible benefit of the combination but is far from conclusive, as highlighted by a 
recently performed secondary analysis of the study data. Further, as described, these 
medications are not without potential side effects. Given the absence of high-quality 
efficacy data and the potential risks, there is clear equipoise regarding the use of HCQ 
and Azithro for patients with COVID-19. A well-powered placebo-controlled trial will 
provide the best opportunity to recruit outpatients with COVID-19 and rigorously evaluate 
the safety and efficacy of these medications.  
 
Justification for Age Restriction 
Children and adolescents will not be included in this trial. Initial information about the 
epidemiology of COVID-19 indicates that the overwhelming burden of severe disease 
occurs among older adults, especially those with comorbidities. Given significant gaps in 
knowledge regarding SARS-CoV-2 infection in this population, and a low incidence of 
severe morbidity/mortality in children, the risk/benefits do not warrant inclusion of this 
population into this trial at this time. 
 
Justification for Comorbidities 
Individuals with comorbidities, such as diabetes and HIV, will be included, as they may 
have a higher risk of hospitalization and life-threatening COVID-19.  
 
Justification for Pregnancy and Breastfeeding 
The proposed doses of HCQ and Azithro have been used safely in pregnant women and 
women who are breastfeeding [29]; therefore, these persons will be eligible for the study.  
 
3.0 
STUDY DESIGN 
This is a phase IIB, double-blind, placebo-controlled randomized trial, designed to 
compare the efficacy of HCQ and Azithro versus placebo to prevent hospitalization and 
death in symptomatic adult outpatients with COVID-19, caused by SARS-CoV-2 
infection. The study is a multicenter trial that will be conducted in the United States. 
 
A total of 2000 participants who start study treatment (approximately 1000 in each 
treatment arm) will be followed on study for 7 days on treatment and an additional 23 
weeks off treatment. Participants who do not start study treatment will be replaced. 
Participants will be randomized 1:1 to receive either 400 mg orally twice a day on Day 
0 followed by 200 mg orally twice a day for 6 days, and Azithro/Placebo 500 mg once 
on Day 0, followed by 250 mg daily for four days (Figure 3-1).  
 
Randomization will be stratified by “high” versus “low” risk of severe disease, where 
“high” risk is defined by any of the following:  
• 
Persons aged 60 years and older 
• 
Persons having at least one of the following conditions:  
o Chronic lung disease or moderate to severe asthma 
o Immunocompromised status due to disease (for example, those living with HIV 
with a CD4+ T-cell count of <200/mm3)  


 
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o Immunocompromised status due to medication (for example, persons taking 20 
mg or more of prednisone equivalents a day, anti-inflammatory monoclonal 
antibody therapies, or cancer therapies) 
o Severe obesity (body mass index [BMI] >40; may be based on self-report of 
height and weight)  
o Hypertension 
o Cardiovascular disease 
o Diabetes 
o Chronic kidney disease 
o Chronic liver disease 
 
Figure 3-1: Study Design 
 
Recruitment 
Participants can be recruited by sites in several ways, which will be enhanced because 
many clinical research sites (CRSs) are participating in COVID-19 screening activities. 
Thus, sites may work with local SARS-CoV-2 testing sites through outreach staff and 
recruitment materials placed at this location. It is also expected that participants will be 
referred to the study immediately upon SARS-CoV-2 diagnosis from partnering testing 
sites or ordering providers who receive test results. Symptomatic persons receiving a 
positive SARS-CoV-2 result by molecular test can be informed about the study 
opportunity and be provided with study site contact information. 
 
Study Visits 
The study is designed to minimize in-person contact between participants and study staff 
or other persons at the CRS. The informed consent process, screening, and 
randomization may be performed remotely, in compliance with institutional and 
regulatory requirements. 
 
At study entry, all participants will have either a remote visit or an in-person study visit at 
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entrance, or while in their car in a parking lot/parking garage. Participants will be given 
study treatment, a study symptom and adherence diary (i.e., Study Diary), and contact 
numbers for the study staff. Participants will provide medical and medication histories, 
and contact information for themselves, including their home address, a list of local 
hospitals where they are likely to seek medical services if needed, and for persons 
who will know about their study participation, in case study staff cannot reach the 
participant. Further, participants will be provided contact information for research staff in 
the event they require hospitalization. Participants will then complete the Pre-Treatment 
page of the Study Diary prior to starting study treatment.  
 
The participant’s first symptom(s) associated with COVID-19 and when it/they occurred 
will be recorded. Participants will also be observed taking their first dose of study 
treatment if it is an in-person visit. 
 
Participants will record their symptoms, temperature (if participant is able to provide), 
medication adherence, and major events such as hospital visits and hospitalization in 
the Study Diary daily on Days 0-20, in the evening (section 6.3.10). Study staff will 
contact participants per the Schedule of Evaluations (SOE) to review study diaries. If 
participants cannot be reached after two attempts 24 hours apart, then their alternative 
contact person(s) will be called.  
 
At Day 20, for non-sampling subset participants, an in-person or remote visit will 
occur for assessment of the primary outcome and collection of the Study Diary. At this 
time the participants are expected to no longer be infectious, if they remain un-
hospitalized. For participants that cannot be reached, the study staff will contact the 
alternative contacts the participant provided to collect information on these outcome 
measures. If the participant is symptomatic on Day 20 and an in-person study visit 
was planned, the in-person study visit may be delayed (refer to section 6.2.3) or 
converted to a remote visit. If a remote Day 20 visit is conducted, arrangements 
should be made for future transfer of Study Diary from the participant to the study 
staff (i.e., mailing the Study Diary or sending images) and provision of 
compensation for study participation.  
 
At weeks 12 and 24, remote visits will be performed to review longer term disease 
course. At these visits, study staff will record any hospitalizations or deaths that occurred 
since the Day 20 visit. Additional approaches (such as querying death registries) may be 
used as feasible at the sites. 
 
Participants will be instructed to contact study staff immediately if they seek medical help 
at any time during the study. 
 
Additional Evaluation Subset 
Some sites will be selected to conduct more in-person visits, depending on availability of 
staff, PPE, and isolation rooms.  
 
At pre-selected sites, at study entry [Day 0] and Days 6 and 20, a subset of 
participants who agree will undergo self-collected nasal swabs, staff-collected NP swab, 


 
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and blood collection on site under appropriate infection control conditions, as described 
below. Single sparse pharmacokinetics (PK) sampling will be collected at Days 6 and 20 
(refer to section 11.0 for details).  
 
Isolation Procedures 
Given that SARS-CoV-2 is spread through respiratory droplets, each site must develop 
procedures to protect study staff and participants of other trials from infectious exposure. 
Each site will have a plan for maximal protection by providing PPE, setting up isolation 
rooms or outside areas, providing special access points or contact with study 
participants. Each site will develop their own set of procedures for such participant 
contact. 
 
4.0  
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
4.1 
Inclusion Criteria 
 
4.1.1 Participant (or legally authorized representative) provides informed consent prior 
to initiation of any study procedures. 
 
4.1.2 Individual ≥18 years of age. 
 
4.1.3 Documentation of confirmed active SARS-CoV-2 infection, as determined by a 
molecular test conducted at any US clinic or laboratory that has a Clinical 
Laboratory Improvement Amendments (CLIA) certification or its equivalent from 
any respiratory specimen collected <96 hours from when the first dose of 
study treatment is expected to be taken. 
 
4.1.4 Experiencing at least one of the following SARS-CoV-2 infection symptoms 
within 24 hours of screening: fever (can be subjective) OR cough OR 
shortness of breath. 
 
4.1.5 Agrees to not participate in another clinical trial for the treatment of COVID-19 or 
SARS-CoV-2 during the study period up until reaching hospitalization or 21 days, 
whichever is earliest. 
 
4.1.6 Agrees to not obtain study medications outside of the A5395 study. 
 
4.2 
Exclusion Criteria  
 
(Medical history can be by self-report. Refer to the A5395 MOPS.) 
 
4.2.1 Need for hospitalization or immediate medical attention in the clinical opinion of 
the study investigator. 
 
4.2.2 History of or current hospitalization for COVID-19. 
 


 
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NOTE: Individuals hospitalized and then discharged, even if only hospitalized for 
1 day, are excluded. 
 
4.2.3 History of ventricular arrhythmia or using antiarrhythmics within the past 30 
days. 
 
4.2.4 Personal or family history of Long QT syndrome. 
 
4.2.5 History of kidney disease. 
 
NOTE A: If the individual responds “yes” but can provide a creatinine clearance 
(CrCl) value of ≥45 mL/min by Cockcroft-Gault equation from within 1 year of 
study entry, the individual may participate. 
 
NOTE B: Please refer to the A5395 PSWP for the website link to the Cockcroft-
Gault calculator. 
 
4.2.6 History of ischemic or structural heart disease. 
 
4.2.7 History of hypokalemia or hypomagnesemia or taking potassium 
supplementation or magnesium supplementation. 
 
4.2.8 Personal medical history of porphyria, retinopathy, severe hepatic impairment, or 
G6PD deficiency.  
 
4.2.9 Use of drugs with possible anti-SARS-CoV-2 activity within 30 days prior to study 
entry, e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, 
chloroquine, hydroxychloroquine, and azithromycin, or participation in a clinical 
trial involving any of these drugs whether for treatment or prophylaxis. 
 
4.2.10 Requirement or expected requirement for a medication that significantly prolongs 
QT intervals or increases risk for QT prolongation (medications summarized 
in section 5.4), from 96 hours prior to study entry through 4 weeks after 
discontinuation of study treatment except for escitalopram, citalopram, 
maprotiline, SC/IM risperidone, carbamazepine, ethosuximine, and 
zonisamide, which should not be used within 7 days prior to study entry. 
 
4.2.11 Loop diuretics are exceptions to exclusion criterion 4.2.10 but these cannot 
be used within 30 days prior to study entry. 
 
4.2.12 Participating in a study where co-enrollment is not allowed.  
 
4.2.13 Receipt of a SARS-CoV-2 vaccination prior to study entry.  
 
4.2.14 Known allergy/sensitivity or any hypersensitivity to components of HCQ, 
azithromycin, or their formulation. 
 


 
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4.2.15 Active drug or alcohol use or dependence that, in the opinion of the site 
investigator, would interfere with adherence to study requirements  
 
4.3 Study Enrollment Procedures 
 
Prior to implementation of this protocol, and any subsequent full version amendments, 
each site must have the protocol and the protocol consent form(s) approved, as 
appropriate, by the institutional review board (IRB)/ethics committee (EC) and any other 
applicable regulatory entity (RE) responsible for oversight of the study. Upon receiving 
final approval, sites will submit all required protocol registration documents to the DAIDS 
Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all of 
the required documents have been received.  
 
Site-specific informed consent forms (ICFs) WILL be reviewed and approved by the 
DAIDS PRO, and sites will receive an Initial Registration Notification from the DAIDS 
PRO that indicates successful completion of the protocol registration process. A copy of 
the Initial Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an amendment, 
sites should implement the amendment immediately. Sites are required to submit an 
amendment registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all required documents 
have been received. Site-specific ICF(s) WILL NOT be reviewed or approved by the 
DAIDS PRO. Sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet. A copy of the Amendment Registration 
Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the 
DAIDS Protocol Registration Manual.  
 
Once a candidate for study entry has been identified, details will be carefully discussed 
with the participant. The participant will be asked to read and sign the approved protocol 
consent form.  
 
Participants from whom a signed informed consent has been obtained may be screened 
and enrolled, if they otherwise qualify. An ACTG Screening Checklist must be entered 
through the DMC Participant Enrollment System.  
 
4.3.1 Protocol Activation 
 
Prior to enrollment, sites must complete the Protocol Activation Checklist found 
on the ACTG Member website. This checklist must be approved prior to any 
screening of participants for enrollment.  
 
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For participants from whom informed consent has been obtained, but who are 
deemed ineligible or who do not enroll into the initial protocol step, an ACTG 
Screening Failure Results form must be completed and keyed into the database. 
Participants who meet the enrollment criteria will be registered to the study 
according to standard ACTG DMC procedures.  
 
4.4 
Co-enrollment Guidelines  
 
For specific questions and approval for co-enrollment in other studies, sites should first 
check the PSWP or contact the protocol team via e-mail as described in the Study 
Management section. 
 
5.0 
STUDY TREATMENT  
 
5.1 
Regimens, Administration, and Duration 
 
Participants will be randomized to receive one of the following two regimens: 
 
ARM A: 
HCQ 400 mg (administered as two 200 mg capsules) orally twice daily for 2 doses 
starting on Day 0, followed by 200 mg (administered as one 200 mg capsule) orally 
twice daily for 12 doses (6 days), PLUS: 
 
Azithro 500 mg (administered as two 250 mg capsules) orally as a single dose on Day 0, 
followed by 250 mg (administered as one 250 mg capsule) orally once daily for 4 doses 
(4 days). 
 
ARM B: 
Placebo for HCQ (administered as two matching placebo capsules) orally twice daily 
for 2 doses starting on Day 0, followed by Placebo for HCQ (administered as one 
200 mg capsule) orally twice daily for 12 doses (6 days), PLUS: 
 
Placebo for Azithro (administered as two matching placebo capsules) orally as a single 
dose on Day 0, followed by Placebo for Azithro (administered as one matching placebo 
capsule) orally once daily for 4 doses (4 days). 
 
HCQ or Placebo for HCQ should be taken with food or a glass of milk. Doses of HCQ or 
Placebo for HCQ should be separated by at least 6 hours. Azithro or Placebo for 
Azithro capsules can be taken with or without food. HCQ or Placebo for HCQ and 
Azithro or Placebo for Azithro may be taken at the same time.  
 
 
5.2 
Study Product Formulation and Preparation 
 
5.2.1 HCQ 200 mg: Supplied as over-encapsulated 200 mg tablets. Store at controlled 
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5.2.2 Azithro 250 mg: Supplied as over-encapsulated 250 mg tablets. Store at 
controlled room temperature 20-25°C. 
 
5.2.3 Placebo for HCQ: Supplied as matching placebo capsules to visually match the 
over-encapsulated HCQ. Store at controlled room temperature 20-25°C. 
 
5.2.4 Placebo for Azithro: Supplied as matching placebo capsules to visually match the 
over-encapsulated Azithro. Store at controlled room temperature 20-25°C. 
 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Acquisition/Distribution 
 
HCQ tablets are manufactured by Watson Pharma, distributed by Actavis 
Pharma, and supplied by Teva Pharmaceuticals. 
 
Azithro tablets are manufactured by Pliva Hrvatska and supplied by Teva 
Pharmaceuticals. 
 
Over-encapsulated HCQ, over-encapsulated Azithro, Placebo for HCQ and 
Placebo for Azithro capsules are manufactured by Eminent Services Corporation 
and supplied by NIAID/DAIT Clinical Product Center (CPC) as matching active 
and placebo capsules. 
 
All study products are available through the National Institute of Allergy and 
Infectious Diseases (NIAID) Clinical Research Products Management Center 
(CRPMC). The site pharmacist should obtain the study product(s) for this 
protocol by following the instructions in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
5.3.2 Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products 
received from the NIAID CRPMC and subsequently dispensed. All unused study 
products in US CRSs must be returned to the NIAID CRPMC (or as otherwise 
directed by the sponsor) after the study is completed or terminated. The 
procedures to be followed are in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.  
 
Refer to the A5395 MOPS for additional protocol-specific instructions 
regarding study product management considerations. 
 


 
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5.4 
Concomitant Medications 
 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medication’s and study agent’s most recent 
package insert, Investigator’s Brochure, or updated information from DAIDS to obtain the 
most current information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found on the ACTG Precautionary and Prohibited 
Medications Database located at http://tprc.pharm.buffalo.edu/home/di_search/. 
 
5.4.1 Prohibited Medications 
• 
Non-study HCQ and Azithro 
• 
Cardiac medications 
o Antiarrhythmic drugs: Class Ia (quinidine, procainamide, disopyramide); 
Class III (dofetilide, ibutilide, sotalol) 
o Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) 
• 
Non-cardiac medications 
o Diphenhydramine  
o Antiepileptic medications (carbamazepine, eslicarazepine, 
ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, 
oxcabazepine, phenobarbital, phenytoin, piracetam, pregabalin, 
Rufinamide, stiripentol, tiagabine, topiramate, sodium valproate, 
valproic acid, zonisamide) 
o Antipsychotic and antidepressant agents: Neuroleptic (haloperidol, 
droperidol, thioridazine, chlorpromazine); Atypical antipsychotics 
(ziprasidone, risperidone, zimeldine, citalopram); Antidepressants 
(amitriptyline, desipramine, imipramine, maprotiline, doxepin, fluoxetine, 
escitalopram, citalopram) 
o Antibiotics: quinolone (levofloxacin, moxifloxacin); Macrolide 
(erythromycin, clarithromycin)  
o Antimalarials (quinine, halofantrine, chloroquine)  
o Antiprotozoal (pentamidine) 
o Antifungal (azole group)  
o Antimotility Agents  
o Methadone 
 
5.4.2 Precautionary Medications 
 
A list of precautionary medications can be generated using the ACTG 
Precautionary and Prohibited Medications Database located at 
http://tprc.pharm.buffalo.edu/home/di_search/ 
  


 
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6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 
6.1 
Schedule of Evaluations (SOE) 
 
EVALUATION 
Screening 
Entry/ 
Day 0 
Post-Entry Evaluations  
Premature Study 
Discontinuation1 
 
0/+7 
Day 2 
Day 4 
Day 6 
Day 9 
Day 13 
Day 17 
Day 20 
Week 
12 
Week 
24 
Visit Windows (days) 
+/-1 
+/-2  
0/+7  
0/+30 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation of SARS-
CoV-2 Result  
X  
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Symptom 
Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medication History 
X 
X 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Secondary Contacts 
Information 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Kit Dispensed  
 
X 
 
 
 
 
 
 
 
 
 
 
Dispensing of Study Drug, 
Confirmation of First Dose, 
and Counseling 
 
X 
 
 
 
 
 
 
 
 
 
 
Distribution of Study Diary 
 
X 
 
 
 
 
 
 
 
 
 
 
Review of Study Diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Review of Treatment 
Adherence 
 
 
X 
X 
X 
X 
 
 
 
 
 
X 
Collection of Study Diary 
 
 
 
 
 
 
 
 
X 
 
 
X 
Remote Contact 
 
X2 
X 
X 
X 
X 
X 
X 
X2 
X 
X 
 
Study Endpoint 
Determination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Status Follow-up 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Household Linkage 
 
 
 
 
 
 
 
 
X^ 
 
 
 
In-person visits at pre-selected sites (optional for participants); additional to the above evaluations  


 
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EVALUATION 
Screening 
Entry/ 
Day 0 
Post-Entry Evaluations  
Premature Study 
Discontinuation1 
 
0/+7 
Day 2 
Day 4 
Day 6 
Day 9 
Day 13 
Day 17 
Day 20 
Week 
12 
Week 
24 
Visit Windows (days) 
+/-1 
+/-2  
0/+7  
0/+30 
Self-collected Nasal Swab 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Nasopharyngeal (NP) Swab 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Hematology 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Chemistry 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Inflammatory Markers 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Stored Plasma  
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Stored Sera 
 
X 
 
 
X 
 
 
 
X 
 
 
X 
Pharmacokinetics (Sparse) 
 
 
 
 
X 
 
 
 
X 
 
 
X 
1See Section 6.2.4 for specific instructions on evaluations to be performed at the Premature Study Discontinuation visit. Some or 
all of the evaluations will be performed, depending on the timing of study discontinuation.  
2Entry/Day 0 and 20 visits may be in-person or remote for non-sampling subset participants 
^Household linkage should be assessed after all participants at the site have been enrolled and by the last enrolled participant’s 
Day 20 visit.


 
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6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 
Screening evaluations must occur prior to the participant starting any study 
medications, treatments, or interventions. 
 
Screening 
Screening evaluations to determine eligibility must be completed prior to study 
entry unless otherwise specified and may be completed remotely or in-person. 
Screening and entry visit may occur on the same day. 
 
At sites that are performing additional NP swab, self-collected nasal swabs, and 
blood collection, those participants that agree to the additional sample collection 
will indicate consent at the screening visit.  
 
In addition to data being collected on participants who enroll into the study, 
demographic, clinical, and laboratory data on screening failures will be captured 
in a Screening Failure Results form and entered into the ACTG database.  
 
6.2.2 Entry Evaluations 
 
Screening and entry visits may be combined. The study entry visit can be either 
a remote or in-person visit. Participants must begin study treatment within 96 
hours of the collection time of the respiratory specimen that was positive 
for SARS-CoV-2 and qualified them for the study. The first dose of study 
treatment must be directly observed at the in-person visit or confirmed remotely 
(by video or telephone) for those with remote study entry visit. The day of the 
first dose is considered Day 0.  
 
Depending on how the screening and study entry/Day 0 visits are 
conducted, randomization must occur after screening but may occur prior 
to the study entry/Day 0 visit, or at the study entry/Day 0 visit. 
 
Those participants that agree to the additional sample collection must have the 
NP swab, self-collected nasal swab, and blood collected prior to receiving the 
first treatment dose.  
 
6.2.3 Post-Entry Evaluations 
 
On-Treatment Evaluations  
Participants will undergo remote evaluations as outlined in the SOE, section 6.1.  
 
Those participants undergoing additional NP swab, self-collected nasal swab, 
and blood collection will be required to have in-person visits at Days 6 and 20. 
 


 
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Post-Treatment Evaluations  
Participants will undergo remote evaluations as outlined in the SOE, Section 6.1. 
Participants not participating in the sampling subset will undergo an in-person 
or remote study visit on Day 20, as outlined in the SOE, Section 6.1. Subset 
participants will have an in-person study visit at Day 20. The Day 20 visit 
may occur anytime during the window outlined in the SOE, Section 6.1. For non-
subset participants, Day 20 in-person visits should be performed only if the 
participant has been afebrile for at least 72 hours and other symptoms have 
improved. If these criteria are not met, the visit should be conducted remotely. If 
a remote Day 20 visit is conducted, arrangements should be made for future 
transfer of diary from the participant to the study staff and provision of 
compensation for study participation.  
 
Study Completion Evaluations  
Participants will undergo a remote evaluation at Week 24. 
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Participants Who Do Not Start Study Treatment 
Participants who are randomized but do not take the first (confirmed) dose of 
study treatment do not need to be followed. A study discontinuation eCRF must 
be completed and any evaluations completed for these participants should also 
be recorded on the Day 0 eCRFs.   
 
Premature Treatment Discontinuation Evaluations  
Participants who discontinue study treatment early should remain on study and 
all evaluations should be performed as outlined in the SOE.  
 
For participants consenting to the optional intensive sampling study, if the 
Day 0 CrCl result is <45 mL/min, as calculated by the Cockcroft-Gault 
equation (see Cockcroft-Gault calculator on the A5395 PSWP), the 
participant will be prematurely discontinued from study treatment. 
 
Premature Study Discontinuation Evaluations  
Participants who discontinue study participation should undergo premature study 
discontinuation evaluations, as outlined in the SOE within 7 days of study 
discontinuation. If study discontinuation occurs on or prior to Day 7, all 
procedures should be performed as described in the SOE for premature study 
discontinuation evaluations. If study discontinuation occurs on or between Day 8 
and Day 20, all evaluations EXCEPT treatment adherence should be performed. 
If study discontinuation occurs after Day 20, all evaluations EXCEPT treatment 
adherence, site-collected NP swab, self-collected nasal swab, and blood 
collection should be performed.  
 
For participants who prematurely discontinue from the study for reasons other 
than withdrawal of consent, sites will attempt to obtain information regarding vital 
status and endpoints per the SOE (see section 6.3.13). 


 
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6.3 
Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol is to be present in the 
source documents. Sites must refer to the Source Document Guidelines on the DAIDS 
website for information about what must be included in the source document: 
https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf. 
 
All stated evaluations are to be recorded on the eCRF unless otherwise specified. Refer 
to section 7.0 for information on the DAIDS AE Grading Table and requirements for 
reporting of AEs. 
 
6.3.1 Informed Consent  
 
Participants will review and provide informed consent to participate in the study 
either over the telephone, by video, or in person. For more information about the 
consent process, please refer to the A5395 MOPS. 
 
6.3.2 Documentation of SARS-CoV-2 Result 
 
Documentation of infection with SARS CoV-2 by a molecular test with a 
positive result from any respiratory specimen collected within 96 hours 
prior to first study product dose. 
 
Section 4.1.3 specifies assay requirements for SARS CoV-2 infection 
documentation. See MOPS for documentation requirements. Active SARS 
CoV-2 infection documentation is recorded on the eCRF. 
 
6.3.3 COVID-19 Symptom Screen 
 
Participants will be asked about their first symptoms related to COVID-19 and 
their current symptoms, to document eligibility. This will include when and what 
symptoms the participant noticed having. A screening questionnaire is posted on 
the DMC Portal in the Forms Management Utility. 
 
6.3.4 Medical History 
 
The medical history must include all signs and symptoms regardless of grade 
and all diagnoses identified by the ACTG criteria for clinical events and other 
diagnoses regardless of grade within the past 14 days. In addition, the following 
diagnoses should be recorded regardless of when the diagnosis was made 
(verbal history is acceptable):  
• 
Hypertension 
• 
Chronic obstructive pulmonary disease 
• 
“Severe Obesity” (BMI > 40) 
• 
Epilepsy requiring medications 


 
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• 
Kidney disease 
• 
Liver disease 
• 
Immunosuppressive conditions 
• 
Reactive airway disease, Asthma 
• 
Autoimmune disease 
• 
Inflammatory bowel disease 
• 
AIDS-defining conditions 
• 
HIV infection 
• 
Bone fractures (verbal history accepted) 
• 
Coronary heart disease 
• 
Heart failure 
• 
Myocarditis 
• 
Arrhythmias 
• 
Valvular heart disease 
• 
Stroke 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
• 
Tuberculosis 
• 
Chronic hepatitis C 
• 
Chronic hepatitis B 
• 
Pregnancy history 
• 
If known by participant if they have been diagnosed with an acute viral 
respiratory infection (influenza, parainfluenza, respiratory syncytial virus, 
rhinovirus) within the previous 14 days. 
 
A Smoking Status questionnaire will be completed at the entry visit as part of 
medical history and recorded on the eCRF. The questionnaire is posted on the 
DMC Portal in the Forms Management Utility.  
 
Any allergies to any medications and their formulations must also be 
documented.  
 
6.3.5 Medication History 
 
A medication history must be present, including start and stop dates. The table 
below lists the medications that must be included in the history at screening and 
updated at entry.  
 
Table 6.3.5-1:  Medication History 
Medication Category 
Complete History or 
Timeframe 
All prescription drugs 
Last 7 days 
Prescription drugs for high blood pressure 
Last 3 months  
Prescription drugs for diabetes and pre-
diabetes 
Last 3 months  


 
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Medication Category 
Complete History or 
Timeframe 
Prescription drugs for lung disease 
Last 3 months  
Prescription drugs for heart disease 
Last 3 months  
Prescription drugs for autoimmune 
disease 
Last 3 months  
Cancer chemotherapy 
Complete history 
Antiretroviral therapy 
Last 3 months 
Immune-based therapy 
Last 3 months 
Blinded study treatment 
Last 12 months  
CoV-related vaccines 
Complete history 
Alternative therapies  
Last 3 months  
Dietary supplements  
Last 3 months  
  
6.3.6 Clinical Assessments 
 
No physical exams will be conducted.  
 
Site clinical investigators will perform a clinical assessment at enrollment for all 
participants. In their clinical judgment, they may identify some participants who 
are ill enough to warrant further clinical evaluation, which may result in 
hospitalization. They will then refer these participants for such evaluation. These 
participants will not start study treatment, and not be included in the analyses. 
While clinical judgement may not be standard across sites, the process should 
balance site variation. 
 
Post entry, see section 8.4 for collection requirements for pregnancy. 
 
Refer to section 7.2 for AE collection requirements.  
 
Concomitant Medications 
Post-entry, the following new and discontinued concomitant medications must be 
recorded: 
• 
High blood pressure medications 
• 
Steroids or other immunosuppressive or immunomodulatory medication 
• 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
• 
Chemotherapy 
• 
Antibiotics, antifungals and antivirals (including antiretrovirals) 
• 
HCQ or chloroquine or any agent felt to have potential COVID-19 activity 
• 
Inhalers 
• 
Agents with QTc prolongation potential and antiarrhythmics listed in section 
5.4.1. 
 
Study Treatment (Intervention) Modifications 


 
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Record any modification to treatment, treatment interruption, and permanent 
discontinuation of treatment, and the reason for the modification, interruption, or 
discontinuation.  
 
6.3.7 Secondary Contact 
 
Sites will capture secondary contact information for two individuals that the site 
can contact if the participant cannot be reached (e.g., spouse, friend, neighbor, 
etc.). Sites will also request their health care provider contact information and a 
few hospitals that the participant is likely to go to if they get sick. Contact 
information for secondary contacts or health care provider will not be recorded on 
any eCRF. If participants cannot be reached after two attempts 24 hours apart, 
then their listed secondary contact person(s) or health care provider will be 
called. At study entry only, sites will record the participant’s home address in site 
records (it will not be reported on the eCRF).  
 
6.3.8 Study Kit Dispensed  
 
The kit will include: 
• 
Copy of informed consent 
• 
Information about the study 
• 
Instructions on study procedures 
• 
Study Diary 
• 
Study medications  
• 
Pocket/wallet card with site staff contact information 
• 
Instructions on what to do if they have worsening symptoms/become 
hospitalized 
• 
Self-addressed stamped envelope for participant to return Study Diary 
at end of study in case Day 20 is remote 
 
6.3.9 Dispensing of Study Product, Confirmation of First Dose, and Counseling 
 
Study product will be dispensed at study entry. Study staff will confirm (via 
video or verbal report) the first dose is taken by the participant with food or a 
glass of milk and record this confirmation on an eCRF. The participant and the 
study staff will record the date and time of the first dose in the Study Diary 
and in site records. Day 0 is the day the participant self-administers the 
first dose of study product. Participants who do not start study treatment will 
be discontinued from the study. 
 
Intensive counseling must be performed at the time the first dose of study 
treatment is observed or confirmed remotely. This counseling should include 
review of the timing of the first dose and the timing for the two subsequent doses.  
 
6.3.10 Study Diary  
 


 
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Distribution of Study Diary 
Participants will be provided a Study Diary at study entry. The Study Diary is 
posted on the DMC Portal in the Forms Management Utility. 
 
Participants will be asked to keep a log of symptoms, temperature (if possible), 
medications they are taking, and major events such as urgent visit to an 
emergency room or clinic and hospitalization in their Study Diary on Days 0-20. 
At study entry, participants will complete the Study Diary prior to study treatment 
initiation. Depending on timing of each participant’s dosing, some may complete 
HCQ/Placebo study treatment on Day 7 instead of Day 6 and need to report a 
Day 7 dose. Participants will be asked to complete the diary each evening. 
 
Review of Study Diary  
The Study Diary will be reviewed by study staff with each participant at the 
remote and in-person visits described in the SOE and the participant’s answers 
recorded in the Participant Study Diary eCRF. If feasible, prior to or during the 
remote study visits, sites will request that the participant send images of each of 
their study diary entries to be reviewed at the next study contact. 
 
Participants who report worsening illness from any cause during the trial may be 
referred to their health care provider or closest emergency room. Such instances 
will be recorded at the time of the notification, and during follow-up to assess 
study endpoints, i.e., hospitalization or death. 
 
Review of Treatment Adherence 
The treatment adherence portion of the Study Diary will be reviewed by study 
staff with each participant at the remote and in-person visits (if applicable), as 
described in the SOE. The participant’s answers of timing of doses taken will be 
recorded in the Adherence Assessment eCRF. If any doses are missed, the 
reason for the missed dose will be recorded.  
 
Collection of Study Diary 
The Study Diary will be collected per the SOE. If Day 20 is conducted 
remotely, arrangements should be made for future transfer of study diary 
from the participant to the study staff (i.e., mailing the study diary or 
sending images). 
 
6.3.11 Remote Contact  
 
Sites will contact participants per the SOE. Participants in the pre-selected site 
subset will have an in-person visit, instead of a remote visit on Days 0, 6, and 20, 
but will be contacted by telephone for that visit if they fail to attend the in-person 
visit. Refer to the A5395 MOPS for the remote contact script. Remote contact 
attempts will be recorded on the eCRF. 
 
6.3.12 Study Endpoint Determination 
 


 
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Study endpoints will be collected per the SOE and outlined in section 10.2. 
These will be recorded on the eCRF. Information about AEs, hospitalizations or 
death should be keyed on the eCRF within 72 hours of a site becoming aware of 
an AE, hospitalization or death. 
 
6.3.13 Vital Status Follow-up 
 
Site personnel should attempt to obtain information regarding vital status 
(including date last seen alive, hospitalization, date of death, and primary cause 
of death) from the participant or other sources (such as family members, 
other designated contacts, hospital the participant stated they would most 
likely go to, clinic/hospital/medical records, and local or national 
databases), per the SOE. Please see MOPS for additional information. 
Information about hospitalizations and deaths should be keyed on the eCRF 
within 72 hours of a site becoming aware of a hospitalization or death. 
 
6.3.14 Household Linkage 
 
At each site, at completion of the Day 20 visit for the last participant enrolled in 
the study at the site, the site will review all home addresses of A5395 participants 
to identify participants who live at the same address. The Household Linkage 
eCRF will be completed, and “linked” participant IDs recorded. 
 
6.3.15 Virologic Studies 
 
Self-Collected Dry Swabs 
At pre-selected sites, a subset of participants may opt to self-collect Dry Swabs 
(nasal swabs) per the SOE. Participants will be instructed by study staff and will 
obtain the swab while observed by study personnel. Additional information can 
be found in the MOPS and the LPC. At study entry (Day 0), the sample should be 
collected prior to the first dose of study treatment. 
 
Nasopharyngeal (NP) Swab 
At pre-selected sites, a subset of participants may opt to have an NP swab per 
the SOE. Additional information can be found in the MOPS and the LPC. At study 
entry (Day 0), the sample should be collected prior to the first dose of study 
treatment. 
 
Samples collected for viral assessment may be evaluated for the emergence of 
antiviral resistance at a future date.  
 
6.3.15 Laboratory Evaluations 
 
Laboratory evaluations will be performed on some participants at pre-selected 
sites. At study entry (Day 0), blood samples should be collected prior to the first 
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Hematology 
Per the SOE, participants will have the option to have a blood draw for complete 
blood cell count (CBC) with automated differential and platelet count. These tests 
will be performed in real-time at the local clinic laboratory. 
 
Chemistry 
Per the SOE, participants will have the option to have a blood draw for liver 
function tests (ALT, ALP, AST, Total Bilirubin, Direct Bilirubin, and Total Protein) 
and renal function tests (BUN, Creatinine, Potassium, Glucose, and Sodium). A 
CrCl will be calculated and recorded by Cockcroft-Gault equation (see 
Cockcroft-Gault calculator on the A5395 PSWP). These tests will be 
performed in real-time at the local clinic laboratory. 
 
Inflammatory Markers 
Per the SOE, participants will have the option to have a blood draw for lactate 
dehydrogenase, C-reactive protein, ferritin and D-dimer. These tests will be 
performed in real-time at the local clinic laboratory. 
 
Stored Plasma  
Per the SOE, blood plasma will be collected and stored for future testing for 
immune responses and drug levels.  
 
Stored Sera 
Per the SOE, blood sera will be collected and stored for future testing for immune 
responses and to compare antibody levels between treatment and control 
samples.  
 
6.3.16 Pharmacokinetics  
 
Per the SOE, single sparse PK sampling will be collected. This will be done on a 
subset of participants who opt to have their blood drawn. Days 6 and 20 blood 
collection may be used to measure drug levels to assess drug adherence or 
surreptitious use of HCQ or Azithro. 
 
7.0 
ADVERSE EVENTS AND STUDY MONITORING 
7.1 
Definition of Adverse Events 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or diagnosis that occurs in a study participant during the conduct of 
the study REGARDLESS of the attribution (i.e., relationship of event to medical 
treatment/study product/device or procedure/intervention). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline condition.  
 


 
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7.2 
Adverse Event Collection Requirements for This Protocol 
 
Post-entry, all AEs must be recorded on the eCRFs within 72 hours if any of the 
following criteria have been met: 
 
• 
All Grade ≥3 AEs 
• 
All cardiac AEs regardless of grade 
• 
All AEs that led to a change in study treatment/intervention regardless of grade 
• 
All AEs meeting SAE definition or EAE reporting requirement 
NOTE: SAEs or events meeting EAE reporting requirements should also be entered into 
the DAIDS Adverse Experience Reporting System (DAERS), an Internet-based reporting 
system. 
 
All AEs that are reported must have their severity graded. To grade AEs, sites must refer 
to the DAIDS AE Grading Table, corrected Version 2.1, July 2017, which can be found 
on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
• 
Results in death 
• 
Is life-threatening illness 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect. 
• 
Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above). 
 
Ventricular arrhythmias, cardiac events requiring intervention or 
hospitalization, and deaths should be reported as soon as possible but no 
later than 24 hours to the A5395 Clinical Management Committee (CMC; e-mail: 
actg.cmcA5395@fstrf.org). If known, sites should indicate if the death was a 
sudden cardiac death. Sudden cardiac death is defined in this study 
as unexpected death from a cardiac cause within 1 hour of onset of symptoms 
OR found dead without clear explanation.  
 
7.3 
Expedited Adverse Event (EAE) Reporting to DAIDS 
 
7.3.1 Expedited Reporting of Adverse Events to DAIDS 
 
Requirements, definitions and methods for expedited reporting of Adverse 
Events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual, which is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids.  
 


 
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The DAIDS Adverse Experience Reporting System (DAERS), an Internet-based 
reporting system, must be used for EAE reporting to DAIDS. In the event of 
system outages or technical difficulties, EAEs may be submitted using the DAIDS 
EAE Form. This form is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov. Please note that site queries may also be sent 
from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety 
Office at (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 Reporting Requirements for this Study 
 
• 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study. 
• 
The study agents for which expedited reporting are required are:  
o HCQ or Placebo for HCQ 
o Azithro or Placebo for Azithro 
• 
In addition to SAEs, other AEs that must be reported in an expedited manner 
are: all ventricular arrhythmias, and cardiac events requiring hospitalization or 
intervention 
 
7.3.3 Grading Severity of Events 
 
The DAIDS AE Grading Table, corrected Version 2.1, July 2017, must be used 
and is available on the DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables.  
 
7.3.4 Expedited AE Reporting Period 
 
• 
The expedited AE reporting period for this study is Day 0 (post first dose of 
study treatment, not including entry pre-treatment assessments) to Day 20. 
• 
After the protocol-defined EAE reporting period (i.e., after Day 20, such as at 
remote visits at Weeks 12 and 24), unless otherwise noted, only suspected, 
unexpected serious adverse reactions (SUSARs), as defined in Version 2.0 
of the DAIDS EAE Manual, will be reported to DAIDS if the study staff 
become aware of the events on a passive basis (from publicly available 
information). 
• 
Any medical condition that is present at the time that the participant is 
screened will be considered as baseline and not reported as an AE. 
However, if the severity of any pre-existing medical condition increases to 
severity level 3 or 4 after starting study treatment, it should be recorded as 
an AE. 
 


 
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7.4 
Study Monitoring 
 
7.4.1 Adverse Events 
 
The DAIDS Clinical Representative will review and assess select EAE reports for 
potential impact on the study participant safety and protocol conduct as per 
DAIDS policies, guidance documents, and SOPs as applicable. The A5395 
protocol chair, vice chairs, and DAIDS Clinical Representative will review all 
deaths on a weekly basis in a blinded fashion. 
 
7.4.2 Interim Review 
 
The protocol team will monitor the conduct of the study via regular summaries of 
screening, accrual, study and study treatment discontinuation, and data and 
specimen completeness. An independent Data and Safety Monitoring Board 
(DSMB) will monitor safety regularly (see section 10.5 for details.)  
 
Detailed plans for study monitoring are outlined in a Study Progress, Data, and 
Safety Monitoring Plan (SPDSMP) developed by the Statistical and Data 
Management Center (SDMC) prior to enrollment of the first participant. 
 
8.0 
CLINICAL MANAGEMENT ISSUES 
 
8.1 
Toxicity  
 
Criteria for participant management, dose adjustments and discontinuation, or changes 
in treatment will be described only for toxicities attributable to the study drugs (HCQ and 
Azithro). The grading system for drug toxicities is located in the DAIDS AE Grading 
Table (see section 7.2).  
 
NOTE: The team must be notified via e-mail within 72 hours regarding toxicities that 
result in a change in study regimen (actg.cmca5395@fstrf.org).  
 
It is possible that some participants will experience transient or prolonged AEs during the 
study. However, it is important to note that, in this trial, the majority of visits will be 
conducted remotely and hence, AEs will be assessed remotely and unplanned study 
visits scheduled if deemed necessary by the site investigator. For any concerning AEs 
that are felt to require clinical intervention, participants should be instructed to contact 
their health care provider or seek urgent or emergent care, or 911 should be called, as 
appropriate.  
 
Treatment may be discontinued without contacting the CMC in advance, but the study 
team should be notified via email within 72 hours of treatment discontinuation, as 
described above.  
 
8.2 
Management of Side Effects of HCQ [78] 
 


 
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Gastrointestinal effects 
Gastrointestinal (GI) symptoms including nausea, vomiting, and diarrhea are common 
with HCQ. HCQ should be administered with food or milk. In the event of GI symptoms, 
the study staff should review with the participant if HCQ is being taken with food, as 
administration of HCQ with food may reduce GI effects. GI side effects do not require 
treatment discontinuation and participants may be referred to their health care provider 
for symptomatic treatment (e.g., antiemetics). However, in the event of any treatment-
related toxicity (GI or other), the site investigator has the option to discontinue study 
treatment if the side effect is intolerable or at their discretion. 
 
Rash 
A range of dermatologic reactions may be observed with HCQ. For pruritus, emollients 
may be used. For other more significant reactions, such as potential allergic skin 
reactions, HCQ should be discontinued immediately, and the participant referred to their 
health care provider or for urgent evaluation and management as appropriate, as 
determined by the site investigator. Over-the-counter topical agents may be 
recommended by the site clinical investigator, if the investigator feels able to make such 
a recommendation.  
 
Hypoglycemia 
Severe hypoglycemia (i.e., hypoglycemia that requires intervention) may occur with 
HCQ. HCQ should be discontinued immediately in participants who develop severe 
hypoglycemia.  
 
Cardiovascular effects 
Cardiomyopathy, QT prolongation, and ventricular arrhythmias have been reported with 
HCQ use. HCQ should be discontinued immediately in participants who experience a 
cardiovascular event, and additional evaluation and management pursued as 
appropriate for the clinical condition, as determined by the site investigator.  
 
In the event of any treatment-related toxicity, the site investigator has the option to 
discontinue study treatment if treatment is intolerable or at the investigator’s discretion. 
Treatment may be discontinued without contacting the A5395 clinical management 
committee (CMC) in advance, but the study team should be notified via email within 72 
hours of treatment discontinuation, as described above.  
 
Dose modification of HCQ will not be allowed in the study. If HCQ/Placebo is 
discontinued for toxicity reasons, all study medications should be discontinued and not 
be restarted.  
 
NOTE: Grades 1 and 2 AEs associated with HCQ require no change in study treatment. 
 
8.3 
Management of Side Effects of Azithro [79] 
 
Hypersensitivity reactions 
Allergic reactions such as angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic 
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administration. Azithromycin should be discontinued immediately in the event of a 
hypersensitivity reaction.  
 
Cardiovascular events and altered cardiac conduction 
Macrolides have been associated with rare QT prolongation and ventricular arrhythmias 
but not Azithro in clinical studies (see Rationale above). Some studies, but not all, have 
described an association between azithromycin and cardiovascular events and mortality 
[41]. Therefore, to be conservative, Azithro should be discontinued immediately in the 
event of a cardiovascular event and additional evaluation and management pursued as 
appropriate for the clinical condition, as determined by the site investigator.  
 
GI symptoms including diarrhea, nausea, and vomiting occur frequently (>10%) in 
azithromycin recipients. Azithro may be administered with food to reduce GI side effects. 
GI side effects do not require treatment discontinuation and participants may be referred 
to their health care provider for symptomatic treatment (e.g., antiemetics). However, in 
the event of any treatment-related toxicity (GI or other), the site investigator has the 
option to discontinue study treatment if the side effect is intolerable or at their discretion.  
 
Dose modification of Azithro will not be allowed in the study. If Azithro/Placebo is 
discontinued for toxicity reasons, all study medications should be discontinued and not 
be restarted.  
 
NOTE: Grades 1 and 2 AEs associated with Azithro require no change in study 
treatment. 
 
8.4 
Pregnancy  
 
The study products may be given in pregnancy. To maximize study staff safety, the 
proposed study will be primarily remote visit based, thus we will not get weights, 
ultrasounds, vitals, physical exams, etc. during study treatment. However, pregnancy 
information and outcomes will be captured on an eCRF, including: gestational age 
during study treatment, and pregnancy outcomes. 
 
8.5 
Breastfeeding 
 
The study products may be given to women who are breastfeeding.  
 
9.0 
CRITERIA FOR DISCONTINUATION 
 
9.1 
Permanent and Premature Treatment Discontinuation 
 
• 
Drug-related toxicity (see section 8.0 Clinical Management Issues). 
• 
Participant experiencing an SAE that is considered at least possibly related to study 
drug. 
• 
Requirement for prohibited concomitant medications (see section 5.4). 
• 
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NOTE: The reason for treatment discontinuation should be documented (e.g., 
concern for AE, lack of efficacy, or other reason).  
• 
Clinical reasons believed life threatening by the physician, even if not addressed in 
the toxicity section of the protocol. 
• 
Day 0 CrCl <45 mL/min, for participants in optional intensive sampling study 
(see section 6.2.4).   
 
9.2 
Premature Study Discontinuation 
 
• 
Failure to take the first (directly observed/confirmed) dose of study treatment at the 
study entry visit. 
• 
Request by the participant to withdraw consent. 
• 
Request of the health care provider if she or he thinks the study is no longer in the 
best interest of the participant. 
• 
At the discretion of the IRB/EC, FDA, NIAID, Office for Human Research Protections 
(OHRP), other government agencies as part of their duties, investigator, or industry 
supporter. 
 
In the event that a participant prematurely discontinues from the study, unless they 
have withdrawn consent, sites will attempt to obtain information regarding vital status 
(including date last seen alive, hospitalization, date of death, and primary cause of 
death) from other sources (such as family members, other designated contacts, or 
clinic records) per section 6.2.4. 
 
10.0 
STATISTICAL CONSIDERATIONS 
 
10.1 
General Design Issues 
 
This is a double-blind placebo-controlled randomized trial, designed to compare the 
efficacy of HCQ and Azithro for the treatment of COVID-19 in adults compared to 
adults receiving placebo to decrease hospitalization and death during SARS-CoV-2 
infection.   
 
10.2 
Outcome Measures 
 
Primary and secondary outcome measures listed below will be addressed in the study’s 
primary Statistical Analysis Plan, which will define the content of the Primary Analysis 
Report. This report will form the basis for the primary study manuscript and results 
reporting to ClinicalTrials.gov.  
 
10.2.1 Primary Outcome Measure 
 
Death from any cause or hospitalization during the 21-day period from and 
including the day of the first (confirmed) dose of study treatment. Hospitalization 
is defined as requiring at least 24 hours of acute care in a hospital or similar 
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to address needs during the COVID-19 pandemic. Evaluation at a hospital or 
similar facility with less than 24 hours of acute care is not considered a 
hospitalization. 
 
10.2.2 Secondary Outcome Measures 
 
10.2.2.1 Death from any cause during the 21-day period from and including the 
day of the first (confirmed) dose of study treatment. 
 
10.2.2.2 Death from any cause or hospitalization or urgent visit to an 
emergency room or clinic during the 21-day period from and including 
the day of the first (confirmed) dose of study treatment. 
 
10.2.2.3 Death from any cause or hospitalization during the 24-week period 
from and including the day of the first (confirmed) dose of study 
treatment. Hospitalization is defined as requiring at least 24 hours of 
acute care in a hospital or similar acute care facility, including 
Emergency Rooms or temporary facilities instituted to address needs 
during the COVID-19 pandemic. Evaluation at a hospital or similar 
facility with less than 24 hours of acute care is not considered a 
hospitalization. 
 
10.2.2.4 Premature discontinuation of study treatment due to an adverse event. 
 
10.2.2.5 Occurrence of any cardiac adverse events from start of study 
treatment through Day 20.  
 
10.2.2.6. Duration of fever defined as the last day in the participant’s daily diary 
card on which a temperature greater than 100.4°F was recorded or a 
potentially antipyretic drug, such as acetaminophen or ibuprofen, was 
taken. 
 
10.2.2.7 Duration of symptoms associated with COVID-19 disease defined as 
the last day in the participant’s daily diary card on which a moderate or 
worse symptom was recorded. The set of targeted symptoms are the 
same ones that are used in many influenza studies, with the addition of 
the symptoms of loss of smell and loss of taste, which have been 
associated with COVID-19 infection. The symptoms from influenza 
studies are: cough, shortness of breath, feeling feverish, fatigue, 
muscle aches, diarrhea, vomiting, nausea, headache, sore throat, 
nasal obstruction (stuffy nose), and nasal discharge (runny nose). 
These symptoms are listed individually on the Study Diary that each 
participant will complete each day. The scoring is that used in 
influenza studies, whereby participants grade each symptom as absent 
(score 0), mild (1), moderate (2), or severe (3). 
 
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score associated with COVID-19 disease over time (through Day 20) 
defined as the sum of scores for the targeted symptoms (defined 
above) in the participant’s daily diary record (each individual symptom 
is scored from 0 to 3). 
10.2.2.9 Time to self-reported return to usual (pre-COVID) health. 
 
10.2.2.10 Level (detectable versus not detectable, and continuous) of SARS-
CoV-2 RNA from self-collected nasal and site-collected NP swabs at 
entry and Days 6 and 20 among subset. 
 
10.2.3 Other Outcomes 
 
10.2.3.1 Worst clinical status assessed using ordinal scale among participants 
who become hospitalized. Ordinal scale defined as: 
• 
Death 
• 
Hospitalized, on invasive mechanical ventilation or ECMO; 
• 
Hospitalized, on non-invasive ventilation or high flow oxygen 
devices; 
• 
Hospitalized, requiring supplemental oxygen; 
• 
Hospitalized, not requiring supplemental oxygen (COVID-19 
related or otherwise) 
 
10.2.3.2  Duration of hospital stay among participants who become hospitalized. 
 
10.2.3.3  ICU admission (yes vs no) among participants who become 
hospitalized. 
 
10.2.3.4  Duration of ICU admission among participants who get admitted to the 
ICU. 
 
 
10.3 
Randomization and Stratification 
 
Eligible participants will be randomized using a 1:1 ratio to each of the study arms using 
permuted blocks with dynamic institutional balancing to minimize imbalances at any 
clinical site.  
 
Randomization will be stratified by “high” vs “low” risk of severe disease, where “high” 
risk is defined by any of the following: age ≥60 years, or having any of the following 
conditions: hypertension, cardiovascular disease, diabetes, chronic kidney disease, 
chronic liver disease, chronic lung disease or moderate to severe asthma, severe 
obesity (BMI >40 based on self-report of height and weight), or immunocompromised 
due to disease or medication.   
 
The study aims to enroll at least 50% of participants in the high-risk stratum. Initially, 
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after at least 200 participants have been enrolled, if fewer than 40% of enrolled 
participants are in the high-risk stratum, then sites may be asked to restrict enrollment to 
the low-risk stratum, such that, for every five participants they enroll in the low-risk 
stratum, at least five participants are enrolled to the high-risk stratum. 
10.4 
Sample Size and Accrual 
 
The proposed sample size is 2000 participants who take the first (confirmed) dose of 
study treatment (approximately 1000 per arm). Participants who are randomized but do 
not take the first (confirmed) dose of study treatment will not be followed and will be 
replaced. 
 
The study accrual rate will depend on the status of the epidemics at each site, but based 
on a survey of possible sites is believed to be 100 to 400 participants per week.  
• 
With 100 participants per week the study should fully accrue in 20 weeks 
• 
With 200 participants per week the study should fully accrue in 10 weeks 
• 
With 400 participants per week the study should fully accrue in 5 weeks 
 
The study is designed to evaluate the efficacy of HCQ and Azithro to prevent 
hospitalizations and death in outpatient adults diagnosed with COVID-19 compared to 
those receiving placebo. The primary analysis will include testing the null hypothesis of 
equality of proportions hospitalized/dying in the two randomized arms, and construction 
of 95% confidence intervals (CIs) for the ratio of proportions between the study arms. 
The primary analysis will focus on comparing the ratio of proportions because of the 
uncertainty in knowing what the hospitalization/death rate will be.  
 
With 2000 participants, the study has 90% power to detect a relative reduction of 33.3% 
in the proportion of participants hospitalized/dying between the study arms (HCQ and 
Azithro vs. placebo), using the following assumptions: 
• 
Proportion hospitalized/dying in the placebo arm is 15% 
• 
Two-sided test of two proportions with 5% Type I error rate 
• 
Three interim analyses and one final analysis, equally spaced, with stopping 
guideline determined using the Lan-DeMets spending function approach with an 
O’Brien and Fleming boundary. 
• 
Allowance for 5% of participants to be lost-to-follow-up prior to being hospitalized or 
dying. 
 
Using this sample size, the following Figure 10.4-1 shows the power to detect effects of 
different sizes (expressed as the ratio of true proportions hospitalized/dying in the HCQ 
and Azithro arm vs placebo arm), for a range of true proportions in the placebo arm. The 
large star indicates the choice of parameters used to design the study: power of 0.9 (i.e., 
90%) to detect a true effect size of 33.3% (i.e., 0.667 ratio of proportions) when the true 
proportion hospitalized/dying in the control arm is 0.15 (i.e., 15%). The power of the 
study to detect an effect of HCQ and Azithro is reduced if the true ratio of proportions 
gets closer to 1.0 and/or if the true proportion hospitalized/dying is lower than 0.15.  


 
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Figure 10.4-1: Treatment/Control Ratio of Proportions Hospitalized/Dying 
 
 
The following Table 10.4-2 shows the power to detect an effect of the HCQ and Azithro 
arm accounting for treatment crossover in the placebo arm (i.e., those on the placebo 
arm who take HCQ and/or Azithro obtained from a source outside the study) for a range 
of crossover proportions assuming that these participants then experience a 10% 
hospitalization/death rate. The power is reduced to less than 80% when there is 15% or 
more crossover in the control arm.   
 
Table 10.4-2: Power to Detect an Effect of the HCQ and Azithro Arm Accounting for 
Treatment Crossover in the Placebo Arm 
Assumed 
Crossover 
Proportion In 
Control Arm 
Assumed Hosp/Death Proportion 
in Control Arm Accounting for 
Crossover 
Power 
Accounting for 
Crossover 
5% 
14.7% 
86.4% 
10% 
14.5% 
83.6% 
12.5% 
14.4% 
82.1% 
15% 
14.2% 
78.8% 
20% 
14% 
75.1% 
  
 
10.5 
Data and Safety Monitoring 
 
A NIAID-appointed Data and Safety Monitoring Board (DSMB) will undertake reviews of 
interim data from the study to help ensure the safety of participants in the study, and to 
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or if there is persuasive evidence of efficacy or lack of efficacy of HCQ and Azithro versus 
placebo in preventing hospitalizations and deaths. The DSMB may also recommend 
termination or modification of the study if it appears futile on operational grounds to 
continue the study as designed. The operation of the DSMB is governed by the NIAID 
DSMB Charter. 
 
To monitor for potential cardiac safety issues, the DSMB will be notified of cases of TdP, 
ventricular arrhythmias and sudden deaths (with treatment assignment), as the study 
team becomes aware of them. 
  
At each interim review, the DSMB will review summaries of data by randomized 
treatment arm for the primary outcome of hospitalization/death, losses to follow-up, 
adverse events, self-report of treatment cross-over, and the secondary outcomes of 
death, study treatment discontinuations and associated reasons, duration of symptoms 
of COVID-19 disease and duration of fever. By-stratum summaries will also be reviewed. 
 
There will be a review of safety data by the DSMB when 250 participants have 
completed Day 20 of follow-up. Unless otherwise recommended by the DSMB, 
interim analyses of both safety and efficacy data will occur weekly from when 
approximately 500 participants have been followed for the primary outcome 
assessed at Day 20. To allow for the possibility that the proportion of 
hospitalizations or death is higher than anticipated, the first review of efficacy and 
safety data may occur earlier, when approximately 62 participants in the two arms 
combined have been hospitalized or have died (62 is the expected number based 
on 15% hospitalizations/deaths in the placebo arm and 10% in the HCQ and 
Azithro arm, with an interim sample size of 500 participants). 
 
As a stopping guideline for greater efficacy of HCQ and Azithro compared with placebo, 
the O’Brien and Fleming boundary will be used. Because this spending function is 
particularly extreme at early interim analyses, a nominal two-sided p-value of <0.001 will 
instead be used to evaluate early efficacy when a more extreme nominal p-value would 
be suggested by the O’Brien and Fleming boundary; this has minimal effect on the 
overall Type I error rate. The stopping guideline will be implemented using the Lan-
DeMets spending function approach to allow for the possibility of changes in the timing 
of interim analyses and/or additional (or fewer) interim analyses if recommended by the 
DSMB. 
 
In considering possible modifications to the study or termination of the study, the DSMB 
may consider other outcome measures besides the primary composite 
hospitalization/death outcome measure, or differences within subgroups. For example, 
the DSMB might make recommendations based on a high level of evidence for a 
difference between randomized arms in the proportion dying. Also, for example, 
recognizing that there may be more hospitalizations/deaths in the higher risk stratum of 
the study, recommendations might be based on a high level of evidence for a difference 
in that stratum in the proportion hospitalized/dying or in the proportion dying. In these 
contexts, a “high level of evidence” might be based on application of the O’Brien and 
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possibility that differences between the treatment arms may be observed at an early 
study time point (for example cumulative proportion at Day 6), however the overall goal 
of the study is to prevent hospitalization and deaths regardless of the timing, and 
therefore the focus of the treatment arm comparisons will be at Day 20. 
 
In the absence of a significant difference between randomized arms that leads to 
termination of the randomized comparison, the study team believes that there is value in 
continuing the randomized comparison of HCQ and Azithro versus placebo to full 
enrollment (i.e., 2000 participants) in order to obtain as much precision as possible and 
to provide maximal information to inform the field.   
 
The DSMB will also monitor operational futility. With respect to operational futility, the 
DSMB may recommend modification or termination of the study if the proportion 
hospitalized/dying in the control arm is low. In particular, the DSMB might recommend 
restricting or closing enrollment to the low risk stratum in favor of increasing enrollment 
to the high-risk stratum. In addition, the DSMB will monitor the loss to follow-up (LTFU) 
rate. As a benchmark, an overall LTFU rate of more than 10% would be cause for 
concern. The DSMB should also monitor the treatment cross-over in the placebo arm by 
participant self-report and, if available, by PK levels of HCQ and Azithro. As a 
benchmark, a crossover rate of more than 10% in the placebo arm would be a cause for 
concern. 
 
10.6 
Analyses 
 
A Statistical Analysis Plan will be developed that describes, in detail, the analyses to 
address the study’s primary and secondary objectives. The following provides an outline 
of the methods for the main comparisons between randomized arms, particularly for the 
primary outcome measure.   
 
All analyses involving randomized comparisons will include all randomized participants 
who received the first (confirmed) dose of study treatment, according to a modified 
intention-to-treat approach. This is motivated by the fact that consent/eligibility 
confirmation and randomization may occur remotely, prior to the study entry visit. For 
those who opt to have an in-person entry visit, it is possible that some randomized 
individuals will not show up. Additionally, it is possible (though unlikely) that some 
participants show up for the in-person study entry visit, but then decline study treatment. 
For participants who have a remote entry visit, confirmation of the first dose of study 
treatment is required.  
 
10.6.1 Primary Outcome Measure 
 
The cumulative proportion of participants hospitalized or dying during the first 21 
days of follow-up will be estimated for each randomized arm, in each risk stratum, 
using Kaplan-Meier methods to take account of losses to follow-up. For each 
stratum, the difference between randomized arms in the estimated log cumulative 
proportion will be calculated and the variance for this difference will be obtained 
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population, the stratum-specific estimated differences in log proportion will be 
combined across strata, weighted by the inverse of the stratum-specific variance 
of the difference. Two-sided 95% confidence intervals (adjusted for multiple 
interim analyses), based on this weighted estimator, and associated p-value for 
the test of no difference between arms will then be obtained. 
 
Participants who prematurely discontinue the study, who are not able to be 
contacted by the site to ascertain outcomes after discontinuation, will have follow 
up censored at the date of last known status.  
 
The above analysis assumes that losses to follow-up are non-informative. As a 
sensitivity analysis of this assumption, causal inference methods, specifically 
inverse probability of censoring, may be used. These methods may also be used 
to evaluate the sensitivity of results to crossover of treatment in the placebo arm 
(i.e., participants taking HCQ and/or Azithro from sources outside of the study).     
 
To evaluate the potential impact of multiple participants enrolling from the same 
household on the primary inference an additional sensitivity, analysis will restrict 
to the first person enrolled form each household. If differences are observed, 
additional considerations will be given to analyses that account for clustering, for 
example, bootstrap methods to estimate the variance of difference in the primary 
outcome between randomized arms.     
 
10.6.2 Secondary Outcomes 
 
The cumulative proportion of participants dying during the first 21 days of follow-
up, and through to 24 weeks, and the cumulative proportion hospitalized/dying 
through to 24 weeks will be analyzed in a similar manner to the primary outcome.  
 
Tolerability (occurrence of premature discontinuation of study treatment due to an 
adverse event) will be evaluated by estimating the proportion of participants who 
discontinue study treatment, and will be compared between arms using binary 
regression with adjustment for a participant’s risk stratum. The proportion of 
participants who experience cardiac adverse events will be analyzed in a similar 
manner. 
 
Duration of fever, duration of symptoms and duration of time to self-reported 
return to usual health will be summarized with descriptive statistics. Participant-
specific durations of fever and symptoms will be compared between study arms 
using a two-sided stratified Wilcoxon test with a 5% Type I error rate. Total 
symptom score will be calculated on each day and the participant-specific area 
under the curve (AUC) over time will also be compared using a two-sided 
stratified Wilcoxon test. Participants who do not have complete diary cards due to 
hospitalization or death will be ranked in these analyses as having poorer 
outcomes than participants who survived without hospitalization. 
 


 
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The comparison of the proportion of participants with detectable SARS-CoV-2 
RNA will use binary regression, with adjustment for risk stratum and pre-treatment 
SARS-CoV-2 RNA level. The model will be fitted using generalized estimating 
equations (GEE) to handle the repeated measurements, where the comparison 
between randomized arms will use a two-sided Wald test. Levels of SARS-CoV2 
RNA levels will be compared between arms using non-parametric Wilcoxon rank-
sum tests, separately at Day 6 and Day 20, considering results below assay limit 
as the lowest rank. 
 
Descriptive summaries of clinical outcomes among those hospitalized will be 
provided by arm, recognizing that this would not be a randomized comparison, if 
restricted to participants who were hospitalized.  
 
10.7 
Unblinding 
 
For unblinding requests, including emergency unblinding, refer to ACTG Standard 
Operating Procedure (SOP)-123, Unblinding Participants, (https://member.mis.s-
3.net/cms/dl/10466/ACTG-123+Unblinding+Participants-V7+011719).    
 
In the event that emergency disclosure of treatment assignment is thought to be 
required, the site investigator must follow ACTG SOP-123, Unblinding Participants. 
 
Planned Unblinding 
Participants will be unblinded at completion of the study. Please refer to ACTG SOP-123 
Unblinding Participants for details.  
 
(1) Sudden/Unplanned Unblinding: The decision to unblind one or more arms, or 
treatment specific to an individual participant, of an ongoing study is made by the team 
in conjunction with the relevant Scientific Committee and the Executive Committee. This 
can occur based on a recommendation from the DSMB or the results of another trial 
(also see the DAIDS SOP “Termination of a Trial or a Single Treatment Arm”).  
 
(2) Participant contact: If the decision is made to unblind, participants should be 
unblinded as soon as possible. Unblinding is conducted through the DMC, which sends 
treatment assignments to the sites soon after the unblinding decision. Every effort 
should be made by the sites to contact participants who have completed follow-up in 
order to explain the study results.  
 
(3) Implications of unblinding on study data: When a treatment comparison is unblinded 
based on an interim analysis, the results of that interim analysis must be reported in 
publications. Data from visits that occurred before the interim review but that were not in 
the database at the data cutoff date have little potential for bias and may be reported 
with a comment. Data from visits that occurred after unblinding are potentially biased 
and must not be used if the intent is to claim that all the data are from a blinded study. In 
unblinding due to both “interim analysis” and the “other trial results” situations, if 
analyses are reported on clinical data or samples taken after the unblinding date, the 
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Unblinding will not occur to allow replacement of participants (see section 6.2.4). Failure 
to initiate study treatment would result in an increase in the applicable limit for enrollment 
into the active or placebo arm (as appropriate) for the designated cohort by the ACTG 
randomization department.  
 
In general, participants who become hospitalized at any time during the study period of 
24 weeks can have their individual study treatment unblinded if essential for their future 
treatment management or if necessary for enrollment into a COVID-19 treatment clinical 
trial. This determination should be made by the Investigator of Record at the ACTG site 
and documented on the eCRF. 
 
If treatment assignment is unblinded, this information should only be shared with the 
physicians responsible for the management of the participant on a need-to-know basis. 
Treatment assignment should not be shared with others. This includes not sharing 
treatment assignment with the study team. 
 
All site e-mails to the team should be carefully worded to prevent unblinding the team. 
 
Unblinding of all study participants will take place after the last participant has completed 
the study, all data have been entered into the database and cleaned for primary and 
secondary outcome measures. For details, please refer to ACTG SOP-123 Unblinding 
Participants. 
 
11.0 
PHARMACOLOGY PLAN 
 
11.1 
Pharmacology Objectives 
 
The pharmacology objectives are: 1) to characterize pharmacokinetics of HCQ and 
Azithro in patients with COVID-19 following administration of study regimen; 2) to 
characterize relationship between HCQ and Azithro pharmacokinetics and rate of viral 
clearance. 
 
11.2 
Pharmacology Study Design   
 
11.2.1 
Overview 
 
Single sparse sample collected at Days 6 and 20 from a subset of participants 
will be analyzed using population pharmacokinetic approach using Bayesian 
methodology, with priors informed by historical controls. The model will be 
supported by 1) sparse sampling corresponding to Days 6 and 20 trough, 
collected in subset of participants (n=200); 2) historical data from healthy 
volunteers and participants treated for COVID 19 in other studies (as Bayesian 
priors). 
 
Population PK modelling will be used to estimate potential difference in HCQ 
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controls. A PK-PD model will be developed to examine the relationship between 
HCQ and Azithro PK, rate of viral clearance and potential clinical outcomes.  
 
PK analysis may also be undertaken to evaluate whether HCQ and/or Azithro 
might have been used by participants in the placebo arm. 
 
11.2.2 
Methods and Timing for Assessing, Recording, and Analyzing PK Outcome 
Measures 
 
Sparse PK sampling: Sparse sampling will be conducted at Days 6 and 20, 
approximately 0-1 hour prior to last or second-to-last dose taken. The exact 
time of 3 doses preceding the PK sampling and the exact time of the PK 
sample collection should be noted. 
 
11.2.3 
PK: Blood Collection and Processing 
 
Detailed blood collection, processing, handling, and storage procedures can be 
found in the A5395 Laboratory Processing Chart (LPC). 
 
11.2.4 
Laboratory Performing the Assays 
 
Plasma HCQ and Azithro concentrations will be determined by a validated 
procedure performed according to written standard operating procedures. The 
intraday accuracy and intraday precision will be obtained with quality control 
samples, which will be analyzed concurrently with each set of participant 
samples. Quality control procedures will be in place to ensure stability of 
sample materials. Plasma assays for HCQ and Azithro are being developed in 
the analytical laboratory at University of California at San Francisco (UCSF).  
 
11.3 
Pharmacological Data Analysis and Modeling Plan 
 
The drug concentration-time data will be analyzed using nonlinear mixed-effects (NLME) 
modeling using the software NONMEM merged with historical control data. We 
anticipate that we will utilize historical model structures to fit the data. The main focus 
will be to estimate potential difference in HCQ and Azithro oral clearance (CL/F) in 
participant treated for COVID-19 and historical controls. Graphical and statistical 
diagnostic tools will be used during model development for model selection and data 
tracking. PK/PD models will be developed to explore the relationship between drug 
concentrations and rate of viral clearance.  
 
11.4 
Anticipated Outcomes 
 
HCQ plasma levels will be associated with increased rate of viral clearance. Baseline 
viral load will also be an important determinant of viral clearance.  
 


 
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12.0 
DATA COLLECTION AND MONITORING  
 
12.1 
Reporting Protocol Deviations 
 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. Important protocol deviations are a subset of protocol 
deviations that may significantly impact the accuracy, and/or reliability of the study data 
or that may significantly affect a participant's rights, safety, or well-being (ICH E3). The 
site principal investigator and personnel are responsible for identifying and reporting 
important deviations. Once important protocol deviations are identified, corrective 
actions are to be developed by the site and implemented promptly. Protocol deviations 
must be sent to the IRB/EC per their guidelines.  
 
For A5395, all protocol deviations that meet the definition of important, as defined in the 
MOPS, relating to participant safety and confidentiality must be recorded on the study 
protocol deviation eCRF. Since the ACTG has in place its SOP-153, Appendix II, 
“Critical Event and Key Protocol Violation Reporting Form,” please also review the 
A5395 MOPS to determine when to use the Critical Event and Key Protocol Violation 
Reporting Form in ACTG 5395. 
 
12.2 
Records to Be Kept 
 
Electronic case report form screens will be made available to sites for data entry. 
Participants must not be identified by name on any data submitted to the DMC. 
Participants will be identified by the patient identification number (PID) and study 
identification number (SID) provided by the ACTG DMC upon randomization. 
 
12.3 
Role of Data Management 
 
12.3.1 
Instructions concerning entering study data on eCRFs will be provided by the 
ACTG DMC. Each CRS is responsible for keying the data in a timely fashion. 
 
12.3.2 
It is the responsibility of the ACTG DMC to ensure the quality of computerized 
data for each ACTG study. This role extends from protocol development to 
generation of the final study databases. 
 
12.4 
Clinical Site Monitoring and Record Availability 
 
12.4.1 
Site monitors under contract to the NIAID will visit participating clinical research 
sites to review the individual participant records, including consent records, 
eCRFs, supporting data, laboratory specimen records, 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 sites’ 
regulatory files to ensure that regulatory requirements are being followed and 
sites’ pharmacies to review product storage and management. 
 


 
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12.4.2 
The site investigator will make study documents (e.g., consent records, drug 
distribution forms, eCRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the FDA, the NIAID, 
the OHRP, the industry supporters or designee, other local, US, and 
international regulatory entities for confirmation of the study data.  
 
12.4.3 
Given the epidemic spread of SARS-CoV-2 and the risk for visiting personnel, 
the study can be monitored remotely by clinical trial monitors. This will be 
decided based on the risk environment at the time of monitoring.  
 
13.0 
PARTICIPANTS 
 
13.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix I) and any subsequent 
modifications will be reviewed and approved by the IRB or EC responsible for oversight 
of the study. Informed consent will be obtained from the participant either through a 
signed consent form or through appropriate remote consenting procedures. 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. 
 
13.2 
Participant Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. 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 ACTG, IRB/EC, the FDA, NIAID, 
OHRP, other local, US, and international regulatory entities as part of their duties.  
 
13.3 
Study Discontinuation 
 
The study may be discontinued at any time by the FDA, ACTG, IRB/EC, NIAID, or 
OHRP as part of their duties to ensure that research participants are protected, or the 
industry supporters. 
 
14.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by ACTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the industry 
supporters prior to submission.  
 


 
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15.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of SARS-CoV-2 and other droplet-borne pathogens can occur 
through contact with persons with active SARS-CoV-2 and infection-contaminated 
needles, blood, and blood products, appropriate blood and secretion precautions will be 
employed by all personnel in the clinical research setting and in drawing of blood and 
shipping and 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 CFR 42 Part 72. Please 
refer to instructions detailed in the International Air Transport Association (IATA) 
Dangerous Goods Regulations.  


 
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16.0 
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75. Yao X, Ye F, Zhang M, et al. In vitro antiviral activity and projection of optimized dosing 
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76. Cao B, Wang Y, Wen D, et al. A trial of lopinavir-ritonavir in adults hospitalized with 
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77. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 viral load in upper respiratory specimens 
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78. LABEL: HYDROXYCHLOROQUINE SULFATE tablet, film coated [Internet]. National 
Institutes of Health. 2020 [cited March 28, 2020]. Available from: 
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d7fdf8dd3ea0. 
79. LABEL: AZITHROMYCIN DIHYDRATE tablet, film coated [Internet]. National Institutes 
of Health. 2019 [cited March 28, 2020]. Available from: 
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3b9e61015e82. 
 


 
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APPENDIX I: SAMPLE INFORMED CONSENT 
 
DIVISION OF AIDS  
AIDS CLINICAL TRIALS GROUP (ACTG) 
 
SAMPLE INFORMED CONSENT 
 
For protocol: A5395 
 
A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of 
Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons with 
COVID-19 
 
FINAL Version 2.0, 4/24/20 
 
 
SHORT TITLE FOR THE STUDY: HCQ and Azithro for Non-hospitalized Persons with COVID-
19 
 
SUMMARY 
 
PURPOSE 
This is a research study and your participation in this study is voluntary. 
The purpose of this study is to evaluate the ability of hydroxychloroquine 
(HCQ) and azithromycin (Azithro) compared to placebo to prevent 
hospitalization or death in persons with COVID-19. 
 
STUDY 
TREATMENT  
There will be study treatment provided and required in this study. It is not 
known whether this study treatment will help your COVID-19 or not. You 
will be randomized to either Group A or Group B. Randomized means 
that your assignment will be random, like rolling dice. In this study, you 
will have a 50/50 chance of receiving either hydroxychloroquine and 
Azithro or Placebos. You and the study doctor will not know what group 
you are in, and therefore, will not know which study treatment you are 
taking (this is also referred to as “double-blinded”). You will take 
hydroxychloroquine/Placebo two (200 mg each) capsules by mouth 
twice a day on the first day, followed by one 200 mg capsule twice a 
day for 6 days. Hydroxychloroquine/Placebo should be taken with food 
or milk. You will also take Azithro/Placebo two (250 mg each) capsules by 
mouth once on the first day and then one capsule (250 mg) every day for 
4 additional days.   
 
NUMBER OF  
 
PARTICIPANTS 
There will be 2 treatment groups of 1000 people, for a total of 2000 
participants. 
 
 


 
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LENGTH OF  
STUDY 
The study will last for about 6 months (7 days on study treatment) 
 
REQUIRED  
ACTIVITIES 
 
Sample collections 
 
 
 
You will report your symptoms and temperature (if you have a 
thermometer at home) and how often you took medication and at what 
time throughout the study. 
   
RISKS  
 
The following are possible: 
• 
Hydroxychloroquine side effects  
o Nausea 
o Diarrhea 
o Vomiting 
o Headache 
o Tiredness 
o Stomach (abdominal) pain 
o Muscle weakness 
 
• 
Possible hydroxychloroquine side effects that are uncommon but 
potentially serious: 
o Serious (including fatal) allergic and skin reaction  
o Fast heart rate or pulse 
o Prolongation of QT interval (heart takes longer than normal to 
recharge between beats) and cases of “torsades de pointes” 
(dangerous fast heart beats) 
o Ventricular tachycardia or fibrillation, a condition of the heart that 
can cause a fast heart rate and increase the risk of stroke and 
heart attack 
o Hypoglycemia (blood sugar is low) 
o Blurry vision 
For US sites that are pre-selected include this: At the start of the study 
you may have some blood collected from a vein in your arm, perform a 
self-collect nose swab, and, in addition, have study staff do a 
nasopharyngeal swab of your nose. You will have both types of nose 
swabs at Day 6 and 20 and blood collected again at Days 6 and 20. All 
blood will be stored. 
 
You will have the option to self-collect a nose swab three times during 
the study. Swabs are used to detect viruses. You will place a swab in 
each nostril and rotate the swab several times. You may also have the 
option of having study staff do three nasopharyngeal swabs (intensive 
nose swabs), if the site is able to do these swabs. 
 


 
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o Muscle pain 
o Death 
 
• 
Azithro side effects 
o Diarrhea 
o Nausea 
o Abdominal pain 
o Vomiting 
 
• 
Possible Azithro side effects that are uncommon but potentially 
serious: 
o Serious (including fatal) allergic and skin reaction  
o Pseudomembranous colitis (swelling or inflammation of the large 
intestine due to overgrowth of Clostridium difficile) 
o New onset of myasthenia gravis (long-term neuromuscular 
disease that leads to skeletal muscle weakness) 
o Exacerbation of myasthenia gravis (weakness in skeletal muscles) 
o Ventricular arrhythmias (occurs more frequently in people with 
heart disease) 
o Severe, and sometimes fatal, hepatotoxicity (liver damage) 
o Prolongation of QT interval (heart takes longer than normal to 
recharge between beats) and cases of “torsades de pointes” 
(heart beats faster than usual) 
o Clostridium difficile (bacteria)-associated diarrhea 
o Death 
 
For US sites that are able to do blood draws, self-collect nasal 
swabs, and perform nasopharyngeal swabs, include the following: 
 
Risks associated with blood draws  
-Pain and bruising at the site of blood draw  
-Infection (rare) 
-Hypotension (lowering of blood pressure) (rare) 
 
Other blood draw risks 
-Anemia (low red blood cell count) (rare) 
-Feeling lightheaded or fainting 
 
Risks associated with nose swabs 
- Stimulating a gag reflex 
- Sneezing 
- Discomfort 


 
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BENEFITS 
If you take part in this study, there may be a direct benefit to you, but no 
guarantee can be made. It is also possible that you may receive no 
benefit from being in this study. Information learned from this study may 
help others who have SARS-CoV-2 infection. 
 
OTHER CHOICES  
Instead of being in this study, you have the option of:  
 
• 
Treatment with prescription drugs available to you by your medical 
provider. 
• 
Treatment with experimental drugs, if you qualify, treatment with “off-
label” treatment with hydroxychloroquine and/or azithromycin if prescribed 
by your medical provider. 
• 
No treatment. 
 
 
INTRODUCTION  
 
You are being asked to take part in this research study because you have been diagnosed with 
SARS-CoV-2 (a new virus that can cause severe pneumonia and death) and have symptoms of 
this infection, commonly known as COVID-19. This study is sponsored by the National Institutes 
of Health (NIH). The doctor in charge of this study at this site is: (insert name of Principal 
Investigator). Before you decide if you want to be a part of this study, we want you to know 
about the study.  
 
This is a consent form. It gives you information about this study. The study staff will talk with you 
about this information. You are free to ask questions about this study at any time. If you agree to 
take part in this study, you will be asked to sign this consent form. You will get a copy to keep. 
 
 
WHY IS THIS STUDY BEING DONE? 
 
SARS-CoV-2 is a new virus that has caused a widespread outbreak of an illness called COVID-
19. In most people it causes a mild to moderate upper respiratory infection, like a “cold”. In 
others, this virus can cause a pneumonia, which can be serious and life-threatening. There is no 
proven therapy for COVID-19. 
 
The investigators of this study would like to know if the medication hydroxychloroquine (HCQ) 
combined with azithromycin (Azithro) can protect people from becoming sick enough from 
SARS-CoV-2 infection to require hospitalization or from dying. This study will gather data on the 
effectiveness of hydroxychloroquine and Azithro to prevent hospitalization and death in adults 
with SARS-CoV-2 infection when compared to Placebo (sugar capsule). Another purpose of this 
study is to see if hydroxychloroquine and Azithro is safe for people who are infected with 
SARS-CoV-2 and have symptoms consistent with COVID-19. 
 
Hydroxychloroquine is currently approved by the Food and Drug Administration (FDA) for 
prevention and treatment of malaria infection and treatment of disease in individuals with 
rheumatoid arthritis, porphyria cutanea tarda (blood disorder that affects the skin), and lupus (an 


 
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autoimmune disease). Azithromycin is currently FDA approved for treating bacterial infections. 
Hydroxychloroquine and Azithro have not previously been tested in a randomized controlled 
trial (people are assigned randomly to study treatment and compared to people not taking study 
treatment) in people to see if they can prevent severe disease from SARS-CoV-2 infection. 
 
 
WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Information Collected at Screening 
If you decide to take part in this study, you will be screened to determine if you qualify for the 
study.  
 
There is some information that we collect on everyone who is screened for an AIDS Clinical 
Trials Group (ACTG) study. As part of the screening, some demographic (such as, age, 
sex/gender, race), clinical (such as disease condition, diagnosis), and laboratory (such as, 
inflammation and SARS-CoV-2 levels) information will be collected from you. We also collect 
information on whether you use (or have used) IV drugs or smoke marijuana or have smoked 
tobacco or other nicotine products. 
 
We will collect this information even if you do not enroll in this study. This information is 
collected so that researchers can determine whether there are patterns and/or common reasons 
why people do not join a study.  
 
Study Visits 
The schedule of visits and study procedures are explained in Attachment B. 
 
You will most likely be screened over the phone, but you also could be screened in person. If 
you qualify for the study, you will have an in-person entry visit to get your study treatment for the 
duration of the study, or a remote (i.e., by telephone or video) visit in which your study treatment 
for the duration of the study will be mailed or delivered to you. The screening and entry visit may 
occur on the same day. You will be randomized to receive either hydroxychloroquine and 
Azithro (Group A) or Placebos (Group B). Randomized means that your assignment will be 
random, like rolling dice. In this study, you will have a 50/50 chance of receiving either 
hydroxychloroquine and Azithro or Placebos. You and the study doctor will not know what 
study group you are in. 
 
If you are in Group A, you will take hydroxychloroquine two (200 mg each) capsules by 
mouth twice a day on the first day, followed by one 200 mg capsule twice a day for 6 
days. Hydroxychloroquine should be taken with food or milk. You will also take two Azithro 
capsules (250 mg each) by mouth once on the first day and then one capsule (250 mg) every 
day for 4 additional days.  
 
If you are in Group B, you will take Placebo hydroxychloroquine two (200 mg each) capsules 
by mouth twice a day on the first day, followed by one 200 mg capsule twice a day for 6 
days. Placebo hydroxychloroquine should be taken with food or milk. You will also take two 
Placebo Azithro capsules (250 mg each) by mouth once on the first day and then one capsule 
(250 mg each) every day for 4 additional days. Study staff will counsel you on how to take 


 
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these study medications. Both study groups are important to the study to answer the study 
questions. 
 
After entry, you will be followed-up by telephone or video a few times. These phone calls will 
take between 30 and 60 minutes to complete. During the study, you will take your temperature if 
you have a thermometer at home and complete a symptom diary.  
 
 
 
If you need medical help at any time during the study, please contact the study staff right away. 
 
Screening Visit (in-person or remote) 
You will be asked for your medical and medication history. You will be asked about your 
symptoms. 
 
Study Entry (in-person or remote) 
Following the screening visit (if not combined with the entry visit), if you qualify for the study, 
you will be asked for your medical and medication history again, be given your study treatment 
and be given a Study Diary packet and complete the Study Diary for that day (if remote visit, 
these items will be mailed or delivered to you). You will be asked to provide contact information 
for people close to you in case study staff cannot reach you during the study. We would like you 
to tell these contacts that you are in the study, so they know they may receive a call from study 
staff. You will also be asked to provide your health care provider’s contact information along 
with the name(s) of the hospital you would likely go to if you get really sick (see consent below 
under “WHAT IF THE SITE CAN NO LONGER REACH ME DURING THE STUDY?”). You will 
also be asked to provide your home address. You will take your study treatment on this day. If 
you have an in-person visit, study staff will observe you taking the study treatment. If you have a 
remote visit, you will need to tell study staff when you have taken the study drug. 
 
 
 
Follow-up Visits 
You will be contacted by phone by study staff on Days 2, 4, 6, 9, 13, and 17, and at 3 and 6 
months after you enter the study. During the study, you will complete a symptom diary. You will 
also be asked questions about how you are taking the study treatment and health care that you 
have accessed. Site staff will also ask you to update your secondary contact information. These 
visits will take between 30 and 60 minutes.  
 
You will have an in-person visit or remote visit on Day 20 to see how you are feeling and for 
you to turn in your Study Diary. If your Day 20 visit is not done in person, you will be called by 
For US sites that are pre-selected, include the following: You may choose to have blood 
collected and stored at entry and on Days 6 and 20. Blood will be collected by venipuncture 
(puncture of the vein). You may choose to self-collect nose swabs and have an intensive 
nose swab at entry and Day 6 and Day 20.  
For US sites that are pre-selected, include the following: You may have blood collected and 
stored, self-collect a nose swab, and have a deeper nose swab. Up to 37 mL of blood will be 
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study staff to do the visit over the phone or by video. Arrangements will be made for you to send 
the symptom diary to the clinic. This visit will take between 30 and 60 minutes. 
 
 
 
If you cannot be reached, the study staff will contact your alternative contacts or your health 
care provider. If you become hospitalized, the study staff will ask your contacts for information 
about you being in the hospital. The study staff will also ask your contacts about death, should 
that occur (see consent below under “WHAT IF THE SITE CAN NO LONGER REACH ME 
DURING THE STUDY?”). 
 
Early discontinuation 
If at any point in the study you want to stop study treatment or stop participating in the study, 
you must contact the site immediately and will be asked to come to the clinic for an extra 
visit. 
 
1. Stopping the study treatment early 
You or your doctor may decide to stop the study treatment that you began at entry.  
 
If you must stop taking the study treatment early, you will continue the study and complete 
the study visits as described in this form.  
 
2. Leaving the study early 
You or your doctor may decide that you will no longer stay in the study or you are notified 
the study is stopped early. You will be asked to complete some evaluations before being 
taken off the study.  
 
 
 
For US sites that are pre-selected, include the following: You will have the option of study 
staff doing a blood draw, self-collect a nose swab, and have an intensive nose swab done by 
study staff at Days 6 and 20. Up to 41 mL of blood will be collected at Day 6 and at Day 20. 
Blood will be stored. You will receive study reimbursement at study entry, and Days 6 and 
20. 
For US sites that are pre-selected, include the following: If you agree to participate in the 
optional procedures, you will have a blood draw, self-collect a nose swab, and have an 
intensive nose swab by study staff if you end the study early. Up to 41 mL of blood will be 
collected and stored.  
 


 
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HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
 
Up to 2000 people will take part in this study. 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
 
You will be in this study for about 6 months (7 days on treatment).  
 
 
WHY WOULD THE DOCTOR TAKE ME OFF THIS STUDY EARLY? 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or cancelled.  
• 
Continuing the study treatment may be harmful to you. 
• 
Your primary care provider requests that you stop participating in the study. 
• 
You do not take your first dose of study treatment when you start the study. 
 
The study doctor may also need to take you off the study medication without your permission if: 
• 
You are taking other medications that should not be taken with the study drug. 
 
If you must stop taking the study treatments before the study is over, the study doctor will ask 
you to continue to be part of the study and return for study visits and procedures.  
 
 
For US sites that are pre-selected, include the following:  
 
CAN I CHOOSE THE TYPES OF RESEARCH THAT MY SAMPLES AND INFORMATION 
ARE USED FOR? 
 
Some of your blood and nose secretions (samples) will be stored and used for testing of 
inflammation, pharmacokinetics (to test how the study drug works in your body), and the 
presence of SARS-CoV-2 that is required for this study.  
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will 
be able to know that the samples or information came from you.  
 
The tests described in this consent are required by this study.  
 


 
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WHAT HAPPENS IF I DECIDE TO PERMANENTLY STOP TAKING STUDY-PROVIDED 
MEDICATIONS? 
 
If you must permanently stop taking study-provided hydroxychloroquine and Azithro or 
Placebo before your study participation is over, the study staff will discuss other options that 
may be of benefit to you. 
 
 
WHAT HAPPENS WHEN I FINISH THE ONE WEEK STUDY-PROVIDED MEDICATIONS? 
 
After you have completed your study participation, the study will not be able to continue to 
provide you with the hydroxychloroquine and Azithro you received on the study. If continuing 
to take these or similar drugs/agents would be of benefit to you, the study staff will discuss how 
you may be able to obtain them.  
 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
There are risks to taking part in any research study. The effectiveness of the study treatments is 
not known. One risk is that the study treatments may not stop you from becoming sicker, being 
hospitalized or dying from SARS-CoV-2. Another risk is that the study treatments used in this 
study may have side effects, some of which are listed below. Additionally, the study drugs tested 
in the study may have unknown side-effects in persons with SARS-CoV-2 infection. In a research 
study, all of the risks or side effects may not be known before you start the study. You need to 
tell your doctor or a member of the study team immediately if you experience any side effects.  
 
Please note that these lists do not include all the side effects seen with these medications. 
These lists include the more serious or common side effects with a known or possible 
relationship to the study drugs. If you have questions concerning the additional side effects, 
please ask the medical staff at your site. 
 
There is a risk of serious and/or life-threatening side effects when non-study medications are 
given with the study treatment. For your safety, you must tell the study doctor or nurse about all 
medications you are taking before you start the study. Medications that are high risk are:  
• 
“Off-label” prescription for hydroxychloroquine, chloroquine, and/or 
azithromycin 
• 
Cardiac medications 
o Antiarrhythmic drugs: Class Ia (quinidine [Quinidex Extentabs, 
Quinaglute, Quinalan, Cardioquin], procainamide [Pronestyl], 
disopyramide [Norpace, Norpace CR]); Class III (dofetilide [Tikosyn], 
ibutilide [Corvert], sotalol [Betapace, Betapace AF, Sorine, Sotylize]) 
o Loop diuretics (furosemide [Furocot, Lasix], bumetanide [Bumex], 
torsemide [Demadex], ethacrynic acid [Edecrin]) 
• 
Non-cardiac medications 
o Diphenhydramine (Benadryl, Banophen, Allermax, Genahist, Sominex, 
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o Antiepileptic medications: Carbamazepine (Tegretol, Carbegen), 
Eslicarazepine (Aptiom), Ethosuximide, Felbamate (Felbatol), 
Gabapentin (Neurontin), Lamotrigine (Lamitcal), Levetiracetam 
(Desitrend, Keppra), Oxcabazepine (Trileptal), Phenobarbital, 
Phenytoin (Dilantin, Epanutin), Piracetam (Nootropil), Pregabalin 
(Alzain, Axalid, Lyrica, Rewisca), Rufinamide (Inovelon), Stiripentol 
(Diacomit), Tiagabine (Gabitril), Topiramate (Topamax), Sodium 
Valproate (Epilim, Episenta, Epival), Valproic Acid (Convulex, 
Depakote, Depakene), Zonisamide (Zonegran) 
o Antipsychotic and antidepressant agents: Neuroleptic (haloperidol 
[Haldol], droperidol [Inapsine], thioridazine [Mellaril, Mellaril-S], 
chlorpromazine [Thorazine, Ormazine]); Atypical antipsychotics 
(ziprasidone [Geodon], risperidone [Risperdal M-Tab, RisperiDONE M-
Tab], zimeldine [Normud, Zelmid], citalopram [CeleXA]); Antidepressants 
(amitriptyline [Elavil, Vanatrip], desipramine [Norpramin], imipramine 
[Tofranil and Tofranil-PM], maprotiline [Ludiomil], doxepin [Silenor, 
SINEquan], fluoxetine [PROzac, PROzac Weekly, Rapiflux, Sarafem, 
Selfemra], escitalopram [Lexapro], citalopram [CeleXA]) 
o Antibiotics: Quinolone (levofloxacin [Levaquin], moxifloxacin [Moxeza, 
Vigamox]); Macrolide (erythromycin [EES 200, EES 400, EES Granules, 
Eryc, Eryped, Eyrped 200, Eyrped 400, Ery-Tab, Erythrocin, Erythrocin 
Stearate, IIosone, PCE, PCE Dispertab], clarithromycin [Biaxin, Biaxin 
Filmtab, Biaxin XL])  
o Antimalarials (quinine [Qualaquin, Quinamm, Quiphile], halofantrine 
[Halfan])  
o Antiprotozoal (pentamidine [Pentam]) 
o Antifungal (azole group [Vfend, Sporanox, Noxafil, Diflucan, Nizoral, 
Mycelex Troche, Cresemba, Onmel, Oravig, Tolsura])  
o Antimotility agents (antidiarrheals) 
o Methadone [Diskets Dispersible, Dolophine, Methadone HCl Intensol, 
Methadose] 
Please contact the study doctor or nurse before starting any of these medications while on the 
study. Also, you must tell the study doctor or nurse before enrolling in any other clinical trials 
while on this study. 
 
If you enroll in this trial and are randomized to receive active hydroxychloroquine and 
azithromycin drugs, and you also receive “off-label” prescription for hydroxychloroquine, 
chloroquine, and/or azithromycin, then there is a risk of over-dosing. It is possible to have 
serious side effects with risk for death. It is important that you do not take hydroxychloroquine 
or Azithro from sources outside of the study, like from your primary doctor. If you do take one or 
both of these drugs from sources outside the study, please let the study staff know right away.  
There is also a risk that these drugs have no benefit for COVID-19, and thus drug exposure 
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Commonly reported side effects of hydroxychloroquine are: 
• 
Nausea 
• 
Diarrhea 
• 
Vomiting 
• 
Headache 
• 
Tiredness 
• 
Stomach (abdominal) pain 
• 
Muscle weakness 
 
Less common, but potentially severe and potentially life-threatening side effects of 
hydroxychloroquine in volunteers were:  
• 
Allergic reactions and rash 
• 
Tachycardia (fast heart rate or pulse) 
• 
Prolongation of QT interval (heart takes longer than normal to recharge between beats) and 
cases of “torsades de pointes” (dangerously fast heart beats) 
• 
Ventricular tachycardia or fibrillation, a condition of the heart that can cause a fast heart rate 
and increase the risk of stroke and heart attack 
• 
Hypoglycemia (blood sugar is low) 
• 
Blurry vision 
• 
Muscle pain 
• 
Death 
 
If you have psoriasis and are randomized to receive hydroxychloroquine, you may experience 
a psoriasis flare. 
 
Side Effects of Azithro 
• 
Diarrhea 
• 
Nausea 
• 
Abdominal pain 
• 
Vomiting 
• 
Pseudomembranous colitis (swelling or inflammation of the large intestine due to overgrowth 
of Clostridium difficile) 
• 
New onset of myasthenia gravis (long-term neuromuscular disease that leads to skeletal 
muscle weakness) 
• 
Exacerbation of myasthenia gravis (weakness in skeletal muscles) 
• 
Ventricular arrhythmias (occurs more frequently in people with heart disease) 
 
The following severe and potentially life-threatening side effects have been reported: 
• 
Serious (including fatal) allergic and skin reaction 
• 
Severe, and sometimes fatal, hepatotoxicity (liver damage) 
• 
Prolongation of QT interval (heart takes longer than normal to recharge between beats) and 
cases of “torsades de pointes” (dangerously fast heart beats) 
• 
Clostridium difficile (bacteria)-associated diarrhea 
• 
Death 
 


 
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As with all drugs, you could have an allergic reaction such as a rash or hives. Allergic reactions 
can be dangerous; if you develop an allergic reaction, you will be given medication (similar to 
Benadryl) to counter the reaction and be taken off study drug. 
 
 
 
 
ARE THERE RISKS RELATED TO PREGNANCY AND BREASTFEEDING? 
 
Pregnancy 
The safety of hydroxychloroquine during pregnancy is not fully established. However, 
pregnant women with lupus and arthritis are recommended to continue hydroxychloroquine 
throughout pregnancy. Studies have shown that taking hydroxychloroquine during pregnancy 
does not harm the fetus. It should be noted that hydroxychloroquine at the dose used in this 
study has not been used before during pregnancy and may involve risks.  
 
In animal studies, no evidence of harm to the fetus due to Azithro was found. When given as 
malaria prevention during pregnancy, Azithro was not shown to harm the fetus.  
 
The study treatment may involve risks to you (or to the embryo or fetus, if you or your partner 
become pregnant), which are currently unforeseen. Let your doctor know immediately if you 
become pregnant. If you become pregnant while on the study, the study staff would like to 
obtain information from you about the outcome of the pregnancy (even if it is after your 
participation in the study ends). 
 
If you are pregnant, please discuss study participation with your OB/GYN provider. 
 
Breastfeeding 
Hydroxychloroquine is excreted in human breast milk. When given at the dose used in this 
study the relative amount of hydroxychloroquine in breast milk is considered safe for infants.  
Azithro is excreted in human milk, but considered safe to use during breastfeeding.  
 
For US sites that are pre-selected, include the following:  
 
Risks Associated with Blood Draw 
Blood draws may cause pain and bruising, and rarely, infection at the site of the blood draw. 
There is also a risk of anemia (low red blood cell count) or hypotension (low blood 
pressure). Sometimes, having blood drawn will cause people to feel lightheaded or even to 
faint. 
 
Risks Associated with Collection of Nasopharyngeal Swabs and Self-collected Nose Swabs 
• 
You may experience mild discomfort related to the insertion of the nasopharyngeal swab 
(intensive nose swab). 
• 
Occasionally there can be a tingling feeling, or slight stinging. 
• 
You may have a gag reflux or sneeze 
 


 
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It is unknown if SARS-CoV-2 is excreted in human breast milk. If you would like to breastfeed 
during this study, please talk to your OB/GYN provider. 
 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
 
No direct benefits should be expected from participating in this study. If you take part in this 
study, there may be a direct benefit to you, but no guarantee can be made. It is also possible 
that you may receive no benefit from being in this study. Information learned from this study 
may help others who have SARS-CoV-2 infection. 
 
 
WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
 
Instead of being in this study you have the choice of: 
 
• 
Treatment with prescription drugs available to you by your medical provider. 
• 
Treatment with experimental drugs, if you qualify, treatment with “off-label” treatment 
with hydroxychloroquine and/or azithromycin if prescribed by your medical provider. 
• 
No treatment. 
 
Please talk to your doctor about these and other choices available to you. Your doctor will 
explain the risks and benefits of these choices.  
 
WHAT ABOUT CONFIDENTIALITY? 
 
We will do everything we can to protect your privacy. In addition to the efforts of the study staff 
to help keep your personal information private, we have gotten a Certificate of Confidentiality 
from the US Federal Government. This certificate means that researchers cannot be forced to 
tell people who are not connected with this study, such as the court system, about your 
participation. Also, any publication of this study will not use your name or identify you 
personally.  
 
Your records may be reviewed by the US Food and Drug Administration (FDA), the ACTG, the 
US Office for Human Research Protections (OHRP), or other local, US, and international 
regulatory entities as part of their duties, (insert name of site) institutional review board (IRB) (a 
committee that protects the rights and safety of participants in research), National Institutes of 
Health (NIH), study staff, study monitors, drug companies supporting this study, and their 
designees. Having a Certificate of Confidentiality does not prevent you from releasing 
information about yourself and your participation in the study. 
 
Even with the Certificate of Confidentiality, if the study staff learns of possible child abuse and/or 
neglect or a risk of harm to yourself or others, we will be required to tell the proper authorities. 
 


 
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A description of this clinical trial will be available on ClinicalTrials.gov, as required by U.S. law. 
This website will not include information that can identify you. At most, the website will include a 
summary of the results. You can search this website at any time.  
 
 
WHAT IF THE SITE CAN NO LONGER REACH ME DURING THE STUDY? 
  
In the event you cannot be reached after multiple attempts to contact you, study staff may try to 
contact you through alternate phone numbers of family, friends, case manager, or 
acquaintances obtained from you at screening and updated at each visit. If you are still unable 
to be reached, we will attempt to obtain information about you from your designated contacts, 
clinic records, or by contacting your health care providers (if you agree).  
 
Contacting Your Health Care Providers 
[Sites to modify per local requirements for obtaining health care records.] 
With your permission, for which you would need to sign a waiver, study staff may contact your 
health care providers or hospitals where you might receive care to determine if you have been 
hospitalized or died while in the study, and the cause of death. Will you allow us to contact your 
health care provider(s) or hospitals to obtain this information?  
 
________ YES ________ NO _______Initials 
 
If you said Yes, please list the names of your health care provider and the hospitals you would 
likely be admitted to, below: 
 
 
 
 
 
 
 
WHAT ARE THE COSTS TO ME? 
 
There will be no cost to you for study-related visits [add the following only if at pre-selected US 
site: laboratory tests,] or procedures. If you require medical care as a result of taking study 
medications, it is possible that your insurance company will not pay for these costs because you 
are taking part in a research study.  You are more likely to require medical care as a result of 
having COVID-19. Costs related to acute care/hospitalization will not be covered by the study. 
 
 
WILL I RECEIVE ANY PAYMENT? 
 
[Insert site-specific information on compensation to study participants.]  
 
 


 
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WHAT HAPPENS IF I AM INJURED? 
 
If you are injured as a result of being in this study, you will be given immediate treatment for 
your injuries. The cost for this treatment will be charged to you or your insurance company. 
There is no program for compensation either through this institution or the National Institutes of 
Health. You will not be giving up any of your legal rights by signing this consent form. 
 
 
WHAT ARE MY RIGHTS AS A RESEARCH PARTICIPANT? 
 
Taking part in this study is completely voluntary. You may choose not to take part in this study 
or leave this study at any time. Your decision will not have any impact on your participation in 
other studies and will not result in any penalty or loss of benefits to which you are otherwise 
entitled. 
 
We will tell you about new information from this or other studies that may affect your health, 
welfare, or willingness to stay in this study. If you want the results of the study, let the study staff 
know. 
 
 
 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
Name of the investigator or other study staff 
• 
Telephone number of above  
 
For questions about your rights as a research participant, contact: 
• 
Name or title of person on the Institutional Review Board (IRB) or other organization 
appropriate for the site 
• 
Telephone number of above 
 
For US sites that are pre-selected, include the following:  
 
In the subset of participants from the pre-selected sites, results from the in-study SARS-CoV-
2 testing and blood work (CBC and chemistries) will be provided to you. These results will 
also be provided to your primary/health care provider if requested by you.  


 
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SIGNATURE PAGE 
 
If you have read this consent form (or had it explained to you), all your questions have been 
answered and you agree to take part in this study, please sign your name below. 
 
 
 
____________________________ 
__________________________________ 
Participant’s Name (print) 
Participant’s Signature and Date 
 
 
____________________________ 
__________________________________ 
Participant’s Legally Authorized 
Legally Authorized Representative 
Representative (print) 
Signature and Date 
(As appropriate) 
 
 
____________________________ 
__________________________________ 
Study Staff Conducting 
Study Staff’s Signature and Date 
Consent Discussion (print)  
 
 
 
____________________________ 
__________________________________ 
Witness’s Name (print) 
Witness’s Signature and Date 
(As appropriate) 
 
 
 
 
 


 
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ATTACHMENT A: CONSENT TO PARTICIPATE IN OPTIONAL INTENSIVE SAMPLING 
STUDY  
  
[Attachment A Consent is only for US sites that are pre-selected to participate in the intensive 
sampling study.] 
  
The optional intensive sampling study includes three different procedures (as described below) 
and will advance the scientific goals of this study but will offer no direct benefit to participants. 
Neither you nor your doctor will receive any results from these procedures because these tests 
are for research purposes only. If you agree to participate in the optional intensive sampling 
study, you must agree to have all three procedures described below done. If you choose not to 
participate in the optional intensive sampling study, it will not affect your ability to take part in the 
main study.  
  
Self-collected nose swabs 
The self-collected nose swabs will be performed by you at [insert site-specific details]. The 
procedure will take about [insert site-specific details]. 
  
Self-collected nose swabs are used to detect respiratory viruses. You will place a swab in each 
nostril and rotate the swab several times. 
  
[Note to sites: Insert details regarding how this procedure is performed in your institution]. 
  
Nasopharyngeal swabs 
The nasopharyngeal swabs will be performed by study staff at [insert site-specific details]. The 
procedure will take about [insert site-specific details]. 
  
Nasopharyngeal swabs are used to detect respiratory viruses. Study staff will tell you how this 
procedure is performed. A swab will be inserted into your nostril. The swab will be placed in 
deep towards the back of your throat. The swab will be in place for several seconds. The swab 
will be slowly removed. This is an uncomfortable procedure.  
  
[Note to sites: Insert details regarding how this procedure is performed in your institution]. 
  
Blood draws and blood storage  
Blood draws will be performed by study staff at [insert site-specific details]. The procedure will 
take about [insert site-specific details]. 
  
[Note to sites: Insert details regarding how this procedure is performed in your institution]. 
  
Please indicate below if you agree to participate in this optional intensive sampling study and 
have all three of these procedures done. No matter what you decide, it will not affect your 
participation in the main study.  
 
Self-collected nose swabs, nasopharyngeal swabs, blood draws and blood storage: 
  
________ (initials) YES, I agree                     ________ (initials) NO, I do not agree 


 
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ATTACHMENT B: EXPLANATION OF STUDY VISITS AND EVALUATIONS 
 
Section A: Study Visits 
Table 1: Schedule for Participants  
Procedure 
Screen-
ing 
Entry 
(in-
person 
or 
remote) 
On study visits 
End Study 
Early 
Days 
Months 
Day 0 
2  
4 
6 
9 
13 
17 
20 
3 
6 
Consent 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm SARS-CoV-2 
Infection 
 
 
 
 
 
 
 
 
 
 
 
 
Questions about 
symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
Questions about your 
health  
 
 
 
 
 
 
 
   
 
 
 
 
Questions about the 
medications you are 
taking 
 
 
 
 
 
 
 
 
 
 
 
 
Secondary contact 
request 
 
 
 
 
 
 
 
 
 
 
 
 
Study kit received 
 
 
 
 
 
 
 
 
 
 
 
 
Remote contact 
 
 
 
 
 
 
 
 
  
 
 
 
Adherence assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Review Study Diary 
 
 
 
 
 
 
 
 
 
 
 
 
Return of Study Diary 
to Study Staff 
 
 
 
 
 
 
 
 
 
 
 
 
Optional Sampling Study Procedures 
In person visit1 
 
 
 
 
 
 
 
 
 
 
 
 
Self-collect nose swab1 
 
 
 
 
 
 
 
 
 
 
 
 
Intensive nose swab1 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collected and 
stored1 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 [Remove if site cannot administer blood draws, self-collect nasal swab, and perform NP swab] 
 
 


 
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Section B: Explanation of Visit Schedule 
 
Screening: This visit may be done in-person or over the phone. It is possible that 
the screening and entry visits are combined. 
 
Entry: This in-person or remote visit will take place after the screening visit. This visit 
may be done at the same time as screening. You will be required to take the first 
dose of study treatment in front of someone from the study staff. If this visit is done 
remotely, you will tell the site that you have taken or are taking the first study dose 
and record the time of your first dose. Study staff will counsel you on how to take 
these study medications. This visit will take place and you should start study 
treatment within 96 hours of the time your positive COVID-19 test was 
performed (when the specimen was collected). 
 
On-study: You will be contacted by phone on Days 2, 4, 6, 9, 13, and 17, and at 3 
(week 12) and 6 months (week 24) after you enter the study.  
 
 
 
Day 20: You will have an in-person or remote visit. If you are not feeling well and 
you cannot do the Day 20 visit in-person, you will be called by study staff to conduct 
the visit by phone or video. Arrangements will be made to send you study payment 
and for you to send the symptom diary to the clinic. 
 
 
 
At months 3 (week 12) and 6 (week 24), you will be contacted by telephone/video. 
 
End study early: if you leave the study after Day 6, all procedures will be done 
indicated in the table except treatment adherence. 
 
 
For US sites that are pre-selected to do blood draws, self-collect nasal swabs, 
and perform NP swabs, include the following: If you choose, you may have an in-
person visit on Days 0 and 6 for a blood draw, an intensive nose swab, and/or a 
self-collected nose swab. 
For US sites that are pre-selected to do blood draws, self-collect nasal swabs, 
and perform nasopharyngeal swabs, include the following: You may choose to 
have blood collected and stored, have study staff perform an intensive nose 
swab, and self-collect a nose swab on Day 20. 
For US sites that are pre-selected to do blood draws, self-collect nasal swabs, and 
perform nasopharyngeal swabs, include the following:  
 
End study early: if you end the study after Day 6, all procedures will be done except 
treatment adherence. Up to 41 mL of blood will be collected. 


 
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Section C: Explanation of Procedures 
 
Confirm SARS-CoV-2 infection: Study staff will confirm that you have SARS  
CoV-2.  
 
Questions about symptoms: You will be asked about symptoms you are 
experiencing.  
 
Questions about your health: Study staff will ask you about any health conditions 
you have and questions about your health in general. 
 
Questions about medications you are taking: Study staff will ask you about 
medication history and medications you are taking while on study. 
 
Secondary contact request: You will be asked to provide contacts close to you (like 
a family member or a neighbor) in case study staff cannot reach you. We ask that 
you tell these contacts about your being in the study, and that they may receive a 
call from study staff if study staff cannot reach you. You will also be asked to provide 
your health care provider contact information. If study staff cannot reach you, they 
will call your secondary contacts. You will also be asked to provide your home 
address at study entry only. 
 
Study kit received: You will receive a kit that includes information about the study, 
instructions on study procedures, the symptom diary, study treatment (you will take 
the first dose of study treatment at the entry visit), instructions on what to do if you 
have worsening symptoms and go to the hospital, and contact information for the 
study staff. You may also receive a self-addressed stamped envelope to mail 
your symptom diary back to the clinic in case your Day 20 study visit is 
remote. 
 
Remote contact: Study staff will call you on the phone, or by video. If study staff 
cannot reach you, they will call your secondary contacts. 
 
Adherence assessment: You will be asked to keep track of how you are taking study 
treatment in the symptom diary (hydroxychloroquine and Azithro or Placebos). 
Study staff will ask you how you are taking your study treatment when they review 
the symptom diary with you. 
 
Review symptom diary: At study entry, you will review the symptom diary in person 
or remotely with study staff. You will complete the first day of the diary with the study 
staff prior to taking your first dose of study medication. You will then fill out the 
diary every day in the evening for 21 days. You will review the diary over the phone 
with study staff at the scheduled visits. They will ask you the questions that are on 
the diary. The questions are about how you are feeling related to COVID-19, other 
medications you are taking, and if you have received any urgent medical care during 
the study. You will also take your temperature, if you have a thermometer at home. 
 


 
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Return of symptom diary to study staff: You will return the symptom diary packet 
back to study staff. 
 
 
 
 
 
 
 
For US sites that are pre-selected, include the following:  
 
In-person visit: Some study visits will be in-person only if you choose 
to have study staff conduct an intensive nose swab, self-collect nose 
swab, or have blood collected and stored. 
 
Blood collected and stored: Blood may be collected from a vein in 
your arm for research tests that may include SARS-CoV-2. Your 
blood will be stored.  
 
Self-collect nose swab: Swabs are used to detect viruses. You will 
place a swab in each nostril and rotate the swab several times. 
Study staff will provide you with further instructions about the nose 
swabs. You will not receive results of these tests. 
 
Intensive nose swab: You will have the option of having study staff 
do nasopharyngeal swabs. They are used to detect respiratory 
viruses. Study staff will tell you how this procedure is performed. A 
swab will be inserted into your nostril. The swab will be placed in 
deep towards to the back of your throat. The swab will be in place for 
several seconds and then slowly removed. This is an uncomfortable 
procedure. You will not receive results of these tests. 
 


 
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ATTACHMENT C: CONSENT FOR USE OF EXTRA SAMPLES 
 
[Attachment C Consent is only for US sites that are pre-selected] 
 
When samples are no longer needed for this study, the ACTG may want to use them in other 
studies and share them with other researchers. These samples are called “extra samples.” The 
ACTG will only allow your extra samples to be used in other studies if you agree to this. If you 
have any questions, please ask. 
 
Identifiers will be removed from your samples and from any private information that has been 
collected about you. This means that no one looking at the labels or at other information will be 
able to know that the samples or information came from you.  
 
Extra samples are stored in a secure central place called a repository. Your samples will be 
stored in the ACTG repository located in the United States. 
 
There is no limit on how long your extra samples will be stored. [Site: Revise the previous 
sentence to insert limits if your regulatory authority imposes them.] 
 
When a researcher wants to use your samples and information, his or her research plan must 
be approved by the ACTG. Also, the researcher’s institutional review board (IRB) or ethics 
committee (EC) will review the plan. [Site: If review by your institution’s IRB/EC/RE is also 
required, insert a sentence stating this.] IRBs/ECs protect the rights and well-being of people in 
research. If the research plan is approved, the ACTG will send your samples to the researcher’s 
location. This means that researchers who are not part of the protocol team may use your 
samples without asking you again for your consent.  
 
You will not be paid for your samples. Also, a researcher may make a new scientific discovery or 
product based on the use of your samples. If this happens, there is no plan to share any money 
with you.  
 
You may withdraw your consent for research on your extra samples at any time and the 
specimens will be discarded. 
 
Please choose the response that matches what you want by putting your initials in the space 
provided. Please ask the staff any questions that you have before you indicate your selection. 
 


 
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Research without Human Genetic Testing  
If you agree, your extra samples may be stored (with usual protection of your identity) and used 
for ACTG-approved research that does not include human genetic testing. 
 
____ (initials) I understand and I agree to this storage and possible use of my samples.  
 
OR 
____ (initials) I understand but I do not agree to this storage and possible use of my samples. 
 
Research with Human Genetic Testing  
Your extra samples will not be used for human genetic testing.  
 
 
 

SAP_001.pdf: 
 
 
 
ACTG A5395 
Primary Statistical Analysis Plan 
 
Version 2.0 
 
A Randomized, Placebo-Controlled, Double-Blind, Trial to 
Evaluate the Efficacy of Hydroxychloroquine and Azithromycin 
to Prevent Hospitalization or Death in Persons with COVID-19 
 
Protocol Version 2.0 with CM #1 
 
ClinicalTrials.gov Identifier: NCT04358068  
 
May 13, 2020 
This is ACTG A5395 SAP Version 2.0 with names of authors, names of publication writing 
team members and analysis timeline redacted. Due to the early termination of the study, 
protocol objectives 1.3.2, 1.3.4, 1.4.3 and 1.4.4 were not pursued.


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 1 of 20 
 
 
Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
VERSION HISTORY ........................................................................................................................ 2 
1 
INTRODUCTION ........................................................................................................................ 3 
1.1 
Purpose ............................................................................................................................ 3 
1.2 
Key Updates to the SAP ................................................................................................. 3 
2 
STUDY OVERVIEW ................................................................................................................... 3 
2.1 
Study Design ................................................................................................................... 3 
2.2 
Hypothesis ....................................................................................................................... 3 
2.3 
Study Objectives ............................................................................................................. 4 
2.3.1 
Primary Objectives ............................................................................................... 4 
2.3.2 
Secondary Objectives .......................................................................................... 4 
2.3.3 
Exploratory Objectives ......................................................................................... 4 
2.4 
Overview of Sample Size Considerations .................................................................... 5 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 5 
3 
OUTCOME MEASURES ........................................................................................................... 6 
3.1 
Primary Outcome Measures .......................................................................................... 6 
3.2 
Secondary Outcome Measures ..................................................................................... 6 
4 
STATISTICAL PRINCIPLES ..................................................................................................... 9 
4.1 
General Considerations ................................................................................................. 9 
4.2 
Analysis Approaches ................................................................................................... 10 
4.2.1 
Analysis of the Primary Objective ...................................................................... 10 
4.2.2 
Analyses of Secondary Safety Objectives ......................................................... 12 
4.2.3 
Analyses of Secondary Efficacy Objectives ....................................................... 12 
4.3 
Interim Analyses ........................................................................................................... 15 
5 
REPORT CONTENTS ............................................................................................................. 15 
5.1 
Flow Diagram................................................................................................................. 15 
5.2 
Accrual and Eligibility .................................................................................................. 16 
5.3 
Baseline Characteristics .............................................................................................. 16 
5.4 
Study Status .................................................................................................................. 16 
5.5 
Study Treatment Status ................................................................................................ 16 
5.6 
Adverse Events ............................................................................................................. 18 
5.7 
Pregnancy ...................................................................................................................... 18 
5.8 
Mortality ......................................................................................................................... 18 
5.9 
Efficacy .......................................................................................................................... 18 
5.10 Subset Analyses (n=200) ............................................................................................. 19 
 


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 2 of 20 
 
 
 
Version History 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
05/08/2020 
2 
SAP update implemented prior to enrollment of any participants. 
Updates include: corrected typos and approaches to handle 
missing values when analyzing self-reported symptoms. 
5/13/2020 
 
 
 


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 3 of 20 
 
 
1 
Introduction 
1.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the proposed content for the primary 
statistical analysis report of ACTG A5395, which addresses the primary, secondary and a subset 
of exploratory objectives of the study. This document also describes the primary and secondary 
outcome measures for which results will be posted on ClinicalTrials.gov and that will be included 
in the primary manuscript. The Primary SAP outlines the general statistical approaches that will 
be used in the analysis of the study and has been developed to facilitate discussion of the 
statistical analysis components among the study team; and to provide agreement between the 
study team and statisticians regarding the statistical analyses to be performed and presented in 
the Primary Analysis Report.  
Analyses for the Primary Analysis Report will be finalized once the last participant has completed 
the Day 20 study visit, all queries on data through Day 20 have been resolved, and the study data 
has been frozen; details on the analysis timeline are located in Appendix 3. In addition, all primary 
and secondary outcomes outlined in this SAP will be submitted to ClinicalTrials.gov within 1 year 
of the Primary Completion Date (PCD); the PCD is defined as the day of the last “Day 20” 
evaluation among all study participants. 
Additional specifications including detailed outlines of tables, figures, and coding descriptions are 
included in the Analysis Implementation Plan (AIP).  
1.2 
Key Updates to the SAP 
The study will open under protocol version 2.0 with Clarification Memo #1; therefore, the first 
statistical analysis plan (version 1.0) is based on this protocol version.  
2 
Study Overview 
2.1 
Study Design 
A5395 is a phase IIB, double-blind, placebo controlled, randomized trial designed to compare the 
efficacy of hydroxychloroquine (HCQ) plus azithromycin (Azithro) versus placebo to prevent 
hospitalization and death in symptomatic adult outpatients with COVID-19.  
Eligible participants will receive study treatment for 7 days followed by 23 weeks of follow up. 
During this time, participants will be assessed for the primary outcome through Day 20, and will 
then have remote visits at week 12 and 24 for assessments of long-term outcomes. 
The study population consists of adults (≥ 18 years of age) with documented SARS-CoV-2 
infection who are experiencing at least one of fever, cough, or shortness of breath, but do not 
require hospitalization.  
2.2 
Hypothesis 
Hydroxychloroquine (HCQ) and Azithromycin (Azithro) will prevent hospitalization and death in 
persons with symptomatic SARS-CoV-2 infection. 


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 4 of 20 
 
 
2.3 
Study Objectives 
This Primary SAP addresses the following primary, secondary, and exploratory objectives listed 
in the study protocol. Other exploratory study objectives in the protocol will be addressed in 
subsequent analysis plans.  
2.3.1 
Primary Objectives 
To determine if HCQ and Azithro will prevent the composite endpoint of either 
hospitalization or death by 21 days after study entry. Hospitalization is defined as ≥24 
hours of acute care [Protocol Objective 1.2.1]. 
2.3.2 
Secondary Objectives 
1) To determine safety of HCQ and Azithro including 1) adverse events (AEs) leading to 
early discontinuation of treatment with HCQ and Azithro or 2) cardiac AEs [Protocol 
Objective 1.3.1]. 
 
2) To determine if HCQ and Azithro reduce the frequency of detection and levels of SARS-
CoV-2 RNA in site-collected collected nasopharyngeal (NP) swabs and self-collected 
swabs in subset of participants [Protocol Objective 1.3.2]. 
 
3) To determine if HCQ and Azithro change the severity and duration of self-reported 
symptom experience of COVID-19 [Protocol Objective 1.3.3]. 
 
4) To determine if HCQ and Azithro will prevent the composite endpoint of either 
hospitalization or death by 24 weeks after study entry. Hospitalization is defined as ≥24 
hours of acute care [Protocol Objective 1.3.4; this objective involves longer-term follow-
up and will be addressed as a supplement to the Primary Analysis Report] 
2.3.3 
Exploratory Objectives 
1) To explore differences in outcomes between HCQ and Azithro versus placebo treatment 
groups among subgroups of the population, notably by sex, race/ethnicity, and risk 
groups defined by age and comorbidities [Protocol Objective 1.4.3]. 
 
2) To explore possible predictors of outcomes across the study population, notably sex, 
race/ethnicity, and risk groups defined by age and co-morbidities [Protocol Objective 
1.4.4]. 
The other exploratory objectives in the protocol will be addressed in separate SAP(s). 
 
 


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 5 of 20 
 
 
2.4 
Overview of Sample Size Considerations 
The proposed sample size is 2000 participants who take the first (confirmed) dose of study 
treatment (approximately 1000 per arm). Participants who are randomized but do not take the first 
(confirmed) dose of study treatment will not be followed and will be replaced. This sample size 
has been chosen to provide 90% power to detect a relative reduction of 33.3% in the proportion 
of participants hospitalized/dying between the study arms (HCQ and Azithro vs placebo). This is 
based on the following assumptions: 
- 
Proportion hospitalized/dying in the placebo arm is 15%; 
- 
Two-sided test of two proportions with 5% Type I error rate; 
- 
Three interim analyses and one final analysis, equally spaced, with stopping guideline 
determined using the Lan-DeMets spending function approach with an O’Brien and 
Fleming boundary; 
- 
Allowance for 5% of participants to be lost-to-follow-up prior to being hospitalized or 
dying. 
Further details on the assumptions and sample size calculation are provided in protocol section 
10.4. 
2.5 
Overview of Formal Interim Monitoring 
A NIAID-appointed Data and Safety Monitoring Board (DSMB) will undertake reviews of interim 
data from the study to help ensure the safety of participants in the study, and to recommend 
changes to the study including termination or modification for safety reasons or if there is 
persuasive evidence of efficacy or lack of efficacy of HCQ and Azithro versus placebo in 
preventing hospitalizations and deaths. At each interim review, the DSMB will review summaries 
of data by unblinded randomized treatment arm for the primary outcome of hospitalization/death, 
losses to follow-up, adverse events, self-report of treatment cross-over, and the secondary 
outcomes of death, study treatment discontinuations (and associated reasons), duration of 
symptoms of COVID-19 and duration of fever. By-stratum summaries will also be reviewed. 
For monitoring the primary efficacy outcome, the O’Brien Fleming boundary will be used as the 
stopping guideline, implemented using the Lan-DeMets spending function. Because at early 
interim reviews the O’Brien Fleming boundary requires extreme p-values to demonstrate greater 
efficacy of the treatment arm compared to placebo, a nominal two-sided p-value of < 0.001 will be 
used. 
There will be a review of safety data by the DSMB when 250 participants have completed Day 20 
of follow-up. Unless otherwise recommended by the DSMB, interim efficacy analyses will occur 
weekly from when approximately 500 participants have been followed for the primary outcome 
assessed at Day 20. If the total number of hospitalizations or deaths is higher than anticipated, 
the first interim efficacy review may occur earlier than planned. This would occur when 
approximately 62 participants in the two arms combined have been hospitalized or have died (62 
is the expected number based on 15% hospitalizations/deaths in the placebo arm and 10% in the 
HCQ and Azithro arm, with an interim sample size of 500 participants). 


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 6 of 20 
 
 
In considering possible modifications to the study or termination of the study, the DSMB may 
consider other outcome measures besides the primary composite hospitalization/death outcome 
measure, or differences within subgroups. There is the possibility that differences between the 
treatment arms may be observed at an early study time point (for example cumulative proportion 
at Day 6); however, the overall goal of the study is to prevent hospitalization and deaths 
regardless of the timing, and therefore the focus of the treatment arm comparisons will be at Day 
20. 
The team does not recommend the DSMB monitor for statistical futility (i.e., stopping early for the 
absence of difference between arms). The DSMB will monitor operational futility. With respect to 
operational futility, the DSMB may recommend modification or termination of the study if the 
proportion hospitalized/dying in the control arm is low. In addition, the DSMB will monitor the loss 
to follow-up (LTFU) rate. As a benchmark, an overall LTFU rate of more than 10% would be 
cause for concern. The DSMB should also monitor the treatment crossover in the placebo arm by 
participant self-report and, if available, by PK levels of HCQ and Azithro. As a benchmark, a 
crossover rate of more than 10% in the placebo arm would be a cause for concern. 
Additional details on interim monitoring are provided in protocol section 10.5. 
3 
Outcome Measures 
All outcome measures are copied from the protocol. Additions, notes, and modifications to 
outcomes are shown in blue. 
3.1 
Primary Outcome Measures 
1) Death from any cause or hospitalization during the 21-day period from and including the 
day of the first (confirmed) dose of study treatment. [For Primary Objective] 
 
Hospitalization is defined as requiring at least 24 hours of acute care in a hospital or 
similar acute care facility, including Emergency Rooms or temporary facilities instituted to 
address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility 
with less than 24 hours of acute care is not considered a hospitalization.  
 
Note:  This will include a 24-hour hospitalization that is initiated on Day 20.  
3.2 
Secondary Outcome Measures 
1) Death from any cause during the 21-day period from and including the day of the first 
(confirmed) dose of study treatment. [Supplementary information for Primary Objective] 
 
2) Death from any cause, or hospitalization, or any urgent visit to an emergency room or 
clinic during the 21-day period from and including the day of the first (confirmed) dose of 
study treatment. [Supplementary information for Primary Objective] 
 
Note:  This outcome includes instances where participants required acute care for less 
than 24 hours.  


ACTG A5395 
Primary Statistical Analysis Plan 
 
Page 7 of 20 
 
 
 
3) Death from any cause or hospitalization during the 24-week period from and including the 
day of the first (confirmed) dose of study treatment. [For Secondary Objective 4, with 
follow-up beyond the PCD] 
 
Note: The definition of hospitalization is the same as the primary outcome. 
 
4) Premature discontinuation of study treatment due to an adverse event. [For Secondary 
Objective 1] 
 
Note:  Premature discontinuation of study treatment is defined as a permanent 
discontinuation of either study treatment (HCQ/Placebo and/or Azithro/Placebo). 
 
5) Occurrence of any cardiac adverse events from start of study treatment through Day 20. 
[For Secondary Objective 1]  
 
Note:  See Appendix 1 for list of applicable MedDRA codes. 
 
6) Any occurrence of fainting by self-report from participant’s daily diary cards from the time 
of starting treatment through Day 20. [For Secondary Objective 1] 
 
Fainting is collected as part of a set of targeted symptoms collected on participant daily 
diary cards, which are completed prior to starting treatment and then in the evening of 
each day from Day 0 to Day 20. Fainting is recorded as absent (score 0), mild (1), 
moderate (2), or severe (3); scores of > 0 are defined as occurrence of fainting. 
 
7) Duration of fever defined as the time from start of study treatment to the last day in the 
participant’s daily diary card on which a temperature greater than 100.40 F was recorded 
or a potentially anti-pyretic drug, such as acetaminophen or ibuprofen, was taken. Diary 
cards are completed at entry prior to starting treatment and then in the evening of each 
day from Day 0 to Day 20. [For Secondary Objective 3] 
 
 
 


ACTG A5395 
Primary Statistical Analysis Plan 
 
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8) Duration of symptoms associated with COVID-19 defined as the time from start of study 
treatment to the last day in the participant’s daily diary card on which a moderate or 
worse targeted symptom was recorded. Diary cards are completed at entry prior to 
starting treatment and then in the evening of each day from Day 0 to Day 20. [For 
Secondary Objective 3] 
 
The set of target symptoms are the same ones that are used in many influenza studies 
with the addition of the symptoms of loss of smell and loss of taste, which have been 
associated with COVID-19. The ones from influenza studies are: cough, shortness of 
breath, feeling feverish, fatigue, muscle aches, diarrhea, vomiting, nausea, headache, 
sore throat, nasal obstruction (stuffy nose), nasal discharge (runny nose). These 
symptoms are listed individually on the study diary that each participant will complete 
each day. The scoring is that used in influenza studies whereby participants grade each 
symptom as absent (score 0), mild (1), moderate (2), or severe (3). 
 
9) Participant-specific area under the curve (AUC) of the total symptom score associated 
with COVID-19 over time (through Day 20) defined as the sum of scores for the targeted 
symptoms (defined above) in the participant’s daily diary record (each individual symptom 
is scored from 0 to 3). Diary cards are completed at entry prior to starting treatment and 
then in the evening of each day from Day 0 to Day 20. [For Secondary Objective 3] 
 
Note: This outcome measure can be considered as a composite severity ordinal 
outcome, as information on hospitalization and death is incorporated with the symptom-
score-based AUCs for participants who did not die and were not hospitalized. 
 
10) Time to self-reported return to (pre-COVID) usual health defined as the time from start of 
study treatment to the first day in the participant’s daily diary card on which they reported 
Yes with no subsequent reports of No. Diary cards are completed at entry prior to starting 
treatment and then in the evening of each day from Day 0 to Day 20. [For Secondary 
Objective 3] 
 
11) SARS-CoV-2 RNA level (detectable versus not detectable) from self-collected nasal 
swabs at entry and days 6 and 20 among a subset of participants. [For Secondary 
Objective 2] 
 
12) SARS-CoV-2 RNA level (detectable versus not detectable) from site-collected NP swabs 
at entry and days 6 and 20 among a subset of participants. [For Secondary Objective 2] 
 
13) SARS-CoV-2 RNA level (continuous, reported as Cycle Number) from self-collected 
nasal swabs at entry and days 6 and 20 among a subset of participants. [For Secondary 
Objective 2] 
 
14) SARS-CoV-2 RNA level (continuous, reported as Cycle Number) from site-collected NP 
swabs at entry and days 6 and 20 among a subset of participants. [For Secondary 
Objective 2] 


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4 
Statistical Principles 
4.1 
General Considerations 
All analyses will include all randomized participants who received the first (confirmed) dose of 
study treatment according to a modified intent-to-treat approach (mITT), with the exception of 
analyses to address protocol objective 1.3.2, which will further be restricted to those in the subset 
who provided NP and/or nasal swabs. Participants who enroll, but do not receive their first 
(confirmed) dose of study treatment will not be included in any analyses.  
Study visit windows for reporting are as defined in the protocol. Key study visits are Entry (Day 0), 
Day 6 or 7, Day 20, and Week 24. Baseline is defined as the last available measure prior to the 
initiation of study treatment. 
Entry (Day 0): First dose of study treatment occurs.  
Day 6 or 7: 
Last day on study treatment.  
 
Note:  Depending on the timing of the first dose on Day 0 the last dose of 
study treatment may occur at the end of Day 6 or the beginning of Day 7 
Day 20: 
Last day primary outcome may occur. 
Week 24: 
Last study visit.  
Statistical comparison across treatment arms of baseline characteristics are not planned because 
the study is randomized and placebo-controlled; hence, any differences should reflect chance 
variation. 
Analyses of primary and secondary outcomes will not adjust for multiple comparisons. Analyses 
of primary outcomes will adjust for the multiple interim reviews using group sequential methods. 
Continuous variables will be summarized using median, interquartile range (Q1 and Q3), 10th and 
90th percentile, and min and max; categorical variables will be summarized using frequency and 
percentage. 
NIH requires the primary analyses of treatment comparisons to be summarized by sex/gender 
and by race/ethnicity and that treatment interactions with sex/gender and race/ethnicity be 
evaluated.  
 
 


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4.2 
Analysis Approaches 
4.2.1 
Analysis of the Primary Objective  
Analysis Population 
The analyses of the primary objective will include all randomized participants who received the 
first (confirmed) dose of study treatment according to a modified intent-to-treat (mITT) approach. 
Participants who start study treatment outside of the protocol-defined study windows (i.e. more 
than 96 hours from SARS-CoV-2 positive test) will be included; however, participants who enroll, 
but do not receive their first dose of study treatment will not be included in the analyses.  
Note: 
Participants who are randomized but do not take the first (confirmed) dose of study 
treatment are not to be followed and will be replaced.  
Analysis Methods 
The analysis of the primary outcome will compare the cumulative proportion of participants 
hospitalized or dying (from any cause), from Day 0 through to Day 20, between randomized arms 
using a ratio of proportions. For analysis purposes, the integer scale will be used as the time 
scale, where Study Day 0 is considered day 1 and Study Day 20 is considered day 21. The 
cumulative proportion will be estimated for each randomized arm in each risk stratum (based on 
stratification factor ‘high’ vs ‘low’ risk) using Kaplan-Meier methods to account for losses to follow 
up (and differential follow-up at the time interim reviews). Participants will have follow up 
censored at the date they were last known to be alive and not hospitalized through Day 20 (i.e. 
integer day 21). The primary analysis assumes non-informative censoring.  
Within each stratum, the absolute difference in the estimated log-cumulative proportion will be 
calculated between randomized arms; the variance for this difference will be obtained using 
Greenwood’s formula. The stratum-specific estimated differences will then be combined across 
strata, weighted by the inverse of the stratum-specific variance of the estimated difference, to 
obtain an overall estimate. Two-sided 95% confidence intervals (CIs) and p-value (for the test of 
no difference between arms) will be obtained, which adjust for the interim analyses; a nominal 
95% CI and p-value will also be provided. By-stratum estimates and corresponding nominal 95% 
CIs and nominal p-values will also be provided, and will not be adjusted for interim looks. 
Sensitivity Analyses of the Primary Outcome 
The following sensitivity analyses are included to evaluate impact of different assumptions on the 
inference of the primary treatment comparisons.  
1) Evaluate the composite outcome of being hospitalized, dying, or lost to follow up. 
Approach: Repeat the primary analysis, but assume all participants who prematurely 
discontinue the study prior to Day 20, who are unable to be contacted by the site 
to ascertain outcomes after discontinuation, had a primary event at Day 20.  


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2) Evaluate the impact of participants who delay starting study treatment (more than 96 hours 
after positive SARS-CoV-2 test, per protocol).  
 
Approach: Repeat primary analysis, but exclude participants who started study treatment 
more than 96 hours after the positive SARS-CoV-2 test, as defined in the 
protocol. 
 
 
3) Evaluate the impact of differential loss-to-follow-up.  
 
Approach:  In the event that differences are observed between the primary analysis and the 
first sensitivity analysis, the impact of participants being LTFU will be explored 
using inverse probability of censoring weights (IPCW). The primary analysis will 
be repeated but, within each arm, participants who are not loss to follow-up will 
be weighted using inverse probability of censoring weights (IPCW) determined by 
baseline variables that predict loss to follow up.  
 
4) Evaluate the impact of participants enrolling from the same household. 
Approach: Repeat the primary analysis only including the first participant who enrolled from 
each household.  
 
In the event that differences are observed between the primary analysis and this 
sensitivity analysis, analysis methods that account for clustering will be 
considered, if feasible. 
 
Subgroup Analyses of the Primary Outcome 
To evaluate the effect of treatment in specific populations, the primary outcome will be assessed 
among different subgroups. The same approaches outlined for the primary analysis will be 
implemented for each subgroup. The difference between treatment arms in the log-proportion will 
be estimated within subgroup, and compared between subgroups by determining the difference 
of the treatment differences. In the event that the proportion of participants in each subgroup is 
low, or the number of events are low, descriptive summaries of the number of hospitalizations 
and deaths will be done. Pre-specified subgroups of interest include: 
1) Sex (Male sex at birth, female sex at birth) 
2) Race (white, non-white) 
3) Ethnicity (Hispanic, non-Hispanic)  
4) ‘Risk of Severe Disease’ Strata (<60 years and no comorbidities, ≥ 60 years or at least 
one comorbidity) 
5) Age Group (<60, ≥60) 
6) Co-morbidity Status (no comorbidities, at least one comorbidity) 
7) Calendar days from first symptom associated with COVID-19 to start of study treatment 
(≤ median days, >median days) 


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Supportive Analyses of the Primary Outcome 
Secondary outcomes 1 and 2 are included as supportive to the primary outcome. The cumulative 
proportion of participants dying (from any cause) from Day 0 through to Day 20 (i.e. integer day 1 
through 21), and the cumulative proportion of participants dying (from any cause), hospitalized, or 
who had an urgent visit to an emergency room or clinic from Day 0 through to Day 20 (i.e. integer 
day 1 through 21), will be analyzed in the same manner as the primary outcome. 
Secondary outcome 3, which corresponds to secondary objective 1.3.4 from the protocol, will be 
analyzed as part a supplemental report (for 24 weeks of follow-up) in the same manner as the 
primary outcome. This outcome evaluates hospitalizations and deaths through week 24, and will 
censor participant follow-up at the date they were last known to be alive and not hospitalized 
through Study Day 167, which corresponds to integer day 168. 
4.2.2 
Analyses of Secondary Safety Objectives 
Premature discontinuation of study treatment due to an adverse event (tolerability), any 
occurrence of fainting by self-report from participant’s daily diaries from start of study treatment 
through Day 20, and occurrence of any cardiac adverse events from start of study treatment 
through Day 20 will be analyzed in the following manner. For each outcome, the proportion of 
participants who experienced each outcome will be estimated and compared between 
randomized arms using log-binomial regression, with log link and adjustment for a participant’s 
risk stratum, in order to obtain a risk ratio estimate. In the event the log-binomial regression 
model fails to converge, a Poisson regression model with robust variance and log-link will be 
used instead. 
The cardiac AEs included in this analysis are shown in Appendix 1 by MedDRA codes; these 
were chosen a priori by the study chairs.  
4.2.3 
Analyses of Secondary Efficacy Objectives 
Analyses of Symptom and Fever Duration 
Analyses of duration of fever, duration of symptoms, and time to self-reported return to usual 
health will be restricted to those who received first (confirmed) dose of study treatment (i.e., mITT 
population). However, duration of fever analyses will further restrict to those participants who ever 
reported a temperature reading from a thermometer.  
Duration of fever, duration of symptoms, and time to self-reported return to usual health will be 
summarized with descriptive statistics. Participant specific durations for each outcome will be 
compared between randomized arms using a two-sided Wilcoxon test stratified by risk stratum 
with a two-sided 5% type I error rate. 
Participants who never report fever or use of anti-pyretic medications will be assigned a duration 
of fever of zero days. A sensitivity analysis will define duration of fever as the time from start of 
study treatment to the last day in the participant’s daily diary card on which a temperature greater 
than 100.40 F was recorded, and will not make any special considerations for participants who 


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indicated use of potentially anti-pyretic drugs (i.e. will not include the use of a potentially anti-
pyretic drug in the definition). In this sensitivity analysis, those who never report fever will be 
assigned duration of fever of zero days.  
Participants who have missing diary cards due to death will be ranked as the worst outcome in 
these analyses. Participants who have missing diary records due to hospitalization will have: 
- 
Daily symptoms assumed to be at least moderate during hospitalization; 
- 
Self-reported return to usual health assumed to be No during hospitalization; 
- 
Fever assumed to be Yes during hospitalization. 
Participants who have missing diary cards not due to death or hospitalization will have all 
available data included in analysis and missing data will be ignored in the analyses of self-report 
return to usual health and fever duration; missing data in analyses of daily symptom will be 
interpolated based on the preceding and succeeding symptoms. 
Supplementary analyses will analyze duration of fever and symptoms using Kaplan-Meier 
methods. These analyses will compare the time to first day of two successive assessments 
without fever and time to first day of two successive assessments without moderate or severe 
symptoms between study arms using the Wilcoxon test stratified by risk stratum. These analyses 
will be restricted to participants who report fever or symptoms, respectively, at Day 0 on the pre-
treatment diary cards. Analyses using IPCW may be considered to account for LTFU. 
Analyses of Total Symptom Score 
Total symptom score will be calculated for each daily diary card for each person by summing the 
individual symptoms reported on the daily diary; symptom scores range from zero to three 
(0=absent, 1=mild, 2=moderate, 3=severe). Participant-specific areas under the curve (AUC) over 
time will be calculated using the trapezoidal rule and is defined as the area below the line formed 
by joining total symptom scores on each daily diary card from the pre-treatment score on Day 0 
through to Day 20. For analysis purposes, pre-treatment diary cards on Day 0 are assigned 
integer day 0; all post-treatment diary cards assigned integer days in the same manner as the 
primary analysis. The AUCs will be rescaled by time by dividing by 21, corresponding to (number 
of daily diary cards between pre-treatment Day 0 and Day 20), in order to provide results on a 
symptom scale from 0 to 42. Participant-specific AUCs will be compared between randomized 
arms using a two-sided Wilcoxon test stratified by risk stratum with a 5% type I error rate.  
Participants who are hospitalized or die between Day 0 and Day 20 will not have their AUC 
calculated. Participants who die will be ranked as having the worst AUC outcome in the analysis. 
All deaths will be ranked as the worst outcome regardless of when they occur between Day 0 and 
Day 20. Participants who are hospitalized will be ranked as having the next worse outcome 
(compared to death) in the analysis, with ranking determined based on the duration of 
hospitalization between Day 0 and Day 20; participants with the longest duration will be ranked as 
having worse outcomes than those with shorter durations.  Duration is defined as the number of 
days hospitalized that includes the day of admission and the day of discharge (i.e., possible 
range from 1 to 21 days) between Day 0 and Day 20. 


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Participants who have incomplete diary cards for reasons other than hospitalization or death will 
be handled in the following manner:  
1) Participants who are missing pre-treatment symptom scores will have their scores 
imputed as the mean pre-treatment total score among participants who have the same 
total symptom scores reported on the post-treatment Day 0 diary cards;  
2) Participants who have intermittent days with no symptom scores reported (i.e., all scores 
missing), the daily diary cards with missing scores will be ignored in AUC calculation, 
which is analogous to interpolating the total symptom scores; 
3) Participants who have diary cards with some, but not all symptoms scores reported, the 
missing symptoms scores will be interpolated based on the preceding and succeeding 
available scores for a given symptom; 
4) Participants who stop completing their symptom diaries before Day 20 will have their last 
total symptom score carried forward through Day 20, and their AUC calculation done as 
noted above. Methods such as multiple imputation or IPCW may be considered if more 
than 10% of participants in either arm stop completing their diaries before Day 20 for 
reasons other than death or hospitalization. 
Analyses of SARS-CoV-2 RNA 
These analyses will be conducted among the subset of participants who had nasal and/or NP 
swabs collected, respectively, and will include all participants who received first (confirmed) dose 
of study treatment. Sensitivity analysis will further restrict to those with detectable SARS-CoV-2 
RNA at Day 0. Analysis will be conducted separately for each swab type. SARS-CoV-2 RNA is 
quantified by the target cycle number (CN), which is the point in the PCR at which SARS-CoV-2 
virus is detected; the number of cycles is inversely related to the amount of virus. Assays will be 
run in batch after the primary completion date. 
The proportion of participants with detectable SARS-CoV-2 RNA will be compared between 
randomized arms using log-binominal regression with log-link and adjustment for risk stratum, 
pre-treatment (Day 0) SARS-CoV-2 CN. For each time point (Day 6 or Day 20), the model will 
include main effects for treatment arm and time, and an interaction between time and treatment to 
evaluate differences between arms. In addition, a joint test of treatment across the two time 
points (2 degrees of freedom) will also be assessed. This model will be fitted using generalized 
estimating equations (GEE) to handle the repeated measurements with unstructured covariance 
matrix. With this model, the comparison between randomized arms will use a two-sided Wald-test 
with 5% type I error rate. 
Non-parametric Wilcoxon rank-sum tests stratified by risk stratum with a 5% type I error rate will 
compare SARS-CoV-2 RNA cycle numbers (continuous) between randomized arms, separately 
at Day 6 and Day 20; results without cycle numbers due to target not detected will be imputed as 
the highest rank. A composite test, simultaneously analyzing Day 6 and Day 20 data will also be 
performed (DeLong ER, DeLong DM, Clarke-Pearson DL. Biometrics. 1988 Sep 1:837-45).  
Missing data are assumed to be missing completely at random (MCAR) and will be ignored in 
analysis. Sensitivity analyses will address possible informative missingness. In particular, results 


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that are missing due to participant hospitalization or death will be imputed as detectable in the 
dichotomous analysis and as the lowest rank the continuous analysis. 
4.3 
Interim Analyses 
The Therapeutics and Prevention DSMB will review interim data from the study including 
descriptive summaries of study conduct and adverse events, and efficacy analyses that contrast 
treatment arms. The primary outcome of death or hospitalization will be compared between 
treatment arms using the statistical methods outlined in this SAP; the secondary outcome of 
death from any cause will be also be compared between treatments arms. Interim efficacy 
analyses are planned to occur weekly from when approximately 500 participants have been 
followed for the primary outcome assessed at Day 20, or earlier if the total number of 
hospitalizations or deaths is higher than anticipated (See SAP Section 2.5 or Protocol Section 
10.5).  
At each interim review, the stopping boundary for the primary analysis will be determined based 
on the proportion of planned maximum information that is available at the given review. The 
statistical information (Fisher’s Information) at a given review will be calculated using the inverse 
of the variance (square of standard error) obtained from Greenwood’s formula as part of the 
primary analysis. The maximum information will be pre-determined using the following formula 
(Tsiatis AA. Statistics in medicine. 2006 Oct 15;25(19):3236-44): 
 
𝑀𝐼= {
(𝑍𝛼/2+𝑍𝛽)
2
𝛿𝐴
2
} ∗(𝐼𝑛𝑓𝑙𝑎𝑡𝑖𝑜𝑛 𝐹𝑎𝑐𝑡𝑜𝑟) = 
(1.96+1.28)2
{ln(0.10
0.15)}
2 ∗1.03 = 65.8. 
However, at early interim reviews, where the O’Brien Fleming spending function is particularly 
extreme, a nominal two-sided p-value of <0.001 will be used instead.  
The interim efficacy analyses will also include two sensitivity analyses. The first will evaluate the 
potential impact of delayed ascertainment of the primary endpoint, as requested by the DSMB 
and using an approach suggested by a DSMB statistician (personal correspondence A.A. Tsiatis). 
The second will assume all participants who prematurely discontinue the study prior to Day 20, 
who are unable to be contacted by the site to ascertain outcomes after discontinuation, had a 
primary event at Day 20. 
5 
Report Contents 
Note: Tables in the primary analysis report will summarize outcomes overall, by treatment arm, 
and by risk strata as appropriate.  
5.1 
Flow Diagram 
 
CONSORT (Flow) diagram including: 
o 
Number of individuals screened; 
o 
Number of participants enrolled/randomized and reasons why participants did not 
enroll; 


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o 
Number of participants who started study treatment and reasons why participants 
did not start treatment; 
o 
Number of participants who discontinued study treatment and study prematurely 
with reasons why. 
5.2 
Accrual and Eligibility 
 
Summary of number participants enrolled by week and site; 
 
Summary of number participants who started treatment by week and site; 
 
Summary of participants with eligibility violations. 
5.3 
Baseline Characteristics 
 
Summary of age (including <60 vs ≥ 60), sex, gender identity, race, ethnicity; 
 
Summary of risk stratification (stratification factor “high” vs “low”); 
 
Summary of comorbidities (defined in protocol section 6.3.4); 
 
Summary of smoking status including cigarettes, cigars, vaping, and marijuana; 
 
Summary of pregnancies; 
 
Summary of COVD-19 symptoms: 
o 
Duration of symptoms prior to start of study treatment 
o 
First symptoms (self-report) 
o 
Symptoms at screening: fever, cough and/or shortness of breath; 
 
Summary of number of participants from same household; 
 
Summary of symptom scores from participant diaries collected prior to starting treatment; 
 
Summary of concomitant medication(s) used at entry obtained from participant diaries; 
collected prior to starting treatment. 
5.4 
Study Status 
 
Summary of participants on vs. off study; 
 
Summary of premature study discontinuations with reasons; 
 
Summary of follow-up time (Day 0 to last contact). 
5.5 
Study Treatment Status 
 
Summary of reasons for not starting study treatment; 
 
Summary of days from randomization to first dose of study treatment; 
 
Summary of participants on vs. off study treatment; 
 
Summary of premature treatment discontinuations with reasons: 
o 
Secondary Safety [Protocol Objective 1.3.1]: Proportion of participants who 
discontinued study treatment due to AE will be compared between arms as noted 
in SAP section 4.2.2;  
 
Summary of treatment adherence including: 
o 
Summary of number of missed doses of HCQ and Azithro overall and by study 
day with reasons; 


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 
Summary of self-reported use of HCQ and/or Azithro. 
 
 


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5.6 
Adverse Events 
 
Summary of all new, post-entry reportable AEs by MedDRA code: 
o 
All grade 3 or higher AEs 
o 
All cardiac AEs regardless of grade 
o 
All AEs that led to a change in study treatment regardless of grade 
o 
All AEs meeting SAE definition or EAE reporting requirement; 
 
Summary of cases of torsade de pointes (TdP), all ventricular arrhythmias, and sudden 
cardiac deaths: 
o 
Defined as events with higher level group terms (HLGTs): 10000032, 10037908, 
10047283, or deaths with primary cause of death field including sudden death on 
the eCRF; 
 
Secondary Safety [Protocol Objective 1.3.1]: Proportion of participants who experienced 
a cardiac AE (defined in Appendix 1) and proportion of participants who self-report 
fainting will be compared between arms as noted in SAP section 4.2.2. 
5.7 
Pregnancy  
 
Summary of individuals who are pregnant at entry and who become pregnant while on 
study, including days/weeks from Day 0, risk stratum, pregnancy outcomes, and maternal 
adverse events. 
5.8 
Mortality 
 
Summary of number of deaths, primary cause of death, time from Day 0 to death, risk 
stratum, and demographics; 
 
Secondary Efficacy [Supplementary for Primary Objective]: Proportion of participants 
dying from any cause will be compared between treatment arms as noted in SAP section 
4.2.1. 
5.9 
Efficacy  
 
Primary Efficacy [Protocol Objective 1.2.1]: Proportion of participants hospitalized or 
dying from any cause will be compared between treatment arms as noted in SAP section 
4.2.1. This analysis includes sensitivity, supportive, and subgroup analyses; 
 
Secondary Efficacy [Protocol Objective 1.3.3]: Summary of duration of fever, symptoms 
and time to self-report return to usual health will be compared between randomized arms 
as noted in SAP section 4.2.3; 
 
Secondary Efficacy [Protocol Objective 1.3.3]: AUC of total symptom score over time will 
be compared between randomized arms as noted in SAP section 4.2.3. 
 
 


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5.10 
Subset Analyses (n=200) 
 
Baseline Characteristics: 
o 
Repeat those outlined in section 5.3 among the subset 
o 
Summary of baseline laboratory values; 
 
Study Status: 
o 
Repeat those outlined in section 5.4; 
 
Study Treatment Status: 
o 
Summary of reasons for not starting study treatment 
o 
Summary of days from randomization to first dose of study treatment 
o 
Summary of participants on vs. off study treatment with reasons 
o 
Summary of treatment adherence including number of missed doses by study 
day, with reasons 
o 
Summary of self-reported use of HCQ and/or Azithro; 
 
Mortality and Hospitalization: 
o 
Summary of number of deaths, primary cause of death, time from Day 0 to death, 
risk stratum, and demographics 
o 
Summary of number of participants hospitalized; 
 
Symptoms: 
o 
Summary of duration of fever, symptoms and time to self-report return to usual 
health; 
 
Efficacy: 
o 
Secondary Efficacy [Protocol Objective 1.3.2]: Proportion of participants with 
detectable SARS-CoV-2 RNA and distribution of SARS-CoV-2 RNA levels 
summarized by CN will be compared between randomized arms in the subset of 
participants with NP and nasal swabs as noted in SAP section 4.2.3. 
 
 
 


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Appendix 1 
Cardiac Adverse Events 
The following Cardiac AEs were identified a priori by the study chairs to be included in the 
analyses of Secondary Objective 1. All AEs are described using MedDRA coding, and fall under 
the SOC Cardiac Disorders (SOC: 10007541).  
 
Level 
Code 
Term 
HLGT 
10007521 
Cardiac arrhythmias 
HLGT 
10011082 
Coronary artery disorders 
HLGT 
10019280 
Heart failures 
HLGT 
10028593 
Myocardial disorders 
HLGT 
10034468 
Pericardial disorders 
HLGT 
10046973 
Cardiac valve disorders 
HLGT 
10082206 
Cardiac disorders, signs and symptoms NEC 
 
Among Endocardial Disorders (HLGT 10014662): 
HLT 
10014660 
Endocardial disorders NEC 
HLT 
10014686 
Endocardial viral infections