Conditions: Coronavirus Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
This Phase III trial four treatment strategies non-critically ill hospitalized participants (not requiring intensive care unit (ICU) admission and/or mechanical ventilation) with SARS CoV-2 infection, Participants will receive hydroxychloroquine or chloroquine with or without azithromycin.

Detailed description:
This Phase III trial will utilize four treatment strategies in non-critically ill hospitalized participants (not requiring mechanical ventilation) with SARS CoV-2 infection, Participants will receive hydroxychloroquine or chloroquine with or without azithromycin. Investigators are primarily interested in the time to recovery. In addition to study medications there will be daily symptom surveys for 14 days, then weekly thereafter for 4 weeks resulting in a total duration of follow up of 42 days. During hospitalization, daily symptom surveys will be completed in conjunction with the study coordinators. On discharge participants will have the option to complete electronic symptom surveys or complete symptom surveys via telephone with study coordinator. In the event that the participant opts for electronic symptom surveys on discharge participants will in addition receive a follow up call from a study coordination every 7 days during the initial 14 day period. In addition, failure to submit a symptom survey will prompt a study follow up call. Data from standard of care SOC will be collected from medical records.

Arms:
arm 1: Arm 1: Hydroxychloroquine 400mg orally twice a day for one day, followed by 200mg twice a day for four consecutive days (Five days in total). The drug will be supplied in 200mg tablets. arm 2: Arm 2: Hydroxychloroquine 400mg orally twice a day for one day, followed by 200mg twice a day for four consecutive days (Five days in total). The drug will be supplied in 200mg tablets.

AND Azithromycin 500mg orally once, followed by 250mg daily for four consecutive days (five days total). The drug will be supplied in 250mg tablets. arm 3: Arm 3: Chloroquine phosphate 1000mg orally once, followed in 12 hours by 500mg, then 500mg orally twice daily for 4 days (Five days in total). The drug will be supplied in 500mg tablets. arm 4: Arm 4: Chloroquine phosphate 1000mg orally once, followed in 12 hours by 500mg, then 500mg orally twice daily for 4 days (Five days in total). The drug will be supplied in 500mg tablets.

AND Azithromycin 500mg orally once, followed by 250mg daily for 4 consecutive days (5 days total).The drug will be supplied in 250mg tablets.

Interventions: intervention 1: Hydroxychloroquine Sulfate intervention 2: Azithromycin intervention 3: Chloroquine Sulfate
Intervention descriptions: intervention 1: anti-rheumatic drug (DMARD) intervention 2: Antibiotic intervention 3: Antimalarial

Protocol document:
Prot_SAP_001.pdf: 
 
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Open-label, randomized clinical trial of hydroxychloroquine alone or hydroxychloroquine 
plus azithromycin or chloroquine alone or chloroquine plus azithromycin in the treatment 
of SARS CoV-2 infection  
 
Version Number: 2.0 
March 30 2020 
 
 


 
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STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
U.S. Code of Federal Regulations applicable to clinical studies (45 CFR 46) 
 
21 CFR 312 
 
ICH GCP E6 
 
Completion of Human Subjects Protection Training 
 
 


 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this clinical study will be conducted according to all stipulations 
of the protocol, including all statements regarding confidentiality, and according to local legal 
and regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
 
Signed: ___________________________________________________ Date________ 
              Jane O’Halloran 
              Investigator, Washington University


 
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PROTOCOL TEAM ROSTER  
 
Chair/Principal Investigator:  
 
 
Jane O’Halloran MD, PhD 
Assistant Professor of Medicine 
Washington University School of Medicine 
Infectious Disease Clinical Research Unit 
620 South Taylor, Suite 200 
St. Louis, MO 63110 
Phone: (314) 286-0345 
Fax: (314)361-5231 
E-mail: janeaohalloran@wustl.edu 
 
Co-Chair 
Rachel Presti, MD, PhD 
Associate Professor of Medicine 
Washington University School of Medicine 
Infectious Disease Clinical Research Unit 
620 South Taylor, Suite 200 
St. Louis, MO 63110 
Phone: (314) 286-0345 
Fax: (314)361-5231 
E-mail: rpresti@wustl.edu 
 
Statistician 
Charles W. Goss 
Instructor in Biostatistics 
Washington University School of Medicine 
Division of Biostatistics 
Phone: (314) 362-4438 
E-mail: cwgoss@wustl.edu 
 
Data Manager 
Rachel Komeshak 
IT Project Manager II,  
Institute for Informatics 
4444 Forest Park Blvd 0635 
komeshak@wustl.edu 
 
 
Investigational Pharmacist 
Kristopher Bakos DPh 
Department of Pharmacy,  
Barnes-Jewish Hospital 
425 South Euclid Avenue  
St. Louis, MO 63110 


 
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Office: (314) 362-9577 
Mobile:(314).363-9184  
Fax: (314) 747-1747  
Kristopher.Bakos@bjc.org 
 
Michael K. Klebert Ph.D. R.N. ANP-BC 
Study Coordinator/Research Instructor 
Washington University School of Medicine 
Infectious Disease Clinical Research Unit 
620 South Taylor, Suite 200 
St. Louis, MO 63110 
Phone: (314) 747-1098 
Fax: (314)361-5231 
E-mail: mklebert@wustl.edu 
 
 
 
 
 
 


 
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Open-label, randomized clinical trial of hydroxychloroquine alone or hydroxychloroquine 
plus azithromycin or chloroquine alone or chloroquine plus azithromycin in the treatment 
of SARS CoV-2 infection  
 
 
 
PROTOCOL SUMMARY 
 
 
Subjects:  Non-ventilated hospitalized participants with SARS-CoV-2 infection 
 
Study Site: Washington University in St Louis/ Barnes Jewish Hospital  
 
Study Duration:  2 years 
 
Number of subjects: 500 
 
Subject Participation Duration:  6 weeks   
 
Description of Study Design: Open-label block randomized study with four arms:  
Arm 1. Hydroxychloroquine alone 
Arm 2. Hydroxychloroquine plus azithromycin  
Arm 3. Chloroquine alone 
Arm 4. Chloroquine plus azithromycin 
 
Primary 
1. Time (hours) from randomization to recovery defined as 1) absence of fever, as 
defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever-
reducing medications AND 2) absence of symptoms of greater than mild severity for 
24 hours AND 3) not requiring supplemental oxygen beyond pre-COVID baseline 
AND 4) freedom from mechanical ventilation or death 
Secondary 
1. Time to resolution of fever defined as at least 48 hours since last temperature ≥ 
38.0°C without the use of fever-reducing medications  
2. Time to improvement in symptoms (scored as mild or absent and remained so for 24 
hour)  
3. Mean improvement in symptom from baseline 
4. Duration of hospitalization  
5. Proportion requiring supplementary oxygen (above baseline usage) at any time 
during follow-up 
6. Duration (days) of requirement for supplementary oxygen  
7. Proportion requiring ICU admission at any time during follow-up 
8. Proportion requiring mechanical ventilation at any time during follow-up 
9. Ventilator free days 
10. All-cause mortality 


 
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BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Coronavirus disease 19 (COVID-19) is a rapidly emerging pandemic caused by severe acute 
respiratory syndrome coronavirus 2 (SARS CoV-2). At the time of writing, over half a million 
people have tested positive for the virus, approximately one sixth of those are located in the US 
with the numbers steadily rising. At present the overall case fatality rate is estimated between 2-
7% with significant variation reported between settings1. The most common symptoms are 
fever, a non-productive cough, malaise and shortness of breath2. The rapid emergence of the 
syndrome globally in combination with a population that does not appear to have any previous 
exposures has led to a rapid utilization of healthcare resources.  In many hardest hit locations 
this has led to rationing of healthcare, and a severe strain of healthcare workers as they 
struggle to provide care to a significantly increased patient caseload.3  
 
At present there are no approved drugs for the management of SARS CoV-2 although a number 
of trials worldwide are actively recruiting. Several candidate drugs have been identified through 
data derived from the SARS CoV outbreak in the early 2000s as potential candidates for 
treatment of SARS-CoV-2 and have limited preliminary data for their use in SARS CoV-2 
infection. Both Chloroquine and hydroxychloroquine have in vitro activity against SARS-CoV-24 
and have been used extensively in the past for management of other medical conditions 
including autoimmune disorders and malaria prophylaxis and treatment. However, despite the 
limited data on the clinical benefit of these agents many international and regional guidelines 
are recommending their use1. Recent limited reports from China showed that chloroquine can 
shorten symptoms, as well as reduce viral load5,6 In a small French study, a combination of 
hydroxychloroquine and azithromycin reportedly appeared to be superior to hydroxychloroquine 
alone however the data was generated from a very small trial6. 
 
Based on pre-clinical evidence of effectiveness and evidence of safety from long-time clinical 
use for other indications, we propose to perform a phase III trial of hospitalized non-ventilated 
participants to assess if hydroxychloroquine and chloroquine in combination with azithromycin 
vs each drug alone improves the time to symptom resolution.  
 
STUDY AIMS/ENDPOINTS  
Primary 
1. Time (hours) from randomization to recovery defined as 1) absence of fever, as 
defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever-
reducing medications AND 2) absence of symptoms of greater than mild severity for 
24 hours AND 3) not requiring supplemental oxygen beyond pre-COVID baseline 
AND 4) freedom from mechanical ventilation or death 
Secondary 
1. Time to resolution of fever defined as at least 48 hours since last temperature ≥ 
38.0°C without the use of fever-reducing medications  


 
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2. Time to improvement in symptoms (scored as mild or absent and remained so for 24 
hour)  
3. Mean improvement in symptom from baseline 
4. Duration of hospitalization  
5. Proportion requiring supplementary oxygen (above baseline usage) at any time 
during follow-up 
6. Duration (days) of requirement for supplementary oxygen  
7. Proportion requiring ICU admission at any time during follow-up 
8. Proportion requiring mechanical ventilation at any time during follow-up 
9. Ventilator free days 
10. All-cause mortality 
 
Exploratory 
1. COVID-19 specific mortality 
2. Number of patients with diagnosed cardiomyopathy 
3. Number of patients with new onset arrhythmia 
 
STUDY DESIGN 
This Phase III trial will utilize four treatment strategies in non-critically ill participants (not 
requiring ICU admission and/or mechanical ventilation) with SARS CoV-2 infection, Participants 
will receive hydroxychloroquine or chloroquine with or without azithromycin. The primary 
outcome will be time from randomization to recovery 
Enrollment 
Hospitalized patients with documented SARS CoV-2 infection will be screened for study 
eligibility. If eligible, consenting participants will be randomized to one of the four arms. Up to 
125 participants will be recruited for each of the study groups, with a planned total enrollment of 
500 participants. Participants will be randomized to either one of the following arms in a 1:1:1:1 
manner. Drugs will be provided by the BJC investigational pharmacy using standardized Epic 
order sets.  If participants are discharged, we will coordinate with the investigational pharmacy 
services to ensure that participants receive the full course of therapy. 
 
Arm 1: Hydroxychloroquine 400mg orally twice a day for one day, followed by 200mg twice a 
day for four consecutive days (Five days in total). The drug will be supplied in 200mg tablets. 
Arm 2: Hydroxychloroquine 400mg orally twice a day for one day, followed by 200mg twice a 
day for four consecutive days (Five days in total). The drug will be supplied in 200mg tablets. 
AND 
Azithromycin 500mg orally once, followed by 250mg daily for four consecutive days (five days 
total). The drug will be supplied in 250mg tablets. 
 
Arm 3: Chloroquine phosphate 1000mg orally once, followed in 12 hours by 500mg, then 
500mg orally twice daily for 4 days (Five days in total). The drug will be supplied in 500mg 
tablets. 


 
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Arm 4: Chloroquine phosphate 1000mg orally once, followed in 12 hours by 500mg, then 
500mg orally twice daily for 4 days (Five days in total). The drug will be supplied in 500mg 
tablets. 
AND 
Azithromycin 500mg orally once, followed by 250mg daily for 4 consecutive days (5 days total). 
The drug will be supplied in 250mg tablets. 
 
 


 
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SUBJECT INCLUSION CRITERIA 
 
 
Hospitalization for management of SARS CoV-2 infection  
 
Positive SARS CoV-2 test 
 
Age >=18 years 
 
Provision of informed consent 
 
Electrocardiogram (ECG) ≤48 hours prior to enrollment  
 
Complete blood count, glucose-6 phosphate-dehydrogenase (G6PD), comprehensive 
metabolic panel and magnesium ≤48 hours prior to enrollment from standard of care.  
 
If participating in sexual activity that could lead to pregnancy, individuals of reproductive 
potential who can become pregnant must agree to use contraception throughout the 
study. At least one of the following must be used throughout the study: 
o Condom (male or female) with or without spermicide 
o Diaphragm or cervical cap with spermicide 
o Intrauterine device (IUD) 
o Hormone-based contraceptive 
SUBJECT EXCLUSION CRITERIA 
 
● Contraindication or allergy to chloroquine,  hydroxychloroquine or azithromycin 
● Current use hydroxychloroquine, chloroquine or azithromycin 
● Concurrent use of another investigational agent 
● Invasive mechanical ventilation 
● Participants  who have any severe and/or uncontrolled medical conditions such as: 
○ unstable angina pectoris, 
○ symptomatic congestive heart failure, 
○ myocardial infarction, 
○ cardiac arrhythmias or know prolonged QTc >470 males, >480 female on ECG 
○ pulmonary insufficiency, 
○ epilepsy (interaction with chloroquine), 
●    Prior retinal eye disease 
●    Concurrent malignancy requiring chemotherapy 
●    Known Chronic Kidney disease, eGFR<30 or dialysis 
●    G-6-PD deficiency, if unknown requires G6PD testing prior to enrollment 
 
Known Porphyria 
 
Known myasthenia gravis 
 
Currently pregnant or planning on getting pregnant while on study 
 
Breast feeding 
 
AST/ALT >five times the upper limit of normal ULN* 
 
Bilirubin >five times the ULN* 
 
Magnesium <1.4 mEq/L* 
 
Calcium <8.4mg/dL >10.6mg/dL* 
 
Potassium <3.5 >5.5 mEg/L* 
●  Current concomitant use of contraindicated drugs including antiarrhythmics, 
antidepressant, anticonvulsants (see Appendix 2 for full list)  
*Patients who do not meet laboratory criteria may be rescreened within 48 hrs. 


 
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Discontinuation criteria 
 
Discontinuation of treatment 
• 
Lack of efficacy, defined as deterioration of the clinical condition or delayed response 
requiring, in the opinion of the investigator, alternative therapy 
• 
Occurrence of an AE that, in the opinion of the investigator, warrants discontinuation of 
the subject from the study drug 
• 
Pregnancy 
 
Discontinuation of study participation 
• 
Withdrawal of consent;  
• 
Investigator or Sponsor decision that withdrawal is in the subject’s best interest  
• 
Lost to follow up (every attempt should be made to contact the subject). Three attempts 
will be made to contact participants electronically or by phone. If unsuccessful, a letter 
will be sent to the participant to encourage follow up. Thereafter if a response is not 
received in 14 days the participant will be considered lost to follow up. 
POTENTIAL RISKS AND BENEFITS 
Potential risks:  
Drug associated risks  
 
Risks of chloroquine: 
The following adverse reactions have been identified during post-approval use of Chloroquine or 
other 4-aminoqunoline compounds. Because these reactions are reported voluntarily from a 
population of uncertain size, it is not always possible to reliably estimate their frequency or 
establish a causal relationship to drug exposure. 
 
Ocular disorders: Maculopathy and macular degeneration have been reported and may be 
irreversible. Irreversible retinopathy with retinal pigmentation changes (bull’s eye appearance) 
and visual field defects (paracentral scotomas) in patients receiving long-term or high-dosage 4-
aminoquinoline therapy have been reported. Visual disturbances (blurring of vision and difficulty 
of focusing or accommodation); nyctalopia; scotomatous vision with field defects of paracentral, 
pericentral ring types, and typically temporal scotomas (e.g., difficulty in reading with words 
tending to disappear, seeing half an object, misty vision, and fog before the eyes) have been 
reported. Reversible corneal opacities have also been reported. 
Immune system disorders: Urticaria, anaphylactic reaction including angioedema. 
Ear and labyrinth disorders: Nerve type deafness; tinnitus, reduced hearing in patients with 
preexisting auditory damage. 
Musculoskeletal and connective tissue-disorders: Sensorimotor disorders, skeletal muscle 
myopathy or neuromyopathy leading to progressive weakness and atrophy of proximal muscle 
groups, depression of tendon reflexes and abnormal nerve conduction. 
Gastrointestinal disorders: Hepatitis increased liver enzymes, anorexia, nausea, vomiting, 
diarrhea, abdominal cramps. 
Skin and subcutaneous tissue disorders: Erythema multiforme, Stevens-Johnson syndrome, 
toxic epidermal necrolysis, exfoliative dermatitis. Pleomorphic skin eruptions, skin and mucosal 


 
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pigmentary changes; lichen planus-like eruptions, pruritus,; drug rash with eosinophilia and 
systemic symptoms (DRESS syndrome); photosensitivity and hair loss and bleaching of hair 
pigment. 
Blood and lymphatic system disorders: Pancytopenia, aplastic anemia, reversible 
agranulocytosis, thrombocytopenia and neutropenia. Hemolytic anemia in G6PD deficient 
patients. 
Nervous system disorders: Convulsions, mild and transient headache, polyneuropathy, acute 
extrapyramidal disorders (such as dystonia, dyskinesia, tongue protrusion, torticollis). 
Neuropsychiatric disorders: Neuropsychiatric changes including psychosis, delirium, anxiety, 
agitation, insomnia, confusion, hallucinations, personality changes, depression, and suicidal 
behavior. 
Cardiac disorders: Hypotension, electrocardiographic changes (particularly, inversion or 
depression of the T-wave with widening of the QRS complex), and cardiomyopathy (which may 
result in cardiac failure and in some cases a fatal outcome). 
Cardiac arrhythmias, conduction disorders such as bundle branch block / atrio-ventricular block, 
QT interval prolongation, torsade de pointes, ventricular tachycardia and ventricular fibrillation 
have been reported with therapeutic doses of Chloroquine as well as with overdose. The risk is 
greater if Chloroquine is administered at high doses. Fatal cases have been reported. 
Metabolic and Nutritional disorders: Hypoglycemia. 
Risk of overdose: Chloroquine is very rapidly and completely absorbed after ingestion. Toxic 
doses of Chloroquine can be fatal. As little as 1 g may be fatal in children. Toxic symptoms can 
occur within minutes. The symptoms of overdosage may include nausea, vomiting, headache, 
drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and 
conduction disorders including QT prolongation, torsades de pointes, ventricular tachycardia 
and ventricular fibrillation, followed by sudden potentially fatal respiratory and cardiac arrest. 
Immediate medical attention is required, as these effects may appear shortly after the overdose. 
Cases of extrapyramidal disorders have also been reported in the context of Chloroquine 
overdose. 
 
Risks of hydroxychloroquine 
Rare (1% to 10%):  
Vision loss due to retinopathy which may be irreversible 
 
Frequency not defined: 
Central nervous system: Ataxia, dizziness, emotional disturbance, emotional lability, headache, 
irritability, lassitude, nervousness, nightmares, psychosis, seizure, sensorineural hearing loss, 
suicidal tendencies, vertigo 
Dermatologic: Acute generalized exanthematous pustulosis, alopecia, bleaching of hair, bullous 
rash, dyschromia (skin and mucosal; black-blue color), erythema multiforme, erythema of skin 
(annulare centrifugum), exacerbation of psoriasis (nonlight sensitive), exfoliative dermatitis, 
lichenoid eruption, maculopapular rash, morbilliform rash, pruritus, skin photosensitivity, 
Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria 
Endocrine & metabolic: Exacerbation of porphyria, weight loss 
Gastrointestinal: Anorexia, diarrhea, nausea, stomach cramps, vomiting 
Hematologic & oncologic: Agranulocytosis, anemia, aplastic anemia, hemolysis (in patients with 
glucose-6-phosphate deficiency), leukopenia, purpuric rash, thrombocytopenia 
Hepatic: Acute hepatic failure (rare), hepatic insufficiency (rare) 
Hypersensitivity: Angioedema 


 
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Neuromuscular & skeletal: Myopathy (including palsy or neuromyopathy, leading to progressive 
weakness and atrophy of proximal muscle groups; may be associated with mild sensory 
changes, loss of deep tendon reflexes, and abnormal nerve conduction) 
Ophthalmic: Accommodation disturbance, corneal changes (transient edema, punctate to lineal 
opacities, decreased sensitivity, deposits, visual disturbances, blurred vision, photophobia 
[reversible on discontinuation]), decreased visual acuity, macular edema, nystagmus disorder, 
optic disc disorder (pallor/atrophy), retinal pigment changes, retinal vascular disease 
(attenuation of arterioles), retinitis pigmentosa, scotoma, vision color changes, visual field defect 
Otic: Tinnitus 
Respiratory: Bronchospasm 
 
<1%, postmarketing, and/or case reports: Cardiomyopathy, epithelial keratopathy (Dosso 2007), 
hypoglycemia (Cansu 2008; Unübol 2011), macular degeneration, maculopathy 
 
Risks of azithromycin: 
Common (>10%):  
Gastrointestinal: Loose stools (≤14%; single-dose regimens tend to be associated with 
increased incidence), vomiting (children, single-dose regimens tend to be associated with 
increased incidence: 1% to 14%; adults: ≤2%; adults, single 2 g dose: 1% to 7%), diarrhea (2% 
to 9%; single-dose regimens 4% to 14%), nausea (≤7%; high single-dose regimens 4% to 18%) 
 
Rare (1% to 10%): 
Cardiovascular: Chest pain (≤1%), palpitations (≤1%) 
Central nervous system: Dizziness (≤1%), drowsiness (≤1%), fatigue (≤1%), headache (≤1%), 
vertigo (≤1%) 
Dermatologic: Skin rash (≤5%; single-dose regimens tend to be associated with increased 
incidence), dermatitis (children: ≤2%), pruritus (≤2%), skin photosensitivity (≤1%) 
Endocrine & metabolic: Increased lactate dehydrogenase (1% to 3%), increased gamma-
glutamyl transferase (1% to 2%), increased serum potassium (1% to 2%), decreased serum 
bicarbonate (adults: ≥1%), decreased serum glucose (adults: >1%) 
Gastrointestinal: Abdominal pain (1% to 7%; single-dose regimens tend to be associated with 
increased incidence), anorexia (≤2%), dysgeusia (≤1%), dyspepsia (≤1%), flatulence (≤1%), 
gastritis (≤1%), melena (adults, multiple-dose regimens: ≤1%), mucositis (≤1%), oral candidiasis 
(≤1%) 
Genitourinary: Vaginitis (≤3%), genital candidiasis (adults, multiple-dose regimens: ≤1%) 
Hematologic & oncologic: Decrease in absolute neutrophil count (children: 15% to 16%; 500 to 
1,500 cells/mm3), decreased hematocrit (adults: >1%), decreased hemoglobin (adults: >1%), 
increased neutrophils (adults: >1%), thrombocythemia (adults: >1%), change in neutrophil count 
(children: ≥1%), eosinophilia (≥1%), lymphocytopenia (≥1%) 
Hepatic: Increased serum ALT (≤6%), increased serum AST (≤6%), increased serum bilirubin 
(≤3%), cholestatic jaundice (≤1%) 
Neuromuscular & skeletal: Increased creatine phosphokinase (1% to 2%) 
Renal: Increased serum creatinine (≤6%), increased blood urea nitrogen (≤1%), nephritis 
(adults, multiple-dose regimens: ≤1%) 
Respiratory: Bronchospasm (≤1%) 
Miscellaneous: Fever (children: (≤2%) 
 
Participants will be fully consented and aware of the potential risks associated with their 
participation in the study and have the knowledge that they can discontinue the study at any 


 
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time. Before a patient is approached, permission will be received from the treating physician. 
Consent will be performed by a physician co-investigator or be delegated to a coordinator under 
the supervision of a physician co-investigator.  A physician co-investigator will review and 
approve all enrollments. Consents may be performed utilizing electronic informed consent as 
possible, but paper informed consent will be available as well. Each subject will be monitored 
carefully and appropriately and will be instructed to contact the study team promptly upon 
noticing any complication or health issues. Should this occur, subjects’ health history will be 
reviewed by the study team. 
 
All subjects asked to participate in the clinical studies will be advised that their participation in 
the studies is entirely voluntary, that they can choose discontinue participation at any time and 
that this will not negatively impact on their access to routine health care. 
 
For participants enrolled under a legal authorized representative (LAR), the PI for the project, or 
a designated research coordinator, will maintain the enrolled subject’s name and date of birth in 
a secured electronic format. Throughout the patient’s stay, they will periodically review if the 
participant has recovered the ability to understand the nature of study participation and to make 
his/her own medical decisions. When this occurs, the enrolled subject will be provided a signed 
copy of the consent document that was originally signed by and provided to the LAR, informed 
that they were enrolled in the study, and the section regarding withdrawal of consent will be 
specifically pointed out to them if they choose to do that. Furthermore, they will be allowed to 
ask questions regarding their participation in the study and the purpose of the study from the 
research coordinator or PI during that encounter. For participants that are scheduled to be 
placed in a LTAC facility or any other facility who are still unable to consent prior to transfer, the 
PI or designated research coordinator will make every effort to have a second copy of the 
signed consent form provided to the LAR and to inform the LAR once again that the participant 
or the LAR can contact the PI in the future at any time as described in the consent form to 
discuss the study or to withdraw consent. 
 
Other risks to staff and research participants 
Given the known contagious potential for COVID-19, we will take several precautions to limit 
risks to staff and other participants following federal, state, local and university guidelines. We 
will ensure that we are following WU/HRPO guidelines as they are updated. 
 
Known Potential Benefits 
Preliminary data suggests that hydroxychloroquine or chloroquine used alone or in combination 
with azithromycin could improve outcomes in SARS CoV-2 infection.  
 
RANDOMIZATION PROCEDURES  
Randomization will be performed by the BJH Investigational Drug Service (IDS) using a 
computer-generated randomization sequence, which will be concealed from investigators and 
the research team through study completion. Consented patients will be randomly assigned to 
one of four open-label treatment cohorts in a 1:1:1:1 ratio using permutation blocks (block size 
will be determined by the study statistician). Medications will be prepared and dispensed by the 
IDS pharmacy and delivered to the appropriate coordinator. The research pharmacy will 
maintain randomization, dispensing, and accountability logs. All medications will be stored in a 


 
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secure location within the research pharmacy and maintained under controlled environmental 
conditions. 
 
Handling of Withdrawals 
Subjects are free to withdraw from the study at any time. 
Subjects may be taken off study without their consent if the study doctor determines that it is in 
the subject’s best interest not to continue to participate in the study.  In addition, the study doctor 
may remove a subject from study participation if the subject is unable to complete the required 
study procedures, or if the study is stopped by the institution, the sponsor, or the Food and Drug 
Administration (FDA) or other health authorities.  If the subject is removed from the study, the 
Principal Investigator or designee will contact the participant to discuss the study stopping 
procedures.   
Participants who withdraw are withdrawn or terminated from the study, or are lost to follow-up 
after study enrollment visit will not be replaced. 
 
STUDY PROCEDURES 
Schedule of events  
 
Screen 
(using 
SOC in 
last 48hr 
Baseline 
Screening 
and baseline 
may be 
combined if 
labs are done 
 
 
 
 
 
 
Weeks 
Week 
 
1 
1 
1 
1 
1 
1 
1-2
3 
4 
5 
6 
Day 
 
0 
1 
2 
3 
4 
5 
6-
14 
21 
28 
35 
42 
Window (hrs) +/- 
 
 
 
6 
6 
6 
6 
24 
48 
48 
48 
48 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
 
SARS CoV-2  
x 
 
 
 
 
 
 
 
 
 
 
 
EKG 
x 
 
 
 
 
 
 
 
 
 
 
 
Medication review 
x 
 
 
 
 
 
 
 
 
 
 
 
Complete blood 
count, 
comprehensive 
metabolic panel 
and magnesium 
x 
 
 
 
 
 
 
 
 
 
 
 
History of Glucose-
6 phosphate-
dehydrogenase 
x 
 
 
 
 
 
 
 
 
 
 
 


 
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 * 
thermometer at home and log 
**  
medical history, study outcomes, AEs, SAEs 
 
Pregancy Test 
Unless done as SOC within the last 7-14 days prior to entry a negative β-HCG (human chorionic 
gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be 
of reproductive will be done. 
 
 
Eligibility  
Participants hospitalized with SARS CoV-2 infection who meet the inclusion/exclusion criterion 
will be enrolled. Standard of care investigations including laboratory test (complete blood count, 
comprehensive metabolic panel, magnesium, and glucose-6-phosphate dehydrogenase) and 
ECG performed within 48 hours will be used to determine study eligibly.  
 
Baseline assessment 
Eligible participants will be consented and randomized according to the procedure outlined 
above. Demographics and clinical parameters will be recorded  
 
Follow up  
Participants will be asked to complete daily symptom surveys for 14 days from randomization, 
then weekly thereafter for 4 weeks resulting in a total duration of follow up of 42 days. During 
hospitalization, daily symptom surveys will be completed in conjunction with the study 
coordinators via telephone. On discharge participants will have the option to complete electronic 
symptom surveys or complete symptom surveys via telephone with study coordinator. In the 
event that the participant opts for electronic symptom surveys on discharge they will also 
(G6PD) deficiency 
assessment 
 (G6PD) lab 
(¥research if 
preformed) 
x¥ 
 
 
 
 
 
 
 
 
 
 
 
Determine eligibility 
 
x 
 
 
 
 
 
 
 
 
 
 
Pregnancy test  
Unless SOC within 7-14 
days 
x 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
Review medical 
record** 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse Drug 
Reaction Collection 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Symptom screen  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Temperature ( from 
medical record 
taken and recorded 
by participant while 
at home* 
 
x 
x* 
x* 
x* 
x* 
x* 
x* 
 
 
 
 


 
Version 2.0. March 30th 2020 
Page 15 of 18 
 
  
 
receive a follow up call from a study coordinator every 7 days during the initial 14 day period. In 
addition, failure to submit a symptom survey will prompt a study follow up call.    
 
On discharge from hospital in addition to completing daily symptom surveys participants will be 
asked to take and record their temperature twice daily with extra recordings performed if 
concern for fever onset. 
 
Symptoms will be collected using the Flu-PRO scale (appendix 1) validated for use in influenza7 
as at present validated tools for COVID-19 are not available.  
 
To assure safety and protocol adherence phone calls to participants will be initiated if there is no 
contact at the designated time points. 
 
End of study visit 
The final study visit will via telephone at 6 weeks post enrollment 
 
Study Duration 
 
Total duration of participation in the study should not exceed 6 weeks  
 
SAFETY ASSESSMENTS 
 
ADVERSE EVENTS AND STUDY MONITORING 
Definition of Adverse Events 
Adverse Event (AE) 
 
An Adverse Event is any untoward medical occurrence observed in a patient that develops or 
worsens from baseline status in association with a subject’s participation in the research, 
whether considered research-related or not. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, disease, or injury 
temporally associated with the research, whether or not considered related to the research. 
 
Serious Adverse Event (SAE) 
 
A Serious Adverse Event is any AE that results in any of the following outcomes: 
 
 
Death 
 
A congenital anomaly, birth defect, or cancer in a baby born to a female subject 
 
Life-threatening adverse experience (places the subject at immediate risk of death from 
the event as it occurred) 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
Persistent or significant disability/incapacity 
 
Based on appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition 
 


 
Version 2.0. March 30th 2020 
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Adverse Drug Effect (ADE) 
 
An Adverse Drug Effect is an AE that is definitely, probably, or possibly related to the use of 
study drug 
 
Unexpected Adverse Drug Effect (UADE) 
 
An Unexpected Adverse Drug Effect is any serious adverse effect on health or safety, or any 
life- threatening problem or death caused by, or associated with study drug, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application; or any other unanticipated serious problem associated with a 
drug that relates to the rights, safety, or welfare of study participants. 
 
Outcome 
 
The clinical course of all AEs should be followed until a medical outcome is determined. The 
clinical outcome of all AEs will be recorded as follows: 
 
Fatal 
 
Not Yet Recovered (Patient did not recover and symptoms/sequelae continue) 
 
Recovered (Patient returned to baseline status) 
 
Recovered with Sequelae (Patient recovered but with clinical sequelae from the event) 
 
Unknown 
Adverse Event Collection Requirements for this protocol 
 
All AEs must be recorded on the eCRFs if any of the following criteria have been met. 
 
All Grade ≥2 AEs 
 
All AEs that led to a change in study treatment regardless of grade 
 
All AEs meeting SAE definition 
 
Started within 7 days after the last dose of study drug 
 
All AEs that are reported must have their severity graded. To grade AEs, refer to the Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), corrected Version 2.1, July 2017. 
 
Serious Adverse Events (SAEs) 
An SAE is defined as any untoward medical occurrence that: 
 
Results in death 
 
Is life-threatening  
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity  
 
Is a congenital anomaly/birth defect 


 
Version 2.0. March 30th 2020 
Page 17 of 18 
 
  
 
 
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). 
 
Reporting Requirements 
 
Adverse events must be reported by study personnel into the Redcap system using the 
electronic case report forms within 3 days of their knowledge of the occurrence.  Investigators 
are responsible for following all relevant local IRB policies and procedures.  The Principal 
Investigator will follow IRB policy in terms of reporting adverse events.  
 
Serious Adverse Events that occur within 6 weeks after randomization must be reported by the 
site investigator or personnel into the Redcap system on the Serious Adverse Event CRF within 
1 working day after the site investigator or personnel first learn of the event. 
For SAEs, the Principal Investigator will review the report and obtain any needed additional 
clarifications concerning the event by direct telephone conversations and/or e-mail with the 
involved providers.  The investigator’s description and categorization of the event, and additional 
relevant information, will then be reviewed by the study’s Safety Officer. The Safety Officer will 
determine if the event was properly categorized. If not, he will provide the Principal Investigator 
with a modified categorization, along with a brief written rationale for re-categorizing the event. 
In nearly all instances, the Safety Officer’s categorization will be considered the final 
categorization of the event.   
Expedited Reporting 
 
Events meeting criteria as an unanticipated problem (UP) or unexpected adverse drug event 
(UADE) will be reported to the IRB within 10 working days of becoming aware of the event 
If the event results in death, it will be reported within 1 working day of becoming aware of the 
event 
All other events that do not meet criteria as a UP or UADE will be reported to WUSTL IRB at the 
time of continuing review 
 
Independent Data and Safety Monitoring Board (IDSMB) 
An IDSMB consisting of members who are independent from the Sponsor will be established. 
The IDSMB will have at least 3 members. The IDSMB will be responsible for reviewing 
outcomes and AEs. The first IDSMB meeting will be held after approximately 100 participants 
have completed treatment. The frequency of subsequent meetings will be decided by the 
IDSMB, but will be not less than every 3 months. The IDSMB may also meet in ad hoc meetings 
at its discretion as needed in response to events occurring in the trial. Additional responsibilities 
for the Committee include confirmation of the safety and appropriateness of the selected dosing 
regimen. After each meeting, the IDSMB will recommend that the study can continue, or may 
recommend changes to the study or stopping the study. Details of the membership and 
responsibilities of the IDSMB will be included in the IDSMB Charter. 
 
The IDSMB will also monitor new developments in COVID-19 research and treatment, and 
factor any related ethical considerations into its determinations as to whether or not the study 
should be terminated for futility for one.  
 
STATISTICAL CONSIDERATIONS 


 
Version 2.0. March 30th 2020 
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The proposed study is a 4-arm parallel group, open-label randomized clinical trial. The 
treatment arms, hydroxychloroquine alone (HCQ), hydroxychloroquine + azithromycin (HCQ + 
AZM), chloroquine alone (CQ) and chloroquine + azithromycin (CQ + AZM) will be randomly 
assigned eligible participants. The primary hypotheses in this study are whether the addition of 
AZM to either HCQ or CQ improve patient recovery rates.   
 
Primary endpoint analysis 
The primary endpoint of this study is the time to recovery following the definition outlined in the 
STUDY AIMS/ENDPOINTS section. Our primary analysis will be to use Kaplan-Meier (KM) 
survival analysis to test the statistical null hypothesis that there is no difference in recovery rates 
between the non-AZM treatment arms and the AZM treatment arms (HCQ vs HCQ + AZM, CQ 
vs CQ + AZM). If either of the AZM arms have significantly faster recovery rates (two-sided P-
value < 0.05) compared to the corresponding non-AZM arm group, then we will conclude that 
the AZM group is superior to the non-AZM group. We will also compare recovery rates between 
the HCQ vs CQ, and HCQ + AZM vs CQ + AZM treatment arms to assess whether HCQ and 
CQ treatments differentially influence recovery. We will then proceed to a multivariable Cox-
regression model that adjusts symptom severity at baseline (sum of presence of fever ≥ 38.0°C 
and total number of ‘Quite a Bit’ or ‘Very much’ responses to the Flu-PRO questionnaire 
[maximum total = 20]). The final model will retain the treatment groups and those covariates that 
are significant (P < 0.05) in the multivariable model and we will report the model-adjusted 
hazard ratios and 95% CI for the treatment groups as well as the covariates. Participants that 
are lost to follow-up or die will be censored at the date of last contact or date of death, 
respectively, and patients that do not recover during the study period will be censored at 42 
days. The primary analysis will be intention-to-treat and a per-protocol analysis will also be 
performed as a secondary analysis of the primary endpoint. Statistical analyses will be 
conducted using PROC LIFETEST and PROC PHREG as appropriate (SAS Institute Inc, Cary, 
NC, USA).    
 
Sensitivity analyses 
In our primary analysis death is treated as a competing risk for recovery (i.e., someone that dies 
will never recover) by censoring subjects at their date of death. Although we anticipate low 
mortality rates (e.g., 1.4%2) censoring patients due to death has the potential to bias recovery 
rate estimates8. In order to assess this assumption we will explore the use of a more complex 
approach that explicitly models the subdistribution of recovery rate9. If results from this analysis 
are substantially different form the primary analysis, then we will use model fit statistics and 
Monte Carlo simulation to determine whether the more complex model better describes the data 
generating process.    
 
Secondary and exploratory endpoint analyses 
Secondary endpoints include time to resolution of fever, time to improvement of symptoms, 
duration of hospitalization, proportion requiring supplementary oxygen above baseline usage, 
duration of requirement for supplementary oxygen, proportion requiring ICU admission, 
proportion requiring mechanical ventilation, ventilator free days, all-cause mortality. Exploratory 
COVID-19 specific mortality, number of patients with diagnosed cardiomyopathy, number of 
patients with new onset arrhythmia. All secondary and exploratory endpoints will be analyzed by 
survival analysis (KM and/or Cox), t-tests, chi-square tests, or Fisher’s exact tests as 
appropriate.  
 
Sample size and power analysis 


 
Version 2.0. March 30th 2020 
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A recent COVID-19 study in the Jiangsu province of China10 indicated that fever in about half of 
COVID-19 infected people lasted less than 7 days. Because this research area is rapidly 
developing and there is limited knowledge about this disease, we use the simple median 
estimate of 7-days as a starting point for our recovery outcome. In addition to attenuation of 
fever, our primary outcome adds criteria that fever must be attenuated for at least 48 hours and 
there needs to be symptom improvement. Given our criteria we assume 11 days as a rough 
estimate for median recovery time in the non-AZM treatment groups to compare the AZM 
treatment groups against in our study. This study is powered to test the hypothesis that HCQ + 
AZM improves recovery rate compared to HCQ alone, and CQ + AZM improves recovery rate 
compared to CQ alone. Assuming a minimum improvement of 4 days in the median recovery 
time (median recovery time of 7-days) and a censoring rate due to death or loss to follow-up of 
0.04 per day, we plan on enrolling a total of 500 participants (125 per arm) which would give us 
just over 80 percent power (1 – β = 82%, α = 0.05) to test our primary hypotheses.        
SOURCE DOCUMENTATION 
 
All source documents will be kept in an appropriately secure office in a locked high density filing 
system in a locked office. 
 
QUALITY CONTROL 
 
All eligibilities and ICFs and a portion of the study case report forms (no less than 10%) will be 
audited by the study quality management personnel.  
 
ETHICS AND PROTECTION OF HUMAN SUBJECTS 
 
Once the study is approved by the Washington University Human Research Protection Office 
(HRPO), recruiting and screening will begin for the study. All subjects or their legally authorized 
representative (LAR) are required to read English, understand and sign the informed consent 
document.  
 
DATA HANDLING AND RECORD KEEPING 
 
Data will be generated and managed according to Washington University School of Medicine 
and HIPAA policy.  
Data will be entered onto a central Redcap database housed at Washington University. All 
research records will be maintained under the two-lock rule with access limited to authorized 
study personnel or regulatory authorities. The study records will be maintained up to seven 
years after the completion of the study. 
 
PUBLICATION POLICY 
 
The PI and co-investigators will participate in manuscript preparation and submission to 
journals. 
 
 
LITERATURE REFERENCE 
1. 
Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients 
Dying in Relation to COVID-19 in Italy. JAMA. 2020. 


 
Version 2.0. March 30th 2020 
Page 20 of 18 
 
  
 
2. 
Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in 
China. N Engl J Med. 2020. 
3. 
Livingston E, Bucher K. Coronavirus Disease 2019 (COVID-19) in Italy. JAMA. 2020. 
4. 
Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is 
effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020;6:16. 
5. 
Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent 
efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci 
Trends. 2020;14(1):72-73. 
6. 
Gautret P, Lagier J-C, Parola P, et al. Hydroxychloroquine and azithromycin as a 
treatment of COVID-19: results of an open-label non-randomized clinical trial. 
International Journal of Antimicrobial Agents. 2020:105949. 
7. 
Powers JH, Guerrero ML, Leidy NK, et al. Development of the Flu-PRO: a patient-
reported outcome (PRO) instrument to evaluate symptoms of influenza. BMC infectious 
diseases. 2016;16:1. 
8. 
Pfirrmann M, Hochhaus A, Lauseker M, Saussele S, Hehlmann R, Hasford J. 
Recommendations to meet statistical challenges arising from endpoints beyond overall 
survival in clinical trials on chronic myeloid leukemia. Leukemia. 2011;25(9):1433-1438. 
9. 
Fine J, Gray R. A Proportional Hazards Model for the Subdistribution of a Competing 
Risk. Journal of the American Statistical Association. 1999;94:496–509. 
10. 
Xu T, Chen C, Zhu Z, et al. Clinical features and dynamics of viral load in imported and 
non-imported patients with COVID-19. Int J Infect Dis. 2020. 


 
Version 2.0. March 30th 2020 
Page 21 of 18 
 
  
 
Appendix 1 Flu-PRO questionnaire (Will be modified to read COVID-19 where 
Flu/influenza referenced) 
Participant ID:____________________________Participant Initials:__________Date:____/_____/_____ 
Influenza Symptoms Questionnaire 
People experience the Flu COVID-19 in different ways. We would like to know about the symptoms you have 
been experiencing during the last 24 hours. For each symptom, please mark one box under the response that 
best matches your experience. Mark the “Not at all” box, if you did not have that symptom in the past 24 
hours. 
What time is it? _____ AMP / PM (please circle) 
Please rate the extent which you had each symptom during the past 24 hours. 
Symptom 
Not at all 
A little bit 
Somewhat 
Quite a bit 
Very much 
Runny of 
dripping nose 
 
 
 
 
 
Congested or 
stuffy nose 
 
 
 
 
 
Scratchy or 
itchy throat 
 
 
 
 
 
Difficulty 
swallowing 
 
 
 
 
 
 
Teary or 
watery eyes 
 
 
 
 
 
Sore or painful 
eyes 
 
 
 
 
 
Eyes sensitive 
to light 
 
 
 
 
 
 
Trouble 
breathing 
 
 
 
 
 
Chest 
congestion 
 
 
 
 
 
Chest tightness
 
 
 
 
 
Dry or hacking 
cough 
 
 
 
 
 
Wet or loose 
cough 
 
 
 
 
 
 
Headache 
Head 
congestion 
 
 
 
 
 
Sinus pressure 
Felt dizzy 
Felt 
lightheaded  
 
 
 
 
 
Appendix 2 Contraindicated* with study drugs (predominantly chloroquine) 


 
Version 2.0. March 30th 2020 
Page 22 of 18 
 
  
 
Type
Medication
Analgesic 
methadone 
Antiarrhythmic 
amiodarone, digoxin, disopyramide, dofetilide (Tikosyn), 
dronedarone (Multaq), flecainide, ibutilide (Corvert), 
procainamide, quiNIDine, sotalol 
Antibiotic 
bedaquiline, clarithromycin, delamanid, rifampin 
Anticonvulsant 
carbamazepine, phenytoin 
Antidepressant 
bupropion, fluoxetine, paroxetine 
Antifungal 
itraconazole, ketoconazole, posaconazole, voriconazole 
Antihormone therapy 
abiraterone, apalutamide, enzalutamide,  
Antimalarial 
artemether/lumefantrine, dapsone, quiNINE, mefloquine 
Antineoplastic 
ceritinib (Zykadia), dabrafenib (Tafinlar), idelalisib, ivosidenib 
(Tibsovo), lenvatinib (Lenvima), mitotane, vandetanib (Caprelsa) 
Antipsychotic 
chlorproMAZINE, ziprasidone 
Antiviral 
cobicistat, darunavir, lopinavir, nelfinavir, ritonavir, saquinavir, 
tipranavir  
Immunosuppressant 
CycloSPORINE 
Misc. 
injection/intravenous 
agalsidase α or β, conivaptan 
*Includes interactions severe enough to require constant monitoring during co-administration 
(Category D)