Hydroxychloroquine,Hydroxychloroquine,Azithromycin in the Treatment of SARS CoV-2 Infection

Study Overview
=================
Brief Summary
-----------------
This Phase III trial four treatment strategies non-critically ill hospitalized participants (not requiring 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 withthe 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 SOC will be collected from medical records.

Official Title
-----------------
WU 352: Open-label, Randomized Controlled Trial of Hydroxychloroquine Alone or Hydroxychloroquine Plus Azithromycin or Chloroquine Alone or Chloroquine Plus Azithromycin in the Treatment of SARS CoV-2 Infection

Conditions
-----------------
Coronavirus Infection

Intervention / Treatment
-----------------
* Drug: Hydroxychloroquine Sulfate
* Drug: Azithromycin
* Drug: Chloroquine Sulfate


Participation Criteria
=================
Eligibility Criteria
-----------------
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: Condom (male or female) with or without spermicide Diaphragm or cervical cap with spermicide Intrauterine device (IUD) Hormone-based contraceptive 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<10 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 <3.3 >5.5 mEg/L*

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxychloroquine alone<br>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. | Drug: Hydroxychloroquine Sulfate<br>* anti-rheumatic drug (DMARD)<br>* Other names: HYDROXYCHLOROQUINE Plaquenil;|
| Active Comparator: Hydroxychloroquine plus azithromycin<br>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. | Drug: Hydroxychloroquine Sulfate<br>* anti-rheumatic drug (DMARD)<br>* Other names: HYDROXYCHLOROQUINE Plaquenil;Drug: Azithromycin<br>* Antibiotic<br>* Other names: COMMON BRAND(S): Zithromax GENERIC NAME(S): Azithromycin;|
| Active Comparator: Chloroquine alone<br>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. | Drug: Chloroquine Sulfate<br>* Antimalarial<br>* Other names: Aralen GENERIC NAME(S): Chloroquine Phosphate;|
| Active Comparator: Chloroquine plus azithromycin<br>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. | Drug: Azithromycin<br>* Antibiotic<br>* Other names: COMMON BRAND(S): Zithromax GENERIC NAME(S): Azithromycin;Drug: Chloroquine Sulfate<br>* Antimalarial<br>* Other names: Aralen GENERIC NAME(S): Chloroquine Phosphate;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hours to recovery | 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 | 42 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time fever resolution | Time to resolution of fever defined as at least 48 hours since last temperature ≥ 38.0°C without the use of fever-reducing medications | 42 days |