Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection

Study Overview
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Brief Summary
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This is a pragmatic, randomized, open-label, incomplete factorial with nested randomization clinical trial evaluating the efficacy and safety of two potential treatments for hospitalized patients with confirmed SARS-CoV-2 infection. Participants who are hospitalized and have a positive nucleic acid amplification test for SARS-CoV-2 will undergo an initial randomization in a 1:1 ratio to one of the following regimens: Arm 1: Standard of care alone Arm 2: Standard of care plus hydroxychloroquine Participants who meet eligibility criteria to receive azithromycin will undergo a second randomization in a 1:1 ratio to receive additional concurrent therapy. This will effectively result in four treatment groups: Standard of care alone Standard of care plus hydroxychloroquine Standard of care plus azithromycin Standard of care plus hydroxychloroquine plus azithromycin

Official Title
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Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection

Conditions
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SARS-CoV-2

Intervention / Treatment
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* Other: Standard of care
* Drug: Hydroxychloroquine
* Drug: Azithromycin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Admitted to participating hospital with symptoms suggestive of COVID-19 infection OR develop symptoms of COVID-19 during hospitalization Subject (or legally authorized representative) can provide written informed consent (in English or Spanish) affirming intention to comply with planned study procedures prior to enrollment Male or female adult aged 12 years or older at the time of enrollment Has laboratory-confirmed SARS-CoV-2 infection determined by a validated nucleic acid amplification assay (public health or commercial) in any respiratory specimen collected within 14 days of randomization Illness of any duration that includes Radiographic evidence of pulmonary infiltrates (chest X-ray or CT scan) OR Clinical documentation of lower respiratory symptoms (cough, shortness of breath, wheezing) OR Any documented SpO2 ≤ 94% on room air OR Any inpatient initiation or supplemental oxygen regardless of documented cause Exclusion Criteria: Participating in any other clinical trial of an experimental agent for COVID-19 On hydroxychloroquine at any time during hospitalization, or within 180 days of hospitalization for COVID-19 regardless of indication History of G6PD deficiency, cirrhosis, long QT syndrome or porphyria of any classification Most recent ECG prior to time of screening with QTc of ≥500 msec Known hypersensitivity to hydroxychloroquine or 4-aminoquinoline derivatives Death anticipated within 48 hours of enrollment Inability to obtain informed consent from the patient or designated medical decision maker

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Patients will be initially randomized to one of two arms in a 1:1 ratio: 1) Standard of care treatment or 2) Standard of care treatment plus 5 days of hydroxychloroquine. Participants who meet eligibility criteria to receive azithromycin will undergo a second randomization in a 1:1 ratio to receive additional concurrent therapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard of care<br> | Other: Standard of care<br>* Standard of care<br>|
| Experimental: Standard of care plus hydroxychloroquine<br>Standard of care plus hydroxychloroquine for 5 days | Other: Standard of care<br>* Standard of care<br>Drug: Hydroxychloroquine<br>* Hydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5<br>|
| Experimental: Standard of care plus azithromycin<br>Standard of care plus azithromycin for 5 days | Other: Standard of care<br>* Standard of care<br>Drug: Azithromycin<br>* Azithromycin will be administered orally or via feeding tube at a dosage of 500 mg on day 1, followed by 250 mg daily on days 2-5<br>|
| Experimental: Standard of care plus hydroxychloroquine plus azithromycin<br>Standard of care plus hydroxychloroquine plus azithromycin for 5 days | Other: Standard of care<br>* Standard of care<br>Drug: Hydroxychloroquine<br>* Hydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5<br>Drug: Azithromycin<br>* Azithromycin will be administered orally or via feeding tube at a dosage of 500 mg on day 1, followed by 250 mg daily on days 2-5<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died During the Index Hospitalization |  | Index hospitalization, up to 46 days | 
| Number of Days on Mechanical Ventilation |  | Baseline | 
| Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization |  | Index hospitalization, up to 46 days | 
| WHO Ordinal Scale Measured at 28 Days After Enrollment | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. | Day 28 | 
| Hospital Length of Stay in Days for the Index Hospitalization |  | Index hospitalization, up to 46 days | 
| Number of Participants With All-cause Study Medication Discontinuation | Number of participants who discontinued study medication for any reason | Index hospitalization, up to 46 days | 
| Number of Participants With Severe Adverse Events |  | Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19