Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection
Condition: SARS-CoV-2
MeSH terms: COVID-19
Intervention: Standard of care; Hydroxychloroquine; Azithromycin
Intervention description: Standard of care; 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; 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
Intervention MeSH terms: Azithromycin; Hydroxychloroquine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention 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)
Enrollment: 11.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No
Keywords: COVID-19

Summary:

      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:

        1. Standard of care alone

        2. Standard of care plus hydroxychloroquine

        3. Standard of care plus azithromycin

        4. Standard of care plus hydroxychloroquine plus azithromycin
    

Eligibility criteria:

        Inclusion Criteria:

          1. Admitted to participating hospital with symptoms suggestive of COVID-19 infection OR
             develop symptoms of COVID-19 during hospitalization

          2. 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

          3. Male or female adult aged 12 years or older at the time of enrollment

          4. 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

          5. 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:

          1. Participating in any other clinical trial of an experimental agent for COVID-19

          2. On hydroxychloroquine at any time during hospitalization, or within 180 days of
             hospitalization for COVID-19 regardless of indication

          3. History of G6PD deficiency, cirrhosis, long QT syndrome or porphyria of any
             classification

          4. Most recent ECG prior to time of screening with QTc of ≥500 msec

          5. Known hypersensitivity to hydroxychloroquine or 4-aminoquinoline derivatives

          6. Death anticipated within 48 hours of enrollment

          7. Inability to obtain informed consent from the patient or designated medical decision
             maker