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

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

Study Overview

• Status: Terminated
• Conditions: SARS-CoV-2
• Intervention / Treatment: Other: Standard of care; Drug: Hydroxychloroquine; Drug: Azithromycin

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Hospital
    • Durham, North Carolina, United States, 27704
      • Duke Regional Hospital
    • Durham, North Carolina, United States, 27710
      • Durham VA Medical Center
    • Raleigh, North Carolina, United States, 27609
      • Duke Raleigh Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of care	Other: Standard of care; Standard of care
Experimental: Standard of care plus hydroxychloroquine; Standard of care plus hydroxychloroquine for 5 days	Other: Standard of care; Standard of care; Drug: Hydroxychloroquine; 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
Experimental: Standard of care plus azithromycin; Standard of care plus azithromycin for 5 days	Other: Standard of care; Standard of care; Drug: Azithromycin; 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
Experimental: Standard of care plus hydroxychloroquine plus azithromycin; Standard of care plus hydroxychloroquine plus azithromycin for 5 days	Other: Standard of care; Standard of care; Drug: Hydroxychloroquine; 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; Drug: Azithromycin; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Jason Stout, MD, Duke University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2020
• Primary Completion (Actual): June 17, 2020
• Study Completion (Actual): June 26, 2020

Study Registration Dates

• First Submitted: April 3, 2020
• First Submitted That Met QC Criteria: April 3, 2020
• First Posted (Actual): April 6, 2020

Study Record Updates

• Last Update Posted (Actual): May 17, 2021
• Last Update Submitted That Met QC Criteria: May 13, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: COVID-19
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Azithromycin; Hydroxychloroquine
• Other Study ID Numbers: PRO00105339

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No