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

• ClinicalTrials.gov Identifier: NCT04335552
• Recruitment Status: Terminated
• First Posted: April 6, 2020
• Last Update Posted: July 31, 2020
• Sponsor: Duke University
• Information provided by (Responsible Party): Duke University

Study Description

Brief 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

Condition or disease	Intervention/treatment	Phase
SARS-CoV-2	Other: Standard of care; Drug: Hydroxychloroquine; Drug: Azithromycin	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• 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)
• Primary Purpose: Treatment
• Official Title: Pragmatic Factorial Trial of Hydroxychloroquine, Azithromycin, or Both for Treatment of Severe SARS-CoV-2 Infection
• Actual Study Start Date: April 17, 2020
• Actual Primary Completion Date: June 17, 2020
• Actual Study Completion Date: June 26, 2020

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. World Health Organization (WHO) ordinal scale measured at 14 days after enrollment [ Time Frame: Day 14 ]
   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.

Secondary Outcome Measures :

1. Rates of death during the index hospitalization [ Time Frame: Index hospitalization, up to 46 days ]
2. Number of days on mechanical ventilation for patients who were on mechanical ventilation at baseline [ Time Frame: Baseline ]
3. Proportion of patients not receiving mechanical ventilation at baseline who progress to requiring mechanical ventilation during the index hospitalization [ Time Frame: Index hospitalization, up to 46 days ]
4. WHO ordinal scale measured at 28 days after enrollment [ Time Frame: Day 28 ]
   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.
5. Hospital length of stay in days for the index hospitalization [ Time Frame: Index hospitalization, up to 46 days ]
6. Rates of all-cause study medication discontinuation [ Time Frame: Index hospitalization, up to 46 days ]
7. Rates of severe adverse events [ Time Frame: Day 14 ]

Eligibility Criteria

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

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

Contacts and Locations

Locations

United States, North Carolina

Duke Regional Hospital

Durham, North Carolina, United States, 27704

Duke University Hospital

Durham, North Carolina, United States, 27710

Durham VA Medical Center

Durham, North Carolina, United States, 27710

Duke Raleigh Hospital

Raleigh, North Carolina, United States, 27609

Sponsors and Collaborators

Duke University

Investigators

• Principal Investigator: Jason Stout, MD; Duke University Hospital

More Information

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT04335552
• Other Study ID Numbers: PRO00105339
• First Posted: April 6, 2020
• Last Update Posted: July 31, 2020
• Last Verified: April 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Duke University:

COVID-19

Additional relevant MeSH terms:

Hydroxychloroquine; Infection; Azithromycin; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents