Evaluating the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19

• ClinicalTrials.gov Identifier: NCT04358068
• Recruitment Status: Terminated
• First Posted: April 22, 2020
• Results First Posted: April 1, 2021
• Last Update Posted: November 16, 2021
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Teva Pharmaceutical Industries, Ltd.
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

Study Description

Brief Summary:

The purpose of this study was to evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Condition or disease	Intervention/treatment	Phase
COVID-19; SARS-CoV 2	Drug: Hydroxychloroquine (HCQ); Drug: Azithromycin (Azithro); Drug: Placebo for Hydroxychloroquine; Drug: Placebo for Azithromycin	Phase 2

Detailed Description:

This Phase IIB study was designed to evaluate the efficacy of hydroxychloroquine (HCQ) and azithromycin (Azithro) to prevent hospitalization or death in symptomatic adult outpatients with COVID-19 caused by SARS-CoV-2 infection.

Participants were randomized 1:1 to receive active or placebo study treatment. The target sample size was 2000 participants, with approximately 1000 in each arm. Stratification was by "high" versus "low" risk of progression to severe COVID-19, where "high risk" was defined as a person age ≥60 years or having at least one of several specified comorbidities.

Participants were prescribed study treatment for 7 days and were to be followed for an additional 24 weeks. Assessments on a subset of participants were planned to include blood collection, self-collected nasal swabs, and nasopharyngeal swabs.

On June 23, 2020, sites were informed that the study was closing to follow-up due to slow enrollment and lack of community enthusiasm. Follow-up through week 24 was not completed for any participant. Participants were asked to complete the Day 20 visit and then were discontinued from the study. Due to the early termination, enrollment into the specimen collection subset did not occur, and results associated with those specimens are not available. Due to the small number of participants enrolled, some statistical tests were not able to be performed and only descriptive results are provided.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19
• Actual Study Start Date: May 13, 2020
• Actual Primary Completion Date: July 8, 2020
• Actual Study Completion Date: July 8, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro); Hydroxychloroquine 400 mg (administered as two 200 mg capsules) orally twice daily for 2 doses starting on Day 0, followed by 200 mg (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS: Azithromycin 500 mg (administered as two 250 mg capsules) orally as a single dose on Day 0, followed by 250 mg (administered as one 250 mg capsule) orally once daily for 4 doses (4 days).	Drug: Hydroxychloroquine (HCQ); Administered orally; Drug: Azithromycin (Azithro); Administered orally
Placebo Comparator: Arm B: Placebo for Hydroxychloroquine and Azithromycin; Placebo for Hydroxychloroquine (administered as two matching placebo capsules) orally twice daily for 2 doses starting on Day 0, followed by Placebo for HCQ (administered as one 200 mg capsule) orally twice daily for 12 doses (6 days), PLUS: Placebo for Azithromycin (administered as two matching placebo capsules) orally as a single dose on Day 0, followed by Placebo for Azithromycin (administered as one matching placebo capsule) orally once daily for 4 doses (4 days).	Drug: Placebo for Hydroxychloroquine; Administered orally; Drug: Placebo for Azithromycin; Administered orally

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Died From Any Cause or Were Hospitalized [ Time Frame: The 20-day period from and including the day of the first dose of study treatment ]
   Hospitalization was defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care was not considered a hospitalization. Formal statistical testing was not conducted due to the small number of participants and events.

Secondary Outcome Measures :

1. Number of Participants Who Died From Any Cause [ Time Frame: The 20-day period from and including the day of the first dose of study treatment ]
   Deaths reported due to any cause (COVID-related or not)
2. Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic [ Time Frame: The 20-day period from and including the day of the first dose of study treatment ]
   Hospitalization was defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care was not considered a hospitalization, but was included for this outcome measure.
3. Number of Participants Who Died From Any Cause or Were Hospitalized Through the End of Follow-up [ Time Frame: From day of the first dose of study treatment to Week 24 ]
   Hospitalization was defined as requiring at least 24 hours of acute care in a hospital or similar acute care facility, including Emergency Rooms or temporary facilities instituted to address needs during the COVID-19 pandemic. Evaluation at a hospital or similar facility with less than 24 hours of acute care was not considered a hospitalization. Due to the early termination of the study, participant followup was discontinued at Day 20. Refer to the primary outcome above for results based on the time frame out to Day 20.
4. Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event [ Time Frame: From start of study treatment through Day 7 ]
   Premature discontinuation of study treatment is defined as a permanent discontinuation of either study treatment (HCQ/Placebo and/or Azithro/Placebo)
5. Number of Participants Who Had Any Cardiac Adverse Events [ Time Frame: From start of study treatment through Day 20 ]
   Cardiac adverse events included in the analysis were chosen a priori by the study chairs
6. Duration of Fever [ Time Frame: Day 0 to Day 20, 21 days total ]
   Defined as the time from study treatment initiation to the last day in the participant's daily diary card on which a temperature greater than 100.4°F was recorded or a potentially antipyretic drug, such as acetaminophen or ibuprofen, was taken. Participants with at least one temperature who never reported fever or use of anti-pyretic medications were assigned a duration of zero days
7. Duration of Symptoms Associated With COVID-19 Disease [ Time Frame: Day 0 to Day 20, 21 days total ]
   Defined as the time from start of study treatment to the last day in the participant's daily diary card on which a moderate or worse targeted symptom was recorded. The set of target symptoms were cough, shortness of breath, feeling feverish, fatigue, muscle aches, diarrhea, vomiting, nausea, headache, sore throat, nasal obstruction (stuffy nose), nasal discharge (runny nose), loss of smell, and loss of taste. Participants who had missing diary records due to hospitalization were assumed to have moderate symptoms during the period of hospitalization in the analysis. Missing diary card records not due to hospitalization were assumed to have absent symptoms.
8. Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time [ Time Frame: Day 0 to Day 20, 21 days total ]
   Defined as the sum of scores for the targeted symptoms (defined in the protocol) in the participant's daily diary record (each symptom was scored from 0-best to 3-worst). Participant-specific areas under the curve (AUC) over time were calculated using the trapezoidal rule and defined as the area below the line formed by joining total symptom scores on each daily diary card from the pre-treatment score on Day 0 through to Day 20. AUCs were rescaled by time by dividing by 21 (corresponding to the number of daily diary cards during follow-up between pre-treatment Day 0 and Day 20), in order to provide results on a symptom scale from 0-best to 42-worst (for non-hospitalized participants). Participants who were hospitalized were assigned a value equal to the sum of the maximum possible scaled AUC (42) and the duration of hospitalization, and thus values >42 were possible. Missing scores between pre-treatment and Day 20 were linearly interpolated. Higher AUCs indicate worse outcomes.
9. Time to Self-reported Return to Usual (Pre-COVID) Health. [ Time Frame: Day 0 to Day 20, 21 days total ]
   Time to self-reported return to (pre-COVID) usual health was defined as the time from the start of study treatment to the first day in the participant's daily diary card on which they responded 'Yes' with no subsequent reports of 'No' to the question "Have you returned to your usual (pre-COVID) health today?" Participants who never reported a 'Yes' response were assigned a duration of 22 days.
10. SARS-CoV-2 RNA Detection Status From Self-collected Nasal and Site-collected NP Swabs Among Subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
    The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
11. SARS-CoV-2 RNA Level (Continuous) From Self-collected Nasal and Site-collected NP Swabs Among Subset [ Time Frame: Measured at entry, Day 6, and Day 20 ]
    The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
12. Number of Participants With an Occurrence of Fainting [ Time Frame: From start of study treatment through Day 20 ]
    Fainting was self-reported on the study diary card as absent (score 0), mild (1), moderate (2), or severe (3); scores of > 0 are defined as an occurrence of fainting

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Documentation of confirmed active severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection from any respiratory specimen collected ≤7 days from when the first dose of study treatment was expected to be taken.

• Experienced at least one of the following SARS-CoV-2 infection symptoms within 24 hours of screening (symptom(s) must be new or worse compared to pre-COVID-19 health status):

  • Fever (can be subjective) or feeling feverish
  • Cough
  • Shortness of breath or difficulty breathing at rest or with exertion
  • Sore throat
  • Body pain or muscle pain
  • Fatigue
  • Headache
• Agreed to not participate in another clinical trial for the treatment of COVID-19 or SARS-CoV-2 during the study period up until reaching hospitalization or 20 days, whichever is earliest.
• Agreed to not obtain study medications outside of the A5395 study.

Exclusion Criteria:

• Need for hospitalization or immediate medical attention in the clinical opinion of the study investigator.
• History of or current hospitalization for COVID-19.
• History of ventricular arrhythmia or use of antiarrhythmics within 30 days prior to entry.
• Personal or family history of Long QT syndrome.
• History of kidney disease.
• History of ischemic or structural heart disease.
• History of hypokalemia or hypomagnesemia or taking potassium supplementation or magnesium supplementation
• Personal medical history of porphyria, retinopathy, severe hepatic impairment, or glucose-6-phosphate dehydrogenase (G6PD) deficiency.
• Used drugs with possible anti-SARS-CoV-2 activity within 30 days prior to study entry, e.g., remdesivir, lopinavir/ritonavir fixed dose combination, ribavirin, chloroquine, hydroxychloroquine, and azithromycin, or participation in a clinical trial involving any of these drugs whether for treatment or prophylaxis.
• Requirement or expected requirement for a medication that significantly prolongs QT intervals or increases risk for QT prolongation.
• Loop diuretics are exceptions to above exclusion criterion but these cannot be used within 30 days prior to study entry.
• Participated in a study where co-enrollment was not allowed.
• Receipt of a SARS-CoV-2 vaccination prior to study entry.
• Known allergy/sensitivity or any hypersensitivity to components of HCQ, azithromycin, or their formulation.

• More than 10 days of any of the following symptoms attributed to the SARS-CoV-2 infection at study entry:

  • Fever (can be subjective) or feeling feverish
  • Cough
  • Shortness of breath or difficulty breathing at rest or with exertion
  • Sore throat
  • Body pain or muscle pain
  • Fatigue
  • Headache
  • Chills
  • Nasal obstruction or congestion
  • Loss of taste or smell
  • Nausea or vomiting
  • Diarrhea

Contacts and Locations

Locations

United States, Alabama

Alabama CRS

Birmingham, Alabama, United States, 35294

United States, California

UCSD Antiviral Research Center CRS

San Diego, California, United States, 92103

Harbor-UCLA CRS

Torrance, California, United States, 90502

United States, District of Columbia

Whitman-Walker Health CRS

Washington, District of Columbia, United States, 20009

United States, Illinois

Northwestern University CRS

Chicago, Illinois, United States, 60611

Rush University CRS

Chicago, Illinois, United States, 60612

United States, North Carolina

Greensboro CRS

Greensboro, North Carolina, United States, 27401

United States, Ohio

Cincinnati Clinical Research Site

Cincinnati, Ohio, United States, 45219

United States, Pennsylvania

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, United States, 15213

United States, Texas

Trinity Health and Wellness Center CRS

Dallas, Texas, United States, 75208

United States, Washington

University of Washington AIDS CRS

Seattle, Washington, United States, 98104-9929

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Teva Pharmaceutical Industries, Ltd.

Investigators

• Study Chair: Davey Smith, MD; University of California, San Diego

  Study Documents (Full-Text)

Documents provided by National Institute of Allergy and Infectious Diseases (NIAID):

Study Protocol  [PDF] April 24, 2020

Statistical Analysis Plan  [PDF] May 13, 2020

Informed Consent Form  [PDF] May 1, 2020

More Information

Additional Information:

Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (Corrected Version 2.1 - July 2017) 

Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010 

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT04358068
• Other Study ID Numbers: ACTG A5395; 38720 ( Other Identifier: DAIDS-ES Registry Number )
• First Posted: April 22, 2020
• Results First Posted: April 1, 2021
• Last Update Posted: November 16, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP)
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.

Access Criteria

• With whom?

  • Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.

• For what types of analyses?

  • To achieve aims in the proposal approved by the AIDS Clinical Trials Group.

• By what mechanism will data be made available?

  • Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Azithromycin; Hydroxychloroquine; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents