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

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Terminated; Phase 2

Conditions: COVID-19; SARS-CoV 2

Treatments: Drug: Azithromycin (Azithro); Drug: Placebo for Hydroxychloroquine; Drug: Placebo for Azithromycin; Drug: Hydroxychloroquine (HCQ)

Study type: Interventional

Funder types: Industry; NIH

Identifiers

NCT04358068

38720 (Other Identifier)

ACTG A5395

Details and patient eligibility

About

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.

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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20 participants in 2 patient groups, including a placebo group

Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro)

Experimental group

Description:

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).

Treatment:

Drug: Azithromycin (Azithro)

Drug: Hydroxychloroquine (HCQ)

Arm B: Placebo for Hydroxychloroquine and Azithromycin

Placebo Comparator group

Description:

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).

Treatment:

Drug: Placebo for Hydroxychloroquine

Drug: Placebo for Azithromycin