Clinical trial NCT04358068: Evaluating the Efficacy of Hydroxychloroquine and Azithromycin to Prevent Hospitalization or Death in Persons With COVID-19
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: COVID-19
SARS-CoV 2
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Teva Pharmaceutical Industries, Ltd.
First posted: 2020-04-22
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Number of Participants Who Died From Any Cause or Were Hospitalized
timeFrame: The 20-day period from and including the day of the first dose of study treatment
Secondary outcomes:
measure: Number of Participants Who Died From Any Cause
timeFrame: The 20-day period from and including the day of the first dose of study treatment
measure: Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic
timeFrame: The 20-day period from and including the day of the first dose of study treatment
measure: Number of Participants Who Died From Any Cause or Were Hospitalized Through the End of Follow-up
timeFrame: From day of the first dose of study treatment to Week 24
measure: Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event
timeFrame: From start of study treatment through Day 7
measure: Number of Participants Who Had Any Cardiac Adverse Events
timeFrame: From start of study treatment through Day 20
measure: Duration of Fever
timeFrame: Day 0 to Day 20, 21 days total
measure: Duration of Symptoms Associated With COVID-19 Disease
timeFrame: Day 0 to Day 20, 21 days total
measure: Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time
timeFrame: Day 0 to Day 20, 21 days total
measure: Time to Self-reported Return to Usual (Pre-COVID) Health.
timeFrame: Day 0 to Day 20, 21 days total
measure: SARS-CoV-2 RNA Detection Status From Self-collected Nasal and Site-collected NP Swabs Among Subset
timeFrame: Measured at entry, Day 6, and Day 20
measure: SARS-CoV-2 RNA Level (Continuous) From Self-collected Nasal and Site-collected NP Swabs Among Subset
timeFrame: Measured at entry, Day 6, and Day 20
measure: Number of Participants With an Occurrence of Fainting
timeFrame: From start of study treatment through Day 20
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: Torrance
country: United States
facility: Harbor-UCLA CRS
state: California
city: Washington
country: United States
facility: Whitman-Walker Health CRS
state: District of Columbia
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Rush University CRS
state: Illinois
city: Greensboro
country: United States
facility: Greensboro CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh CRS
state: Pennsylvania
city: Dallas
country: United States
facility: Trinity Health and Wellness Center CRS
state: Texas
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
Study officials:
affiliation: University of California, San Diego
name: Davey Smith, MD
role: STUDY_CHAIR
References: