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

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ClinicalTrials.gov Identifier: NCT04358068
Recruitment Status : Recruiting
First Posted : April 22, 2020
Last Update Posted : June 1, 2020
Sponsor:
Collaborator:
Teva Pharmaceuticals Industries LTD
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
The purpose of this study is 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 will 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 will be randomized 1:1 to receive active/placebo study treatment as follows: HCQ/Placebo 400 mg orally twice a day on Day 0 followed by 200 mg orally twice a day for 6 days, and Azithro/Placebo 500 mg once on Day 0, followed by 250 mg daily for 4 days.

Stratification will be by "high" versus "low" risk of progression to severe COVID-19, where "high risk" is defined as a person age ≥60 years or having at least one of several specified comorbidities.

Participants will receive study treatment for 7 days and will be followed for an additional 23 weeks. Assessments on a subset of 200 participants will include blood collection, self-collected nasal swabs, and nasopharyngeal swabs.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 2000 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 1, 2020
Estimated Primary Completion Date : October 9, 2020
Estimated Study Completion Date : March 5, 2021


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




Primary Outcome Measures :
  1. Proportion of participants who died from any cause or were hospitalized [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
    Hospitalization is 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 is not considered a hospitalization.


Secondary Outcome Measures :
  1. Proportion of participants who died from any cause [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
  2. Proportion of participants who died from any cause, or were hospitalized, or had an urgent visit to emergency room or clinic [ Time Frame: Measured during the 21-day period from and including the day of the first (confirmed) dose of study treatment ]
  3. Proportion of participants who died from any cause or were hospitalized through the end of follow-up [ Time Frame: Measured during the 24-week period from and including the day of the first (confirmed) dose of study treatment ]
    Hospitalization is 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 is not considered a hospitalization.

  4. Proportion of participants who prematurely discontinue study treatment due to an adverse event [ Time Frame: Measured through Day 7 ]
  5. Proportion of participants who had any cardiac adverse events [ Time Frame: Measured from start of study treatment through Day 20 ]
  6. Duration of fever [ Time Frame: Measured through Day 20 ]
    Defined as 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.

  7. Duration of symptoms associated with COVID-19 disease [ Time Frame: Measured through Day 20 ]
    Defined as the last day in the participant's daily diary card on which a moderate or worse symptom was recorded

  8. Participant-specific area under the curve (AUC) of the symptom score associated with COVID-19 disease over time [ Time Frame: Measured through Day 20 ]
    Defined as the sum of scores for the targeted symptoms (defined in the protocol) in the participant's daily diary record (each individual symptom is scored from 0 to 3).

  9. Time to self-reported return to usual (pre-COVID) health. [ Time Frame: Measured through Day 20 ]
  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 ]
  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 ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.
  • Experiencing at least one of the following SARS-CoV-2 infection symptoms within 24 hours of screening: fever (can be subjective) OR cough OR shortness of breath.
  • Agrees 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 21 days, whichever is earliest.
  • Agrees 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 using antiarrhythmics within the past 30 days.
  • 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.
  • Use of 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.
  • Participating in a study where co-enrollment is 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04358068


Locations
Show Show 24 study locations
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Teva Pharmaceuticals Industries LTD
Investigators
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Study Chair: Davey Smith, MD University of California, San Diego
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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    Key Record Dates
Last Update Posted: June 1, 2020
Last Verified: May 2020
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://actgnetwork.org/about-actg/templates-and-forms. Researchers of approved proposals will need to sign an AIDS Clinical Trials Group Data Use Agreement before receiving the data.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Azithromycin
Hydroxychloroquine
Anti-Bacterial Agents
Anti-Infective Agents
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antirheumatic Agents