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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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COVID-19, SARS-CoV 2

Intervention / Treatment
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* Drug: Hydroxychloroquine (HCQ)
* Drug: Azithromycin (Azithro)
* Drug: Placebo for Hydroxychloroquine
* Drug: Placebo for Azithromycin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro)<br>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)<br>* Administered orally<br>Drug: Azithromycin (Azithro)<br>* Administered orally<br>|
| Placebo Comparator: Arm B: Placebo for Hydroxychloroquine and Azithromycin<br>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<br>* Administered orally<br>Drug: Placebo for Azithromycin<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died From Any Cause or Were Hospitalized | 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. | The 20-day period from and including the day of the first dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died From Any Cause | Deaths reported due to any cause (COVID-related or not) | The 20-day period from and including the day of the first dose of study treatment | 
| Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic | 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. | The 20-day period from and including the day of the first dose of study treatment | 
| Number of Participants Who Died From Any Cause or Were Hospitalized Through the End of Follow-up | 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. | From day of the first dose of study treatment to Week 24 | 
| Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event | Premature discontinuation of study treatment is defined as a permanent discontinuation of either study treatment (HCQ/Placebo and/or Azithro/Placebo) | From start of study treatment through Day 7 | 
| Number of Participants Who Had Any Cardiac Adverse Events | Cardiac adverse events included in the analysis were chosen a priori by the study chairs | From start of study treatment through Day 20 | 
| Duration of Fever | 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 | Day 0 to Day 20, 21 days total | 
| Duration of Symptoms Associated With COVID-19 Disease | 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. | Day 0 to Day 20, 21 days total | 
| Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time | 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. | Day 0 to Day 20, 21 days total | 
| Time to Self-reported Return to Usual (Pre-COVID) Health. | 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. | Day 0 to Day 20, 21 days total | 
| SARS-CoV-2 RNA Detection Status From Self-collected Nasal and Site-collected NP Swabs Among Subset | The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report | Measured at entry, Day 6, and Day 20 | 
| SARS-CoV-2 RNA Level (Continuous) From Self-collected Nasal and Site-collected NP Swabs Among Subset | The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report | Measured at entry, Day 6, and Day 20 | 
| Number of Participants With an Occurrence of Fainting | 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 | From start of study treatment through Day 20 |