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

Sponsor
National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
Overall Status
Terminated
CT.gov ID
NCT04358068
Collaborator
Teva Pharmaceutical Industries, Ltd. (Industry)
20
11
2
1.8
1.8
1

Study Details

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
  • 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
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 :
Jul 8, 2020
Actual Study Completion Date :
Jul 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 [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 [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 [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 [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 [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 [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 [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 [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 [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. [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 [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 [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 [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

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Site City State Country Postal Code
1 Alabama CRS Birmingham Alabama United States 35294
2 UCSD Antiviral Research Center CRS San Diego California United States 92103
3 Harbor-UCLA CRS Torrance California United States 90502
4 Whitman-Walker Health CRS Washington District of Columbia United States 20009
5 Northwestern University CRS Chicago Illinois United States 60611
6 Rush University CRS Chicago Illinois United States 60612
7 Greensboro CRS Greensboro North Carolina United States 27401
8 Cincinnati Clinical Research Site Cincinnati Ohio United States 45219
9 University of Pittsburgh CRS Pittsburgh Pennsylvania United States 15213
10 Trinity Health and Wellness Center CRS Dallas Texas United States 75208
11 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)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT04358068
Other Study ID Numbers:
  • ACTG A5395
  • 38720
First Posted:
Apr 22, 2020
Last Update Posted:
Nov 16, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Participants were enrolled between 13MAY2020 and 15JUN2020 at US based clinical research sites
Pre-assignment Detail
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Period Title: Overall Study
STARTED 9 11
COMPLETED 7 9
NOT COMPLETED 2 2

Baseline Characteristics

Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin Total
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally Total of all reporting groups
Overall Participants 7 9 16
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
44
35
39
Age, Customized (Count of Participants)
< 60 years
5
71.4%
9
100%
14
87.5%
>= 60 years
2
28.6%
0
0%
2
12.5%
Sex: Female, Male (Count of Participants)
Female
7
100%
4
44.4%
11
68.8%
Male
0
0%
5
55.6%
5
31.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
2
28.6%
2
22.2%
4
25%
Not Hispanic or Latino
5
71.4%
6
66.7%
11
68.8%
Unknown or Not Reported
0
0%
1
11.1%
1
6.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
0
0%
0
0%
0
0%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
1
14.3%
0
0%
1
6.3%
White
6
85.7%
8
88.9%
14
87.5%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
1
11.1%
1
6.3%
Region of Enrollment (participants) [Number]
United States
7
100%
9
100%
16
100%
Risk of progression to severe disease (Count of Participants)
High risk
4
57.1%
2
22.2%
6
37.5%
Low risk
3
42.9%
7
77.8%
10
62.5%
Time from symptom onset to treatment start (days) [Median (Full Range) ]
Median (Full Range) [days]
5
4
5

Outcome Measures

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

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
0
0%
1
11.1%
2. Secondary Outcome
Title Number of Participants Who Died From Any Cause
Description Deaths reported due to any cause (COVID-related or not)
Time Frame The 20-day period from and including the day of the first dose of study treatment

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
0
0%
0
0%
3. Secondary Outcome
Title Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic
Description 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.
Time Frame The 20-day period from and including the day of the first dose of study treatment

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
1
14.3%
1
11.1%
4. Secondary Outcome
Title Number of Participants Who Died From Any Cause or Were Hospitalized Through the End of Follow-up
Description 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.
Time Frame From day of the first dose of study treatment to Week 24

Outcome Measure Data

Analysis Population Description
Due to the early termination of the study, the data were not collected
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 0 0
5. Secondary Outcome
Title Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event
Description Premature discontinuation of study treatment is defined as a permanent discontinuation of either study treatment (HCQ/Placebo and/or Azithro/Placebo)
Time Frame From start of study treatment through Day 7

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
0
0%
1
11.1%
6. Secondary Outcome
Title Number of Participants Who Had Any Cardiac Adverse Events
Description Cardiac adverse events included in the analysis were chosen a priori by the study chairs
Time Frame From start of study treatment through Day 20

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
0
0%
0
0%
7. Secondary Outcome
Title Duration of Fever
Description 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
Time Frame Day 0 to Day 20, 21 days total

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment and reported at least one temperature on the diary card
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 8
Median (Full Range) [days]
0
0
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro), Arm B: Placebo for Hydroxychloroquine and Azithromycin
Comments
Type of Statistical Test Superiority
Comments Participant specific durations were compared between randomized arms using a two-sided Wilcoxon test with a two-sided 5% type I error rate
Statistical Test of Hypothesis p-Value 0.51
Comments Wilcoxon Test was not stratified by high/low risk because of the small number enrolled
Method Wilcoxon (Mann-Whitney)
Comments
8. Secondary Outcome
Title Duration of Symptoms Associated With COVID-19 Disease
Description 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.
Time Frame Day 0 to Day 20, 21 days total

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Median (Full Range) [days]
11.0
10.0
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro), Arm B: Placebo for Hydroxychloroquine and Azithromycin
Comments
Type of Statistical Test Superiority
Comments Participant specific durations were compared between randomized arms using a two-sided Wilcoxon test with a two-sided 5% type I error rate
Statistical Test of Hypothesis p-Value 0.79
Comments Wilcoxon Test was not stratified by high/low risk because of the small number enrolled
Method Wilcoxon (Mann-Whitney)
Comments
9. Secondary Outcome
Title Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time
Description 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.
Time Frame Day 0 to Day 20, 21 days total

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Median (Full Range) [score on a scale]
4.0
2.8
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro), Arm B: Placebo for Hydroxychloroquine and Azithromycin
Comments
Type of Statistical Test Superiority
Comments Participant specific AUCs were compared between randomized arms using a two-sided Wilcoxon test with a two-sided 5% type I error rate
Statistical Test of Hypothesis p-Value 0.53
Comments Wilcoxon Test was not stratified by high/low risk because of the small number enrolled
Method Wilcoxon (Mann-Whitney)
Comments
10. Secondary Outcome
Title Time to Self-reported Return to Usual (Pre-COVID) Health.
Description 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.
Time Frame Day 0 to Day 20, 21 days total

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Median (Full Range) [days]
17.0
10.0
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro), Arm B: Placebo for Hydroxychloroquine and Azithromycin
Comments
Type of Statistical Test Superiority
Comments Participant specific durations were compared between randomized arms using a two-sided Wilcoxon test with a two-sided 5% type I error rate
Statistical Test of Hypothesis p-Value 0.83
Comments Wilcoxon Test was not stratified by high/low risk because of the small number enrolled
Method Wilcoxon (Mann-Whitney)
Comments
11. Secondary Outcome
Title SARS-CoV-2 RNA Detection Status From Self-collected Nasal and Site-collected NP Swabs Among Subset
Description The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
Time Frame Measured at entry, Day 6, and Day 20

Outcome Measure Data

Analysis Population Description
The virology substudy did not open to enrollment and thus no data on virologic outcomes are available
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 0 0
12. Secondary Outcome
Title SARS-CoV-2 RNA Level (Continuous) From Self-collected Nasal and Site-collected NP Swabs Among Subset
Description The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
Time Frame Measured at entry, Day 6, and Day 20

Outcome Measure Data

Analysis Population Description
The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 0 0
13. Secondary Outcome
Title Number of Participants With an Occurrence of Fainting
Description 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
Time Frame From start of study treatment through Day 20

Outcome Measure Data

Analysis Population Description
Participants who initiated study treatment
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
Measure Participants 7 9
Count of Participants [Participants]
1
14.3%
1
11.1%

Adverse Events

Time Frame From enrollment to the end of follow up (Participants were asked to complete the Day 20 visit and then were discontinued from the study)
Adverse Event Reporting Description Post-entry adverse event (AE) reporting requirements were: All Grade ≥3 AEs; All cardiac AEs regardless of grade; All AEs that led to a change in study treatment/intervention regardless of grade; All AEs meeting SAE definition or EAE reporting requirement. DAIDS AE Grading Table, Version 2.1 and DAIDS EAE Manual Version 2.0 were used for this study.
Arm/Group Title Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Arm/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). Hydroxychloroquine (HCQ): Administered orally Azithromycin (Azithro): Administered orally 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). Placebo for Hydroxychloroquine: Administered orally Placebo for Azithromycin: Administered orally
All Cause Mortality
Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/9 (0%) 0/11 (0%)
Serious Adverse Events
Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/9 (0%) 1/11 (9.1%)
Infections and infestations
COVID-19 0/9 (0%) 1/11 (9.1%)
Other (Not Including Serious) Adverse Events
Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) Arm B: Placebo for Hydroxychloroquine and Azithromycin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/9 (22.2%) 3/11 (27.3%)
Ear and labyrinth disorders
Tinnitus 0/9 (0%) 1/11 (9.1%)
Gastrointestinal disorders
Diarrhoea 1/9 (11.1%) 1/11 (9.1%)
Nausea 2/9 (22.2%) 0/11 (0%)
General disorders
Pyrexia 1/9 (11.1%) 0/11 (0%)
Infections and infestations
Urinary tract infection 1/9 (11.1%) 0/11 (0%)
Nervous system disorders
Ageusia 1/9 (11.1%) 1/11 (9.1%)
Anosmia 1/9 (11.1%) 1/11 (9.1%)
Psychiatric disorders
Confusional state 0/9 (0%) 1/11 (9.1%)
Respiratory, thoracic and mediastinal disorders
Cough 1/9 (11.1%) 2/11 (18.2%)
Dyspnoea 1/9 (11.1%) 0/11 (0%)
Nasal obstruction 0/9 (0%) 1/11 (9.1%)

Limitations/Caveats

The study was terminated early 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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title ACTG Clinicaltrials.gov Coordinator
Organization ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company
Phone (301) 628-3348
Email ACTGCT.gov@fstrf.org
Responsible Party:
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT04358068
Other Study ID Numbers:
  • ACTG A5395
  • 38720
First Posted:
Apr 22, 2020
Last Update Posted:
Nov 16, 2021
Last Verified:
Oct 1, 2021