COVID-19, SARS-CoV 2
Conditions
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.
Interventions
Administered orally
DRUGAzithromycin (Azithro)
Administered orally
DRUGPlacebo for Hydroxychloroquine
Administered orally
Administered orally
Sponsors
Teva Pharmaceutical Industries, Ltd.
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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) |
| 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 |
| 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 |
| 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) |
| 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. |
| 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. |
| 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 |
| 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 |
| 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 |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants were enrolled between 13MAY2020 and 15JUN2020 at US based clinical research sites
Participants by arm
| Arm | Count |
|---|---|
| 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).
Hydroxychloroquine (HCQ): Administered orally
Azithromycin (Azithro): Administered orally | 7 |
| 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).
Placebo for Hydroxychloroquine: Administered orally
Placebo for Azithromycin: Administered orally | 9 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not initiate study treatment | 2 | 2 |
Baseline characteristics
| Characteristic | Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Arm B: Placebo for Hydroxychloroquine and Azithromycin | Total |
|---|---|---|---|
| Age, Continuous | 44 years | 35 years | 39 years |
| Age, Customized < 60 years | 5 Participants | 9 Participants | 14 Participants |
| Age, Customized >= 60 years | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 6 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 14 Participants |
| Region of Enrollment United States | 7 participants | 9 participants | 16 participants |
| Risk of progression to severe disease High risk | 4 Participants | 2 Participants | 6 Participants |
| Risk of progression to severe disease Low risk | 3 Participants | 7 Participants | 10 Participants |
| Sex: Female, Male Female | 7 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 0 Participants | 5 Participants | 5 Participants |
| Time from symptom onset to treatment start | 5 days | 4 days | 5 days |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 11 |
| other Total, other adverse events | 2 / 9 | 3 / 11 |
| serious Total, serious adverse events | 0 / 9 | 1 / 11 |
Outcome results
Primary
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.
Time frame: The 20-day period from and including the day of the first dose of study treatment
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants Who Died From Any Cause or Were Hospitalized | 0 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants Who Died From Any Cause or Were Hospitalized | 1 Participants |
Secondary
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
Time frame: Day 0 to Day 20, 21 days total
Population: Participants who initiated study treatment and reported at least one temperature on the diary card
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Duration of Fever | 0 days |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Duration of Fever | 0 days |
p-value: 0.51Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Day 0 to Day 20, 21 days total
Population: Participants who initiated study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Duration of Symptoms Associated With COVID-19 Disease | 11.0 days |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Duration of Symptoms Associated With COVID-19 Disease | 10.0 days |
p-value: 0.79Wilcoxon (Mann-Whitney)
Secondary
Number of Participants Who Died From Any Cause
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
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants Who Died From Any Cause | 0 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants Who Died From Any Cause | 0 Participants |
Secondary
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.
Time frame: The 20-day period from and including the day of the first dose of study treatment
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic | 1 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants Who Died From Any Cause, or Were Hospitalized, or Had an Urgent Visit to Emergency Room or Clinic | 1 Participants |
Secondary
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.
Time frame: From day of the first dose of study treatment to Week 24
Population: Due to the early termination of the study, the data were not collected
Secondary
Number of Participants Who Had Any Cardiac Adverse Events
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
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants Who Had Any Cardiac Adverse Events | 0 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants Who Had Any Cardiac Adverse Events | 0 Participants |
Secondary
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)
Time frame: From start of study treatment through Day 7
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event | 0 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants Who Prematurely Discontinue Study Treatment Due to an Adverse Event | 1 Participants |
Secondary
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
Time frame: From start of study treatment through Day 20
Population: Participants who initiated study treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Number of Participants With an Occurrence of Fainting | 1 Participants |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Number of Participants With an Occurrence of Fainting | 1 Participants |
Secondary
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.
Time frame: Day 0 to Day 20, 21 days total
Population: Participants who initiated study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time | 4.0 score on a scale |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Participant-specific Area Under the Curve (AUC) of the Symptom Score Associated With COVID-19 Disease Over Time | 2.8 score on a scale |
p-value: 0.53Wilcoxon (Mann-Whitney)
Secondary
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
Time frame: Measured at entry, Day 6, and Day 20
Population: The virology substudy did not open to enrollment and thus no data on virologic outcomes are available
Secondary
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
Time frame: Measured at entry, Day 6, and Day 20
Population: The virology substudy did not open to enrollment and thus no data on virologic outcomes are available to report
Secondary
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.
Time frame: Day 0 to Day 20, 21 days total
Population: Participants who initiated study treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Hydroxychloroquine (HCQ) and Azithromycin (Azithro) | Time to Self-reported Return to Usual (Pre-COVID) Health. | 17.0 days |
| Arm B: Placebo for Hydroxychloroquine and Azithromycin | Time to Self-reported Return to Usual (Pre-COVID) Health. | 10.0 days |
p-value: 0.83Wilcoxon (Mann-Whitney)