SARS-CoV-2
Conditions
Keywords
COVID-19
Brief summary
This is a pragmatic, randomized, open-label, incomplete factorial with nested randomization clinical trial evaluating the efficacy and safety of two potential treatments for hospitalized patients with confirmed SARS-CoV-2 infection. Participants who are hospitalized and have a positive nucleic acid amplification test for SARS-CoV-2 will undergo an initial randomization in a 1:1 ratio to one of the following regimens: Arm 1: Standard of care alone Arm 2: Standard of care plus hydroxychloroquine Participants who meet eligibility criteria to receive azithromycin will undergo a second randomization in a 1:1 ratio to receive additional concurrent therapy. This will effectively result in four treatment groups: 1. Standard of care alone 2. Standard of care plus hydroxychloroquine 3. Standard of care plus azithromycin 4. Standard of care plus hydroxychloroquine plus azithromycin
Interventions
OTHERStandard of care
Standard of care
DRUGHydroxychloroquine
Hydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5
DRUGAzithromycin
Azithromycin will be administered orally or via feeding tube at a dosage of 500 mg on day 1, followed by 250 mg daily on days 2-5
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients will be initially randomized to one of two arms in a 1:1 ratio: 1) Standard of care treatment or 2) Standard of care treatment plus 5 days of hydroxychloroquine. Participants who meet eligibility criteria to receive azithromycin will undergo a second randomization in a 1:1 ratio to receive additional concurrent therapy.
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Admitted to participating hospital with symptoms suggestive of COVID-19 infection OR develop symptoms of COVID-19 during hospitalization 2. Subject (or legally authorized representative) can provide written informed consent (in English or Spanish) affirming intention to comply with planned study procedures prior to enrollment 3. Male or female adult aged 12 years or older at the time of enrollment 4. Has laboratory-confirmed SARS-CoV-2 infection determined by a validated nucleic acid amplification assay (public health or commercial) in any respiratory specimen collected within 14 days of randomization 5. Illness of any duration that includes * Radiographic evidence of pulmonary infiltrates (chest X-ray or CT scan) OR * Clinical documentation of lower respiratory symptoms (cough, shortness of breath, wheezing) OR * Any documented SpO2 ≤ 94% on room air OR * Any inpatient initiation or supplemental oxygen regardless of documented cause
Exclusion criteria
1. Participating in any other clinical trial of an experimental agent for COVID-19 2. On hydroxychloroquine at any time during hospitalization, or within 180 days of hospitalization for COVID-19 regardless of indication 3. History of G6PD deficiency, cirrhosis, long QT syndrome or porphyria of any classification 4. Most recent ECG prior to time of screening with QTc of ≥500 msec 5. Known hypersensitivity to hydroxychloroquine or 4-aminoquinoline derivatives 6. Death anticipated within 48 hours of enrollment 7. Inability to obtain informed consent from the patient or designated medical decision maker
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | Day 14 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Days on Mechanical Ventilation | Baseline | — |
| Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | Index hospitalization, up to 46 days | — |
| WHO Ordinal Scale Measured at 28 Days After Enrollment | Day 28 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities. |
| Number of Participants Who Died During the Index Hospitalization | Index hospitalization, up to 46 days | — |
| Number of Participants With All-cause Study Medication Discontinuation | Index hospitalization, up to 46 days | Number of participants who discontinued study medication for any reason |
| Number of Participants With Severe Adverse Events | Day 14 | — |
| Hospital Length of Stay in Days for the Index Hospitalization | Index hospitalization, up to 46 days | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Standard of care: Standard of care | 2 |
| Standard of Care Plus Hydroxychloroquine Standard of care plus hydroxychloroquine for 5 days
Standard of care: Standard of care
Hydroxychloroquine: Hydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5 | 4 |
| Standard of Care Plus Azithromycin Standard of care plus azithromycin for 5 days
Standard of care: Standard of care
Azithromycin: Azithromycin will be administered orally or via feeding tube at a dosage of 500 mg on day 1, followed by 250 mg daily on days 2-5 | 3 |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin Standard of care plus hydroxychloroquine plus azithromycin for 5 days
Standard of care: Standard of care
Hydroxychloroquine: Hydroxychloroquine will be administered orally or via feeding tube at a dosage of 800 mg on day 1, followed by 600 mg daily on days 2-5
Azithromycin: Azithromycin will be administered orally or via feeding tube at a dosage of 500 mg on day 1, followed by 250 mg daily on days 2-5 | 2 |
| Total | 11 |
Baseline characteristics
| Characteristic | Standard of Care | Total | Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Standard of Care Plus Azithromycin | Standard of Care Plus Hydroxychloroquine |
|---|---|---|---|---|---|
| Age, Continuous | 56.3 years STANDARD_DEVIATION 20.5 | 54.7 years STANDARD_DEVIATION 12.9 | 50.3 years STANDARD_DEVIATION 12.5 | 57.0 years STANDARD_DEVIATION 4.2 | 59.0 years STANDARD_DEVIATION 14.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 6 Participants | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 5 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 7 Participants | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment United States | 2 Participants | 11 Participants | 2 Participants | 3 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 8 Participants | 2 Participants | 2 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 1 / 4 | 2 / 3 | 1 / 2 |
| other Total, other adverse events | 0 / 1 | 0 / 4 | 0 / 3 | 0 / 2 |
| serious Total, serious adverse events | 0 / 1 | 1 / 4 | 1 / 3 | 0 / 2 |
Outcome results
Primary
World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time frame: Day 14
Population: Intention to treat (includes all randomized, excludes 1 participant who withdrew prior to outcome measurement)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | 1 units on a scale | — |
| Standard of Care Plus Hydroxychloroquine | World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | 2.5 units on a scale | Standard Deviation 3 |
| Standard of Care Plus Azithromycin | World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | 5.3 units on a scale | Standard Deviation 3.8 |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | World Health Organization (WHO) Ordinal Scale Measured at 14 Days After Enrollment | 4.5 units on a scale | Standard Deviation 5 |
Secondary
Hospital Length of Stay in Days for the Index Hospitalization
Time frame: Index hospitalization, up to 46 days
Population: Intention to treat excluding 1 participant who withdrew
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Hospital Length of Stay in Days for the Index Hospitalization | 6 days | — |
| Standard of Care Plus Hydroxychloroquine | Hospital Length of Stay in Days for the Index Hospitalization | 9 days | Standard Deviation 11 |
| Standard of Care Plus Azithromycin | Hospital Length of Stay in Days for the Index Hospitalization | 14.7 days | Standard Deviation 14.6 |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Hospital Length of Stay in Days for the Index Hospitalization | 2.5 days | Standard Deviation 0.7 |
Secondary
Number of Days on Mechanical Ventilation
Time frame: Baseline
Population: Intention to treat (1 participant who withdrew excluded)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Number of Days on Mechanical Ventilation | 0 days | — |
| Standard of Care Plus Hydroxychloroquine | Number of Days on Mechanical Ventilation | 5.5 days | Standard Deviation 11 |
| Standard of Care Plus Azithromycin | Number of Days on Mechanical Ventilation | 8.67 days | Standard Deviation 15 |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Number of Days on Mechanical Ventilation | 0 days | Standard Deviation 0 |
Secondary
Number of Participants Who Died During the Index Hospitalization
Time frame: Index hospitalization, up to 46 days
Population: Intention to treat (1 participant who withdrew not included)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants Who Died During the Index Hospitalization | 0 Participants |
| Standard of Care Plus Hydroxychloroquine | Number of Participants Who Died During the Index Hospitalization | 1 Participants |
| Standard of Care Plus Azithromycin | Number of Participants Who Died During the Index Hospitalization | 2 Participants |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Number of Participants Who Died During the Index Hospitalization | 1 Participants |
Secondary
Number of Participants With All-cause Study Medication Discontinuation
Number of participants who discontinued study medication for any reason
Time frame: Index hospitalization, up to 46 days
Population: Intention to treat excluding 1 participant who withdrew
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With All-cause Study Medication Discontinuation | 0 Participants |
| Standard of Care Plus Hydroxychloroquine | Number of Participants With All-cause Study Medication Discontinuation | 0 Participants |
| Standard of Care Plus Azithromycin | Number of Participants With All-cause Study Medication Discontinuation | 0 Participants |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Number of Participants With All-cause Study Medication Discontinuation | 0 Participants |
Secondary
Number of Participants With Severe Adverse Events
Time frame: Day 14
Population: Intention to treat excluding 1 participant who withdrew
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Participants With Severe Adverse Events | 0 Participants |
| Standard of Care Plus Hydroxychloroquine | Number of Participants With Severe Adverse Events | 1 Participants |
| Standard of Care Plus Azithromycin | Number of Participants With Severe Adverse Events | 1 Participants |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Number of Participants With Severe Adverse Events | 0 Participants |
Secondary
Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization
Time frame: Index hospitalization, up to 46 days
Population: Intention to treat excluding 1 participant who withdrew
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Standard of Care | Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | 0 Participants |
| Standard of Care Plus Hydroxychloroquine | Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | 1 Participants |
| Standard of Care Plus Azithromycin | Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | 1 Participants |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | 0 Participants |
Secondary
WHO Ordinal Scale Measured at 28 Days After Enrollment
The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen - requiring ongoing medical care (COVID-19 related or otherwise); 6) Hospitalized, not requiring supplemental oxygen - no longer requires ongoing medical care; 7) Not hospitalized, limitation on activities and/or requiring home oxygen; 8) Not hospitalized, no limitations on activities.
Time frame: Day 28
Population: Intention to treat excluding 1 participant who withdrew
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | WHO Ordinal Scale Measured at 28 Days After Enrollment | 1 score on a scale | — |
| Standard of Care Plus Hydroxychloroquine | WHO Ordinal Scale Measured at 28 Days After Enrollment | 2.8 score on a scale | Standard Deviation 3.5 |
| Standard of Care Plus Azithromycin | WHO Ordinal Scale Measured at 28 Days After Enrollment | 5.3 score on a scale | Standard Deviation 3.8 |
| Standard of Care Plus Hydroxychloroquine Plus Azithromycin | WHO Ordinal Scale Measured at 28 Days After Enrollment | 4.5 score on a scale | Standard Deviation 5 |