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Poor recruitment, strong evidence from larger trials of no therapeutic benefit
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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:
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Standard of care | Active Comparator |
| |
| Standard of care plus hydroxychloroquine | Experimental | Standard of care plus hydroxychloroquine for 5 days |
|
| Standard of care plus azithromycin | Experimental | Standard of care plus azithromycin for 5 days |
|
| Standard of care plus hydroxychloroquine plus azithromycin | Experimental | Standard of care plus hydroxychloroquine plus azithromycin for 5 days |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Standard of care | Other | Standard of care |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Day 14 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Died During the Index Hospitalization | Index hospitalization, up to 46 days | |
| 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 |
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Inclusion Criteria:
Admitted to participating hospital with symptoms suggestive of COVID-19 infection OR develop symptoms of COVID-19 during hospitalization
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
Male or female adult aged 12 years or older at the time of enrollment
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
Illness of any duration that includes
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jason Stout, MD | Duke University Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke Regional Hospital | Durham | North Carolina | 27704 | United States | ||
| Duke University Hospital |
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| ID | Title | Description |
|---|---|---|
| FG000 | Standard of Care | Standard of care: Standard of care |
| FG001 | 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 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 7, 2020 | Apr 21, 2021 |
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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.
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| Hydroxychloroquine | Drug | 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 | Drug | 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 |
|
| Index hospitalization, up to 46 days |
| 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. | Day 28 |
| Hospital Length of Stay in Days for the Index Hospitalization | Index hospitalization, up to 46 days |
| Number of Participants With All-cause Study Medication Discontinuation | Number of participants who discontinued study medication for any reason | Index hospitalization, up to 46 days |
| Number of Participants With Severe Adverse Events | Day 14 |
| Durham |
| North Carolina |
| 27710 |
| United States |
| Durham VA Medical Center | Durham | North Carolina | 27710 | United States |
| Duke Raleigh Hospital | Raleigh | North Carolina | 27609 | United States |
| FG002 | 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 |
| FG003 | 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 |
| COMPLETED |
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| NOT COMPLETED |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Standard of Care | Standard of care: Standard of care |
| BG001 | 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 |
| BG002 | 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 |
| BG003 | 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 |
| BG004 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Standard Deviation | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Intention to treat (includes all randomized, excludes 1 participant who withdrew prior to outcome measurement) | Posted | Mean | Standard Deviation | units on a scale | Day 14 |
|
|
| ||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants Who Died During the Index Hospitalization | Intention to treat (1 participant who withdrew not included) | Posted | Count of Participants | Participants | Index hospitalization, up to 46 days |
| ||||||||||||||||||||||||||||||||||||||
| Secondary | Number of Days on Mechanical Ventilation | Intention to treat (1 participant who withdrew excluded) | Posted | Mean | Standard Deviation | days | Baseline |
| |||||||||||||||||||||||||||||||||||||
| Secondary | Number of Patients Not Receiving Mechanical Ventilation at Baseline Who Progress to Requiring Mechanical Ventilation During the Index Hospitalization | Intention to treat excluding 1 participant who withdrew | Posted | Count of Participants | Participants | Index hospitalization, up to 46 days |
| ||||||||||||||||||||||||||||||||||||||
| 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. | Intention to treat excluding 1 participant who withdrew | Posted | Mean | Standard Deviation | score on a scale | Day 28 |
| ||||||||||||||||||||||||||||||||||||
| Secondary | Hospital Length of Stay in Days for the Index Hospitalization | Intention to treat excluding 1 participant who withdrew | Posted | Mean | Standard Deviation | days | Index hospitalization, up to 46 days |
| |||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With All-cause Study Medication Discontinuation | Number of participants who discontinued study medication for any reason | Intention to treat excluding 1 participant who withdrew | Posted | Count of Participants | Participants | Index hospitalization, up to 46 days |
| |||||||||||||||||||||||||||||||||||||
| Secondary | Number of Participants With Severe Adverse Events | Intention to treat excluding 1 participant who withdrew | Posted | Count of Participants | Participants | Day 14 |
|
2 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Standard of Care | Standard of care: Standard of care | 0 | 1 | 0 | 1 | 0 | 1 |
| EG001 | 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 | 1 | 4 | 1 | 4 | 0 | 4 |
| EG002 | 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 | 2 | 3 | 1 | 3 | 0 | 3 |
| EG003 | 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 | 1 | 2 | 0 | 2 | 0 | 2 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Acute renal failure | Renal and urinary disorders | Systematic Assessment |
| ||
| Acute respiratory failure | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | Acute respiratory failure requiring intubation |
|
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Jason Stout, MD, MHS | Duke University | 919-668-0826 | jason.stout@dm.duke.edu |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 1, 2020 | May 13, 2021 | SAP_003.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 13, 2020 | Apr 21, 2021 | ICF_002.pdf |
| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D059039 | Standard of Care |
| D006886 | Hydroxychloroquine |
| D017963 | Azithromycin |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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| Male |
|
| Not Hispanic or Latino |
|
| Unknown or Not Reported |
|
| Asian |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
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|
|
|
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
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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 |
| OG003 | 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 |
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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 |
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