Acute Respiratory Infection, Coronavirus, SARS-CoV Infection
Conditions
Keywords
COVID-19
Brief summary
ORCHID is a multicenter, blinded, placebo-controlled, randomized clinical trial evaluating hydroxychloroquine for the treatment of adults hospitalized with COVID-19. Patients, treating clinicians, and study personnel will all be blinded to study group assignment.
Detailed description
Effective therapies for COVID-19 are urgently needed. Hydroxychloroquine is an antimicrobial agent with immunomodulatory and antiviral properties that has demonstrated in vitro activity against SARS-CoV-2, the virus that causes COVID-19. Preliminary reports suggest potential efficacy in small human studies. Clinical trial data are needed to determine whether hydroxychloroquine is effective in treating COVID-19. Study Aim: To compare the effect of hydroxychloroquine versus placebo on clinical outcomes, measured using the COVID Ordinal Outcomes Scale at Day 15, among adults with COVID-19 requiring hospitalization. Study Hypothesis: Among adults hospitalized with COVID-19, administration of hydroxychloroquine will improve clinical outcomes at Day 15. .
Interventions
DRUGHydroxychloroquine
Hydroxychloroquine is available in 200 mg oral tablets of hydroxychloroquine sulfate. For this COVID-19 trial, we will use an oral or enteral dose of hydroxychloroquine 400 mg twice daily on the day of enrollment, then 200 mg twice daily for the next 4 days for a 5 day total course.
DRUGPlacebo
Participants randomized to the control group will receive a dose of placebo enterally twice daily for 5 days (a total of 10 doses). The placebo pills will be as similar as possible to the hydroxychloroquine pills to ensure blinding.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Patients, treating clinicians, trial personnel, and outcome assessors will be blinded to group assignment.
Intervention model description
Eligible participants will be randomized 1:1 to hydroxychloroquine versus placebo. Randomization will be stratified by site and be in permuted blocks of variable size.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years 2. Currently hospitalized or in an emergency department with anticipated hospitalization. 3. Symptoms of acute respiratory infection, defined as one or more of the following: 1. cough 2. fever (\> 37.5° C / 99.5° F) 3. shortness of breath (operationalized as any of the following: subjective shortness of breath reported by patient or surrogate; tachypnea with respiratory rate ≥22 /minute; hypoxemia, defined as SpO2 \<92% on room air, new receipt of supplemental oxygen to maintain SpO2 ≥92%, or increased supplemental oxygen to maintain SpO2 ≥92% for a patient on chronic oxygen therapy). 4. sore throat 4. Laboratory-confirmed SARS-CoV-2 infection within the past 10 days prior to randomization.
Exclusion criteria
1. Prisoner 2. Pregnancy 3. Breast feeding 4. Symptoms of acute respiratory infection for \>10 days before randomization 5. \>48 hours between meeting inclusion criteria and randomization 6. Seizure disorder 7. Porphyria cutanea tarda 8. Diagnosis of Long QT syndrome 9. QTc \>500 ms on electrocardiogram within 72 hours prior to enrollment 10. Known allergy to hydroxychloroquine, chloroquine, or amodiaquine 11. Receipt in the 12 hours prior to enrollment, or planned administration during the 5-day study period that treating clinicians feel cannot be substituted for another medication, of any of the following: amiodarone; cimetidine; dofetilide; phenobarbital; phenytoin; sotalol 12. Receipt of \>1 dose of hydroxychloroquine or chloroquine in the 10 days prior to enrollment 13. Inability to receive enteral medications 14. Refusal or inability to be contacted on Day 15 for clinical outcome assessment if discharged prior to day 15 15. Previous enrollment in this trial 16. The treating clinical team does not believe equipoise exists regarding the use of hydroxychloroquine for the treatment of this patient
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) | Assessed on study day 15 | We will determine the COVID Ordinal Scale for all patients on study day 15 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) | assessed on study day 8 | We will determine the COVID Ordinal Scale on study day 8 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
| COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) | assessed on study day 29 | We will determine the COVID Ordinal Scale on study day 29 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
| All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) | assessed on study day 15 | Vital status of the patient on day 15 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status. |
| All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) | assessed on study day 29 | Vital status of the patient at day 28 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status. |
| Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 | Enrollment to Day 28 | We will determine the number of patients who are either dead or on ECMO ( extracorporeal membrane oxygenation) between enrollment and day 28 |
| COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) | assessed on study day 3 | We will determine the COVID Ordinal Scale for all patients on study day 3 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms) |
| Ventilator-free Days Through Day 28 | 28 days after randomization | Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days. |
| Vasopressor-free Days Through Day 28 | 28 days after randomization | The number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 are assigned zero vasopressor free days. |
| ICU-free Days to Day 28 | 28 days after randomization | The number of days spent out of the ICU to day 28. Patients who die prior to day 28 are assigned zero ICU free days. |
| Hospital-free Days to Day 28 | 28 days after randomization | Defined as 28 days minus the number of days from randomization to discharge home.If a patient has not been discharged home prior to day 28 or dies prior to day 28, hospital free days will be zero. |
| Oxygen-free Days Through Day 28 | 28 days after randomization | The number of calendar days between randomization and 28 days later that the patient is alive and without the use of oxygen therapy. Patients who die prior to day 28 are assigned zero oxygen free days. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Thrombocytopenia to Day 28 | 28 days after randomization | We will determine the number of patients that experience thrombocytopenia between randomization and day 28 |
| Number of Patients With Lymphopenia to Day 28 | 28 days after randomization | We will determine the number of patients that experience lymphopenia between randomization and day 28 |
| Time to Recovery, Defined as Time to Reaching Level 5, 6, or 7 on the COVID Outcomes Scale, Which is the Time to the Earlier of Final Liberation From Supplemental Oxygen or Hospital Discharge | 28 days after randomization | Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge. Patients who die prior to day 28 are assigned 28 days for time to recovery. |
| Number of Patients With Severe Dermatologic Reaction to Day 28 | 28 days after randomization | We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28 |
| Number of Patients With Seizures to Day 28 | 28 days after randomization | We will determine the number of patients that experience seizure between randomization and day 28 |
| Number of Patients With Atrial Arrhythmia to Day 28 | 28 days after randomization | We will determine the number of patients that experience atrial arrhythmia between randomization and day 28 |
| Number of Patients With Ventricular Arrhythmia to Day 28 | 28 days after randomization | We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28 |
| Number of Patients With Cardiac Arrest to Day 28 | 28 days after randomization | We will determine the number of patients that experience cardiac arrest between randomization and day 28 |
| Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28 | 28 days after randomization | We will determine the number of patients that experience elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit of normal between randomization and day 28 |
| Number of Patients With Acute Pancreatitis Arrest to Day 28 | 28 days after randomization | We will determine the number of patients that experience acute pancreatitis between randomization and day 28 |
| Number of Patients With Acute Kidney Injury to day28 | 28 days after randomization | We will determine the number of patients that experience acute kidney injury between randomization and day 28 |
| Number of Patients With Receipt of Renal Replacement Therapy to Day 28 | 28 days after randomization | We will determine the number of patients that experience renal replacement therapy between randomization and day 28 |
| Number of Patients With Symptomatic Hypoglycemia to Day 28 | 28 days after randomization | We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28 |
| Number of Patients With Neutropenia to Day 28 | 28 days after randomization | We will determine the number of patients that experience neutropenia between randomization and day 28 |
| Number of Patients With Anemia to Day 28 | 28 days after randomization | We will determine the number of patients that experience anemia between randomization and day 28 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hydroxychloroquine Participants assigned to the hydroxychloroquine arm will receive hydroxychloroquine sulfate 400 mg twice daily on the day of enrollment, then 200 mg twice daily for the next 4 days for a 5 day total course.
Hydroxychloroquine: Hydroxychloroquine is available in 200 mg oral tablets of hydroxychloroquine sulfate.
For this COVID-19 trial, we will use an oral or enteral dose of hydroxychloroquine 400 mg twice daily on the day of enrollment, then 200 mg twice daily for the next 4 days for a 5 day total course. | 242 |
| Placebo Participants randomized to the control group will receive a dose of placebo enterally twice daily for 5 days (a total of 10 doses). The placebo pills will be as similar as possible to the hydroxychloroquine pills to ensure blinding.
Placebo: Participants randomized to the control group will receive a dose of placebo enterally twice daily for 5 days (a total of 10 doses). The placebo pills will be as similar as possible to the hydroxychloroquine pills to ensure blinding. | 237 |
| Total | 479 |
Baseline characteristics
| Characteristic | Hydroxychloroquine | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 58 years | 57 years | 57 years |
| Alanine aminotransferase | 30 U/L | 31 U/L | 34 U/L |
| Aspartate aminotransferase | 39 U/L | 41 U/L | 45 U/L |
| Bilateral infiltrates on chest imaging | 147 Participants | 292 Participants | 145 Participants |
| Body mass index | 31.3 kg/m^2 | 31.1 kg/m^2 | 31.1 kg/m^2 |
| Chronic Conditions Chronic artery disease | 19 Participants | 42 Participants | 23 Participants |
| Chronic Conditions Chronic kidney disease | 28 Participants | 42 Participants | 14 Participants |
| Chronic Conditions Chronic obstructive pulmonary disease | 18 Participants | 39 Participants | 21 Participants |
| Chronic Conditions Diabetes | 88 Participants | 166 Participants | 78 Participants |
| Chronic Conditions Hypertension | 136 Participants | 253 Participants | 117 Participants |
| COVID outcomes scale category at randomization 2: Hospitalized, receiving ECMO or invasive mechanical ventilation | 13 Participants | 32 Participants | 19 Participants |
| COVID outcomes scale category at randomization 3: Hospitalized, receiving noninvasive ventilation or nasal high flow oxygen | 28 Participants | 55 Participants | 27 Participants |
| COVID outcomes scale category at randomization 4: Hospitalized, receiving supplemental oxygen without positive pressure or high flow | 116 Participants | 224 Participants | 108 Participants |
| COVID outcomes scale category at randomization 5: Hospitalized, not receiving supplemental oxygen | 85 Participants | 168 Participants | 83 Participants |
| Creatinine | 0.95 mg/dL | 0.91 mg/dL | 0.90 mg/dL |
| Duration of symptoms prior to randomization | 5 days | 5 days | 5 days |
| Living at home in the community prior to hospitalization | 190 Participants | 373 Participants | 183 Participants |
| Location at time of randomization Emergency department | 34 Participants | 72 Participants | 38 Participants |
| Location at time of randomization Hospital ward | 157 Participants | 289 Participants | 132 Participants |
| Location at time of randomization Intensive care unit | 37 Participants | 91 Participants | 54 Participants |
| Platelet count | 199 cells ×10^3/μL | 199 cells ×10^3/μL | 200 cells ×10^3/μL |
| QTc interval | 430 milliseconds | 433 milliseconds | 435 milliseconds |
| Race/Ethnicity, Customized American Indian or Alaska Native | 5 Participants | 13 Participants | 8 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 11 Participants | 7 Participants |
| Race/Ethnicity, Customized Hispanic | 91 Participants | 178 Participants | 87 Participants |
| Race/Ethnicity, Customized Multi-race | 1 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 2 Participants | 6 Participants | 4 Participants |
| Race/Ethnicity, Customized Non-Hispanic Black | 57 Participants | 112 Participants | 55 Participants |
| Race/Ethnicity, Customized Non-Hispanic White | 72 Participants | 137 Participants | 65 Participants |
| Sex: Female, Male Female | 107 Participants | 212 Participants | 105 Participants |
| Sex: Female, Male Male | 135 Participants | 267 Participants | 132 Participants |
| Symptoms of acute respiratory infection Cough | 143 Participants | 283 Participants | 140 Participants |
| Symptoms of acute respiratory infection Fever (temperature > 37.5 degrees celsius) | 138 Participants | 270 Participants | 132 Participants |
| Symptoms of acute respiratory infection Shortness of breath | 175 Participants | 343 Participants | 168 Participants |
| Time between hospital presentation and randomization | 22.2 hours | 22.5 hours | 22.7 hours |
| Total SOFA score at enrollment | 2 score | 2 score | 2 score |
| Vasopressor use at enrollment | 8 Participants | 28 Participants | 20 Participants |
| White blood cell count | 6.0 cells ×10^3/μL | 5.9 cells ×10^3/μL | 5.9 cells ×10^3/μL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 25 / 242 | 25 / 237 |
| other Total, other adverse events | 30 / 242 | 21 / 237 |
| serious Total, serious adverse events | 14 / 242 | 11 / 237 |
Outcome results
Primary
COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization)
We will determine the COVID Ordinal Scale for all patients on study day 15 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms)
Time frame: Assessed on study day 15
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) | 6 score on a scale |
| Placebo | COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization) | 6 score on a scale |
Comparison: Outcome measure was adjusted for age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization.95% CI: [0.73, 1.42]
Secondary
All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization)
Vital status of the patient on day 15 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status.
Time frame: assessed on study day 15
Population: Outcome was measured in participants with available data on vital status. One patient in the hydroxychloroquine group and one patient in the placebo group were lost to follow-up for vital status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) | 18 Participants |
| Placebo | All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization) | 14 Participants |
95% CI: [0.68, 3.57]
Secondary
All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization)
Vital status of the patient at day 28 will be determined using any of the following methods: medical record review, phone calls to patient or proxy. There were two patients for whom we were unable to collect their vital status.
Time frame: assessed on study day 29
Population: Outcome was measured in participants with available data on vital status. One patient in the hydroxychloroquine group and one patient in the placebo group were lost to follow-up for vital status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) | 25 Participants |
| Placebo | All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization) | 25 Participants |
95% CI: [0.54, 2.09]
Secondary
COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization)
We will determine the COVID Ordinal Scale on study day 29 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms)
Time frame: assessed on study day 29
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) | 6 score on a scale |
| Placebo | COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization) | 6 score on a scale |
Comparison: Outcome measure is adjusted for : age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization.95% CI: [0.69, 1.38]
Secondary
COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization)
We will determine the COVID Ordinal Scale for all patients on study day 3 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms)
Time frame: assessed on study day 3
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) | 4 score on a scale |
| Placebo | COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization) | 4 score on a scale |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.9, 1.81]
Secondary
COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization)
We will determine the COVID Ordinal Scale on study day 8 COVID Ordinal Scale defined as: 1. Death 2. Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) 3. Hospitalized on non-invasive ventilation or high flow nasal cannula 4. Hospitalized on supplemental oxygen 5. Hospitalized not on supplemental oxygen 6. Not hospitalized with limitation in activity (continued symptoms) 7. Not hospitalized without limitation in activity (no symptoms)
Time frame: assessed on study day 8
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) | 5 score on a scale |
| Placebo | COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization) | 6 score on a scale |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.84, 1.61]
Secondary
Hospital-free Days to Day 28
Defined as 28 days minus the number of days from randomization to discharge home.If a patient has not been discharged home prior to day 28 or dies prior to day 28, hospital free days will be zero.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | Hospital-free Days to Day 28 | 21 days |
| Placebo | Hospital-free Days to Day 28 | 20 days |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.85, 1.61]
Secondary
ICU-free Days to Day 28
The number of days spent out of the ICU to day 28. Patients who die prior to day 28 are assigned zero ICU free days.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | ICU-free Days to Day 28 | 28 days |
| Placebo | ICU-free Days to Day 28 | 28 days |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.84, 1.88]
Secondary
Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28
We will determine the number of patients who are either dead or on ECMO ( extracorporeal membrane oxygenation) between enrollment and day 28
Time frame: Enrollment to Day 28
Population: Outcome was measured in participants with available data on vital status or ECMO. One patient in the hydroxychloroquine group and one patient in the placebo group were lost to follow-up for vital status.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 | 29 Participants |
| Placebo | Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28 | 28 Participants |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.6, 2.14]
Secondary
Oxygen-free Days Through Day 28
The number of calendar days between randomization and 28 days later that the patient is alive and without the use of oxygen therapy. Patients who die prior to day 28 are assigned zero oxygen free days.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | Oxygen-free Days Through Day 28 | 21 days |
| Placebo | Oxygen-free Days Through Day 28 | 20 days |
Comparison: Outcome measure was adjusted for age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.68, 1.34]
Secondary
Vasopressor-free Days Through Day 28
The number of calendar days between randomization and 28 days later that the patient is alive and without the use of vasopressor therapy. Patients who die prior to day 28 are assigned zero vasopressor free days.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | Vasopressor-free Days Through Day 28 | 28 days |
| Placebo | Vasopressor-free Days Through Day 28 | 28 days |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.61, 1.72]
Secondary
Ventilator-free Days Through Day 28
Ventilator-free days is defined to be 28 days minus the duration of mechanical ventilation through day 28. Participants who do not survive to day 28 are assigned zero ventilator-free days.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | Ventilator-free Days Through Day 28 | 28 days |
| Placebo | Ventilator-free Days Through Day 28 | 28 days |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.76, 2.08]
Other Pre-specified
Number of Patients With Acute Kidney Injury to day28
We will determine the number of patients that experience acute kidney injury between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Acute Kidney Injury to day28 | 37 Participants |
| Placebo | Number of Patients With Acute Kidney Injury to day28 | 37 Participants |
95% CI: [0.59, 1.59]
Other Pre-specified
Number of Patients With Acute Pancreatitis Arrest to Day 28
We will determine the number of patients that experience acute pancreatitis between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Acute Pancreatitis Arrest to Day 28 | 5 Participants |
| Placebo | Number of Patients With Acute Pancreatitis Arrest to Day 28 | 6 Participants |
95% CI: [0.24, 2.7]
Other Pre-specified
Number of Patients With Anemia to Day 28
We will determine the number of patients that experience anemia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Anemia to Day 28 | 139 Participants |
| Placebo | Number of Patients With Anemia to Day 28 | 120 Participants |
95% CI: [0.92, 1.89]
Other Pre-specified
Number of Patients With Atrial Arrhythmia to Day 28
We will determine the number of patients that experience atrial arrhythmia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Atrial Arrhythmia to Day 28 | 15 Participants |
| Placebo | Number of Patients With Atrial Arrhythmia to Day 28 | 11 Participants |
95% CI: [0.61, 3.02]
Other Pre-specified
Number of Patients With Cardiac Arrest to Day 28
We will determine the number of patients that experience cardiac arrest between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Cardiac Arrest to Day 28 | 10 Participants |
| Placebo | Number of Patients With Cardiac Arrest to Day 28 | 4 Participants |
95% CI: [0.78, 8.12]
Other Pre-specified
Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28
We will determine the number of patients that experience elevation in aspartate aminotransferase or alanine aminotransferase to twice the local upper limit of normal between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28 | 50 Participants |
| Placebo | Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28 | 65 Participants |
95% CI: [0.45, 1.05]
Other Pre-specified
Number of Patients With Lymphopenia to Day 28
We will determine the number of patients that experience lymphopenia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Lymphopenia to Day 28 | 92 Participants |
| Placebo | Number of Patients With Lymphopenia to Day 28 | 87 Participants |
95% CI: [0.73, 1.53]
Other Pre-specified
Number of Patients With Neutropenia to Day 28
We will determine the number of patients that experience neutropenia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Neutropenia to Day 28 | 4 Participants |
| Placebo | Number of Patients With Neutropenia to Day 28 | 4 Participants |
95% CI: [0.24, 3.96]
Other Pre-specified
Number of Patients With Receipt of Renal Replacement Therapy to Day 28
We will determine the number of patients that experience renal replacement therapy between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Receipt of Renal Replacement Therapy to Day 28 | 10 Participants |
| Placebo | Number of Patients With Receipt of Renal Replacement Therapy to Day 28 | 14 Participants |
95% CI: [0.3, 1.58]
Other Pre-specified
Number of Patients With Seizures to Day 28
We will determine the number of patients that experience seizure between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Seizures to Day 28 | 1 Participants |
| Placebo | Number of Patients With Seizures to Day 28 | 0 Participants |
95% CI: [-1, 1.8]
Other Pre-specified
Number of Patients With Severe Dermatologic Reaction to Day 28
We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Severe Dermatologic Reaction to Day 28 | 1 Participants |
| Placebo | Number of Patients With Severe Dermatologic Reaction to Day 28 | 1 Participants |
95% CI: [0.06, 15.74]
Other Pre-specified
Number of Patients With Symptomatic Hypoglycemia to Day 28
We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Symptomatic Hypoglycemia to Day 28 | 10 Participants |
| Placebo | Number of Patients With Symptomatic Hypoglycemia to Day 28 | 8 Participants |
95% CI: [0.48, 3.18]
Other Pre-specified
Number of Patients With Thrombocytopenia to Day 28
We will determine the number of patients that experience thrombocytopenia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Thrombocytopenia to Day 28 | 4 Participants |
| Placebo | Number of Patients With Thrombocytopenia to Day 28 | 5 Participants |
95% CI: [0.21, 2.94]
Other Pre-specified
Number of Patients With Ventricular Arrhythmia to Day 28
We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28
Time frame: 28 days after randomization
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hydroxychloroquine | Number of Patients With Ventricular Arrhythmia to Day 28 | 5 Participants |
| Placebo | Number of Patients With Ventricular Arrhythmia to Day 28 | 6 Participants |
95% CI: [0.24, 2.7]
Other Pre-specified
Time to Recovery, Defined as Time to Reaching Level 5, 6, or 7 on the COVID Outcomes Scale, Which is the Time to the Earlier of Final Liberation From Supplemental Oxygen or Hospital Discharge
Time to recovery, defined as time to reaching level 5, 6, or 7 on the COVID Outcomes Scale, which is the time to the earlier of final liberation from supplemental oxygen or hospital discharge. Patients who die prior to day 28 are assigned 28 days for time to recovery.
Time frame: 28 days after randomization
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hydroxychloroquine | Time to Recovery, Defined as Time to Reaching Level 5, 6, or 7 on the COVID Outcomes Scale, Which is the Time to the Earlier of Final Liberation From Supplemental Oxygen or Hospital Discharge | 5 days |
| Placebo | Time to Recovery, Defined as Time to Reaching Level 5, 6, or 7 on the COVID Outcomes Scale, Which is the Time to the Earlier of Final Liberation From Supplemental Oxygen or Hospital Discharge | 6 days |
Comparison: Outcome measure was adjusted for: age, sex, baseline COVID Outcome Scale category, baseline Sequential Organ Failure Assessment score, and duration of acute respiratory infection symptoms prior to randomization95% CI: [0.69, 1.35]