ORCHID: Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT04332991
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 479
• Locations: 40
• Arms: 2
• Actual Duration (Months): 3.7
• Patients Per Site: 12
• Patients Per Site Per Month: 3.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Coronavirus; Acute Respiratory Infection; SARS-CoV Infection	Drug: Hydroxychloroquine; Drug: Placebo	Phase 3

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.

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Study Design

• Study Type: Interventional
• Actual Enrollment: 479 participants
• Allocation: Randomized
• Intervention Model: Parallel 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.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.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Patients, treating clinicians, trial personnel, and outcome assessors will be blinded to group assignment.
• Primary Purpose: Treatment
• Official Title: Outcomes Related to COVID-19 Treated With Hydroxychloroquine Among In-patients With Symptomatic Disease
• Actual Study Start Date: Apr 2, 2020
• Actual Primary Completion Date: Jun 19, 2020
• Actual Study Completion Date: Jul 23, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hydroxychlorquine 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.	Drug: 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.
Placebo Comparator: 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.	Drug: 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.

Outcome Measures

Primary Outcome Measures

1. 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: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)

Secondary Outcome Measures

1. 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: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)

2. 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: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)

3. 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: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)

4. 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.

5. 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.

6. 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

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

Other Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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:

4. cough

5. fever (> 37.5° C / 99.5° F)

6. 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).

7. sore throat

8. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85721
2	UCSF Fresno	Fresno	California	United States	93701
3	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095
4	UC Davis Medical Center	Sacramento	California	United States	95817
5	UCSF Medical Center	San Francisco	California	United States	94143
6	Stanford University	Stanford	California	United States	94305
7	Medical Center of Aurora	Aurora	Colorado	United States	80045
8	University of Colorado Hospital	Aurora	Colorado	United States	80045
9	Denver Health Medical Center	Denver	Colorado	United States	80204
10	St. Joseph Hospital	Denver	Colorado	United States	80218
11	University of Florida	Gainesville	Florida	United States	32608
12	University of Kentucky	Lexington	Kentucky	United States	40506
13	University Medical Center	New Orleans	Louisiana	United States	70112
14	Maine Medical Center	Portland	Maine	United States	04102
15	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
16	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
17	Brigham and Women's Hospital	Boston	Massachusetts	United States	02445
18	Baystate Medical Center	Springfield	Massachusetts	United States	01199
19	St. Vincent's Hospital	Worcester	Massachusetts	United States	01608
20	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
21	Henry Ford Medical Center	Detroit	Michigan	United States	48025
22	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216
23	Montefiore Medical Center-Weiler	Bronx	New York	United States	10461
24	Montefiore Medical Center-Moses	Bronx	New York	United States	10467
25	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina	United States	27157
26	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
27	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
28	Ohio State University Wexner Medical Center	Columbus	Ohio	United States	43210
29	Oregon Health and Science University	Portland	Oregon	United States	97239
30	Penn State Hershey Medical Center	Hershey	Pennsylvania	United States	17033
31	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
32	UPMC Presbyterian/Mercy/Shadyside	Pittsburgh	Pennsylvania	United States	15261
33	Medical University of South Carolina	Charleston	South Carolina	United States	29425
34	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37221
35	University of Texas Health Science Center	Houston	Texas	United States	77030
36	Intermountain Medical Center	Murray	Utah	United States	84107
37	University of Utah Hospital	Salt Lake City	Utah	United States	84132
38	VCU Medical Center	Richmond	Virginia	United States	23298
39	Harborview Medical Center	Seattle	Washington	United States	98104
40	Swedish Hospital First Hill	Seattle	Washington	United States	98122

Sponsors and Collaborators

• Massachusetts General Hospital
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Boyd Taylor Thompson, MD, Massachusetts General Hospital

Study Documents (Full-Text)

• Study Protocol - Jun 4, 2020
• Statistical Analysis Plan - Jun 17, 2020

More Information

Additional Information:

• Website for the PETAL Network

Publications

None provided.

• Responsible Party: Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT04332991
• Other Study ID Numbers: PETAL 05 Orchid
• First Posted: Apr 3, 2020
• Last Update Posted: Mar 17, 2021
• Last Verified: Mar 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Boyd Taylor Thompson, Co-Prinicipal Investigator PETAL CCC, Massachusetts General Hospital: COVID-19
• Additional relevant MeSH terms: Infections; Communicable Diseases; COVID-19; Respiratory Tract Infections; Severe Acute Respiratory Syndrome; Hydroxychloroquine

Study Results

Participant Flow

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	242	237
COMPLETED	242	237
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Hydroxychloroquine	Placebo	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	242	237	479
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	58	57	57
Sex: Female, Male (Count of Participants)
Female	107 44.2%	105 44.3%	212 44.3%
Male	135 55.8%	132 55.7%	267 55.7%
Race/Ethnicity, Customized (Count of Participants)
Non-Hispanic White	72 29.8%	65 27.4%	137 28.6%
Non-Hispanic Black	57 23.6%	55 23.2%	112 23.4%
Hispanic	91 37.6%	87 36.7%	178 37.2%
Asian	4 1.7%	7 3%	11 2.3%
Native Hawaiian or other Pacific Islander	2 0.8%	4 1.7%	6 1.3%
Multi-race	1 0.4%	1 0.4%	2 0.4%
American Indian or Alaska Native	5 2.1%	8 3.4%	13 2.7%
Living at home in the community prior to hospitalization (Count of Participants)
Count of Participants [Participants]	190 78.5%	183 77.2%	373 77.9%
Body mass index (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	31.3	31.1	31.1
Chronic Conditions (Count of Participants)
Hypertension	136 56.2%	117 49.4%	253 52.8%
Diabetes	88 36.4%	78 32.9%	166 34.7%
Chronic kidney disease	28 11.6%	14 5.9%	42 8.8%
Chronic artery disease	19 7.9%	23 9.7%	42 8.8%
Chronic obstructive pulmonary disease	18 7.4%	21 8.9%	39 8.1%
Location at time of randomization (Count of Participants)
Hospital ward	157 64.9%	132 55.7%	289 60.3%
Intensive care unit	37 15.3%	54 22.8%	91 19%
Emergency department	34 14%	38 16%	72 15%
Symptoms of acute respiratory infection (Count of Participants)
Shortness of breath	175 72.3%	168 70.9%	343 71.6%
Cough	143 59.1%	140 59.1%	283 59.1%
Fever (temperature > 37.5 degrees celsius)	138 57%	132 55.7%	270 56.4%
Duration of symptoms prior to randomization (days) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [days]	5	5	5
Time between hospital presentation and randomization (hours) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [hours]	22.2	22.7	22.5
COVID outcomes scale category at randomization (Count of Participants)
2: Hospitalized, receiving ECMO or invasive mechanical ventilation	13 5.4%	19 8%	32 6.7%
3: Hospitalized, receiving noninvasive ventilation or nasal high flow oxygen	28 11.6%	27 11.4%	55 11.5%
4: Hospitalized, receiving supplemental oxygen without positive pressure or high flow	116 47.9%	108 45.6%	224 46.8%
5: Hospitalized, not receiving supplemental oxygen	85 35.1%	83 35%	168 35.1%
Vasopressor use at enrollment (Count of Participants)
Count of Participants [Participants]	8 3.3%	20 8.4%	28 5.8%
Total SOFA score at enrollment (score) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [score]	2	2	2
White blood cell count (cells ×10^3/μL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells ×10^3/μL]	6.0	5.9	5.9
Platelet count (cells ×10^3/μL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells ×10^3/μL]	199	200	199
Creatinine (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	0.95	0.90	0.91
Aspartate aminotransferase (U/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [U/L]	39	45	41
Alanine aminotransferase (U/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [U/L]	30	34	31
Bilateral infiltrates on chest imaging (Count of Participants)
Count of Participants [Participants]	147 60.7%	145 61.2%	292 61%
QTc interval (milliseconds) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [milliseconds]	430	435	433

Outcome Measures

1. Primary Outcome

Title	COVID Outcomes Scale Score on Study Day 15 (14 Days After Randomization)
Description	We will determine the COVID Ordinal Scale for all patients on study day 15 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)
Time Frame	Assessed on study day 15

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [score on a scale]	6	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group.

2. Secondary Outcome

Title	COVID Ordinal Outcomes Scale on Study Day 3 (2 Days After Randomization)
Description	We will determine the COVID Ordinal Scale for all patients on study day 3 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)
Time Frame	assessed on study day 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [score on a scale]	4	4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; 0.90 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

3. Secondary Outcome

Title	COVID Ordinal Outcomes Scale on Study Day 8 (7 Days After Randomization)
Description	We will determine the COVID Ordinal Scale on study day 8 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)
Time Frame	assessed on study day 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [score on a scale]	5	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

4. Secondary Outcome

Title	COVID Ordinal Outcomes Scale on Study Day 29 (28 Days After Randomization)
Description	We will determine the COVID Ordinal Scale on study day 29 COVID Ordinal Scale defined as: Death Hospitalized on invasive mechanical ventilation or ECMO ( extracorporeal membrane oxygenation) Hospitalized on non-invasive ventilation or high flow nasal cannula Hospitalized on supplemental oxygen Hospitalized not on supplemental oxygen Not hospitalized with limitation in activity (continued symptoms) Not hospitalized without limitation in activity (no symptoms)
Time Frame	assessed on study day 29

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [score on a scale]	6	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.38
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

5. Secondary Outcome

Title	All-location, All-cause Mortality Assessed on Study Day 15 (14 Days After Randomization)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	241	236
Count of Participants [Participants]	18 7.4%	14 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.56
	Confidence Interval	(2-Sided) 95%; 0.68 to 3.57
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

6. Secondary Outcome

Title	All-location, All-cause Mortality Assessed on Study Day 29 (28 Days After Randomization)
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	241	236
Count of Participants [Participants]	25 10.3%	25 10.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.54 to 2.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

7. Secondary Outcome

Title	Number of Patients Dead or With Receipt of ECMO Between Enrollment and Day 28
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	241	236
Count of Participants [Participants]	29 12%	28 11.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; 0.60 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

8. Secondary Outcome

Title	Oxygen-free Days Through Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	21	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.68 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

9. Secondary Outcome

Title	Ventilator-free Days Through Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	28	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.76 to 2.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

10. Secondary Outcome

Title	Vasopressor-free Days Through Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	28	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.72
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

11. Secondary Outcome

Title	ICU-free Days to Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	28	28

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

12. Secondary Outcome

Title	Hospital-free Days to Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	21	20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.17
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated more favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

13. Other Pre-specified Outcome

Title	Number of Patients With Seizures to Day 28
Description	We will determine the number of patients that experience seizure between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	1 0.4%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 1.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Other Pre-specified Outcome

Title	Number of Patients With Atrial Arrhythmia to Day 28
Description	We will determine the number of patients that experience atrial arrhythmia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	15 6.2%	11 4.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.61 to 3.02
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

15. Other Pre-specified Outcome

Title	Number of Patients With Ventricular Arrhythmia to Day 28
Description	We will determine the number of patients that experience ventricular arrhythmia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	5 2.1%	6 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.24 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

16. Other Pre-specified Outcome

Title	Number of Patients With Cardiac Arrest to Day 28
Description	We will determine the number of patients that experience cardiac arrest between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	10 4.1%	4 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.51
	Confidence Interval	(2-Sided) 95%; 0.78 to 8.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

17. Other Pre-specified Outcome

Title	Number of Patients With Elevation in Aspartate Aminotransferase or Alanine Aminotransferase to Twice the Local Upper Limit of Normal to Day 28
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	50 20.7%	65 27.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

18. Other Pre-specified Outcome

Title	Number of Patients With Acute Pancreatitis Arrest to Day 28
Description	We will determine the number of patients that experience acute pancreatitis between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	5 2.1%	6 2.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.24 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

19. Other Pre-specified Outcome

Title	Number of Patients With Acute Kidney Injury to day28
Description	We will determine the number of patients that experience acute kidney injury between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	37 15.3%	37 15.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

20. Other Pre-specified Outcome

Title	Number of Patients With Receipt of Renal Replacement Therapy to Day 28
Description	We will determine the number of patients that experience renal replacement therapy between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	10 4.1%	14 5.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.30 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

21. Other Pre-specified Outcome

Title	Number of Patients With Symptomatic Hypoglycemia to Day 28
Description	We will determine the number of patients that experience symptomatic hypoglycemia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	10 4.1%	8 3.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.23
	Confidence Interval	(2-Sided) 95%; 0.48 to 3.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

22. Other Pre-specified Outcome

Title	Number of Patients With Neutropenia to Day 28
Description	We will determine the number of patients that experience neutropenia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	4 1.7%	4 1.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.24 to 3.96
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

23. Other Pre-specified Outcome

Title	Number of Patients With Lymphopenia to Day 28
Description	We will determine the number of patients that experience lymphopenia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	92 38%	87 36.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.73 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

24. Other Pre-specified Outcome

Title	Number of Patients With Anemia to Day 28
Description	We will determine the number of patients that experience anemia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	139 57.4%	120 50.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

25. Other Pre-specified Outcome

Title	Number of Patients With Thrombocytopenia to Day 28
Description	We will determine the number of patients that experience thrombocytopenia between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	4 1.7%	5 2.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.21 to 2.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

26. Other Pre-specified Outcome

Title	Number of Patients With Severe Dermatologic Reaction to Day 28
Description	We will determine the number of patients that experience severe dermatologic reaction between randomization and day 28
Time Frame	28 days after randomization

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Count of Participants [Participants]	1 0.4%	1 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.06 to 15.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

27. Other Pre-specified Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Hydroxychloroquine	Placebo
Arm/Group Description	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.	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.
Measure Participants	242	237
Median (Inter-Quartile Range) [days]	5	6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hydroxychloroquine, Placebo
	Comments	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
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratios greater than 1.0 indicated less favorable outcomes for patients in the hydroxychloroquine group compared with the placebo group

Adverse Events

Time Frame	Subjects were assessed for adverse events from enrollment through study day 29 or discharge, whichever occurs first. Investigators will determine if the event is serious or related to study drug.
Arm/Group Title	Hydroxychlorquine		Placebo
Arm/Group Description	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.		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.
All Cause Mortality
	Hydroxychlorquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/242 (10.3%)		25/237 (10.5%)
Serious Adverse Events
	Hydroxychlorquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/242 (5.8%)		11/237 (4.6%)
Cardiac disorders
Cardiac Arrest	0/242 (0%)	0	2/237 (0.8%)	2
Myocardial Infarction	1/242 (0.4%)	1	0/237 (0%)	0
Ventricular Tachycardia	0/242 (0%)	0	1/237 (0.4%)	1
Gastrointestinal disorders
Abdominal Distension	0/242 (0%)	0	1/237 (0.4%)	1
Bleeding Gastrointestinal	1/242 (0.4%)	1	0/237 (0%)	0
Gall stones	0/242 (0%)	0	1/237 (0.4%)	1
Nausea, Vomiting, Hematemesis	1/242 (0.4%)	1	0/237 (0%)	0
Obstruction Bowel	1/242 (0.4%)	1	0/237 (0%)	0
General disorders
Death	2/242 (0.8%)	2	0/237 (0%)	0
Investigations
Hypokalemia	0/242 (0%)	0	1/237 (0.4%)	1
Reaction Nonspecific	1/242 (0.4%)	1	1/237 (0.4%)	1
Musculoskeletal and connective tissue disorders
Hematoma Muscle	1/242 (0.4%)	1	0/237 (0%)	0
Joint Pain	1/242 (0.4%)	1	0/237 (0%)	0
Nervous system disorders
Edema Cerebral	1/242 (0.4%)	1	0/237 (0%)	0
Encephalopathy	1/242 (0.4%)	1	0/237 (0%)	0
Headache	0/242 (0%)	0	1/237 (0.4%)	1
Intracranial hemorrhage	0/242 (0%)	0	1/237 (0.4%)	1
Stroke	1/242 (0.4%)	1	2/237 (0.8%)	2
Respiratory, thoracic and mediastinal disorders
Hypoxia	2/242 (0.8%)	2	0/237 (0%)	0
Pneumothorax	2/242 (0.8%)	2	0/237 (0%)	0
Respiratory Distress	1/242 (0.4%)	1	0/237 (0%)	0
Shortness of Breath	1/242 (0.4%)	1	0/237 (0%)	0
Vascular disorders
Hemorrhage Retroperitoneal	0/242 (0%)	0	1/237 (0.4%)	1
Other (Not Including Serious) Adverse Events
	Hydroxychlorquine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/242 (12.4%)		21/237 (8.9%)
Blood and lymphatic system disorders
Leukocytosis	1/242 (0.4%)	1	0/237 (0%)	0
Cardiac disorders
Atrial Arrythmia	1/242 (0.4%)	1	2/237 (0.8%)	2
Bradycardia	0/242 (0%)	0	2/237 (0.8%)	2
Cardiac Arrhythmia	0/242 (0%)	0	1/237 (0.4%)	1
Cardiomyopathy	1/242 (0.4%)	1	0/237 (0%)	0
Chest Pain	2/242 (0.8%)	2	0/237 (0%)	0
Conduction Disorder	0/242 (0%)	0	1/237 (0.4%)	1
EKG Abnormality: Non-Specific	0/242 (0%)	0	1/237 (0.4%)	1
Premature Ventricular Contractions	1/242 (0.4%)	1	1/237 (0.4%)	1
Prolonged QTc	2/242 (0.8%)	2	3/237 (1.3%)	3
Sinus Bradycardia	0/242 (0%)	0	1/237 (0.4%)	1
Endocrine disorders
Hypoglycemia	0/242 (0%)	0	1/237 (0.4%)	1
Gastrointestinal disorders
Diarrhea	0/242 (0%)	0	1/237 (0.4%)	1
Nausea	2/242 (0.8%)	2	1/237 (0.4%)	1
Nausea, Vomiting	1/242 (0.4%)	1	0/237 (0%)	0
Nausea, Diarrhea	0/242 (0%)	0	1/237 (0.4%)	1
General disorders
Contrast Extravasation	1/242 (0.4%)	1	0/237 (0%)	0
Immune system disorders
Allergic Reaction	1/242 (0.4%)	1	0/237 (0%)	0
Investigations
ALT Increased	1/242 (0.4%)	1	0/237 (0%)	0
AST Increased	1/242 (0.4%)	1	0/237 (0%)	0
Multiple Liver Function Tests Abnormal	10/242 (4.1%)	10	3/237 (1.3%)	3
Nervous system disorders
Headache	3/242 (1.2%)	3	2/237 (0.8%)	2
Neuropathy Peripheral	0/242 (0%)	0	1/237 (0.4%)	1
Renal and urinary disorders
Kidney Function Abnormal	1/242 (0.4%)	1	0/237 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	1/242 (0.4%)	1	1/237 (0.4%)	1
Skin and subcutaneous tissue disorders
Itching	0/242 (0%)	0	1/237 (0.4%)	1
Rash	1/242 (0.4%)	1	1/237 (0.4%)	1
Vascular disorders
Flushing	0/242 (0%)	0	1/237 (0.4%)	1
Vagal Reaction	1/242 (0.4%)	1	0/237 (0%)	0
Nosebleed	0/242 (0%)	0	1/237 (0.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

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