Pre-exposure Prophylaxis for SARS-Coronavirus-2

• ClinicalTrials.gov Identifier: NCT04328467
• Recruitment Status: Completed
• First Posted: March 31, 2020
• Results First Posted: June 30, 2021
• Last Update Posted: July 2, 2021
• Sponsor: University of Minnesota
• Information provided by (Responsible Party): University of Minnesota

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: COVID-19; Corona Virus Infection; ARDS; Acute Respiratory Distress Syndrome
• Interventions: Drug: Hydroxychloroquine; Other: Placebo
• Enrollment: 1483

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Period Title: Overall Study
Started	494	495	494
Completed	490	493	493
Not Completed	4	2	1
Reason Not Completed
Did not meet inclusion criteria after randomization	4	2	1

Baseline Characteristics

Arm/Group Title		Intervention Once Weekly	Intervention Twice Weekly	Control Group	Total
Arm/Group Description		400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral	Total of all reporting groups
Overall Number of Baseline Participants		494	495	494	1483
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	494 participants	495 participants	494 participants	1483 participants
		42; (35 to 49)	41; (35 to 49)	40; (34 to 48)	41; (35 to 48)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	494 participants	495 participants	494 participants	1483 participants
	Female	261 52.8%	258 52.1%	241 48.8%	760 51.2%
	Male	233 47.2%	237 47.9%	253 51.2%	723 48.8%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	494 participants	495 participants	494 participants	1483 participants
White or Caucasian		431 87.2%	421 85.1%	419 84.8%	1271 85.7%
Black of African		5 1.0%	5 1.0%	10 2.0%	20 1.3%
Asian		23 4.7%	23 4.6%	29 5.9%	75 5.1%
Native Hawaiian or Pacific Islander		0 0.0%	1 0.2%	1 0.2%	2 0.1%
Hispanic or Latino		18 3.6%	22 4.4%	18 3.6%	58 3.9%
Native American or Alaska Native		4 0.8%	7 1.4%	8 1.6%	19 1.3%
Middle Eastern		6 1.2%	5 1.0%	4 0.8%	15 1.0%
South Asian		17 3.4%	18 3.6%	12 2.4%	47 3.2%
Other		3 0.6%	1 0.2%	4 0.8%	8 0.5%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants	Number Analyzed	494 participants	495 participants	494 participants	1483 participants
United States		493	494	493	1480
Canada		1	1	1	3

Outcome Measures

1. Primary Outcome

Title	COVID-19-free Survival
Description	Outcome reported as the number of participants in each arm who are COVID-19-free at the end of study treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	464 93.9%	468 94.5%	454 91.9%

2. Secondary Outcome

Title	Number of Confirmed SARS-CoV-2 Detection
Description	Outcome reported as the number of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	29 5.9%	29 5.9%	39 7.9%

3. Secondary Outcome

Title	Incidence of Possible COVID-19 Symptoms
Description	Outcome reported as the count of participants in each arm who report COVID-19-related symptoms during study treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	29 5.9%	28 5.7%	38 7.7%

4. Secondary Outcome

Title	Incidence of All-cause Study Medicine Discontinuation
Description	Outcome reported as the count of participants in each arm who discontinue study medication use for any reason during treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	119 24.1%	158 31.9%	133 26.9%

5. Secondary Outcome

Title	Ordinal Scale of COVID-19 Disease Maximum Severity if COVID-19 Diagnosed at Study End
Description	Participants will self-report COVID-19 status on an ordinal scale as follows: No illness (score=1), Illness with outpatient observation (score=2), Hospitalization (or post-hospital discharge) (score=3), or Hospitalization with ICU stay or death (score=4). Possible scores range from 1-4 with higher scores indicating greater disease severity.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

Measure was only collected for one participant in the twice-weekly intervention group and one participant in the control group. No participants in the once-weekly intervention group were sampled for this measure.

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	0	1	1
Mean (Standard Deviation); Unit of Measure: score on a scale
		1 [1] (NA)	1 [1] (NA)

[1]

Only one data point was collected, therefore a measure of dispersion could not be calculated.

6. Secondary Outcome

Title	Incidence of Hospitalization for COVID-19 or Death
Description	Outcome reported as the number of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	3 0.6%	8 1.6%	9 1.8%

7. Secondary Outcome

Title	Incidence of Possible Study Medication-related Side Effects
Description	Outcome reported as the number of participants in each arm who experience possible medication-related side effects during study treatment.
Time Frame	up to 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intervention Once Weekly	Intervention Twice Weekly	Control Group
Arm/Group Description:	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral	Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
Overall Number of Participants Analyzed	494	495	494
Measure Type: Count of Participants; Unit of Measure: Participants
	148 30.0%	168 33.9%	100 20.2%

Adverse Events

Time Frame	up to 12 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Intervention Once Weekly		Intervention Twice Weekly		Control Group
Arm/Group Description	400 mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral		400mg orally once, followed by 400mg 6 to 8 hours later, thereafter 400mg twice weekly for the duration of follow up, up to 12 weeks Hydroxychloroquine: Hydroxychloroquine; 200mg tablet; oral		Placebo 2 tabs once, followed by 2 tabs 6 to 8 hours later, thereafter two tabs weekly or twice weekly for the duration of follow up, up to 12 weeks Placebo: Placebo; tablet; oral
All-Cause Mortality
	Intervention Once Weekly		Intervention Twice Weekly		Control Group
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/494 (0.00%)		0/495 (0.00%)		0/494 (0.00%)
Serious Adverse Events
	Intervention Once Weekly		Intervention Twice Weekly		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/494 (0.61%)		6/495 (1.21%)		8/494 (1.62%)
Cardiac disorders
Chest Pain †	0/494 (0.00%)	0	0/495 (0.00%)	0	2/494 (0.40%)	2
Heart Palpitations †	0/494 (0.00%)	0	0/495 (0.00%)	0	2/494 (0.40%)	2
Tachycardia †	0/494 (0.00%)	0	0/495 (0.00%)	0	1/494 (0.20%)	1
Atrial Fibrillation †	0/494 (0.00%)	0	0/495 (0.00%)	0	2/494 (0.40%)	2
Endocrine disorders
Hyperthyroid †	0/494 (0.00%)	0	0/495 (0.00%)	0	1/494 (0.20%)	1
Gastrointestinal disorders
Diverticulitis †	1/494 (0.20%)	1	0/495 (0.00%)	0	0/494 (0.00%)	0
General disorders
Other Not Specified †	0/494 (0.00%)	0	2/495 (0.40%)	2	0/494 (0.00%)	0
Injury, poisoning and procedural complications
Motor Vehicle Accident †	0/494 (0.00%)	0	1/495 (0.20%)	1	0/494 (0.00%)	0
Renal and urinary disorders
Urinary Tract Infection †	0/494 (0.00%)	0	1/495 (0.20%)	1	1/494 (0.20%)	1
Surgical and medical procedures
Hysteroscopy †	1/494 (0.20%)	1	0/495 (0.00%)	0	0/494 (0.00%)	0
Spinal Surgery †	1/494 (0.20%)	1	0/495 (0.00%)	0	0/494 (0.00%)	0
Elective Coronary Angiogram †	0/494 (0.00%)	0	1/495 (0.20%)	1	0/494 (0.00%)	0
Gall Bladder Surgery †	0/494 (0.00%)	0	1/495 (0.20%)	1	0/494 (0.00%)	0
Sarcoidosis Biopsy †	0/494 (0.00%)	0	0/495 (0.00%)	0	1/494 (0.20%)	1
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Intervention Once Weekly		Intervention Twice Weekly		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/494 (0.00%)		0/495 (0.00%)		0/494 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Radha Rajasingham, MD
• Organization: University of Minnesota
• Phone: 612-626-8171
• EMail: radha@umn.edu

Publications of Results:

Rajasingham R, Bangdiwala AS, Nicol MR, Skipper CP, Pastick KA, Axelrod ML, Pullen MF, Nascene AA, Williams DA, Engen NW, Okafor EC, Rini BI, Mayer IA, McDonald EG, Lee TC, Li P, MacKenzie LJ, Balko JM, Dunlop SJ, Hullsiek KH, Boulware DR, Lofgren SM; COVID PREP team. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial. Clin Infect Dis. 2021 Jun 1;72(11):e835-e843. doi: 10.1093/cid/ciaa1571.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lofgren SM, Nicol MR, Bangdiwala AS, Pastick KA, Okafor EC, Skipper CP, Pullen MF, Engen NW, Abassi M, Williams DA, Nascene AA, Axelrod ML, Lother SA, MacKenzie LJ, Drobot G, Marten N, Cheng MP, Zarychanski R, Schwartz IS, Silverman M, Chagla Z, Kelly LE, McDonald EG, Lee TC, Hullsiek KH, Boulware DR, Rajasingham R. Safety of Hydroxychloroquine Among Outpatient Clinical Trial Participants for COVID-19. Open Forum Infect Dis. 2020 Oct 19;7(11):ofaa500. doi: 10.1093/ofid/ofaa500. eCollection 2020 Nov.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT04328467
• Other Study ID Numbers: MED-2020-28720
• First Submitted: March 27, 2020
• First Posted: March 31, 2020
• Results First Submitted: June 25, 2021
• Results First Posted: June 30, 2021
• Last Update Posted: July 2, 2021