Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP)

• ClinicalTrials.gov Identifier: NCT04308668
• Recruitment Status: Completed
• First Posted: March 16, 2020
• Results First Posted: May 13, 2021
• Last Update Posted: May 13, 2021
• Sponsor: University of Minnesota
• Collaborators: McGill University Health Centre/Research Institute of the McGill University Health Centre; University of Manitoba; University of Alberta
• 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: Corona Virus Infection; Acute Respiratory Distress Syndrome; SARS-CoV Infection; Coronavirus; Coronavirus Infections
• Interventions: Drug: Hydroxychloroquine; Other: Placebo
• Enrollment: 1312

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Treatment	Placebo
Arm/Group Description	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Period Title: Overall Study
Started	658	654
Completed	622	612
Not Completed	36	42
Reason Not Completed
Lost to Follow-up	32	38
Withdrawal by Subject	4	4

Baseline Characteristics

Arm/Group Title		Treatment	Placebo	Total
Arm/Group Description		Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days	Total of all reporting groups
Overall Number of Baseline Participants		658	654	1312
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	658 participants	654 participants	1312 participants
		42 (12)	42 (12)	42 (12)
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
Sex	Number Analyzed	654 participants	650 participants	1304 participants
	Female	354 54.1%	336 51.7%	690 52.9%
	Male	300 45.9%	314 48.3%	614 47.1%
Non-binary	Number Analyzed	4 participants	4 participants	8 participants
	Female	2 50.0%	2 50.0%	4 50.0%
	Male	2 50.0%	2 50.0%	4 50.0%
		[1] Measure Analysis Population Description: While biological sex at birth was the question, 4 persons in each arm did not identify as male or female.
Race/Ethnicity, Customized [1]; Measure Type: Count of Participants; Unit of measure: Participants
American Indian or Alaska Native	Number Analyzed	658 participants	654 participants	1312 participants
		4 0.6%	2 0.3%	6 0.5%
Asian/South Asian	Number Analyzed	658 participants	654 participants	1312 participants
		204 31.0%	206 31.5%	410 31.3%
Native Hawaiian or Pacific Islander	Number Analyzed	658 participants	654 participants	1312 participants
		5 0.8%	4 0.6%	9 0.7%
Black or African American	Number Analyzed	658 participants	654 participants	1312 participants
		28 4.3%	24 3.7%	52 4.0%
White	Number Analyzed	658 participants	654 participants	1312 participants
		363 55.2%	379 58.0%	742 56.6%
Hispanic or Latino	Number Analyzed	658 participants	654 participants	1312 participants
		37 5.6%	36 5.5%	73 5.6%
Middle Eastern	Number Analyzed	658 participants	654 participants	1312 participants
		14 2.1%	9 1.4%	23 1.8%
Unknown/Not Reported	Number Analyzed	658 participants	654 participants	1312 participants
		12 1.8%	10 1.5%	22 1.7%
		[1] Measure Description: Participants could identify as more than one Race/Ethnicity
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
Canada	Number Analyzed	658 participants	654 participants	1312 participants
		30 4.6%	29 4.4%	59 4.5%
United States	Number Analyzed	658 participants	654 participants	1312 participants
		628 95.4%	625 95.6%	1253 95.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Active COVID-19 Disease at Day 14 Among Those Who Were Asymptomatic at Baseline
Description	Number of participants at 14 days post enrollment with active COVID19 disease among those who were asymptomatic at baseline.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	414	407
Measure Type: Count of Participants; Unit of Measure: Participants
	49 11.8%	58 14.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.35
	Comments	[Not Specified]
	Method	Fisher Exact
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.4
	Confidence Interval	(2-Sided) 95%; -7.0 to 2.2
	Estimation Comments	Values represent percentages. Experimental treatment arm compared with the placebo control arm.

2. Primary Outcome

Title	Change in Disease Severity Over 14 Days Among Those Who Are Symptomatic at Baseline
Description	Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
Time Frame	baseline and 14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	212	211
Mean (Standard Error); Unit of Measure: score on a scale
	-2.6 (.12)	-2.33 (.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Treatment, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.117
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.27
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Rate of Hospitalization
Description	Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	645	641
Measure Type: Count of Participants; Unit of Measure: Participants
	5 0.8%	9 1.4%

4. Secondary Outcome

Title	Rate of Death
Description	Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease through study completion of 14 days. For those hospitalized within the 14-day study period, the protocol specified follow up would occur for up to 90 days to capture the final outcome of participants' hospitalization. Approximately 30-days was the maximal follow up for hospitalization outcome needed in the trial.
Time Frame	Approximately 30 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	645	641
Measure Type: Count of Participants; Unit of Measure: Participants
	1 0.2%	1 0.2%

5. Secondary Outcome

Title	Rate of Confirmed SARS-CoV-2 Detection
Description	Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	414	407
Measure Type: Count of Participants; Unit of Measure: Participants
	11 2.7%	9 2.2%

6. Secondary Outcome

Title	Occurrence of Symptoms Compatible With COVID-19 (Possible Disease)
Description	Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID-19 infection.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	414	407
Measure Type: Count of Participants; Unit of Measure: Participants
	48 11.6%	55 13.5%

7. Secondary Outcome

Title	Rate of All-Cause Study Medicine Discontinuation or Withdrawal
Description	Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	645	641
Measure Type: Count of Participants; Unit of Measure: Participants
	97 15.0%	63 9.8%

8. Secondary Outcome

Title	Overall Symptom Severity at 5 and 14 Days
Description	Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
Time Frame	5 and 14 days

Outcome Measure Data

Analysis Population Description

Early preemptive treatment trial (n=423 symptomatic participants with data)

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	212	211
Mean (95% Confidence Interval); Unit of Measure: score on a scale
Day 5	-2.22; (-2.53 to -1.9)	-2.05; (-2.37 to -1.73)
Day 14	-3.36; (-3.62 to -3.09)	-3.08; (-3.35 to -2.81)

9. Secondary Outcome

Title	Number of Participants With Severe COVID-19 Disease at 14 Days Among Those Who Are Symptomatic at Trial Entry
Description	Participants will self-report disease severity status as one of the following 3 options; no COVID19 illness (score of 1), COVID19 illness with no hospitalization (score of 2), or COVID19 illness with hospitalization or death (score of 3). Increased scale score indicates greater disease severity. Outcome is reported as the number of participants who report a score of 3.
Time Frame	14 days

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment	Placebo
Arm/Group Description:	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days	Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
Overall Number of Participants Analyzed	231	234
Measure Type: Count of Participants; Unit of Measure: Participants
	5 2.2%	8 3.4%

Adverse Events

Time Frame	Approximately 30-days
Adverse Event Reporting Description	Reporting period was for onset of adverse events within 14 days. All hospitalizations were followed for up to 90 days for final resolution of outcome. Approximately 30 days was the maximal duration needed to capture final outcome.
Arm/Group Title	Treatment		Placebo
Arm/Group Description	Participants in this arm will receive the study drug. Hydroxychloroquine: 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days		Participants in this arm will receive a placebo treatment. Placebo: 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days
All-Cause Mortality
	Treatment		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	1/658 (0.15%)		1/654 (0.15%)
Serious Adverse Events
	Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/658 (0.91%)		11/654 (1.68%)
Cardiac disorders
Hospitalizations not related to COVID or study medicine † [1]	0/658 (0.00%)	0	2/654 (0.31%)	2
Infections and infestations
COVID-related hospitalization † [2]	6/658 (0.91%)	6	9/654 (1.38%)	9
† Indicates events were collected by systematic assessment; [1] Adjudication was conducted by blinded investigators.; [2] n=5 vs. n=8 hospitalizations in early treatment population, n=1 vs. n=1 hospitalizations in postexposure prophylaxis population
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Treatment		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	367/658 (55.78%)		148/654 (22.63%)
Ear and labyrinth disorders
Tinnitus †	16/658 (2.43%)	16	8/654 (1.22%)	8
Eye disorders
Visual changes †	7/658 (1.06%)	7	5/654 (0.76%)	5
Gastrointestinal disorders
Nausea or upset stomach †	146/658 (22.19%)	146	53/654 (8.10%)	53
Diarrhea, abdominal pain, vomiting †	131/658 (19.91%)	131	35/654 (5.35%)	35
General disorders
Irritability, dizziness, vertigo †	39/658 (5.93%)	39	26/654 (3.98%)	26
Headache †	15/658 (2.28%)	15	8/654 (1.22%)	8
Taste change or dry mouth †	3/658 (0.46%)	3	3/654 (0.46%)	3
Hot flashes, night sweats, palpitations †	2/658 (0.30%)	2	1/654 (0.15%)	1
Fatigue †	1/658 (0.15%)	1	1/654 (0.15%)	1
Other †	1/658 (0.15%)	1	2/654 (0.31%)	2
Immune system disorders
Allergic reaction (non-anaphylaxis) †	6/658 (0.91%)	6	1/654 (0.15%)	1
Psychiatric disorders
Panic †	0/658 (0.00%)	0	1/654 (0.15%)	1
Skin and subcutaneous tissue disorders
Skin reaction †	10/658 (1.52%)	10	4/654 (0.61%)	4
† Indicates events were collected by systematic assessment

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: David Boulware, MD, MPH
• Organization: University of Minnesota
• Phone: 6125552020
• EMail: covid19@umn.edu

Publications of Results:

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, Lofgren SM, Okafor EC, Skipper CP, Nascene AA, Nicol MR, Abassi M, Engen NW, Cheng MP, LaBar D, Lother SA, MacKenzie LJ, Drobot G, Marten N, Zarychanski R, Kelly LE, Schwartz IS, McDonald EG, Rajasingham R, Lee TC, Hullsiek KH. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med. 2020 Aug 6;383(6):517-525. doi: 10.1056/NEJMoa2016638. Epub 2020 Jun 3.

Skipper CP, Pastick KA, Engen NW, Bangdiwala AS, Abassi M, Lofgren SM, Williams DA, Okafor EC, Pullen MF, Nicol MR, Nascene AA, Hullsiek KH, Cheng MP, Luke D, Lother SA, MacKenzie LJ, Drobot G, Kelly LE, Schwartz IS, Zarychanski R, McDonald EG, Lee TC, Rajasingham R, Boulware DR. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19 : A Randomized Trial. Ann Intern Med. 2020 Oct 20;173(8):623-631. doi: 10.7326/M20-4207. Epub 2020 Jul 16. Erratum in: Ann Intern Med. 2021 Mar;174(3):435.

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.

Skipper CP, Boulware DR. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19. Ann Intern Med. 2021 Mar;174(3):434-435. doi: 10.7326/L20-1426.

Nicol MR, Boulware DR, Rajasingham R. Reply to author. Clin Infect Dis. 2020 Dec 4. pii: ciaa1809. doi: 10.1093/cid/ciaa1809. [Epub ahead of print]

Other Publications:

Lother SA, Abassi M, Agostinis A, Bangdiwala AS, Cheng MP, Drobot G, Engen N, Hullsiek KH, Kelly LE, Lee TC, Lofgren SM, MacKenzie LJ, Marten N, McDonald EG, Okafor EC, Pastick KA, Pullen MF, Rajasingham R, Schwartz I, Skipper CP, Turgeon AF, Zarychanski R, Boulware DR. Post-exposure prophylaxis or pre-emptive therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): study protocol for a pragmatic randomized-controlled trial. Can J Anaesth. 2020 Sep;67(9):1201-1211. doi: 10.1007/s12630-020-01684-7. Epub 2020 May 7.

Pastick KA, Okafor EC, Wang F, Lofgren SM, Skipper CP, Nicol MR, Pullen MF, Rajasingham R, McDonald EG, Lee TC, Schwartz IS, Kelly LE, Lother SA, Mitjà O, Letang E, Abassi M, Boulware DR. Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19). Open Forum Infect Dis. 2020 Apr 15;7(4):ofaa130. doi: 10.1093/ofid/ofaa130. eCollection 2020 Apr. Review.

Al-Kofahi M, Jacobson P, Boulware DR, Matas A, Kandaswamy R, Jaber MM, Rajasingham R, Young JH, Nicol MR. Finding the Dose for Hydroxychloroquine Prophylaxis for COVID-19: The Desperate Search for Effectiveness. Clin Pharmacol Ther. 2020 Oct;108(4):766-769. doi: 10.1002/cpt.1874. Epub 2020 Jun 1.

Ingraham NE, Boulware D, Sparks MA, Schacker T, Benson B, Sparks JA, Murray T, Connett J, Chipman JG, Charles A, Tignanelli CJ. Shining a light on the evidence for hydroxychloroquine in SARS-CoV-2. Crit Care. 2020 Apr 28;24(1):182. doi: 10.1186/s13054-020-02894-7.

Pullen MF, Pastick KA, Williams DA, Nascene AA, Bangdiwala AS, Okafor EC, Hullsiek KH, Skipper CP, Lofgren SM, Engen N, Abassi M, McDonald EG, Lee TC, Rajasingham R, Boulware DR. Lessons Learned From Conducting Internet-Based Randomized Clinical Trials During a Global Pandemic. Open Forum Infect Dis. 2020 Dec 28;8(2):ofaa602. doi: 10.1093/ofid/ofaa602. eCollection 2021 Feb. Review.

Okafor EC, Pastick KA, Rajasingham R. Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. Reply. N Engl J Med. 2020 Sep 10;383(11):1089. doi: 10.1056/NEJMc2023617. Epub 2020 Jul 15.

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

Akhtar S, Das JK, Ismail T, Wahid M, Saeed W, Bhutta ZA. Nutritional perspectives for the prevention and mitigation of COVID-19. Nutr Rev. 2021 Feb 11;79(3):289-300. doi: 10.1093/nutrit/nuaa063.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT04308668
• Other Study ID Numbers: MED-2020-28673
• First Submitted: March 11, 2020
• First Posted: March 16, 2020
• Results First Submitted: April 26, 2021
• Results First Posted: May 13, 2021
• Last Update Posted: May 13, 2021