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

Tracking Information

• First Submitted Date: March 11, 2020
• First Posted Date: March 16, 2020
• Results First Submitted Date: April 26, 2021
• Results First Posted Date: May 13, 2021
• Last Update Posted Date: May 13, 2021
• Actual Study Start Date: March 17, 2020
• Actual Primary Completion Date: May 20, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 28, 2021)

• Number of Participants With Active COVID-19 Disease at Day 14 Among Those Who Were Asymptomatic at Baseline [ Time Frame: 14 days ]
  Number of participants at 14 days post enrollment with active COVID19 disease among those who were asymptomatic at baseline.
• Change in Disease Severity Over 14 Days Among Those Who Are Symptomatic at Baseline [ Time Frame: baseline and 14 days ]
  Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)

Original Primary Outcome Measures (submitted: March 11, 2020)

• Incidence of COVID19 Disease [ Time Frame: 14 days ]
  Number of participants at 14 days post enrollment with active COVID19 disease.
• Ordinal Scale of COVID19 Disease Severity [ Time Frame: 14 days ]
  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 percent of participants who fall into each category per arm.

Current Secondary Outcome Measures (submitted: May 11, 2021)

• Rate of Hospitalization [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.
• Rate of Death [ Time Frame: Approximately 30 days ]
  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.
• Rate of Confirmed SARS-CoV-2 Detection [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.
• Occurrence of Symptoms Compatible With COVID-19 (Possible Disease) [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID-19 infection.
• Rate of All-Cause Study Medicine Discontinuation or Withdrawal [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.
• Overall Symptom Severity at 5 and 14 Days [ Time Frame: 5 and 14 days ]
  Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe)
• Number of Participants With Severe COVID-19 Disease at 14 Days Among Those Who Are Symptomatic at Trial Entry [ Time Frame: 14 days ]
  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.

Original Secondary Outcome Measures (submitted: March 11, 2020)

• Incidence of Hospitalization [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease.
• Incidence of Death [ Time Frame: 90 days ]
  Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease.
• Incidence of Confirmed SARS-CoV-2 Detection [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who have confirmed SARS-CoV-2 infection.
• Incidence of Symptoms Compatible with COVID19 (possible disease) [ Time Frame: 90 days ]
  Outcome reported as the number of participants in each arm who self-report symptoms compatible with COVID19 infection.
• Incidence of All-Cause Study Medicine Discontinuation or Withdrawal [ Time Frame: 14 days ]
  Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Post-exposure Prophylaxis / Preemptive Therapy for SARS-Coronavirus-2
• Official Title: Post-exposure Prophylaxis or Preemptive Therapy for SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial

Brief Summary

Study Objective:

1. To test if post-exposure prophylaxis with hydroxychloroquine can prevent symptomatic COVID-19 disease after known exposure to the SARS-CoV-2 coronavirus.
2. To test if early preemptive hydroxychloroquine therapy can prevent disease progression in persons with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity.

Detailed Description

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing COVID19. The current strategy uses a public health model of identifying infected cases, isolation, and quarantine to stop transmission. Once exposed, observation is standard-of-care. Therapy is generally not given to persons who are not hospitalized. The doses of hydroxychloroquine being used are within the normal standard FDA-approved doses.

Hydroxychloroquine may have antiviral effects against SARS-COV2 which may prevent COVID-19 disease or early preemptive therapy may decrease disease severity. This trial will use a modification of standard malaria dosing of hydroxychloroquine to provide post-exposure prophylaxis to prevent disease or preemptive therapy for those with early symptoms. People around the the United States and Canada can participate to help answer this critically important question. No in-person visits are needed.

This trial is targeting 5 groups of people NATIONWIDE to participate:

1. If you are symptomatic with a positive COVID-19 test within the first 4 days of symptoms and are not hospitalized; OR
2. If you live with someone who has been diagnosed with COVID-19, with your last exposure within the last 4 days, and do not have any symptoms; OR
3. If you live with someone who has been diagnosed with COVID-19, and your symptoms started within the last 4 days; OR
4. If you have had occupational exposure with known exposure to someone with lab-confirmed COVID-19 within the last 4 days and do not have symptoms; OR
5. If you have had occupational exposure with known exposure to someone with lab-confirmed COVID-19 within the last 4 days AND have compatible symptoms starting within the last 4 days;

You may participate if you live anywhere in the United States (including territories) or in the Canadian Provinces of Quebec, Manitoba, Alberta, or Ontario.

For information on how to participate in the research trial, go to covidpep.umn.edu or email covid19@umn.edu for instructions. Please check your spam folder if you email.

In Canada, for trial information, please go to: www.covid-19research.ca

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Asymptomatic participants are randomized and analyzed separate from symptomatic participants.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

Condition

• Corona Virus Infection
• Acute Respiratory Distress Syndrome
• SARS-CoV Infection
• Coronavirus
• Coronavirus Infections

Intervention

• 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
  Other Name: Plaquenil
• Other: Placebo
  4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days

Study Arms

• Experimental: Treatment
  Participants in this arm will receive the study drug.
  Intervention: Drug: Hydroxychloroquine
• Placebo Comparator: Placebo
  Participants in this arm will receive a placebo treatment.
  Intervention: Other: Placebo

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, Mitja 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.
• 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. No abstract available.
• 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.
• 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. No abstract available.
• 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. No abstract available.
• Nicol MR, Boulware DR, Rajasingham R. Reply to Neves. Clin Infect Dis. 2021 Oct 5;73(7):e1772-e1774. doi: 10.1093/cid/ciaa1809. No abstract available.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 26, 2021): 1312
• Original Estimated Enrollment (submitted: March 11, 2020): 1500
• Actual Study Completion Date: May 20, 2020
• Actual Primary Completion Date: May 20, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Provision of informed consent
• Exposure to a COVID19 case within 4 days as either a household contact or occupational exposure, OR
• Symptomatic COVID19 case with confirmed diagnosis within 4 days of symptom onset OR symptomatic high risk exposure with known COVID19 contact and within 4 days of symptom onset;

Exclusion Criteria:

• Current hospitalization
• Allergy to hydroxychloroquine
• Retinal eye disease
• Known glucose-6 phosphate dehydrogenase (G-6-PD) deficiency
• Known chronic kidney disease, stage 4 or 5 or receiving dialysis
• Structural or ischemic heart disease
• Personal or Family History of Prolonged QT syndrome
• Weight < 50 kg
• Known Porphyria
• Current use of: hydroxychloroquine or cardiac medicines of: flecainide, Tambocor; amiodarone, Cordarone, Pacerone; digoxin or Digox, Digitek, Lanoxin; procainamide or Procan, Procanbid, propafenone, Rythmal, sotalol;

• Current use of medicines which prolong the QT interval including:

  • Antimicrobials: levofloxacin, ciprofloxacin, moxifloxacin, azithromycin, clarithromycin, erythromycin, ketoconazole, itraconazole, or mefloquine
  • Antidepressants: amitriptyline, citalopram, desipramine, escitalopram, imipramine, doxepin, fluoxetine, wellbutrin, or venlafaxine
  • Antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone
  • Methadone
  • Sumatriptan, zolmitriptan

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT04308668
• Other Study ID Numbers: MED-2020-28673
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified dataset will be available within 1 month of publication.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Time Frame: at time of publication
• Access Criteria: To be publicly provided. Please register at the website to receive the dataset.
• URL: https://covidpep.umn.edu/data

• Current Responsible Party: University of Minnesota
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Minnesota
• Original Study Sponsor: Same as current

Collaborators

• McGill University Health Centre/Research Institute of the McGill University Health Centre
• University of Manitoba
• University of Alberta

Investigators

• Principal Investigator: David Boulware, MD, MPH; University of Minnesota

• PRS Account: University of Minnesota
• Verification Date: May 2021