Pre-exposure Prophylaxis for SARS-Coronavirus-2

Pre-exposure Prophylaxis for SARS-Coronavirus-2: A Pragmatic Randomized Clinical Trial

Objective: To determine if pre-exposure prophylaxis with hydroxychloroquine is effective for the prevention of COVID-19 disease.

Study Overview

• Status: Completed
• Conditions: COVID-19; Acute Respiratory Distress Syndrome; Corona Virus Infection; ARDS
• Intervention / Treatment: Drug: Hydroxychloroquine; Other: Placebo

Detailed Description

The current standard of care is observation and quarantine after exposure to COVID-19. There is no approved treatment or prophylaxis for COVID-19.

As of March 6, 2020, the CDC estimates that the transmission of SARS-CoV2 after a U.S. household close contract is 10.5% (95%CI, 2.9 to 31.4%). Among all close contacts, the SARS-CoV2 transmission rate is estimated at 0.45% (95%CI, 0.12 to 1.6%) by the CDC. These estimates are based on monitoring of travel-associated COVID19 cases. Conversely, in a setting with community transmission, the secondary attack rate in China was 35% (95%CI, 27-44%) based on 48 transmissions among 137 persons in 9 index patients.

Chloroquine or Hydroxychloroquine may have antiviral effects against SARS-COV2 which may prevent COVID-19 disease or reduce disease severity. It is not known at what dosing hydroxychloroquine may be effective for pre-exposure prophylaxis.

• Study Type: Interventional
• Enrollment (Actual): 1483
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Nationwide Enrollment via Internet, please email: covid19@umn.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

- A healthcare worker at high risk for COVID-19 exposure (defined below):

• Persons primarily working in emergency departments (physicians, nurses, ancillary staff, triage personnel)
• Persons primarily working in intensive care units (physicians, nurses, ancillary staff, respiratory therapists)
• Persons performing aerosol generating procedures (i.e. anesthesiologists, nurse anesthetists (CRNAs)
• First responders (i.e. EMTs, paramedics)

Exclusion Criteria:

• Active COVID-19 disease
• Prior COVID-19 disease
• Current fever, cough, shortness of breath
• Allergy to chloroquine or hydroxychloroquine
• Prior retinal eye disease
• Known Chronic Kidney disease, Stage 4 or 5 or dialysis
• Known glucose-6 phosphate dehydrogenase (G-6-PD) deficiency
• Weight <40 kg
• Prolonged QT syndrome
• Current use of hydroxychloroquine, chloroquine, or cardiac medicines of flecainide, amiodarone, digoxin, procainamide, or propafenone
• Current use of medications with known significant drug-drug interactions: artemether, lumefantrine, mefloquine, tamoxifen, or methotrexate.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Once Weekly; 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	Drug: Hydroxychloroquine; Hydroxychloroquine; 200mg tablet; oral; Other Names: Plaquenil
Experimental: Intervention Twice Weekly; 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	Drug: Hydroxychloroquine; Hydroxychloroquine; 200mg tablet; oral; Other Names: Plaquenil
Placebo Comparator: Control Group; 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	Other: Placebo; Placebo; tablet; oral

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Confirmed SARS-CoV-2 Detection	Outcome reported as the number of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment.	up to 12 weeks
Incidence of Possible COVID-19 Symptoms	Outcome reported as the count of participants in each arm who report COVID-19-related symptoms during study treatment.	up to 12 weeks
Incidence of All-cause Study Medicine Discontinuation	Outcome reported as the count of participants in each arm who discontinue study medication use for any reason during treatment.	up to 12 weeks
Ordinal Scale of COVID-19 Disease Maximum Severity if COVID-19 Diagnosed at Study End	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.	up to 12 weeks
Incidence of Hospitalization for COVID-19 or Death	Outcome reported as the number of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment.	up to 12 weeks
Incidence of Possible Study Medication-related Side Effects	Outcome reported as the number of participants in each arm who experience possible medication-related side effects during study treatment.	up to 12 weeks

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Radha Rajasingham, MD, University of Minnesota

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2020
• Primary Completion (Actual): July 13, 2020
• Study Completion (Actual): July 13, 2020

Study Registration Dates

• First Submitted: March 27, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Actual): July 2, 2021
• Last Update Submitted That Met QC Criteria: June 30, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Infant, Newborn, Diseases; Lung Injury; Infant, Premature, Diseases; Coronavirus Infections; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: MED-2020-28720

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No