Will Hydroxychloroquine Impede or Prevent COVID-19

NCT04341441 | Terminated Phase 3 Results DMC FDA Drug

• 1 other identifier: 1410401
• Study Type: interventional
• Target: 624
• Locations: 1 country
• Sites: 1

Brief Summary

This is a prospective, multi-site study designed to evaluate whether the use of hydroxychloroquine in healthcare workers (HCW), Nursing Home Workers (NHW), first responders (FR), and Detroit Department of Transportation bus drivers (DDOT) in SE, Michigan, can prevent the acquisition, symptoms and clinical COVID-19 infection The primary objective of this study is to determine whether the use of daily or weekly oral hydroxychloroquine (HCQ) therapy will prevent SARS-CoV-2 infection and COVID-19 viremia and clinical COVID-19 infection healthcare workers (HCW) and first responders (FR) (EMS, Fire, Police, bus drivers) in Southeast Michigan. Preventing COVID-19 transmission to HCW, FR, and Detroit Department of Transportation (DDOT) bus drivers is a critical step in preserving the health care and first responder force, the prevention of COVID-19 transmission in health care facilities, with the potential to preserve thousands of lives in addition to sustaining health care systems and civil services both nationally and globally. If efficacious, further studies on the use of hydroxychloroquine to prevent COVID-19 in the general population could be undertaken, with a potential impact on hundreds of thousands of lives.

Conditions

COVID-19; Coronavirus; Coronavirus Infections; SARS-CoV 2

Keywords

COVID-19; Coronavirus; Healthcare Workers; SARS-CoV 2; First Responders; Emergency Medical Technicians; Paramedics; Firefighters; Police Officers; Detroit; Michigan; Henry Ford Hospital

Outcome Measures

Primary Outcomes (1)

• To Determine if the Use of Hydroxychloroquine as Preventive Therapy Decreases the Rate of Acquisition of SARS-CoV 2 Infections With Clinical COVID-19 Disease in Study Participants for Each Randomized Treatment Arm as Compared to Placebo.

  The rate of acquisition of SARS-CoV 2 infections and clinical COVID-19 disease (number of events) in study participants for each randomized hydroxychloroquine treatment arm was compared to the placebo treatment arm. This included both symptomatic and asymptomatic patients.

  8 Weeks

Secondary Outcomes (10)

• Determine the Effect of Hydroxychloroquine Dose in the Prevention of COVID-19 Viremia and Disease.

  8 Weeks

• Assess the Impact of Chronic Weight-based Dosing of HCQ for COVID-19 Prevention.

  8 Weeks

• Comparison of the Rate of SARS-CoV 2 Infections as Measured by IgM/IgG Seroconversion in Study Participants Receiving Randomized HCQ Versus Placebo.

  8 Weeks

• Compare the Seroprevalence of SARS-CoV 2 IgM and/or IgG Positive Samples at Study Entry and Study Conclusion in All Participants Receiving HCQ Compared to Those Receiving Placebo.

  8 Weeks

• Comparison of the Emergence of Clinical Symptoms or COVID-19 Diagnosis in Participants Presenting Asymptomatically at Study Entry But Identified as Seropositive by Serology at Entry Between the Randomized Treatment Arms and Comparator Arm.

  8 Weeks

Study Arms (4)

Study Drug - Daily Dose

ACTIVE COMPARATOR

The daily hydroxychloroquine treatment arm will receive a 200 mg oral dose daily following day 1 dose of 400 mg orally once. This dose represents approximately half the standard weight-based dosing recommended for management of autoimmune diseases and therefore less likely to produce side effects than standard of care.

Drug: Hydroxychloroquine - Daily Dosing; Diagnostic Test: Monitoring Visit - Baseline; Diagnostic Test: Monitoring Visit - Week 4; Diagnostic Test: Monitoring Visit - Week 8; Other: Weekly Assessment

Study Drug - Weekly Dose

ACTIVE COMPARATOR

The once weekly randomized treatment arm will receive the proposed dose of hydroxychloroquine for prophylaxis of malaria is 6.5 mg/kg per dose (maximum of 400mg per dose) administered orally weekly on the same day of each week. This is based on the recommended dose for prophylaxis of malaria.

Drug: Hydroxychloroquine - Weekly Dosing; Diagnostic Test: Monitoring Visit - Baseline; Diagnostic Test: Monitoring Visit - Week 4; Diagnostic Test: Monitoring Visit - Week 8; Other: Weekly Assessment

Placebo

ACTIVE COMPARATOR

All treatment groups will receive placebo pills to have the patients take 2 pills a day. The randomized placebo arm will receive placebo pills made to resemble the daily dosing of HCQ. Similarly, the once a week treatment arm will receive placebo pills for the days not on HCQ medication.

Other: Placebo oral tablet; Diagnostic Test: Monitoring Visit - Baseline; Diagnostic Test: Monitoring Visit - Week 4; Diagnostic Test: Monitoring Visit - Week 8; Other: Weekly Assessment

Non-Randomized Active Comparator

ACTIVE COMPARATOR

A non-randomized comparator group will be enrolled in the study comprising of healthcare workers and first responders who are chronically on oral hydroxychloroquine as part of their standard of care for their autoimmune disease(s). This will be an open enrollment group and will provide information of chronic weight-based daily therapy of HCQ effectiveness as a prophylactic/preventive strategy.

Diagnostic Test: Monitoring Visit - Baseline; Diagnostic Test: Monitoring Visit - Week 4; Diagnostic Test: Monitoring Visit - Week 8; Other: Weekly Assessment

Interventions

Hydroxychloroquine - Daily Dosing DRUG

The daily hydroxychloroquine treatment arm will receive a 200 mg oral dose daily following day 1 dose of 400 mg orally once. This dose represents approximately half the standard weight-based dosing recommended for management of autoimmune diseases and therefore less likely to produce side effects than standard of care. All treatment groups will receive placebo pills to have the patients take 2 pills a day.

Also known as: Study Drug - Daily, Daily Oral Dosing

Study Drug - Daily Dose

Hydroxychloroquine - Weekly Dosing DRUG

The once weekly randomized treatment arm will receive the proposed dose of hydroxychloroquine for prophylaxis of malaria is 6.5 mg/kg per dose (maximum of 400 mg per dose) administered orally weekly on the same day of each week. This is based on the recommended dose for prophylaxis of malaria All treatment groups will receive placebo pills to have the patients take 2 pills a day.

Also known as: Weekly Oral Dosing

Study Drug - Weekly Dose

Placebo oral tablet OTHER

Participants randomized to this arm will be provided with daily dosing of oral placebo to have the patients take 2 pills a day.. Participants will receive a monitoring phone call at 4 weeks post study entry to monitor for COVID-19 symptoms and medication side effects. At week 8, participants will provide additional samples of whole blood. Additional studies will include serology, inflammatory and other disease associated markers. Clinical data and location of main work area will be collected.

Also known as: Placebo

Placebo

Monitoring Visit - Baseline DIAGNOSTIC_TEST

Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint.

Also known as: Baseline Monitoring Visit

Non-Randomized Active Comparator; Placebo; Study Drug - Daily Dose; Study Drug - Weekly Dose

Monitoring Visit - Week 4 DIAGNOSTIC_TEST

Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint.

Also known as: Week 4 - Monitoring Visit

Non-Randomized Active Comparator; Placebo; Study Drug - Daily Dose; Study Drug - Weekly Dose

Monitoring Visit - Week 8 DIAGNOSTIC_TEST

Face-to-face monitoring visit to obtain monitoring questionnaires to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects, and collect study blood samples. Three (3) blood specimens will be collected from each Participant using the sterile procedure as routine standard of care. A total of five (5) 10 mL tubes of whole blood will be collected at each timepoint.

Also known as: Week 8 - Monitoring Visit

Non-Randomized Active Comparator; Placebo; Study Drug - Daily Dose; Study Drug - Weekly Dose

Weekly Assessment OTHER

Participants will be asked to contact the study team if COVID-19 infection is established at any time during the study. For study weeks 1,2,3,5,6 \&7, Participants will receive a monitoring questionnaire to assess for COVID-19 symptoms/diagnosis, adherence and medication side effects. These monitoring visits will be done by telephone and/or electronic encounters (virtual visits, email), whichever method the patient prefers to encourage adherence to the monitoring.

Also known as: Monitoring Call

Non-Randomized Active Comparator; Placebo; Study Drug - Daily Dose; Study Drug - Weekly Dose

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant is willing and able to provide informed consent.
• Participant is 18-75 years of age.
• Participant does not have symptoms of respiratory infection, including cough, fevers (temperature \>38.0C), difficulty breathing, shortness of breath, chest pains, malaise, myalgia, headaches, nausea or vomiting, or other symptoms associated with COVID-19.
• Participant is willing to provide blood samples for the study.
• Subject agrees to all aspects of the study.

You may not qualify if:

• Participant unable or unwilling to provide informed consent.
• Participant has any of the symptoms above or screens positive for possible COVID-19 disease.
• Participant is currently enrolled in a study to evaluate an investigational drug.
• Vulnerable populations deemed inappropriate for study by the site Principal Investigator.
• The participant has a known allergy/hypersensitivity or has a medication or co-morbidity (including history of gastric bypass, epilepsy, cardiovascular disease or renal failure) that prevents the use of HCQ (see pharmacy section).
• The participant is a woman of childbearing age whose pregnancy status is unknown and is not willing to use 2 methods of contraception.
• The participant is pregnant or nursing.
• The participant was diagnosed with retinopathy prior to study entry.
• The participant has a diagnosis of porphyria prior to study entry.
• The participant has renal failure with a creatinine clearance of \<10 ml/min, pre-dialysis or requiring dialysis.
• The Participant has a family history of Sudden Cardiac Death.
• The participant is currently on diuretic therapy.
• The participant has a history of known Prolonged QT Syndrome.
• The participant is already taking any of the following medications: Abiraterone acetate, Agalsidase, Amodiaquine, Azithromycin, Conivaptan, Dabrafenib, Dacomitinib, Dapsone (Systemic), Digoxin, Enzalutamide, Fusidic Acid (Systemic), Idelalisib, Lanthanum, Lumefantrine, Mefloquine, Mifepristone, Mitotane, Pimozide, QT-prolonging Agents, Stiripentol).

Sponsors & Collaborators

• Henry Ford Health System: lead

Study Sites (1)

Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Related Publications (10)

• Bai Y, Yao L, Wei T, Tian F, Jin DY, Chen L, Wang M. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA. 2020 Apr 14;323(14):1406-1407. doi: 10.1001/jama.2020.2565.

  PMID: 32083643 BACKGROUND

• Chang D, Xu H, Rebaza A, Sharma L, Dela Cruz CS. Protecting health-care workers from subclinical coronavirus infection. Lancet Respir Med. 2020 Mar;8(3):e13. doi: 10.1016/S2213-2600(20)30066-7. Epub 2020 Feb 13. No abstract available.

  PMID: 32061333 BACKGROUND

• Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, Li Y, Hu Z, Zhong W, Wang M. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov. 2020 Mar 18;6:16. doi: 10.1038/s41421-020-0156-0. eCollection 2020. No abstract available.

  PMID: 32194981 BACKGROUND

• Vincent MJ, Bergeron E, Benjannet S, Erickson BR, Rollin PE, Ksiazek TG, Seidah NG, Nichol ST. Chloroquine is a potent inhibitor of SARS coronavirus infection and spread. Virol J. 2005 Aug 22;2:69. doi: 10.1186/1743-422X-2-69.

  PMID: 16115318 BACKGROUND

• Ben-Zvi I, Kivity S, Langevitz P, Shoenfeld Y. Hydroxychloroquine: from malaria to autoimmunity. Clin Rev Allergy Immunol. 2012 Apr;42(2):145-53. doi: 10.1007/s12016-010-8243-x.

  PMID: 21221847 BACKGROUND

• Mohammad S, Clowse MEB, Eudy AM, Criscione-Schreiber LG. Examination of Hydroxychloroquine Use and Hemolytic Anemia in G6PDH-Deficient Patients. Arthritis Care Res (Hoboken). 2018 Mar;70(3):481-485. doi: 10.1002/acr.23296. Epub 2018 Feb 9.

  PMID: 28556555 BACKGROUND

• Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20.

  PMID: 32205204 BACKGROUND

• Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.

  PMID: 32150618 BACKGROUND

• Lim HS, Im JS, Cho JY, Bae KS, Klein TA, Yeom JS, Kim TS, Choi JS, Jang IJ, Park JW. Pharmacokinetics of hydroxychloroquine and its clinical implications in chemoprophylaxis against malaria caused by Plasmodium vivax. Antimicrob Agents Chemother. 2009 Apr;53(4):1468-75. doi: 10.1128/AAC.00339-08. Epub 2009 Feb 2.

  PMID: 19188392 BACKGROUND

• Howard DR, Brown JM, Todd S, Gregory WM. Recommendations on multiple testing adjustment in multi-arm trials with a shared control group. Stat Methods Med Res. 2018 May;27(5):1513-1530. doi: 10.1177/0962280216664759. Epub 2016 Sep 19.

  PMID: 27647808 BACKGROUND

MeSH Terms

Conditions

COVID-19; Coronavirus Infections

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Limitations and Caveats

Study has been terminated. Interim analysis did not reveal any safety concerns by the DSMB with hydroxychloroquine treatment, but unblinded data did not provide support to continue due to low numbers of events. Event rate did not meet projected magnitude; given low recruitment potential, it is unlikely that a positive result will occur.

Results Point of Contact

• Title: John McKinnon, MD, MSc
• Organization: Henry Ford Health System

jmckinn3@hfhs.org

313-916-8828

Study Officials

• William W O'Neill, MD

  Henry Ford Health System

  PRINCIPAL INVESTIGATOR

• Dee Dee Wang, MD

  Henry Ford Health System

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Blinded randomization will be performed by the Henry Ford Hospital Public Health Sciences investigators once the participants are determined to be eligible for enrollment. Randomization will be stratified by study site and risk of exposure based on location of work and type of work. Once enrolled, each Participant will be assigned a unique identifier (detailed in the full protocol). This number, along with the assigned site number, will constitute the Subject Identifier (Subject ID).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, Center for Structural Heart Disease

Model Details: This is a prospective, multi-site study designed to evaluate whether the use of hydroxychloroquine in healthcare workers (HCW) and first responders (FR) in southeast (SE) Michigan, can prevent the acquisition, symptoms and clinical COVID-19 infection. The study will randomize a total of 3,000 Healthcare Workers and First Responders, age ≥18 years or older, through the Henry Ford Health System, Detroit COVID Consortium. The participants who meeting study entry criteria and are not on HCQ prior to study enrollment will be randomized in a 1:1:1 blinded comparison of daily or weekly oral hydroxychloroquine versus oral placebo for 8 weeks. A fourth non-randomized comparator group will be enrolled in the study comprising of HCW who are chronically on HCQ as part of their standard of care for their autoimmune disease(s). This will be an open enrollment group and will provide information of chronic weight-based daily therapy of HCQ effectiveness as a prophylactic/preventive strategy.

Study Record Dates

• First Submitted: April 7, 2020
• First Posted: April 10, 2020
• Study Start: April 7, 2020
• Primary Completion: December 15, 2020
• Study Completion: December 15, 2020
• Last Updated: June 21, 2022
• Results First Posted: June 21, 2022

Record last verified: 2022-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)