PROLIFIC ChemoprophylaxisTrial (COVID-19)

ChemoPROphyLaxIs For covId-19 Infectious Disease (the PROLIFIC Trial)

The number of confirmed cases of COVID-19 infectious disease arising from the SARS-CoV-2 coronavirus is rising substantially and rapidly, with the potential to overwhelm the ability of the entire National Health Service (NHS) to cope with the increased demand. The availability of personal protective equipment is limited and reports of high risk procedures such as aerosol generating procedures (e.g. intubation for the sickest patients) is a source of great concern for infection transmission. Frontline NHS staff with direct patient contact have the highest likelihood of exposure to SARS-CoV-2 and development of COVID-19 disease. Efforts to protect these workers from development of COVID-19, using drugs to prevent the disease, require urgent evaluation.

Study Overview

• Status: Unknown
• Conditions: COVID-19
• Intervention / Treatment: Drug: Hydroxychloroquine - Daily dosing; Drug: Hydroxychloroquine - Weekly Dosing; Other: Matched Placebo Hydroxychloroquine

Detailed Description

The number of confirmed cases of COVID-19 infectious disease arising from the SARS-CoV-2 coronavirus is rising substantially and rapidly, with the potential to overwhelm the ability of the entire National Health Service (NHS) to cope with the increased demand. The availability of personal protective equipment is limited and reports of high risk procedures such as aerosol generating procedures (e.g. intubation for the sickest patients) is a source of great concern for infection transmission. Frontline NHS staff with direct patient contact have the highest likelihood of exposure to SARS-CoV-2 and development of COVID-19 disease. Efforts to protect these workers from development of COVID-19, using drugs to prevent the disease, require urgent evaluation.

This trial will be a double-blind, randomized, placebo-controlled trial in a cohort of frontline healthcare workers, who will potentially be exposed to SARS-CoV-2. Eligible participants will be frontline NHS workers aged 18 to 70 years who work in a healthcare setting with direct patient care. Participants will be randomised to one of 3 arms and receive either: (1) Hydroxychloroquine Daily (loading phase: 800mg for first 2 days; maintenance phase: 1 x 200mg tablet every day) + weekly placebo; (2) Hydroxychloroquine weekly (loading phase: 800mg for first 2 days; maintenance phase: 2 x 200mg tablets every 7th day/weekly) + daily placebo, or (3) placebo (daily and weekly).

Participants will be reviewed at an interim visit 6 weeks after baseline and again and the end of the study treatment in 90 days (approximately 3 months) after randomization. Participants will also complete brief questions about their health weekly while on treatment (remotely, via app/web/phone-based interface).

• Study Type: Interventional
• Enrollment (Anticipated): 1000
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ella James, PhD; Phone Number: 01223 349762; Email: ella.james@addenbrookes.nhs.uk
• Study Contact Backup: Name: Heike Templin; Phone Number: 01223 250874; Email: heike.templin@addenbrookes.nhs.uk

Study Locations

• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Recruiting
    • Cambridge University Hospitals NHS Foundation Trust

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

To be included in the trial the participant MUST:

1. Have given written informed consent to participate
2. Be aged 18 years to 70 years
3. Not previously have been diagnosed with COVID-19
4. Work in a high-risk secondary or tertiary healthcare setting (hospitals accepting COVID-19 patients) with direct patient-facing care

Exclusion Criteria:The presence of any of the following will mean participants are ineligible:

1. Known COVID-19 positive test at baseline (if available)
2. Symptomatic for possible COVID-19 at baseline
3. Known hypersensitivity reaction to HCQ, chloroquine or 4-aminoquinolines
4. Known retinal disease
5. Known porphyria
6. Known chronic kidney disease (CKD; eGFR<30ml/min)
7. Known epilepsy
8. Known heart failure or conduction problems
9. Known significant liver disease (Gilbert's syndrome is permitted)
10. Known glucose-6-phosphate dehydrogenase (G6PD) deficiency

11. Currently taking any of the following contraindicated medications:

    1. Digoxin
    2. Chloroquine
    3. Halofantrine
    4. Amiodarone
    5. Moxifloxacin
    6. Cyclosporin
    7. Mefloquine
    8. Praziquantel
    9. Ciprofloxacin
    10. Clarithromycin
    11. Prochlorperazine
    12. Fluconazole
12. Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine
13. Currently breastfeeding
14. Unable to be followed-up during the trial
15. Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit
16. Not able to use or have access to a modern phone device/web-based technology
17. Any other clinical reason which may preclude entry in the opinion of the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Hydroxychloroquine - Daily dosing; Hydroxychloroquine Daily (loading phase: 800mg for first 2 days; maintenance phase: 1 x 200mg tablet every day) + weekly placebo, for approximately 90 days. Route: Oral. Pharmaceutical form: Tablet	Drug: Hydroxychloroquine - Daily dosing; Active HCQ: Days 1-2: Loading phase - 400mg (2 x 200mg capsules) taken TWICE A DAY for 2 days Days 3 onwards: Maintenance Phase - 200mg (1 x 200mg capsule) taken ONCE A DAY, every day for 90 days (~3 months), Matched Placebo HCQ: Days 3 onwards: Maintenance Phase - 2 capsules taken ONCE A WEEK on the same day each week (every 7th day) for 90 days (~3 months)
Active Comparator: Hydroxychloroquine - Weekly dosing; Hydroxychloroquine weekly (loading phase: 800mg for first 2 days; maintenance phase: 2 x 200mg tablets every 7th day/weekly) + daily placebo, for approximately 90 days. Route: Oral. Pharmaceutical form: Tablet	Drug: Hydroxychloroquine - Weekly Dosing; Active HCQ: Days 1-2: Loading Phase - 400mg (2 x 200mg capsules) taken TWICE A DAY for 2 days Days 3 onwards: Maintenance Phase - 400mg (2 x 200mg capsules) taken ONCE A WEEK on the same day each week (every 7th day) for 90 days (~3 months) Matched Placebo HCQ: Days 3 onwards: Maintenance Phase - 1 capsule taken ONCE A DAY for 90 days (~3 months)
Placebo Comparator: Placebo; Placebo arm - 2 tablets twice daily for first 2 days (loading phase), followed by 1 tablet every day for 90 days plus 2 tablets every 7th day, for approximately 90 days. Route: Oral. Pharmaceutical form: Tablet	Other: Matched Placebo Hydroxychloroquine; Matched placebo HCQ - daily dosing: Days 1-2: Loading Phase - 2 capsules taken TWICE A DAY for 2 days Days 3 onwards: Maintenance Phase - 1 capsule taken ONCE A DAY for 90 days (~3 months) Matched placebo HCQ - weekly dosing Days 3 onwards: Maintenance Phase - 2 capsules taken ONCE A WEEK on the same day each week (every 7th day) for 90 days (~3 months)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to positive COVID-19 disease	Time taken for incidence of COVID-19 disease between Hydroxychloroquine and placebo arms	Assessed up to 90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of COVID-19 test positive cases	Number of COVID-19 symptoms based on clinical guidelines and test positive infections per study arm	Assessed up to 90 days
Number of COVID-19 serological test positive cases	Number of test positive COVID-19 serological test positive cases per study arm	Assessed up to 90 days
Severity of COVID-19 disease between each arm	Severity based on hospitalisation	Assessed up to 90 days
Number of common COVID-19 complications between each arm	Number of common COVID-19 complications between arms	Assessed up to 90 days

Collaborators and Investigators

• Sponsor: Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2020
• Primary Completion (Anticipated): October 31, 2020
• Study Completion (Anticipated): April 1, 2021

Study Registration Dates

• First Submitted: April 7, 2020
• First Submitted That Met QC Criteria: April 15, 2020
• First Posted (Actual): April 20, 2020

Study Record Updates

• Last Update Posted (Actual): May 13, 2020
• Last Update Submitted That Met QC Criteria: May 11, 2020
• Last Verified: May 1, 2020

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Coronavirus; COVID-19; Hydroxychloroquine; chemoprophylaxis
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antirheumatic Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Hydroxychloroquine
• Other Study ID Numbers: PROLIFIC2020 (A095583)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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