PROLIFIC ChemoprophylaxisTrial (COVID-19)

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Hydroxychloroquine - Daily dosing
* Drug: Hydroxychloroquine - Weekly Dosing
* Other: Matched Placebo Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be included in the trial the participant MUST: Have given written informed consent to participate Be aged 18 years to 70 years Not previously have been diagnosed with COVID-19 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: Known COVID-19 positive test at baseline (if available) Symptomatic for possible COVID-19 at baseline Known hypersensitivity reaction to HCQ, chloroquine or 4-aminoquinolines Known retinal disease Known porphyria Known chronic kidney disease (CKD; eGFR<30ml/min) Known epilepsy Known heart failure or conduction problems Known significant liver disease (Gilbert's syndrome is permitted) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency Currently taking any of the following contraindicated medications: Digoxin Chloroquine Halofantrine Amiodarone Moxifloxacin Cyclosporin Mefloquine Praziquantel Ciprofloxacin Clarithromycin Prochlorperazine Fluconazole Currently taking hydroxychloroquine or having a clinical indication for taking hydroxychloroquine Currently breastfeeding Unable to be followed-up during the trial Current or future involvement in the active treatment phase of other interventional research studies (excluding observational/non-interventional studies) before study follow-up visit Not able to use or have access to a modern phone device/web-based technology Any other clinical reason which may preclude entry in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Hydroxychloroquine - Daily dosing<br>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<br>* 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)<br>|
| Active Comparator: Hydroxychloroquine - Weekly dosing<br>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<br>* 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)<br>|
| Placebo Comparator: Placebo<br>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<br>* 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)<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Coronavirus, COVID-19, chemoprophylaxis, Hydroxychloroquine