Efficacy of Various Doses of Hydroxychloroquine in Pre-Exposure Prophylaxis for COVID 19

Study Overview
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Brief Summary
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Hydroxychloroquine has been approved by FDA as one of the treatment options for COVID 19.Healthcare personnel are amongst those at highest risk to contract the disease. Several health authorities are now recommending the use of hydroxychloroquine as pre-exposure prophylaxis is in health care personnel. Several studies are on going in this context. However there is a controversy regarding the dosage regimen. This drug has a half life of 22.4 days. In this study we will be comparing three different doses of Hydroxychloroquine and additionally have a control group in order to determine the efficacy of hydroxychloroquine as pre- exposure prophylaxis in healthcare personnel in various doses.

Detailed Description
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Study design: Phase 2 proof of concept study Study Type: Interventional (Clinical Trial) Estimated Enrollment : at least 200 participants Since the investigators have no current data on pre-exposure prophylaxis to calculate sample size statistically, so a minimum of 50 participants in each arm will be recruited including 20% attrition rate. The investigators will be recruiting a minimum of 200 participants in the study , that is at least 50 in each of the four arms. Allocation: Randomized Intervention Model: Parallel Assignment Study model: Parallel group interventional study Location: SZABMU/PIMS Study duration: a minimum of 12 weeks from recruitment Materials and Methods: Participants will be recruited after approval from Ethical Review Board .A written informed consent will be taken from all participants. Participants fulfilling the eligibility criteria will be randomized to 4 arms. Arm Intervention /treatment Experimental group 1: Hydroxychloroquine 400 mg twice a day 1,followed by 400 mg weekly for a total of 12 weeks Drug: Hydroxychloroquin HCQ 200 mg, oral Experimental group 2:Hydroxychloroquine 400 mg on day 1 followed by 400mg once every 3 weeks for a total of 12 weeks Drug: Hydroxychloroquin HCQ 200 mg, oral Experimental group 3:Hydroxychloroquine 200 mg on day 1 followed by 200 mg once every 3 weeks for a total of 12 weeks Drug: Hydroxychloroquin HCQ 200 mg, oral Control Group : Placebo 200mg will be given on day 1 followed by Placebo 200mg every three weeks for a total of 12 weeks. Base line characteristics of all participants will be recorded including age ,gender,role of healthcare personnel, comorbidities, and drugs the participant is using. Samples will be collected for complete picture blood, liver and renal function tests and electrocardiogram. These tests will also be conducted every month till the end of the trial and the participants will be monitored for any adverse effects. During the study duration all participants will self- report any symptoms related to COVID 19 and any adverse reactions from the drug. Participants having COVID 19 symptoms at any time will be tested by the gold standard test PCR for SARS-COV-2 using nasopharyngeal and oropharyngeal swabs. All participants at the end of the study will have PCR for SARS-COV-2 and if available IgM and IgG serology to find out if they had any infection, did not get infected at all or only had asymptomatic or mild infection.

Official Title
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Comparative Efficacy of Various Doses of Hydroxychloroquine in Pre-Exposure Prophylaxis for COVID 19 in Healthcare Personnel

Conditions
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COVID 19

Intervention / Treatment
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* Drug: Hydroxychloroquine Sulfate 200 MG
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria after taking a written informed consent: A healthcare worker at high risk for COVID19 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, gastroenterologists performing endoscopy, Pulmonologists performing bronchoscopy); First responders (i.e. EMTs, paramedics) ; Persons working in the departments of General Medicine, Pulmonology, Infectious disease and Isolation wards. Exclusion Criteria: Active COVID-19 disease; Confirmed prior COVID-19 disease; Current fever, cough, shortness of breath; Contraindication or hypersensitivity to chloroquine or hydroxychloroquine ad hypersensitivity to 4-aminoquinoline compounds; Pregnancy; Lactation; 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; Current use of chloroquine,hydroxychloroquine or cardiac medicines like flecainide, amiodarone, digoxin, procainamide, or propafenone; Current use of medications with known significant drug-drug interactions: artemether, lumefantrine, mefloquine, tamoxifen or methotrexate; Current use of medications causing QT interval prolongation like: macrolides,antipsychotics,quinolones,antihistamines,SSRIs,tricyclic antidepressants, antifungals; Recent Myocardial Infarction; History of Epilepsy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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
Interventional Model Description: Participants fulfilling the eligibility criteria will be randomized to 4 arms by using Random Allocation Software version-2 Arm Intervention /treatment Experimental group 1: Hydroxychloroquine 400 mg twice a day 1,followed by 400 mg weekly for a total of 12 weeks Experimental group 2:Hydroxychloroquine 400 mg on day 1 followed by 400 mg once every 3 weeks for a total of 12 weeks Experimental group 3:Hydroxychloroquine 200 mg on day 1 followed by 200 mg once every 3 weeks for a total of 12 weeks Control Group :Placebo 200mg will be given on day 1 followed by Placebo 200mg every three weeks for a total of 12 weeks..
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Hydroxychloroquine Sulphate will be administered at a dose of 400mg twice a day on day 1 followed by 400 mg once a week for a total of 12 weeks | Drug: Hydroxychloroquine Sulfate 200 MG<br>* Hydroxychloroquine Sulphate 200 mg tablets will be prescribed and instituted orally at the doses and regimens described<br>* Other names: Tab HCQ;|
| Experimental: Arm 2<br>Hydroxychloroquine Sulphate will be admoinistered at a dose of 400 mg on day 1 followed by 400mg once every 3 weeks for at total of 12 weeks | Drug: Hydroxychloroquine Sulfate 200 MG<br>* Hydroxychloroquine Sulphate 200 mg tablets will be prescribed and instituted orally at the doses and regimens described<br>* Other names: Tab HCQ;|
| Experimental: Arm 3<br>Hydroxychloroquine Sulphate will be administered at a dose of 200 mg on day 1 followed by 200 mg once every 3 weeks for a total of 12 weeks | Drug: Hydroxychloroquine Sulfate 200 MG<br>* Hydroxychloroquine Sulphate 200 mg tablets will be prescribed and instituted orally at the doses and regimens described<br>* Other names: Tab HCQ;|
| Placebo Comparator: Arm 4<br>Control group will recieve Placebo 200mg on day 1 followed by Placebo 200mg every three weeks for 12 weeks | Other: Placebo<br>* Control group will receive a Placebo tablet. Placebo 200mg will be given on Day 1 followed by Placebo 200mg every three weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| COVID-19-free survival in experimental arms compared to placebo | Outcome reported as the percentage of participants in each arm who are COVID-19-free at the end of study treatment | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of confirmed SARS-COV-2 detection | Outcome reported as the percent of participants in each arm who have a confirmed SARS-CoV-2 infection during study treatment. | 12 weeks | 
| Incidence of possible COVID-19 symptoms | Outcome reported as the percent of participants in each arm who report COVID-19-related symptoms during study treatment | 12 weeks | 
| Incidence of all-cause study medicine discontinuation | Outcome reported as the percent of participants in each arm who discontinue study medication use for any reason during treatment. | 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), Hospitalization with ICU stay (score 4),Death from COVID 19(score=5) Possible scores range from 1-5 with higher scores indicating greater disease severity. | 12 weeks | 
| Incidence of Hospitalization for COVID-19 or death | Outcome reported as the percent of participants in each arm who are hospitalized or expire due to COVID-19 during study treatment. | 12 weeks | 
| Incidence of study medication-related adverse events | Outcome reported as the percent of participants experiencing any possible adverse events from Hydroxychloroquine | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pre-exposure prophylaxis, Healthcare personnel