Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP Canada)

Study Overview
=================
Brief Summary
-----------------
Study Objective: To test if early preemptive hydroxychloroquine therapy can prevent disease progression in persons with known symptomatic COVID-19 disease, decreasing hospitalizations and symptom severity.

Detailed Description
-----------------
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a rapidly emerging viral infection causing COVID19. Therapy is generally not given to persons who are not hospitalized. Hydroxychloroquine may have antiviral effects against SARS-CoV2 which may decrease disease severity when given early. This trial will use a modification of standard malaria dosing of hydroxychloroquine to provide preemptive therapy for those with early symptoms. This study is a continuation of NCT04308668 which looked at post-exposure prophylaxis (now closed) and early treatment in the USA (now closed, data to be pooled) and Canada (which continues in this study). On April 28, 2020 NCT04308668 changed its primary outcome to symptomatic improvement in the preemptive therapy arm. This study continues enrollment for the primary ordinal outcome of hospitalization; hospitalization with intensive care stay; or death. People in the participating Canadian provinces can help answer this critically important question. No in-person visits are needed. The doses of hydroxychloroquine being used have been approved by Health Canada. This trial is targeting the following groups of people: If you are symptomatic with a positive COVID-19 test within the first 4 days of symptoms and are not hospitalized; OR If you have had occupational exposure with known exposure to someone with lab-confirmed COVID-19 within the last 14 days AND have compatible symptoms starting within the last 4 days; You may participate if you live anywhere in the Canadian Provinces of Quebec, Manitoba, Alberta, British Columbia, Newfoundland or Ontario. For information on how to participate in the research trial, go to: www.covid-19research.ca

Official Title
-----------------
Preemptive Therapy for SARS-Coronavirus-2 (COVID-19 PEP Canada)

Conditions
-----------------
Corona Virus Infection, SARS-CoV Infection, Coronavirus

Intervention / Treatment
-----------------
* Drug: Hydroxychloroquine
* Drug: Placebo oral tablet


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 years of age or older AND provision of informed consent WITH Symptomatic COVID-19 disease with confirmed diagnosis with PCR+ SARS-CoV-2 within <= 4 days of symptoms OR Healthcare worker with compatible symptoms with exposure to known PCR+ case <= 14 days (and no available/pending testing for the individual). Exclusion Criteria: Current hospitalization Allergy to chloroquine or hydroxychloroquine Severe diarrhea and/or vomiting Significant hepatic impairment defined as known cirrhosis with history of hepatic encephalopathy or ascites. Prior retinal eye disease Concurrent malignancy requiring chemotherapy Known Chronic Kidney disease, Stage 4 or 5 or dialysis. Known glucose-6 phosphate dehydrogenase (G6PD) deficiency. Known ventricular arrythmia, known prolonged QTc interval, or any known episode of sudden cardiac death Known Porphyria Weight <40 kg Known Pregnancy of Breastfeeding Current use of chloroquine or hydroxychloroquine Current use of Artemether, Dapsone, Lumefantrine or Mefloquine Current use of Cardiac medicines: amiodarone, digoxin, dofetilide, flecainide, procainamide, sotalol, or propafenone Current use of the following antimicrobials: levofloxacin, ciprofloxacin, moxifloxacin, azithromycin, clarithromycin, erythromycin, ketoconazole, or itraconazole Current use of the following antidepressants: amitriptyline, citalopram, desipramine, escitalopram, imipramine, doxepin, fluoxetine, sertraline, bupropion (Wellbutrin), or venlafaxine Current use of the following antipsychotic or mood stabilizers: haloperidol, droperidol, lithium, quetiapine, thioridazine, ziprasidone Current use of methadone Current use of Sumatriptan, Zolmitriptan other than as needed Current use of systemic chemotherapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment<br>Participants in this arm will receive the study drug, hydroxychloroquine. | Drug: Hydroxychloroquine<br>* 200mg tablet; 800 mg orally once, followed in 6 to 8 hours by 600 mg, then 600mg once a day for 4 consecutive days<br>|
| Placebo Comparator: Placebo<br>Participants in this arm will receive a placebo treatment. | Drug: Placebo oral tablet<br>* 4 placebo tablets once, followed in 6 to 8 hours by 3 tablets, then 3 tablets once-a-day for 4 consecutive days<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ordinal Scale of COVID19 Disease Severity at 14 days | Participants will self-report disease severity status as one of the following 3 options; no COVID19 illness (score of 1), COVID19 illness with no hospitalization (score of 2), or COVID19 illness with hospitalization or death (score of 3). Increased scale score indicates greater disease severity. Outcome is reported as the percent of participants who fall into each category per arm. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Hospitalization | Outcome reported as the number of participants in each arm who require hospitalization for COVID19-related disease. | 14 days | 
| Incidence of COVID-19 related Death | Outcome reported as the number of participants in each arm who expire due to COVID-19-related disease. | 90 days | 
| Incidence of all-cause Death | Outcome reported as the number of participants in each arm who expire due to all causes. | 90 days | 
| Incidence of All-Cause Study Medicine Discontinuation or Withdrawal | Outcome reported as the number of participants in each arm who discontinue or withdraw medication use for any reason. | 14 days | 
| Overall symptom severity at 5 and 14 days | Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe) | 5 and 14 days | 
| Overall change in disease severity over 14 days among those who are symptomatic at baseline | Repeated Measure mixed regression model of change in: Visual Analog Scale 0-10 score of rating overall symptom severity (0 = no symptoms; 10 = most severe) | 14 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COVID-19, SARS-COV-2, Coronavirus, Corona virus