Randomized Clinical Trial for the Prevention of SARS-CoV-2 Infection (COVID-19) in Healthcare Personnel

Study Overview
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Brief Summary
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Healthcare workers are particularly at risk of SARS-CoV-2. This study aims to assess the efficacy of a daily single dose of tenofovir disoproxil fumarate (TDF) (245 mg)/ Emtricitabine (FTC) (200 mg), a daily single dose of hydroxychloroquine (HC) (200 mg), a daily single dose of TDF (245 mg)/FTC (200 mg) plus HC (200 mg) versus placebo, during 12 weeks in: (1) reducing the incidence of symptomatic disease and (2) reducing clinical severity COVID-19 among hospital healthcare workers aged 18 to 70 years in public and private hospitals in Spain.

Detailed Description
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Healthcare workers are particularly at risk of SARS-CoV-2. In the absence of a vaccine, other strategies aiming to reduce the development of COVID-19 in the population, more specifically in healthcare workers is being sought. Administration of effective drugs to people at risk of developing an infectious disease is well accepted and is part of clinical practice. To date there are few on-going randomized clinical trial on Pre-exposure prophylaxis (PrEP) evaluating chloroquine and hydroxychloroquine efficacy for health care workers and other groups at high risk. Existing recent and scarce literature shows that RNA synthesis nucleos(t)ide analogue inhibitors, acting as viral RNA chain terminators, like TDF, abacavir or lamivudine, amongst others, could have an effect against SARS-CoV-2 infection. Worldwide, there is broad evidence of the use, safety and tolerability of hydroxychloroquine (200 mg) and TDF/FTC (245 mg/200 mg). This study aims to assess the efficacy of a daily single dose of TDF (245 mg)/FTC (200 mg), a daily single dose of HC (200 mg), a daily single dose of TDF (245 mg)/FTC (200 mg) plus HC (200 mg) versus placebo, during 12 weeks in: (1) reducing the incidence of symptomatic disease and (2) reducing clinical severity COVID-19 among hospital healthcare workers aged 18 to 70 years in public and private hospitals in Spain. Sample size calculations are based on the primary outcome; number of symptomatic confirmed infections by SARS-CoV-2. Briefly, 4.000 participants will be assigned to one of the 4 groups, through 1:1:1:1 randomization. Duration of prophylactic treatment will be 12 weeks from early April 2020 till early July 2020. Follow up of participants will continue up to 4 weeks after last dose of treatment. All participants will be assessed on a monthly basis. Interim analyses will be performed on monthly bases.

Official Title
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Prevention of SARS-CoV-2 (COVID-19) Through Pre-Exposure Prophylaxis With Tenofovir Disoproxil Fumarate/Emtricitabine and Hydroxychloroquine in Healthcare Personnel: Randomized Clinical Trial Controlled With Placebo

Conditions
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Coronavirus Infection

Intervention / Treatment
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* Drug: Emtricitabine/tenofovir disoproxil
* Drug: Hydroxychloroquine
* Drug: Placebo: Emtricitabine/tenofovir disoproxil Placebo
* Drug: Placebo: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants that, after receiving appropriate information on the study design, objectives, possible risks and acknowledging they have the right to withdraw from the study consent at any time, sing the informed consent for participation in the study. Male or female aged 18-70years. Health care workers in public or private hospitals in areas of risk of SARS-CoV-2 transmission. No previous diagnosis of SARS-CoV-2 (COVID-19) infection plus no symptoms compatible with SARS-CoV-2 (COVID-19) since 1st of March 2020 until the date of enrolment in the study. Understanding of the aim of the study and, therefore, acknowledging they have not been on any drug aiming at pre exposure prophylaxis against SARS-CoV-2 (COVID-19) since 1st of March 2020. This also includes PrEP for HIV. Negative pregnancy test during the previous 7 days to start treatments or more than 2 years after menopause. Women of reproductive age and their partners should commit to use and highly effective contraceptive method ( double barrier, hormonal contraception), during the study period and until 6 months after the last dose of treatment. Exclusion Criteria: Having symptoms suggestive of COVID-19 infection HIV infection Active hepatitis B infection. Renal failure with estimated glomerular filtration rate (GFR) < 60 ml/min) and patients on Hemodialysis. Osteoporosis Myasthenia gravis Pre-existent maculopathy. Retinitis pigmentosa Bradycardia < 50bpm Weight < 40kg Participant with any immunosuppressive condition or hematological disease. Have taken any medications such as PrEP against SARS-CoV-2 from March 1, 2020 until trial entry (also includes PrEP for HIV). Treatment with drugs that may prolong QT in the last month before randomization for more than 7 days including: azithromycin, chlorpromazine, cisapride, clarithromycin, domperidone, droperidol, erythromycin, halofantrine, haloperidol, lumefantrine, mefloquine, methadone, pentamidine, procainamide, quinidine, quinine, sotalol, sparfloxacin, thioridazine, amiodarone. Breastfeeding Known allergy to any of the medication used in this trial

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Emtricitabine/Tenofovir<br>Tenofovir Disoproxil Fumarate 245 mg/Emtricitabine 200 mg + Placebo of Hydroxychloroquine 200 mg Strength: 200 mg/245 mg tablets Dose: one tablet once a day (both at dinner) | Drug: Emtricitabine/tenofovir disoproxil<br>* Emtricitabine/tenofovir disoproxil, 200 mg/245 mg tablets. A dose of one tablet once a day will be administered.<br>Drug: Placebo: Hydroxychloroquine<br>* Placebo: Tablets similar in appearance to Hydroxychloroquine<br>|
| Experimental: Hydroxychloroquine<br>Hydroxychloroquine 200 mg + Placebo of Tenofovir Disoproxil Fumarate 245 mg/Emtricitabine 200 mg Strength: 200 mg tablets Dose: one tablet once a day (both at dinner) | Drug: Hydroxychloroquine<br>* Hydroxychloroquine, 200 mg tablets. A dose of one tablet once a day will be administered.<br>Drug: Placebo: Emtricitabine/tenofovir disoproxil Placebo<br>* Placebo: Tablets similar in appearance to Emtricitabine/tenofovir disoproxil<br>|
| Experimental: Emtricitabine/Tenofovir+Hydroxychloroquine<br>Tenofovir Disoproxil Fumarate 245 mg/Emtricitabine 200 mg + Hydroxychloroquine 200 mg Strength FTC/TDF:200 mg/245 mg tablets Strength HC: 200 mg tablets Dose: one tablet FTC/TDF plus one tablet HC once a day (at dinner) | Drug: Emtricitabine/tenofovir disoproxil<br>* Emtricitabine/tenofovir disoproxil, 200 mg/245 mg tablets. A dose of one tablet once a day will be administered.<br>Drug: Hydroxychloroquine<br>* Hydroxychloroquine, 200 mg tablets. A dose of one tablet once a day will be administered.<br>|
| Placebo Comparator: Placebo<br>Placebo of Tenofovir Disoproxil Fumarate 245 mg/Emtricitabine 200 mg + Placebo of Hydroxychloroquine 200 mg Placebo tablets with similar appearance to study drugs. Dose: one tablet once a day (both at dinner) | Drug: Placebo: Emtricitabine/tenofovir disoproxil Placebo<br>* Placebo: Tablets similar in appearance to Emtricitabine/tenofovir disoproxil<br>Drug: Placebo: Hydroxychloroquine<br>* Placebo: Tablets similar in appearance to Hydroxychloroquine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of confirmed symptomatic infections of SARS-CoV-2 (COVID-19) |  | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity of disease in confirmed infected participants of SARS-CoV-2 (COVID-19) | assessed by: No symptoms Mild symptoms: general malaise, fever, cough, myalgia, asthenia. Moderate symptoms: mild symptoms plus shortness of breath, Severe symptoms: mild symptoms plus respiratory insufficiency that requires admission in intensive care unit and mechanical ventilation | 12 weeks | 
| Duration of symptoms in confirmed infected participants of SARS-CoV-2 (COVID-19) measured in days |  | 12 weeks | 

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