The Impact of Camostat Mesilate on COVID-19 Infection

Study Overview
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Brief Summary
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SARS-CoV-2, one of a family of human coronaviruses, was initially identified in December 2019 in Wuhan city. This new coronavirus causes a disease presentation which has now been named COVID-19. The virus has subsequently spread throughout the world and was declared a pandemic by the World Health Organisation on 11th March 2020. As of 18 March 2020, there are 198,193 number of confirmed cases with an estimated case-fatality of 3%. There is no approved therapy for COVID-19 and the current standard of care is supportive treatment. SARS-CoV-2 exploits the cell entry receptor protein angiotensin converting enzyme II (ACE-2) to access and infect human cells. The interaction between ACE2 and the spike protein is not in the active site. This process requires the serine protease TMPRSS2. Camostat Mesilate is a potent serine protease inhibitor. Utilizing research on severe acute respiratory syndrome coronavirus (SARS-CoV) and the closely related SARS-CoV-2 cell entry mechanism, it has been demonstrated that SARS-CoV-2 cellular entry can be blocked by camostat mesilate. In mice, camostat mesilate dosed at concentrations similar to the clinically achievable concentration in humans reduced mortality following SARS-CoV infection from 100% to 30-35%.

Detailed Description
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Cohort 1 - enrolment into the cohort of hospitalized patients has been completed (31 Dec 2020). Study results are publicly available at EClinicilMedicine, see link https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00129-2/fulltext Cohort 2 - outpatients - remains open for enrolment

Official Title
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The Impact of Camostat Mesilate on COVID-19 Infection: An Investigator-initiated Randomized, Placebo-controlled, Phase IIa Trial

Conditions
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Corona Virus Infection

Intervention / Treatment
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* Drug: Camostat Mesilate
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Cohort 1) Documented COVID-19 infection as evidenced by positive PCR (or comparable clinical assay) for SARS-CoV-2 Less than 48 hours since time of hospital admission OR if hospital-acquired COVID-19 is suspected, less than 48 hrs since onset of symptoms Adolescents and adults age >=18 years Subject or legally authorized representative able to give informed consent Admitted to hospital Cohort 2) Documented COVID-19 infection as evidenced by positive PCR (or comparable clinical assay) for SARS-CoV-2 One or more of the following symptoms of COVID-19 infection: fever, cough, expectoration, shortness of breath, myalgia, fatigue, or head ache No more than 5 days since the beginning of symptom onset Adolescents and adults age >=18 years Subject (or legally authorized representative, for Cohort 1 only) able to give informed consent Do not require immediate hospitalization (newly diagnosed COVID-19 patients who are discharged within 24 hrs of hospital admission are eligible for enrollment) Must be willing to fill out a daily symptom diary Must be available for a daily phone call Must be willing to take their own temperature at least once a day Exclusion criteria Any condition that, in the Investigator's opinion, will prevent adequate compliance with study therapy (e.g. the patient is considered to be moribund within the next 72 hrs or has uncontrolled substance abuse that prevents adherence to study medication). Patients needing ventilator treatment are eligible to be enrolled if they fulfill the other in/exclusion criteria. The following laboratory values at baseline (Day 0): Serum total bilirubin ≥3 ULN Estimated glomerular filtration rate (eGFR) ≤30 mL/min (based on serum creatinine) Known hypersensitivity to Camostat Mesilate Women who are pregnant or breastfeeding, or with a positive pregnancy test as determined by a positive urine or blood beta- human chorionic gonadotropin test during screening or women of child bearing potential* who are unwilling or unable to use an acceptable method of contraception (combined estrogen and progestogen hormonal contraception (oral, intravaginal or transdermal), progesteron-only hormonal contraception (oral, injectable or implantable), intrauterine device or intrauterine hormone-releasing system) to avoid pregnancy during the study. Sexual abstinence will only be accepted in cases where this reflect the usual lifestyle.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There are 2 cohorts: Cohort 1 - hospitalized patients (n=180); Cohort 2 - outpatients (n=400). All participants in the two cohorts are randomized to one of two arms
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>2 pills 3 times daily for 5 days | Drug: Placebo oral tablet<br>* Placebo<br>* Other names: Placebo;|
| Experimental: Camostat Mesilate<br>2x100 mg pills 3 times daily for 5 days | Drug: Camostat Mesilate<br>* Serine protease inhibitor that blocks TMPRSS-2 mediated cell entry of SARS-CoV-2<br>* Other names: Foipan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cohort 1: Days to clinical improvement from study enrolment | Clinical improvement defined as live hospital discharge OR a 2 point improvement (from time of enrolment) in disease severity rating on the 7-point ordinal scale | 30 days | 
| Cohort 2: Days to clinical improvement from study enrolment | Days to clinical improvement from study enrolment defined no fever for at least 48 hrs AND improvement in other symptoms (e.g. cough, expectoration, myalgia, fatigue, or head ache) | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation, as measured by AEs, Adverse Reactions (ARs), SAEs, Serious ARs (SARs) |  | 30 days | 
| Cohort 1: Clinical status as assessed by the 7-point ordinal scale at day 7, 14 and 30 | The ordinal scale is an assessment of the clinical status at the first assessment of a given study day. The scale is as follows: 1) Death; 2) Hospitalized, on invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO); 3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; 4) Hospitalized, requiring supplemental oxygen; 5) Hospitalized, not requiring supplemental oxygen; 6) Not hospitalized, limitation on activities; 7) Not hospitalized, no limitations on activities. | 30 days | 
| Cohort 1: Day 30 mortality | Mortality | 30 days | 
| Cohort 1: Change in NEW(2) score from baseline to day 30 | NEWS2 | 30 days | 
| Cohort 1: Admission to ICU | ICU | 30 days | 
| Cohort 1: Use of invasive mechanical ventilation or ECMO | invasive mechanical ventilation or ECMO | 30 days | 
| Cohort 1: Duration of supplemental oxygen (days) | Nasal or high-flow oxygen | 30 days | 
| Cohort 1+2: Days to self-reported recovery (e.g. limitations in daily life activities) during telephone interviews conducted at day 30 | Subjective clinical improvement | 30 days | 
| Cohort 2: Number participant-reported secondary infection of housemates | No of new COVID-19 infections in the household | 30 days | 
| Cohort 2: Time to hospital admission related to COVID-19 infection | Hospital admission | 30 days | 

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