Reconvalescent Plasma/Camostat Mesylate Early in SARS-CoV-2 Q-PCR (COVID-19) Positive High-risk Individuals

Study Overview
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Brief Summary
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This study is a 4-arm, multicenter, randomized, partly double- blind, controlled trial to evaluate the safety and efficacy of convalescent serum (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 and high risk for moderate/severe COVID-19. The working hypothesis to be tested in the RES-Q-HR study is that the early use of convalescent plasma (CP) or camostat mesylate (Foipan®) reduces the likelihood of disease progression to modified WHO stages 4b-8 in SARS-CoV-2 positive adult patients at high risk of moderate or severe COVID-19 progression. The primary endpoint of the study is the cumulative number of individuals who progressed to or beyond category 4b on the modified WHO (World Health Organization) COVID-19 ordinal scale within 28 days after randomization.

Detailed Description
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The novel coronavirus designated SARS CoV-2, and the disease caused by this virus designated COVID-19. No treatment is available for early disease stages and non-hospitalized patients to date. This trial focusses on SARS-CoV-2 positive patients with pre-existing risk factors for a moderate or severe COVID-19 disease course. This study is a 4-arm, multicenter, randomized, partly double-blind, controlled trial to evaluate the safety and efficacy of convalescent serum (CP) or camostat mesylate with control or placebo in adult patients diagnosed with SARS-CoV-2 and high risk for moderate/severe COVID-19. Camostat mesylate acts as an inhibitor of the host cell serine protease TMPRSS2 and prevents the virus from entering the cell. Convalescent plasma (CP) represents another antiviral strategy in terms of passive immunization. The working hypothesis to be tested in the RES-Q HR study is that the early use of convalescent plasma (CP) or camostat mesylate (Foipan®) reduces the likelihood of disease progression to modified WHO stages 4b-8 in SARS-CoV-2 positive adult patients at high risk of moderate or severe COVID-19 progression.

Official Title
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Reconvalescent Plasma / Camostat Mesylate Early in Sars-CoV-2 Q-PCR (COVID-19) Positive High-risk Individuals

Conditions
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Corona Virus Infection, SARS-CoV-2 Infection, SARS-CoV-2 PCR Test Positive, SARS-CoV-2 Acute Respiratory Disease

Intervention / Treatment
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* Biological: Convalescent plasma
* Drug: Camostat Mesilate
* Drug: Placebo for Camostat Mesilate
* Other: Standard of Care (SoC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Individuals (female, male, diverse) ≥ 18 years with SARS-CoV-2 infection, confirmed by PCR before study enrollment SARS-CoV-2 positive PCR ≤ 3 days old (date of NP swab) Presence of ≥ 1 SARS-CoV-2 typical symptom (fever, cough, shortness of breath, sore throat, headache, fatigue, smell/and or taste disorder, diarrhea, abdominal symptoms, exanthema) and symptom duration <= 3 days. Ability to provide written informed consent Presence of at least one of the following criteria: Patients > 75 years Patients > 65 years with at least one other risk factor (BMI >35 kg/m2, coronary artery disease, chronic kidney disease (CKD) with glomerular filtration rate (GFR) <60 ml/min but >= 30 ml/min, diabetes mellitus, active tumor disease) Patients with a BMI >35 kg/m2 with at least one other risk factor (CAD, CKD with GFR <60 ml/min but >= 30 ml/min, diabetes mellitus, active tumor disease) Patients with a BMI >40 kg/m2 Patients with chronic obstructive pulmonary disease (COPD) and/or pulmonary fibrosis Exclusion Criteria: Age <18 years Unable to give informed consent Pregnant women or breast-feeding mothers Previous transfusion reaction or other contraindication to a plasma transfusion Known hypersensitivity to camostat mesylate and/or severe pancreatitis Volume stress due to CP administration would be intolerable Known IgA deficiency Life expectancy < 6 months Duration SARS-CoV-2 typical symptoms > 3 days SARS-CoV-2 PCR detection older than 3 days SARS-CoV-2 associated clinical condition >= WHO stage 3 (patients hospitalized for other reasons than COVID-19 may be included if they fulfill all inclusion and none of the exclusion criteria). Previously or currently hospitalized due to SARS-CoV-2 Previous antiviral therapy for SARS-CoV-2 alanine aminotransferase (ALT) or aspartate transferase (AST) > 5 times upper limit of normal (ULN) at screening Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial) Chronic kidney disease with GFR < 30 ml/min Concurrent or planned anticancer treatment during trial period Accommodation in an institution due to legal orders (§40(4) AMG). Any psycho-social condition hampering compliance with the study protocol. Evidence of current drug or alcohol abuse. Use of other investigational treatment within 5 half-lives of enrollment is prohibited Previous use of convalescent plasma for COVID-19 Concomitant proven influenza A infection Patients with organ or bone marrow transplant in the three months prior to Screening Visit

Ages Eligible for Study
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Minimum Age: 18 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: The study is a multicenter trial that will be conducted in approx. 10 - 15 centers in Germany. At each center, patients will be randomized into four groups: two treatment groups and two control groups. The randomization rate in this study is two to one (2:1) in favor to therapy, i.e. included patients have twice the chance to receive interventional therapy than placebo / SoC.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: convalescent plasma (CP)<br>Administration of 2 units of CP (neutralizing anti-SARS-CoV-2 antibody titer of at least 1:160) on day 1 | Biological: Convalescent plasma<br>* transfusion of convalescent plasma (CP) with neutralizing antibodies against anti-SARS-CoV-2 ((titer of at least 1:160)<br>|
| Other: Standard of Care<br>Standard of care allowed | Other: Standard of Care (SoC)<br>* Control Arm for convalescent plasma (CP)<br>|
| Experimental: Camostat Mesilate<br>Tablets 600 mg per day in 3 doses over 7 days | Drug: Camostat Mesilate<br>* Tablets over 7 days, daily dose of 600 mg split into 3 doses<br>|
| Placebo Comparator: Placebo camostat<br>Placebo Tablets in 3 doses over 7 days (blinded) | Drug: Placebo for Camostat Mesilate<br>* Placebo Tablets over 7 days, split into 3 doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| WHO ordinal Covid-19 scale up to day 28 | The primary endpoint of the study is the number of individuals whose clinical status is on the COVID-19 modified WHO ordinal scale ≥ 4b up to and including day 28 | up to and including day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative number WHO categories 4b-8 | Cumulative number of persons in the respective treatment arms versus SoC/placebo in WHO categories 4b-8 | day 8, day 14, day 56 and day 90 | 
| Cumulative number WHO categories 3-4a | Cumulative number of persons in the respective treatment arms versus SoC/placebo in WHO categories 3-4a | day 8, day 14, day 28, day 56 and day 90 | 
| Not hospitalized | Cumulative number of participants not hospitalized at day 90 | at day 90 | 
| All-cause mortality | All-cause mortality at day 90 | at day 90 | 
| Reinfection | Number of patient with SARS-CoV-2 reinfection up to day 90 | up to day 90 | 
| Secondary sclerosing cholangitis (SSC) | Number of patient with secondary sclerosis cholangitis at day 90 | at day 90 | 
| chronic pulmonary disease as sequelae from COVID-19 | Number of patient with COVID-19 associated chronic pulmonary disease | at day 90 | 
| patients with remdesivir treatment | The proportion of patients with remdesivir therapy | up to day 90 | 
| COVID-19 WHO status of patients at start of remdesivir treatment | The clinical status on the WHO COVID-19 ordinal scale of at the start of remdesivir treatment WHO ordinal scale ranges from 0 to 8; whereas 0 = no COVID-19 infection and 8 = death | up to day 90 | 
| patients with dexamethasone treatment | The proportion of patients on dexamethasone therapy | up to day 90 | 
| COVID-19 WHO status of patients at start of dexamethasone treatment | The clinical status on the WHO COVID-19 ordinal scale of at the start of dexamethasone treatment WHO ordinal scale ranges from 0 to 8; whereas 0 = no COVID-19 infection and 8 = death | up to day 90 | 
| resolution of COVID-19 symptoms | Time to resolution of COVID-19 related symptoms (e.g. fever) | until day of resolution up to day 90 | 
| negative SARS-CoV-2-PCR test | Time to first negative SARS-CoV-2-PCR (polymerase chain reaction) | until day of first negative test up to day 90 | 
| Oxygen therapy | Duration of oxygen therapy (in days) | number of days with oxygen therapy up to day 90 | 
| COVID-19 pneumonia | Frequency of occurrence of COVID-19 pneumonia | up to day 90 | 
| Percentage of participants requiring mechanical ventilation | Percentage of participants in each group with need for mechanical ventilation | up to day 90 | 
| Number of ventilation days per participant up to day 90 | Number of ventilation days per participant up to day 90 | up to day 90 | 
| hospital stay and intensive care | Duration of hospital stay (in days), duration in intensive care/intermediate care (IMC) (in days) | up to day 90 | 
| Mortality | All-cause mortality at day 28 | at day 28 | 
| SAEs | Cumulative incidence of Serious Adverse Events (SAE) per group within 90 days follow up | up to day 90 | 
| Grade 3/4 AEs | Cumulative incidence of grade 3/4 Adverse Events (AE) per group | up to day 90 | 
| SARS-CoV-2 antibody IgA concentrations | SARS-CoV-2 antibody concentrations (IgA in g/l) in serum on day 8, day 14, day 90 | on day 8, day 14, day 90 | 
| SARS-CoV-2 antibody IgG concentrations | SARS-CoV-2 antibody concentrations (IgG in g/l) in serum on day 8, day 14, day 90 | on day 8, day 14, day 90 | 
| SARS-CoV-2 neutralizing antibody titers | SARS-CoV-2 neutralizing antibody titers in serum on day 8, day 14, day 90 | on day 8, day 14, day 90 | 
| Plasma treatment screening failures | Number of screening failures due to the lack of a suitable plasma preparation | up to day 8 (End of treatment) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SARS-CoV-2, Covid-19, camostat mesilate, reconvalescent plasma, TMPRSS2