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

• ClinicalTrials.gov Identifier: NCT04681430
• Recruitment Status: Recruiting
• First Posted: December 23, 2020
• Last Update Posted: February 1, 2021
• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborator: The Federal Ministry of Health, Germany (Bundesministerium für Gesundheit, BMG)
• Information provided by (Responsible Party): Heinrich-Heine University, Duesseldorf

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Corona Virus Infection; SARS-CoV-2 Infection; SARS-CoV-2 PCR Test Positive; SARS-CoV-2 Acute Respiratory Disease	Biological: Convalescent plasma; Drug: Camostat Mesilate; Drug: Placebo for Camostat Mesilate; Other: Standard of Care (SoC)	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 1094 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment

Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: The camostat mesylate and its placebo group will be double blinded while the CP and its placebo will be open label.
• Primary Purpose: Treatment
• Official Title: Reconvalescent Plasma / Camostat Mesylate Early in Sars-CoV-2 Q-PCR (COVID-19) Positive High-risk Individuals
• Actual Study Start Date: January 8, 2021
• Estimated Primary Completion Date: May 2021
• Estimated Study Completion Date: November 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. WHO ordinal Covid-19 scale up to day 28 [ Time Frame: up to and including 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

Secondary Outcome Measures :

1. Cumulative number WHO categories 4b-8 [ Time Frame: day 8, day 14, day 56 and day 90 ]
   Cumulative number of persons in the respective treatment arms versus SoC/placebo in WHO categories 4b-8
2. Cumulative number WHO categories 3-4a [ Time Frame: day 8, day 14, day 28, day 56 and day 90 ]
   Cumulative number of persons in the respective treatment arms versus SoC/placebo in WHO categories 3-4a
3. Not hospitalized [ Time Frame: at day 90 ]
   Cumulative number of participants not hospitalized at day 90
4. All-cause mortality [ Time Frame: at day 90 ]
   All-cause mortality at day 90
5. Reinfection [ Time Frame: up to day 90 ]
   Number of patient with SARS-CoV-2 reinfection up to day 90
6. Secondary sclerosing cholangitis (SSC) [ Time Frame: at day 90 ]
   Number of patient with secondary sclerosis cholangitis at day 90
7. chronic pulmonary disease as sequelae from COVID-19 [ Time Frame: at day 90 ]
   Number of patient with COVID-19 associated chronic pulmonary disease
8. patients with remdesivir treatment [ Time Frame: up to day 90 ]
   The proportion of patients with remdesivir therapy
9. COVID-19 WHO status of patients at start of remdesivir treatment [ Time Frame: up to day 90 ]
   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
10. patients with dexamethasone treatment [ Time Frame: up to day 90 ]
    The proportion of patients on dexamethasone therapy
11. COVID-19 WHO status of patients at start of dexamethasone treatment [ Time Frame: up to day 90 ]

    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

12. resolution of COVID-19 symptoms [ Time Frame: until day of resolution up to day 90 ]
    Time to resolution of COVID-19 related symptoms (e.g. fever)
13. negative SARS-CoV-2-PCR test [ Time Frame: until day of first negative test up to day 90 ]
    Time to first negative SARS-CoV-2-PCR (polymerase chain reaction)
14. Oxygen therapy [ Time Frame: number of days with oxygen therapy up to day 90 ]
    Duration of oxygen therapy (in days)
15. COVID-19 pneumonia [ Time Frame: up to day 90 ]
    Frequency of occurrence of COVID-19 pneumonia
16. Percentage of participants requiring mechanical ventilation [ Time Frame: up to day 90 ]
    Percentage of participants in each group with need for mechanical ventilation
17. Number of ventilation days per participant up to day 90 [ Time Frame: up to day 90 ]
    Number of ventilation days per participant up to day 90
18. hospital stay and intensive care [ Time Frame: up to day 90 ]
    Duration of hospital stay (in days), duration in intensive care/intermediate care (IMC) (in days)
19. Mortality [ Time Frame: at day 28 ]
    All-cause mortality at day 28
20. SAEs [ Time Frame: up to day 90 ]
    Cumulative incidence of Serious Adverse Events (SAE) per group within 90 days follow up
21. Grade 3/4 AEs [ Time Frame: up to day 90 ]
    Cumulative incidence of grade 3/4 Adverse Events (AE) per group
22. SARS-CoV-2 antibody IgA concentrations [ Time Frame: on day 8, day 14, day 90 ]
    SARS-CoV-2 antibody concentrations (IgA in g/l) in serum on day 8, day 14, day 90
23. SARS-CoV-2 antibody IgG concentrations [ Time Frame: on day 8, day 14, day 90 ]
    SARS-CoV-2 antibody concentrations (IgG in g/l) in serum on day 8, day 14, day 90
24. SARS-CoV-2 neutralizing antibody titers [ Time Frame: on day 8, day 14, day 90 ]
    SARS-CoV-2 neutralizing antibody titers in serum on day 8, day 14, day 90
25. Plasma treatment screening failures [ Time Frame: up to day 8 (End of treatment) ]
    Number of screening failures due to the lack of a suitable plasma preparation

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Individuals (female, male, diverse) ≥ 18 years with SARS-CoV-2 infection, confirmed by PCR before study enrollment
2. SARS-CoV-2 positive PCR ≤ 3 days old (date of NP swab)
3. 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.
4. Ability to provide written informed consent

5. 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:

1. Age <18 years
2. Unable to give informed consent
3. Pregnant women or breast-feeding mothers
4. Previous transfusion reaction or other contraindication to a plasma transfusion
5. Known hypersensitivity to camostat mesylate and/or severe pancreatitis
6. Volume stress due to CP administration would be intolerable
7. Known IgA deficiency
8. Life expectancy < 6 months
9. Duration SARS-CoV-2 typical symptoms > 3 days
10. SARS-CoV-2 PCR detection older than 3 days
11. 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).
12. Previously or currently hospitalized due to SARS-CoV-2
13. Previous antiviral therapy for SARS-CoV-2
14. alanine aminotransferase (ALT) or aspartate transferase (AST) > 5 times upper limit of normal (ULN) at screening
15. Liver cirrhosis > Child A (patients with Child B/C cirrhosis are excluded from the trial)
16. Chronic kidney disease with GFR < 30 ml/min
17. Concurrent or planned anticancer treatment during trial period
18. Accommodation in an institution due to legal orders (§40(4) AMG).
19. Any psycho-social condition hampering compliance with the study protocol.
20. Evidence of current drug or alcohol abuse.
21. Use of other investigational treatment within 5 half-lives of enrollment is prohibited
22. Previous use of convalescent plasma for COVID-19
23. Concomitant proven influenza A infection
24. Patients with organ or bone marrow transplant in the three months prior to Screening Visit

Contacts and Locations

Contacts

Contact: Verena Keitel-Anselmino, Prof.Dr.med.; +49211-81-16330; keitelan@uni-duesseldorf.de

Locations

Germany

Abteilung Infektiologie Klinik für Innere Medizin II Department Innere Medizin Universitätsklinikum Freiburg; Not yet recruiting

Freiburg im Breisgau, Baden-Württemberg, Germany, 79106

Contact: Winfried Kern, Prof. Dr. med. +49761 270 18190 winfried.kern@uniklinik-freiburg.de

Klinik und Poliklinik für Innere Medizin II Klinikum rechts der Isar Technische Universität München; Recruiting

München, Bavaria, Germany, 81675

Contact: Christoph Spinner, PD Dr. med. +49 89 41 40 24 55 christoph.spinner@mri.tum.de

Universitätsklinikum Frankfurt Medizinische Klinik 2: Hämatologie, Onkologie, Hämostaseologie, Rheumatologie, Infektiologie/HIV; Not yet recruiting

Frankfurt am Main, Hessen, Germany, 60590

Contact: Timo Wolf, PD Dr. med. +49 69 6301 5452 Timo.Wolf@kgu.de

Universitätsklinikum Düsseldorf Klinik für Hepatologie und Infektiologie; Recruiting

Duesseldorf, Germany, 40225

Contact: Verena Keitel, Univ. Prof. Dr. med. +492118118268 RESQ-Studie@med.uni-duesseldorf.de

Sponsors and Collaborators

Heinrich-Heine University, Duesseldorf

The Federal Ministry of Health, Germany (Bundesministerium für Gesundheit, BMG)

Investigators

• Principal Investigator: Verena Keitel-Anselmino, Prof.Dr.med.; Klinik für Gastroenterologie, Hepatologie und Infektiologie Universitätsklinikum Düsseldorf

More Information

• Responsible Party: Heinrich-Heine University, Duesseldorf
• ClinicalTrials.gov Identifier: NCT04681430
• Other Study ID Numbers: RES-Q-HR; 2020-004695-18 ( EudraCT Number )
• First Posted: December 23, 2020
• Last Update Posted: February 1, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Heinrich-Heine University, Duesseldorf:

SARS-CoV-2; Covid-19; camostat mesilate; reconvalescent plasma; TMPRSS2

Additional relevant MeSH terms:

Infection; Communicable Diseases; Coronavirus Infections; Severe Acute Respiratory Syndrome; Respiration Disorders; Respiratory Tract Diseases; Virus Diseases; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Respiratory Tract Infections; Gabexate; Camostat; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Trypsin Inhibitors; Serine Proteinase Inhibitors; Anticoagulants