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

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

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.

Study Overview

• Status: Completed
• Conditions: Corona Virus Infection; SARS-CoV-2 Infection; SARS-CoV-2 Acute Respiratory Disease; SARS-CoV-2 PCR Test Positive
• Intervention / Treatment: Biological: Convalescent plasma; Other: Standard of Care (SoC); Drug: Camostat Mesilate; Drug: Placebo for Camostat Mesilate

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 Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2

Contacts and Locations

Study Locations

• Germany
  • Baden-Württemberg
    • Freiburg im Breisgau, Baden-Württemberg, Germany, 79106
      • Abteilung Infektiologie Klinik für Innere Medizin II Department Innere Medizin Universitätsklinikum Freiburg
  • Bavaria
    • München, Bavaria, Germany, 81675
      • Klinik und Poliklinik für Innere Medizin II Klinikum rechts der Isar Technische Universität München
  • Hessen
    • Frankfurt am Main, Hessen, Germany, 60590
      • Universitätsklinikum Frankfurt Medizinische Klinik 2: Hämatologie, Onkologie, Hämostaseologie, Rheumatologie, Infektiologie/HIV
  • North Rhine Westphalia
    • Duesseldorf, North Rhine Westphalia, Germany, 40225
      • Universitätsklinikum Düsseldorf Klinik für Hepatologie und Infektiologie
  • North Rhine-Westphalia
    • Dortmund, North Rhine-Westphalia, Germany, 44137
      • Klinikum Dortmund
    • Essen, North Rhine-Westphalia, Germany, 45147
      • Universitätsklinikum Essen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / 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)
OTHER: 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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Heinrich-Heine University, Duesseldorf
• Collaborators: 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

Publications and helpful links

General Publications

• Keitel V, Jensen B, Feldt T, Fischer JC, Bode JG, Matuschek C, Bolke E, Budach W, Plettenberg C, Scheckenbach K, Kindgen-Milles D, Timm J, Muller L, Kolbe H, Stohr A, Calles C, Hippe A, Verde P, Spinner CD, Schneider J, Wolf T, Kern WV, Nattermann J, Zoufaly A, Ohmann C, Luedde T; RES-Q-HR Trial Team. Reconvalescent plasma/camostat mesylate in early SARS-CoV-2 Q-PCR positive high-risk individuals (RES-Q-HR): a structured summary of a study protocol for a randomized controlled trial. Trials. 2021 May 17;22(1):343. doi: 10.1186/s13063-021-05181-0.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 8, 2021
• Primary Completion (ACTUAL): October 29, 2021
• Study Completion (ACTUAL): October 29, 2021

Study Registration Dates

• First Submitted: December 17, 2020
• First Submitted That Met QC Criteria: December 22, 2020
• First Posted (ACTUAL): December 23, 2020

Study Record Updates

• Last Update Posted (ACTUAL): February 10, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: SARS-CoV-2; Covid-19; TMPRSS2; camostat mesilate; reconvalescent plasma
• Additional Relevant MeSH Terms: Pathologic Processes; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; COVID-19; Coronavirus Infections; Infections; Communicable Diseases; Respiration Disorders; Respiratory Tract Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Anticoagulants; Trypsin Inhibitors; Camostat; Gabexate
• Other Study ID Numbers: RES-Q-HR; 2020-004695-18 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No