A Clinical Trial of Convalescent Plasma Compared to Best Supportive Care for Treatment of Patients With Severe COVID-19 (CAPSID)

• ClinicalTrials.gov Identifier: NCT04433910
• Recruitment Status: Completed
• First Posted: June 16, 2020
• Last Update Posted: March 17, 2021
• Sponsor: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
• Information provided by (Responsible Party): Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen

Tracking Information

• First Submitted Date: May 6, 2020
• First Posted Date: June 16, 2020
• Last Update Posted Date: March 17, 2021
• Actual Study Start Date: August 30, 2020
• Actual Primary Completion Date: January 21, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 15, 2020)

Composite endpoint of survival and no longer fulfilling criteria of severe COVID-19. [ Time Frame: Day 21 ]

Dichotomous composite endpoint of survival and no longer fulfilling criteria of severe COVID-19. All criteria must be met in order to fulfil the primary endpoint.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: June 15, 2020)

• Time to clinical improvement [ Time Frame: day 0 to discharge within a 60 day period ]
  Time to clinical improvement (defined as time from randomization to an improvement of two points on the WHO R&D Blueprint seven-category ordinal scale for clinical improvement)(Key secondary endpoint)
• Frequency and severity of adverse events by CTCAE v5.0, (Key secondary endpoint) [ Time Frame: day 0 to discharge within a 60 day period ]
• Case fatality rate [ Time Frame: on day 21, 35 and 60 ]
• Length of hospital stay Length of hospital stay (if applicable) [ Time Frame: day 0 to 60 ]
• Length of stay in ICU [ Time Frame: day 0 to 60 ]
• Duration of ventilation support / ECMO [ Time Frame: day 0 to 60 ]
• Time until negative SARS-CoV-2 PCR (nasopharyngeal sample) [ Time Frame: day 0 to 60 ]
• Predictive value of comorbidities [ Time Frame: day 0 to 60 ]
  Comorbidities will be assessed and correlated to clinical improvement (WHO scale), mortality, length of stay in ICU (days) and length of hospital stay (days)
• Predictive value of coagulation markers [ Time Frame: day 0 to 60 ]
  Correlation of coagulation markers (D-Dimers, prothrombin time, Partial Thromboplastin Time, ATIII, Fibrinogen) with clinical improvement (WHO scale), mortality, length of stay in ICU (days) and length of hospital stay (days)
• Predictive value of inflamation [ Time Frame: day 0 to 60 ]
  Corelation of Inflammation (laboratory testing: CRP, IL-6, Ferritin, Blood cell Count) with clinical improvement (WHO scale), mortality, length of stay in ICU (days) and length of hospital stay (days)
• Percentage of former COVID-19 patients willing to donate qualifying for plasma donation. [ Time Frame: through study completion, an average of 8 months ]
• Amount of Plasma Units that could be collected for the clinical trial [ Time Frame: through study completion, an average of 8 months ]
• Titer of anti-SARS-CoV-2 in transfused plasma units [ Time Frame: any plasmaphereseis, through study completion, an average of 8 months ]
• Impact of donor characteristics on anti-SARS-CoV-2 humoral response [ Time Frame: up to 60 days ]
  Anti-SARS-CoV-2-antibody titers will be correlated with age; gender; severity of COVID-19; interval between resolution of symptoms and plasmapheresis of plasma donors
• Course of anti-SARS-CoV-2 titer in both patient groups at different time points related to transfusion of convalescent plasma [ Time Frame: up to 60 days ]
• Correlation of anti-SARS-CoV-2 titer in transfused plasma units and primary and key secondary outcomes. [ Time Frame: day 0 to 60 ]
  Correlation of antibody titers with: 1. "Survival and no longer fulfilling criteria of severe COVID-19"; 2. Change in WHO ordinal scale; 3. Time to clinical improvement; 4. Length of hospital stay; 5. Length of ICU stay; 6. Length of mechanical Ventilation or ECMO support.
• Effect of timing of plasma transfusions [ Time Frame: day 0 to 60 ]
  Effect of timing of plasma transfusions on outcome: comparison of early treatment, i.e. day 1, 3 and 5 in convalescent plasma group vs. delayed treatment, i.e. day 15, 17, 19 in patients crossing over from control group due to progressive disease on day-14 assessment.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Clinical Trial of Convalescent Plasma Compared to Best Supportive Care for Treatment of Patients With Severe COVID-19
• Official Title: A Randomized, Prospective, Open Label Clinical Trial on the Use of Convalescent Plasma Compared to Best Supportive Care in Patients With Severe COVID-19

Brief Summary

This is a randomized, prospective, multicenter, open label clinical trial of convalescent plasma compared to best supportive care for treatment of patients with severe COVID-19.

The aim of the study is to explore the therapeutic effect of convalescent plasma transfusions on the survival and course of disease of patients with severe COVID-19. Convalescent plasma will be collected from recovered COVID-19 patients.

Patients with severe COVID-19 will be randomly assigned to two groups. Patients in the treatment group will receive covalescent plasma (250 - 325 ml) on days 1, 3 and 5. Patients in the control group will receive best supportive care. Clinical condition in all patients will be evaluated on day 14. In case of progressive COVID-19 on day 14 compared to baseline, patients in the control group may be switched to treatment with convalescent plasma on days 15, 17 and 19.

Fifty-three patients will be included in each group. Data of each patient will be collected until discharge but nor longer than day 60.

Detailed Description

This is a randomized, prospective, multicentre, open label clinical trial of convalescent plasma compared to best supportive care for treatment of patients with severe COVID-19.

The primary Endpoint is a dichotomous composite endpoint of survival and no longer fulfilling criteria of severe COVID-19 within 21 days after randomization. All criteria must be met in order to fulfil the primary endpoint.

Key secondary endpoints are time to clinical improvement (defined as time from randomization to an improvement of two points on the WHO R&D Blueprint seven-category ordinal scale for clinical improvement), the frequency and severity of adverse events and the case fatality rate on day 21, 35 and 60. Further secondary endpoints refer to the course of anti-SARS-CoV-2 antibodies in plasma donors and treated patients and the impact of donor criteria on the effectiveness of plasma units.

Patients with severe COVID-19 defined by a respiratory rate ≥ 30 breaths / minute under ambient air or the requirement of any type of ventilation support or the need for ICU treatment can be included in the trial. It is planned to enrol 106 patients. Patients will be stratified according to ventilation support and/or extracorporeal oxygenation and/or ICU treatment and will be equally asigned to two groups. The treatment group receives convalescent plasma (250 - 325 ml) on day 1, 3 and 5 and the control group will receive best supportive care. Clinical condition in all patients will be evaluated on day 14. In case of progressive COVID-19 on day 14 compared to baseline (i.e. day 0), patients in the control group may be switched to treatment with convalescent plasma on days 15, 17 and 19. A patient switching from the control group to convalescent plasma group because of progressive COVID-19 on day 14 will be considered as failure of the primary endpoint at final evaluation of the primary endpoint on day 21.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: COVID-19

Intervention

Drug: Convalesscent Plasma

Transfusion

Study Arms

• Experimental: Convalescent plasma
  Convalescent plasma transfusion on day 1, 3 and 5.
  Intervention: Drug: Convalesscent Plasma
• No Intervention: Best supportive care
  Best supportive care, cross over for patients with progressive disease on day 14 with convalescent plasma transfusion on day 15, 17 and 19.

Publications *

• Korper S, Schrezenmeier EV, Rincon-Arevalo H, Gruner B, Zickler D, Weiss M, Wiesmann T, Zacharowski K, Kalbhenn J, Bentz M, Dollinger MM, Paul G, Lepper PM, Ernst L, Wulf H, Zinn S, Appl T, Jahrsdorfer B, Rojewski M, Lotfi R, Dorner T, Jungwirth B, Seifried E, Furst D, Schrezenmeier H. Cytokine levels associated with favorable clinical outcome in the CAPSID randomized trial of convalescent plasma in patients with severe COVID-19. Front Immunol. 2022 Oct 6;13:1008438. doi: 10.3389/fimmu.2022.1008438. eCollection 2022.
• Korper S, Weiss M, Zickler D, Wiesmann T, Zacharowski K, Corman VM, Gruner B, Ernst L, Spieth P, Lepper PM, Bentz M, Zinn S, Paul G, Kalbhenn J, Dollinger MM, Rosenberger P, Kirschning T, Thiele T, Appl T, Mayer B, Schmidt M, Drosten C, Wulf H, Kruse JM, Jungwirth B, Seifried E, Schrezenmeier H; CAPSID Clinical Trial Group. Results of the CAPSID randomized trial for high-dose convalescent plasma in patients with severe COVID-19. J Clin Invest. 2021 Oct 15;131(20):e152264. doi: 10.1172/JCI152264.
• Conzelmann C, Gilg A, Gross R, Schutz D, Preising N, Standker L, Jahrsdorfer B, Schrezenmeier H, Sparrer KMJ, Stamminger T, Stenger S, Munch J, Muller JA. An enzyme-based immunodetection assay to quantify SARS-CoV-2 infection. Antiviral Res. 2020 Sep;181:104882. doi: 10.1016/j.antiviral.2020.104882. Epub 2020 Jul 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 15, 2020): 106
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: February 22, 2021
• Actual Primary Completion Date: January 21, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Patients with SARS-CoV-2 infection and

1. age ≥ 18 years and ≤ 75 years
2. SARS-CoV-2 infection confirmed by PCR (BAL, sputum, nasal and/or pharyngeal swap)

3. severe disease defined by at least one of the following:

   1. respiratory rate ≥ 30 breaths / minute under ambient air
   2. requirement of any type of ventilation support
   3. needs ICU treatment
4. Written informed consent by patient or legally authorized representative

Exclusion Criteria:

1. Accompanying diseases other than COVID-19 with an expected survival time of less than 12 months.
2. Previous treatment with any SARS-CoV-2-convalescent plasma
3. In the opinion of the clinical team, progression to death is imminent and inevitable within the next 48 hours, irrespective of the provision of treatment
4. Interval > 72 hours since start of ventilation support
5. Not considered eligible for extracorporeal oxygenation support (even in case of severe ARDS according to Berlin classification with Horovitz-Index < 100 mg Hg)
6. Chronic obstructive lung disease (COPD), stage 4
7. Lung fibrosis with UIP pattern in CT und severe emphysema
8. Chronic heart failure NYHA >= 3 and/or pre-existing reduction of left ventricular ejection fraction to ≤ 30%
9. Shock of any type requiring ≥ 0.5 µg/kg/min noradrenaline (or equivalent) or requiring more than two types of vasopressor medication for more than 8 hours
10. Liver cirrhosis Child C
11. Liver failure: Bilirubin > 5xULN and elevation of ALT /AST (at least one >10xULN).
12. Any history of adverse reactions to plasma proteins
13. Known deficiency of immunoglobulin A
14. Pregnancy
15. Breastfeeding women
16. Volume overload until sufficiently treated
17. Participation in another clinical trial with an investigational medicinal product

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04433910
• Other Study ID Numbers: CAPSID2020-DRK-BSD; 2020-001310-38 ( EudraCT Number )
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
• Original Responsible Party: Same as current
• Current Study Sponsor: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Hubert Schrezenmeier, Prof.Dr.; IKT Ulm
• Study Director: Erhard Seifried, Prof.Dr.Dr.; German Red Cross Blood Service

• PRS Account: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
• Verification Date: March 2021