Clinical trial NCT04433910: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: COVID-19
Keywords: convalescent plasma
Lead sponsor: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
Sponsor class: OTHER
First posted: 2020-06-16
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Composite endpoint of survival and no longer fulfilling criteria of severe COVID-19.
timeFrame: Day 21
Secondary outcomes:
measure: Time to clinical improvement
timeFrame: day 0 to discharge within a 60 day period
measure: Frequency and severity of adverse events by CTCAE v5.0, (Key secondary endpoint)
timeFrame: day 0 to discharge within a 60 day period
measure: Case fatality rate
timeFrame: on day 21, 35 and 60
measure: Length of hospital stay Length of hospital stay (if applicable)
timeFrame: day 0 to 60
measure: Length of stay in ICU
timeFrame: day 0 to 60
measure: Duration of ventilation support / ECMO
timeFrame: day 0 to 60
measure: Time until negative SARS-CoV-2 PCR (nasopharyngeal sample)
timeFrame: day 0 to 60
measure: Predictive value of comorbidities
timeFrame: day 0 to 60
measure: Predictive value of coagulation markers
timeFrame: day 0 to 60
measure: Predictive value of inflamation
timeFrame: day 0 to 60
measure: Percentage of former COVID-19 patients willing to donate qualifying for plasma donation.
timeFrame: through study completion, an average of 8 months
measure: Amount of Plasma Units that could be collected for the clinical trial
timeFrame: through study completion, an average of 8 months
measure: Titer of anti-SARS-CoV-2 in transfused plasma units
timeFrame: any plasmaphereseis, through study completion, an average of 8 months
measure: Impact of donor characteristics on anti-SARS-CoV-2 humoral response
timeFrame: up to 60 days
measure: Course of anti-SARS-CoV-2 titer in both patient groups at different time points related to transfusion of convalescent plasma
timeFrame: up to 60 days
measure: Correlation of anti-SARS-CoV-2 titer in transfused plasma units and primary and key secondary outcomes.
timeFrame: day 0 to 60
measure: Effect of timing of plasma transfusions
timeFrame: day 0 to 60
measure: Long term survival
timeFrame: 15 month
measure: Frequency of long COVID-19
timeFrame: 15 month
measure: Resolution of pneumonia and functional recovery
timeFrame: 15 month
measure: Patient Reported Outcome: FACIT Fatigue Score
timeFrame: 15 month
measure: Patient Reported Outcome: FACIT Dyspnea Score
timeFrame: 15 month
measure: Patient Reported Outcome: EQ-5D-5L visual Scale
timeFrame: 15 month
measure: Patient Reported Outcome:EQ-5D-5L cross walk
timeFrame: 15 month
measure: Laboratory markers: D-Dimers
timeFrame: 15 month
measure: Laboratory markers: Fibrinogen
timeFrame: 15 month
measure: Laboratory markers: CRP
timeFrame: 15 month
measure: Laboratory markers: Ferritin
timeFrame: 15 month
measure: Laboratory markers: IL-6
timeFrame: 15 month
measure: Severity of long COVID-19
timeFrame: 15 month
measure: Duration of long COVID-19
timeFrame: 15 month
Other outcomes:
Locations:
city: Ulm
country: Germany
facility: University Hospital Ulm
state: Baden-Württmberg
city: Frankfurt
country: Germany
facility: University Hopsital Frankfurt
state: Hessia
city: Homburg
country: Germany
facility: Saarland University Hospital
state: Saarland
city: Berlin
country: Germany
facility: University Hospital Berlin, Charite
city: Dresden
country: Germany
facility: Universitiy Hospital Dresden
city: Düsseldorf
country: Germany
facility: University Düsseldorf
city: Freiburg
country: Germany
facility: University Hospital Freiburg
city: Gießen
country: Germany
facility: University Hospital Gießen
city: Greifswald
country: Germany
facility: University Hopsital Greifswald
city: Karlsruhe
country: Germany
facility: Städtisches Klinikum Karslruhe
city: Kiel
country: Germany
facility: Universtity Hospital Schleswig-Holstein
city: Lübeck
country: Germany
facility: Universtity Hospital Schleswig-Holstein
city: Mannheim
country: Germany
facility: University Hospital Mannheim
city: Marburg
country: Germany
facility: University Hospital Marburg
city: Stuttgart
country: Germany
facility: Klinikum Stuttgart
city: Tübingen
country: Germany
facility: University Hospital Tübingen
Study officials:
affiliation: IKT Ulm
name: Hubert Schrezenmeier, Prof.Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: German Red Cross Blood Service
name: Erhard Seifried, Prof.Dr.Dr.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.