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

Phase 2

Completed

• Conditions: COVID-19
• Interventions: Drug: Convalesscent Plasma

• Registration Number: NCT04433910
• Lead Sponsor: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen

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 Timeline

• Study First Submitted: 2020-05-06
• Study First Submitted QC: 2020-06-15
• Study First Posted: 2020-06-16
• Study Start: 2020-08-30
• Primary Completion: 2021-01-21
• Study Completion: 2022-03-25
• Status Verified: 2023-09
• Last Update Submitted: 2023-09-12
• Last Update Posted: 2023-09-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 106

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Convalescent plasma	Convalesscent Plasma	Convalescent plasma transfusion on day 1, 3 and 5.

Primary Outcome Measures

Name	Time	Method
Composite endpoint of survival and no longer fulfilling criteria of severe COVID-19.	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.

Secondary Outcome Measures

Name	Time	Method
Time to clinical improvement	day 0 to discharge within a 60 day period	Time to clinical improvement (defined as days from randomization to an improvement of two points on the WHO R\&D Blueprint seven-category ordinal scale for clinical improvement) (Key secondary endpoint)
Duration of ventilation support / ECMO	day 0 to 60
Frequency and severity of adverse events by CTCAE v5.0, (Key secondary endpoint)	day 0 to discharge within a 60 day period
Case fatality rate	on day 21, 35 and 60
Length of hospital stay Length of hospital stay (if applicable)	day 0 to 60
Predictive value of comorbidities	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	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	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)
Amount of Plasma Units that could be collected for the clinical trial	through study completion, an average of 8 months
Titer of anti-SARS-CoV-2 in transfused plasma units	any plasmaphereseis, through study completion, an average of 8 months
Impact of donor characteristics on anti-SARS-CoV-2 humoral response	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
Length of stay in ICU	day 0 to 60
Time until negative SARS-CoV-2 PCR (nasopharyngeal sample)	day 0 to 60	time to first negative PCR will be assessed
Percentage of former COVID-19 patients willing to donate qualifying for plasma donation.	through study completion, an average of 8 months
Course of anti-SARS-CoV-2 titer in both patient groups at different time points related to transfusion of convalescent plasma	up to 60 days	Neutralizing anti-SARS-CoV-2 titers were measured by PRNT
Correlation of anti-SARS-CoV-2 titer in transfused plasma units and primary and key secondary outcomes.	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	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.
Long term survival	15 month	Long term survival up to 15 months after randomisation (patients in CCP group\* compared to control group) or first plasma donation (CCP donors). And high-titer group versus low -titer group versus control.
Frequency of long COVID-19	15 month	Frequency of long COVID-19\* up to 15 months after randomisation (patients in CCP group\* compared to control group) or first plasma donation (CCP donors).And high-titer group versus low -titer group versus control.
Resolution of pneumonia and functional recovery	15 month	Resolution of pneumonia and functional recovery\* in patients (CCP group compared to control group and donors). Assessment will be done by CTCAE 5.0 and structured interview. And high-titer group versus low -titer group versus control.
Patient Reported Outcome: FACIT Fatigue Score	15 month	FACIT Fatigue Score: 0-53 : The higher the score, the better the quality of life Comparisons between patients CCP group compared to control group and donors and high-titer group versus low -titer group versus control group.
Patient Reported Outcome: FACIT Dyspnea Score	15 month	FACIT Dyspnea Score 1 and 2: 0-30 : The lhigher the score the worse is the dypnea Comparisons between patients CCP group compared to control group and donors and high-titer group versus low -titer group versus control group.
Patient Reported Outcome: EQ-5D-5L visual Scale	15 month	EQ-5D-5L visual scale: 0-100, The lower the socre, the worse is the health state Comparisons between patients CCP group compared to control group and donors and high-titer group versus low -titer group versus control group.
Patient Reported Outcome:EQ-5D-5L cross walk	15 month	EQ-5D-5L cross walk score: 0-1.0 The lower the socre, the worse is the health state Comparisons between patients CCP group compared to control group and donors and high-titer group versus low -titer group versus control group.
Laboratory markers: D-Dimers	15 month	D-Dimers will be correlated with the Levels of SARS-CoV-2 antodies as a measure of anti-SARS-CoV-2 immunity and compared between the patient groups (in patients: CCP group compared to control group and donors). The effect of SARS-CoV-2 vaccination\* in control group, CCP group and CCP donors will also be taken into account.Measures will also be compeared between high-titer group versus low -titer group versus control group.
Laboratory markers: Fibrinogen	15 month	Fibronogen will be correlated with the Levels of SARS-CoV-2 antodies as a measure of anti-SARS-CoV-2 immunity and compared between the patient groups (in patients: CCP group compared to control group and donors). The effect of SARS-CoV-2 vaccination\* in control group, CCP group and CCP donors will also be taken into account.Measures will also be compeared between high-titer group versus low -titer group versus control group.
Laboratory markers: CRP	15 month	CRP will be correlated with the Levels of SARS-CoV-2 antodies as a measure of anti-SARS-CoV-2 immunity and compared between the patient groups (in patients: CCP group compared to control group and donors). The effect of SARS-CoV-2 vaccination\* in control group, CCP group and CCP donors will also be taken into account.Measures will also be compeared between high-titer group versus low -titer group versus control group.
Laboratory markers: Ferritin	15 month	Ferritin will be correlated with the Levels of SARS-CoV-2 antodies as a measure of anti-SARS-CoV-2 immunity and compared between the patient groups (in patients: CCP group compared to control group and donors). The effect of SARS-CoV-2 vaccination\* in control group, CCP group and CCP donors will also be taken into account.Measures will also be compeared between high-titer group versus low -titer group versus control group.
Laboratory markers: IL-6	15 month	IL-6 will be correlated with the Levels of SARS-CoV-2 antodies as a measure of anti-SARS-CoV-2 immunity and compared between the patient groups (in patients: CCP group compared to control group and donors). The effect of SARS-CoV-2 vaccination\* in control group, CCP group and CCP donors will also be taken into account.Measures will also be compeared between high-titer group versus low -titer group versus control group.
Severity of long COVID-19	15 month	Severity of long COVID-19\* up to 15 months after randomisation (patients in CCP group\* compared to control group) or first plasma donation (CCP donors). Grading according Post-COVID-19 Scale from 0 (no functional limitations) to 4 (severe functional limitations). Measures will also be compeared between high-titer group versus low -titer group versus control group.
Duration of long COVID-19	15 month	Duration of long COVID-19\* up to 15 months after randomisation (patients in CCP group\* compared to control group) or first plasma donation (CCP donors). Measures will also be compeared between high-titer group versus low -titer group versus control group.

Trial Locations

Locations (15)

University Düsseldorf; 🇩🇪 Düsseldorf, Germany

University Hopsital Frankfurt; 🇩🇪 Frankfurt, Hessia, Germany

University Hospital Berlin, Charite; 🇩🇪 Berlin, Germany

University Hospital Gießen; 🇩🇪 Gießen, Germany

University Hopsital Greifswald; 🇩🇪 Greifswald, Germany

Universitiy Hospital Dresden; 🇩🇪 Dresden, Germany

Klinikum Stuttgart; 🇩🇪 Stuttgart, Germany

University Hospital Ulm; 🇩🇪 Ulm, Baden-Württmberg, Germany

University Hospital Freiburg; 🇩🇪 Freiburg, Germany

Städtisches Klinikum Karslruhe; 🇩🇪 Karlsruhe, Germany

Saarland University Hospital; 🇩🇪 Homburg, Saarland, Germany

University Hospital Marburg; 🇩🇪 Marburg, Germany

University Hospital Tübingen; 🇩🇪 Tübingen, Germany

Universtity Hospital Schleswig-Holstein; 🇩🇪 Lübeck, Germany

University Hospital Mannheim; 🇩🇪 Mannheim, Germany