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

COVID-19 Clinical Trial

— CAPSID  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04433910
• Other study ID #: CAPSID2020-DRK-BSD
• Secondary ID: 2020-001310-38
• Status: Completed
• Phase: Phase 2
• Start date: August 30, 2020
• Est. completion date: March 25, 2022

Study information

• Verified date: September 2023
• Source: Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: March 25, 2022
• Est. primary completion date: January 21, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• COVID-19

Intervention

Drug:
• Convalesscent Plasma
Transfusion

Locations

Country	Name	City	State
Germany	University Hospital Berlin, Charite	Berlin
Germany	Universitiy Hospital Dresden	Dresden
Germany	University Düsseldorf	Düsseldorf
Germany	University Hopsital Frankfurt	Frankfurt	Hessia
Germany	University Hospital Freiburg	Freiburg
Germany	University Hospital Gießen	Gießen
Germany	University Hopsital Greifswald	Greifswald
Germany	Saarland University Hospital	Homburg	Saarland
Germany	Städtisches Klinikum Karslruhe	Karlsruhe
Germany	Universtity Hospital Schleswig-Holstein	Kiel
Germany	Universtity Hospital Schleswig-Holstein	Lübeck
Germany	University Hospital Mannheim	Mannheim
Germany	University Hospital Marburg	Marburg
Germany	Klinikum Stuttgart	Stuttgart
Germany	University Hospital Tübingen	Tübingen
Germany	University Hospital Ulm	Ulm	Baden-Württmberg

Sponsors (1)

Lead Sponsor	Collaborator
Deutsches Rotes Kreuz DRK-Blutspendedienst Baden-Wurttemberg-Hessen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite endpoint of survival and no longer fulfilling criteria of severe COVID-19.	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.	Day 21
Secondary	Time to clinical improvement	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)	day 0 to discharge within a 60 day period
Secondary	Frequency and severity of adverse events by CTCAE v5.0, (Key secondary endpoint)		day 0 to discharge within a 60 day period
Secondary	Case fatality rate		on day 21, 35 and 60
Secondary	Length of hospital stay Length of hospital stay (if applicable)		day 0 to 60
Secondary	Length of stay in ICU		day 0 to 60
Secondary	Duration of ventilation support / ECMO		day 0 to 60
Secondary	Time until negative SARS-CoV-2 PCR (nasopharyngeal sample)	time to first negative PCR will be assessed	day 0 to 60
Secondary	Predictive value of comorbidities	Comorbidities will be assessed and correlated to clinical improvement (WHO scale), mortality, length of stay in ICU (days) and length of hospital stay (days)	day 0 to 60
Secondary	Predictive value of coagulation markers	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)	day 0 to 60
Secondary	Predictive value of inflamation	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)	day 0 to 60
Secondary	Percentage of former COVID-19 patients willing to donate qualifying for plasma donation.		through study completion, an average of 8 months
Secondary	Amount of Plasma Units that could be collected for the clinical trial		through study completion, an average of 8 months
Secondary	Titer of anti-SARS-CoV-2 in transfused plasma units		any plasmaphereseis, through study completion, an average of 8 months
Secondary	Impact of donor characteristics on anti-SARS-CoV-2 humoral response	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	up to 60 days
Secondary	Course of anti-SARS-CoV-2 titer in both patient groups at different time points related to transfusion of convalescent plasma	Neutralizing anti-SARS-CoV-2 titers were measured by PRNT	up to 60 days
Secondary	Correlation of anti-SARS-CoV-2 titer in transfused plasma units and primary and key secondary outcomes.	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.	day 0 to 60
Secondary	Effect of timing of plasma transfusions	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.	day 0 to 60
Secondary	Long term survival	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.	15 month
Secondary	Frequency of long COVID-19	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.	15 month
Secondary	Resolution of pneumonia and functional recovery	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.	15 month
Secondary	Patient Reported Outcome: FACIT Fatigue Score	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.	15 month
Secondary	Patient Reported Outcome: FACIT Dyspnea Score	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.	15 month
Secondary	Patient Reported Outcome: EQ-5D-5L visual Scale	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.	15 month
Secondary	Patient Reported Outcome:EQ-5D-5L cross walk	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.	15 month
Secondary	Laboratory markers: D-Dimers	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.	15 month
Secondary	Laboratory markers: Fibrinogen	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.	15 month
Secondary	Laboratory markers: CRP	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.	15 month
Secondary	Laboratory markers: Ferritin	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.	15 month
Secondary	Laboratory markers: IL-6	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.	15 month
Secondary	Severity of long COVID-19	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.	15 month
Secondary	Duration of long COVID-19	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.	15 month