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

Study Overview
=================
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.

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

Conditions
-----------------
COVID-19

Intervention / Treatment
-----------------
* Drug: Convalesscent Plasma


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with SARS-CoV-2 infection and age ≥ 18 years and ≤ 75 years SARS-CoV-2 infection confirmed by PCR (BAL, sputum, nasal and/or pharyngeal swap) severe disease defined by at least one of the following: respiratory rate ≥ 30 breaths / minute under ambient air requirement of any type of ventilation support needs ICU treatment Written informed consent by patient or legally authorized representative Exclusion Criteria: Accompanying diseases other than COVID-19 with an expected survival time of less than 12 months. Previous treatment with any SARS-CoV-2-convalescent plasma 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 Interval > 72 hours since start of ventilation support Not considered eligible for extracorporeal oxygenation support (even in case of severe ARDS according to Berlin classification with Horovitz-Index < 100 mg Hg) Chronic obstructive lung disease (COPD), stage 4 Lung fibrosis with UIP pattern in CT und severe emphysema Chronic heart failure NYHA >= 3 and/or pre-existing reduction of left ventricular ejection fraction to ≤ 30% 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 Liver cirrhosis Child C Liver failure: Bilirubin > 5xULN and elevation of ALT /AST (at least one >10xULN). Any history of adverse reactions to plasma proteins Known deficiency of immunoglobulin A Pregnancy Breastfeeding women Volume overload until sufficiently treated Participation in another clinical trial with an investigational medicinal product

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Convalescent plasma<br>Convalescent plasma transfusion on day 1, 3 and 5. | Drug: Convalesscent Plasma<br>* Transfusion<br>|
| No Intervention: Best supportive care<br>Best supportive care, cross over for patients with progressive disease on day 14 with convalescent plasma transfusion on day 15, 17 and 19. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| Length of stay in ICU |  | day 0 to 60 | 
| Duration of ventilation support / ECMO |  | day 0 to 60 | 
| Time until negative SARS-CoV-2 PCR (nasopharyngeal sample) | time to first negative PCR will be assessed | day 0 to 60 | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of former COVID-19 patients willing to donate qualifying for plasma donation. |  | through study completion, an average of 8 months | 
| 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 | 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
convalescent plasma