Convalescent Plasma Therapy - Zurich Protocol

Study Overview
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Brief Summary
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This is an open-label, single-center, phase I study to assess the safety and efficacy of convalescent plasma therapy (CPT) obtained from donors who were tested positive for SARS-CoV-2 and fully recovered from the infection and administered to patients who are infected with the new coronavirus and present dyspnea or a poor prognosis

Detailed Description
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The outbreak of a new highly contagious and life-threatening infective disease was first reported in China in December 2019. Regardless of the undertaken containing measures, its spreading could not be effectively stopped and currently we are confronting the pandemic diffusion of a newly identified Coronavirus (SARS-CoV-2) (1). This causes a systemic disease, known as (Coronavirus Disease-19) COVID-19, characterised by a broad spectrum of clinical manifestations, including ineffective hyper-inflammation and severe pneumonia, with provisional epidemiologic data indicating a mortality rate of 0.1-15% (2). Do to the lack of vaccination, specific anti-virus sera or monoclonal antibodies, the therapeutic efforts to limit COVID-19 mostly rely on the empirical use of anti-viral drugs. Therefore, being the option of an active immunisation not available and because of the controversial efficacy of the available anti-viral therapies (3), we suggest the option of a passive immunisation for those patients who are infected with the new coronavirus and present dyspnea or a poor prognosis. The use of convalescent plasma, i.e. plasma obtained from donors who were tested positive for SARS-CoV-2 and fully recovered from the infection, could provide a rapid protection, limiting the observed evolution of COVID-19 towards life-threating manifestations (7-9). When carried on according to standardised measures, the transfusion of plasma is highly safe (10-11) and we assume that products containing anti- SARS-CoV- 2 antibodies will provide the recipients a passive immunity through different mechanisms, including viral neutralisation, antibody-dependent cellular cytotoxicity and/or phagocytosis.

Official Title
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A Phase i, Open-label, Single-centre Clinical Study to Evaluate Safety and Efficacy of Passive Immunization of High-risk SARS-CoV-2 Positive Patients With Convalescent Plasma Therapy

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Convalescent plasma


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A) Proven Sars-CoV-2 by PCR and hospitalization for COVID-19 in combination with either (1) or (2): Age ≥50 AND (at least one): Pre-existing cardiovascular disease Diabetic disease Immunodeficiency/immunosuppression Neoplastic disease COPD or chronic liver disease or chronic renal failure Age ≥18 AND (at least one): SpO2 ≤ 94% on room air or requiring supplemental oxygen at screening Typical changes on chest x-ray and/or lung-CT scan Immunosuppression or neoplastic disease B) Informed Consent as documented by signature (Appendix Informed Consent Form) of the patient or, in case of inability, of the next relative/care-taking person. In the latter case, an independent doctor will also be involved and her/his signature will be required in order to enrol the patient. Exclusion Criteria: Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product (FFP) Known IgA deficiency Cytokine Release Syndrome grade ≥3 (see score)* ARDS Patients already hospitalized in intensive care unit and/or already receiving mechanical ventilation Known or suspected non-compliance, drug or alcohol abuse Previous enrolment into the current study Enrolment of the investigator, his/her family members, employees and other dependent persons Women who are pregnant or breast feeding Intention to become pregnant during the course of the study Lack of safe contraception, defined as: Female participants of childbearing potential, not using and not willing to continue using a medically reliable method of contraception for the entire study duration, such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices, or who are not using any other method considered sufficiently reliable by the investigator in individual cases. Please note that female participants who are surgically sterilised / hysterectomised or post-menopausal for longer than 2 years are not considered as being of child bearing potential
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is an open-label, single-center, phase I study to assess the safety and efficacy of convalescent plasma therapy (CPT).
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Convalescent plasma|Convalescent plasma will be delivered as FFP. Three units of 200ml CP/FFP harvested from one donor will be transfused to one recipient, i.e. there will be a match between donor and recipient and each recipient will receive CP/FFP only from one donor. CP/FFP will be administered intravenously at the infusion rate of 100ml/hour, starting from day 0, with a new transfusion every 24 hours, for a total of 3 transfusions (see scheme).|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of CPT applied to COVID-19 patients | Absence of clinical signs of Transfusion Related Lung Inflammation (TRALI) and/or allergic reactions and/or Transfusion Associated Circulatory Overload (TACO) | clinical observation up to 48 hours after the last dose of plasma | 
| Safety of CPT applied to COVID-19 patients | Absence of laboratory signs of haemolytic reactions | 1 week (laboratory monitoring up to 7 days after the last administration of plasma) | 
| Improvement of respiratory frequency | Respiratory frequency will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of O2-saturation | O2-Saturation will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of Inflammatory markers (C Reactive Protein, CRP) | CRP will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of Inflammatory markers (Ferritin) | Ferritin will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of Inflammatory markers (IL-6) | IL-6 will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of coagulation-markers (D-dimer) | D-Dimer will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of coagulation-markers (Fibrinogen) | Fibrinogen will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Improvement of coagulation-markers (LDH) | LDH will be measured at each study visit | 3 weeks after the last administration of plasma | 
| Prevention of ICU-admission | clinical conditions will be assessed throughout the study | 3 weeks after the last administration of plasma | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterisation of virus reaction to plasma Therapy | Measurement of viral load after plasma therapy | 10 Weeks | 
| Characterisation of the dynamic of humoral response after therapy | Measurement of antibody-titres after plasma therapy | 10 Weeks | 
| Better characterize the the in-vivo anti-virus humoral response against SARS-CoV-2. | Performance of neutralisation assay after administration of plasma | 10 Weeks |