Efficacy and Safety of Novel Treatment Options for Adults With COVID-19 Pneumonia

Study Overview
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Brief Summary
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CCAP is an investigator-initiated multicentre, randomized, double blinded, placebo-controlled trial, which aims to assess the safety and efficacy of treatment with convalescent plasma for patients with moderate-severe COVID-19. Participants will be randomized 2:1 to two parallel treatment arms: Convalescent plasma, and intravenous placebo. Primary outcome is a composite endpoint of all-cause mortality or need of invasive mechanical ventilation up to 28 days.

Detailed Description
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The study is a randomized, double blinded, placebo-controlled, multicenter study with two parallel treatment arms consisting of either convalescent plasma or intravenous placebo. We plan to enroll a total of 1100 patients yielding a statistical power of 80 % to show a 30% relative reduction in risk of mechanical ventilation or death at day 28. Patients with confirmed COVID-19 infection and signs compatible with pneumonia will be enrolled in the study. The participants will be randomized 2:1 to the parallel treatment arms, and receive either single dose infusion treatment. The primary outcome is a composite endpoint of all-cause mortality or need of invasive mechanical ventilation up to 28 days. Interim analysis will be performed frequently. As new knowledge of treatment options for COVID-19 have emerged, the treatment arms including sarilumab, baricitininb, hydroxychloroquine and oral placebo have been terminated.

Official Title
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Efficacy and Safety of Treatment With Convalescent Plasma for Adults With COVID-19 Pneumonia. A Double-blinded, Randomized, Multicenter Placebo-controlled Trial

Conditions
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COVID, Corona Virus Infection, Viral Pneumonia

Intervention / Treatment
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* Biological: Convalescent anti-SARS-CoV-2 plasma
* Other: Infusion placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age Confirmed COVID-19 infection by presence of SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR) Evidence of pneumonia given by at least one of the following: SpO2 ≤93% on ambient air or PaO2/FiO2 <300 mmHg/40 kPa OR Radiographic findings compatible with COVID-19 pneumonia For women of childbearing potential: Negative pregnancy test and willingness to use contraceptive (consistent with local regulations) during study period Signed Informed Consent Form by any patient capable of giving consent, or, when the patient is not capable of giving consent, by his or her legal/authorized representatives Exclusion Criteria: In the opinion of the investigator, progression to death is imminent and inevitable within the next 24 hours, irrespective of the provision of treatment Participating in other drug clinical trials (participation in COVID-19 antiviral trials may be permitted if approved by sponsor)* Pregnant or breastfeeding, positive pregnancy test in a pre-dose examination Any serious medical condition or abnormality of clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

Ages Eligible for Study
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Minimum Age: 18 Years

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Adaptive multi-arm trial comparing convalescent plasma against control group. Interim analyses are included at 300 and 700 included participants to compare the effect and safety of the experimental treatment to control (placebo). The results of the interim analyses are used to decide if the treatments should be discontinued due to either futility or harm. The study is discontinued if either of the predefined stopping criteria are met. Additional experimental treatments may be added as they become available. Any efficacious treatment identified in this or any other high-quality RCT may become the new SOC after consensus by national and international societies, and, thus, the control arm will change accordingly and in parallel.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Convalescent plasma<br>Will receive active treatment with convalescent anti-SARS-CoV-2 plasma (600 ml) as a single dose iv infusion in addition to standard care. | Biological: Convalescent anti-SARS-CoV-2 plasma<br>* Single infusion of convalescent anti-SARS-CoV-2 plasma (2 x 300 mL)<br>* Other names: Convalescent plasma;|
| Placebo Comparator: Infusion placebo<br>Will receive placebo treatment with saline 0.9% (2 x 300 ml) as an iv single dose infusion in addition to standard care. | Other: Infusion placebo<br>* Saline 0.9% (600 ml) as an iv single dose infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality or need of invasive mechanical ventilation | Composite outcome | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of adverse events | Number of participants with adverse events with possible relation to study drug | 90 days | 
| Frequency of severe adverse events | Number of participants with serious adverse events according to International Council of Harmonisation-Good Clinical Practice (ICH-GCP) guidelines | 90 days | 
| Time to improvement of at least 2 categories relative to baseline on a 7-category ordinal scale of clinical status | Number of days to improvement of at least 2 categories relative to baseline on the ordinal scale. Categories are as follows: Death; Hospitalized, in intensive care requiring Extracorporeal Membrane Oxygenation (ECMO) or mechanical ventilation; Hospitalized, on non-invasive ventilation or high-flow oxygen device; Hospitalized, requiring supplemental oxygen; Hospitalized, not requiring supplemental oxygen; Not hospitalized, limitation on activities and/or requiring home oxygen; Not hospitalized, no limitations on activities | 90 days | 
| Ventilator-free days | Number of days without mechanical ventilation | 28 days | 
| Organ failure-free days | Number of days without organ-failure | 28 days | 
| Duration of ICU stay | Number of days in ICU | 90 days | 
| Mortality rate | Number of deaths by any cause | 7, 14, 21, 28 and 90 days | 
| Length of hospital stay | Days from the date of hospital admission for COVID-19 to the date of discharge | 90 days | 
| Duration of supplemental oxygen | Days requiring supplement oxygen | 90 days |