Efficacy and Safety Study of IV Ravulizumab in Patients With COVID-19 Severe Pneumonia

Study Overview
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Brief Summary
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This study evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of ravulizumab administered in adult participants with coronavirus disease 2019 (COVID-19) severe pneumonia, acute lung injury, or acute respiratory distress syndrome. Participants were randomly assigned to receive ravulizumab in addition to best supportive care (BSC) (2/3 of the participants) or BSC alone (1/3 of the participants). BSC consisted of medical treatment and/or medical interventions per routine hospital practice.

Official Title
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A Phase 3 Open-label, Randomized, Controlled Study to Evaluate the Efficacy and Safety of Intravenously Administered Ravulizumab Compared With Best Supportive Care in Patients With COVID-19 Severe Pneumonia, Acute Lung Injury, or Acute Respiratory Distress Syndrome

Conditions
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COVID-19 Severe Pneumonia, Acute Lung Injury, Acute Respiratory Distress Syndrome, Pneumonia, Viral

Intervention / Treatment
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* Biological: Ravulizumab
* Other: BSC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or female participants ≥ 18 years of age and ≥ 40 kilograms at the time of providing informed consent. Confirmed diagnosis of severe acute respiratory syndrome coronavirus 2 infection (for example, via polymerase chain reaction and/or antibody test) presenting as severe COVID-19 requiring hospitalization. Severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by computed tomography or X-ray at Screening or within the 3 days prior to Screening, as part of the participant's routine clinical care. Respiratory distress requiring mechanical ventilation, which can be either invasive (requiring endotracheal intubation) or noninvasive (with continuous positive airway pressure or bilevel positive airway pressure). Female participants of childbearing potential and male participants with female partners of childbearing potential must follow protocol specified contraception guidance for avoiding pregnancy for 8 months after treatment with the study drug. Exclusion Criteria: Participant was not expected to survive for more than 24 hours. Participant was on invasive mechanical ventilation with intubation for more than 48 hours prior to Screening. Severe pre-existing cardiac disease (that is, New York Heart Association Class 3 or Class 4, acute coronary syndrome or persistent ventricular tachyarrhythmias). Participant had an unresolved Neisseria meningitidis infection. Used the following medications and therapies: Current treatment with a complement inhibitor or Intravenous immunoglobulin within 4 weeks prior to randomization on Day 1 Treatment with investigational therapy in a clinical study within 30 days before randomization, or within 5 half-lives of that investigational therapy, whichever was greater. Exceptions: Investigational therapies were allowed if received as part of BSC through an expanded access protocol or emergency approval for the treatment of COVID-19. Investigational antiviral therapies (such as remdesivir) were allowed even if received as part of a clinical study. Female participants who were breastfeeding or who have a positive pregnancy test result at Screening. History of hypersensitivity to any ingredient contained in the study drug, including hypersensitivity to murine proteins. Participant who was not currently vaccinated against Neisseria meningitidis, unless the participant agrees to receive prophylactic treatment with appropriate antibiotics for at least 8 months after the last infusion of study drug or until at least 2 weeks after the participant receives vaccination against Neisseria meningitidis.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 - Ravulizumab + BSC<br> | Biological: Ravulizumab<br>* Weight-based doses of ravulizumab were administered intravenously on Days 1, 5, 10, and 15.<br>* Other names: ALXN1210;Other: BSC<br>* Participants received medications, therapies, and interventions per standard hospital treatment protocols.<br>|
| Other: Group 2 - BSC alone<br> | Other: BSC<br>* Participants received medications, therapies, and interventions per standard hospital treatment protocols.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29 | Survival (based on all-cause mortality) in Participants in the ITT Population at Day 29 was analyzed. The result for the survival was estimated survival combined over all imputations. | Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number Of Days Free Of Mechanical Ventilation At Day 29 | The number of days free of mechanical ventilation was defined as the total number of days from Day 1 to Day 29 without invasive or non-invasive mechanical ventilation. | Day 29 | 
| Number of Days the Participants Were Alive and Not in ICU | The number of days that the participants were alive and not in the ICU from Day 1 through Day 29 are presented. | Day 1 through Day 29 | 
| Change From Baseline In Sequential Organ Failure Assessment (SOFA) At Day 29 | Baseline was defined as the last available assessment on or before Day 1 for all participants. Participants were evaluated using the SOFA score, an assessment tool that included a review of 6 organ systems: respiratory, renal, hepatic, cardiac, coagulation, and central nervous system. Each organ system was scored from 0 to 4 points using the worst value observed within the previous 24 hours. The total score ranged from 0 to 24, with a higher score indicating a worse condition. | Baseline, Day 29 | 
| Change From Baseline In Peripheral Capillary Oxygen Saturation/Fraction Of Inspired Oxygen (SpO2/FiO2) At Day 29 | Oxygenation was measured using the SpO2 and the amount of supplemental oxygen as measured by the FiO2 received by taking the ratio of these 2 measures at the same time point. | Baseline, Day 29 | 
| Number of Days the Participants Were Alive and Not in the Hospital | The number of days that the participants were alive and not in the hospital from Day 1 through Day 29 are presented. | Day 1 through Day 29 | 
| Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | For this analysis, 2 participants in Group 1 (Ravulizumab + BSC) and 1 participant in Group 2 (BSC Alone) were censored at Day 90. The estimated number of participants alive for this analysis was calculated using the method of Kaplan and Meier (KM) and compared using a log-rank test stratified by intubated or not intubated on Day 1 as a sensitivity analysis. This Outcome Measure was designed to project an estimate of how many participants would be alive and not the actual number of alive participants. All-Cause Mortality data is provided in the Adverse Events Section. | Up to Day 60 and Up to Day 90 | 
| Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29 | Results are reported in micrograms/milliliter (μg/mL). | Day 1 and Day 29 | 
| Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29 |  | Baseline, Day 29 | 
| Change From Baseline In Terminal Complement Complex C5b-9 At Day 29 |  | Baseline, Day 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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acute lung injury, acute respiratory distress syndrome, antibodies, monoclonal, humanized, COVID-19, hospitalization, pneumonia, severe pneumonia, severe acute respiratory syndrome, severe acute respiratory syndrome coronavirus 2, randomized controlled study, ravulizumab, respiratory distress syndrome, adult, Ultomiris, viral