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

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

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.

Study Overview

• Status: Terminated
• Conditions: Pneumonia, Viral; Acute Respiratory Distress Syndrome; Acute Lung Injury; COVID-19 Severe Pneumonia
• Intervention / Treatment: Biological: Ravulizumab; Other: BSC

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Hauts De Seine
    • Garches, Hauts De Seine, France, 92380
      • Hôpital Raymond Poincaré
  • Val De Marne
    • Créteil, Val De Marne, France, 94000
      • Hôpital Henri Mondor
    • Le Kremlin-Bicêtre cedex, Val De Marne, France, 94275
      • Hôpital Bicêtre
• Japan
  • Tokyo
    • Minato-Ku, Tokyo, Japan, 105-8471
      • Jikei University Hospital
    • Shinjuku-Ku, Tokyo, Japan, 160-0023
      • Tokyo Medical University Hospital
  • Tokyo-To
    • Bunkyō-Ku, Tokyo-To, Japan, 113-8519
      • Medical Hospital, Tokyo Medical and Dental University
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Barcelona
    • L'Hospitalet De Llobregat, Barcelona, Spain, 08907
      • Hospital Universitari de Bellvitge
• United Kingdom
  • Greater London
    • London, Greater London, United Kingdom, SE5 9RS
      • King's College Hospital
    • London, Greater London, United Kingdom, W12 0HS
      • Hammersmith Hospital
  • Merseyside
    • Liverpool, Merseyside, United Kingdom, L7 8XP
      • Royal Liverpool University Hospital
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B15 2TH
      • Queen Elizabeth Hospital
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • St James's University Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Central Arkansas Veterans Healthcare System
  • California
    • Los Angeles, California, United States, 90033
      • LAC/USC Health Center
    • Orange, California, United States, 92868
      • UC Irvine Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • MedStar Georgetown University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Florida
    • Jacksonville, Florida, United States, 32209
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kentucky
    • Louisville, Kentucky, United States, 40241
      • Norton HealthCare
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Baltimore VA Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Minnesota
    • Mankato, Minnesota, United States, 56001
      • Mayo Clinic Health System
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10016
      • NYU Langone Health Center
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Baptist Memorial Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
  • Wisconsin
    • Eau Claire, Wisconsin, United States, 54703
      • Mayo Clinic Health System in Eau Claire
    • La Crosse, Wisconsin, United States, 54601
      • Mayo Clinic Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or female participants ≥ 18 years of age and ≥ 40 kilograms at the time of providing informed consent.
2. 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.
3. 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.
4. 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).
5. 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:

1. Participant was not expected to survive for more than 24 hours.
2. Participant was on invasive mechanical ventilation with intubation for more than 48 hours prior to Screening.
3. Severe pre-existing cardiac disease (that is, New York Heart Association Class 3 or Class 4, acute coronary syndrome or persistent ventricular tachyarrhythmias).
4. Participant had an unresolved Neisseria meningitidis infection.

5. Used the following medications and therapies:

   • Current treatment with a complement inhibitor or
   • Intravenous immunoglobulin within 4 weeks prior to randomization on Day 1

6. 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.
7. Female participants who were breastfeeding or who have a positive pregnancy test result at Screening.
8. History of hypersensitivity to any ingredient contained in the study drug, including hypersensitivity to murine proteins.
9. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
• WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance, 28 January 2020.
• McEneny-King AC, Monteleone JPR, Kazani SD, Ortiz SR. Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019. Infect Dis Ther. 2021 Jun;10(2):1045-1054. doi: 10.1007/s40121-021-00425-7. Epub 2021 Apr 7.
• Smith K, Pace A, Ortiz S, Kazani S, Rottinghaus S. 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: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Jul 13;21(1):639. doi: 10.1186/s13063-020-04548-z.
• Java A, Apicelli AJ, Liszewski MK, Coler-Reilly A, Atkinson JP, Kim AH, Kulkarni HS. The complement system in COVID-19: friend and foe? JCI Insight. 2020 Aug 6;5(15):e140711. doi: 10.1172/jci.insight.140711.

Study record dates

Study Major Dates

• Study Start (Actual): May 10, 2020
• Primary Completion (Actual): February 8, 2021
• Study Completion (Actual): April 8, 2021

Study Registration Dates

• First Submitted: April 28, 2020
• First Submitted That Met QC Criteria: April 28, 2020
• First Posted (Actual): April 30, 2020

Study Record Updates

• Last Update Posted (Actual): May 24, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: COVID-19; pneumonia; acute lung injury; hospitalization; acute respiratory distress syndrome; severe acute respiratory syndrome coronavirus 2; severe pneumonia; viral; respiratory distress syndrome, adult; Ultomiris; antibodies, monoclonal, humanized; severe acute respiratory syndrome; randomized controlled study; ravulizumab
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Wounds and Injuries; Disease; Infant, Newborn, Diseases; Infant, Premature, Diseases; Thoracic Injuries; COVID-19; Syndrome; Pneumonia; Pneumonia, Viral; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Ravulizumab
• Other Study ID Numbers: ALXN1210-COV-305

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Alexion has a public commitment to allow requests for access to study data and will be supplying a protocol, CSR, and plain language summaries.
• IPD Sharing Supporting Information Type: Study Protocol; Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No