Back to resultsEfficacy and Safety Study of IV Ravulizumab in Patients With COVID-19 Severe Pneumonia
Primary Purpose
COVID-19 Severe Pneumonia, Acute Lung Injury, Acute Respiratory Distress Syndrome
Status
Terminated
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Ravulizumab
BSC
Sponsored by
About this trial
This is an interventional treatment trial for COVID-19 Severe Pneumonia focused on measuring 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
Eligibility Criteria
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.
Sites / Locations
- Central Arkansas Veterans Healthcare System
- LAC/USC Health Center
- UC Irvine Medical Center
- MedStar Georgetown University Hospital
- University of Florida
- Mayo Clinic Florida
- Rush University Medical Center
- Norton Healthcare
- Baltimore VA Medical Center
- Massachusetts General Hospital
- Brigham and Women's Hospital
- Boston Medical Center
- Henry Ford Hospital
- Mayo Clinic Health System
- Mayo Clinic
- Washington University School of Medicine
- NYU Langone Health Center
- Icahn School of Medicine at Mount Sinai
- Westchester Medical Center
- Medical University of South Carolina
- Baptist Memorial Hospital
- Houston Methodist Hospital
- Mayo Clinic Health System in Eau Claire
- Mayo Clinic Health System
- Hôpital Raymond Poincaré
- Hôpital Henri Mondor
- Hôpital Bicêtre
- Medical Hospital, Tokyo Medical and Dental University
- Jikei University Hospital
- Tokyo Medical University Hospital
- Hospital Universitari de Bellvitge
- Hospital Universitari Vall d'Hebron
- Hospital Clinic de Barcelona
- Hospital Universitario Ramon y Cajal
- King's College Hospital
- Hammersmith Hospital
- Royal Liverpool University Hospital
- Queen Elizabeth Hospital
- St James's University Hospital
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Other
Arm Label
Group 1 - Ravulizumab + BSC
Group 2 - BSC alone
Arm Description
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
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.
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.
Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29
Results are reported in micrograms/milliliter (μg/mL).
Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29
Change From Baseline In Terminal Complement Complex C5b-9 At Day 29
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04369469
Brief Title
Efficacy and Safety Study of IV Ravulizumab in Patients With COVID-19 Severe Pneumonia
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
May 2022
Overall Recruitment Status
Terminated
Why Stopped
Met futility bar at interim analysis
Study Start Date
May 10, 2020 (Actual)
Primary Completion Date
February 8, 2021 (Actual)
Study Completion Date
April 8, 2021 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19 Severe Pneumonia, Acute Lung Injury, Acute Respiratory Distress Syndrome, Pneumonia, Viral
Keywords
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
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
202 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Group 1 - Ravulizumab + BSC
Arm Type
Experimental
Arm Title
Group 2 - BSC alone
Arm Type
Other
Intervention Type
Biological
Intervention Name(s)
Ravulizumab
Other Intervention Name(s)
Ultomiris, ALXN1210
Intervention Description
Weight-based doses of ravulizumab were administered intravenously on Days 1, 5, 10, and 15.
Intervention Type
Other
Intervention Name(s)
BSC
Intervention Description
Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Primary Outcome Measure Information:
Title
Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29
Description
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.
Time Frame
Day 29
Secondary Outcome Measure Information:
Title
Number Of Days Free Of Mechanical Ventilation At Day 29
Description
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.
Time Frame
Day 29
Title
Number of Days the Participants Were Alive and Not in ICU
Description
The number of days that the participants were alive and not in the ICU from Day 1 through Day 29 are presented.
Time Frame
Day 1 through Day 29
Title
Change From Baseline In Sequential Organ Failure Assessment (SOFA) At Day 29
Description
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.
Time Frame
Baseline, Day 29
Title
Change From Baseline In Peripheral Capillary Oxygen Saturation/Fraction Of Inspired Oxygen (SpO2/FiO2) At Day 29
Description
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.
Time Frame
Baseline, Day 29
Title
Number of Days the Participants Were Alive and Not in the Hospital
Description
The number of days that the participants were alive and not in the hospital from Day 1 through Day 29 are presented.
Time Frame
Day 1 through Day 29
Title
Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90
Description
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.
Time Frame
Up to Day 60 and Up to Day 90
Title
Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29
Description
Results are reported in micrograms/milliliter (μg/mL).
Time Frame
Day 1 and Day 29
Title
Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29
Time Frame
Baseline, Day 29
Title
Change From Baseline In Terminal Complement Complex C5b-9 At Day 29
Time Frame
Baseline, Day 29
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Central Arkansas Veterans Healthcare System
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
LAC/USC Health Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
UC Irvine Medical Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
MedStar Georgetown University Hospital
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
University of Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32209
Country
United States
Facility Name
Mayo Clinic Florida
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32224
Country
United States
Facility Name
Rush University Medical Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Norton Healthcare
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40241
Country
United States
Facility Name
Baltimore VA Medical Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Brigham and Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Boston Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02118
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Mayo Clinic Health System
City
Mankato
State/Province
Minnesota
ZIP/Postal Code
56001
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
NYU Langone Health Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Icahn School of Medicine at Mount Sinai
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Westchester Medical Center
City
Valhalla
State/Province
New York
ZIP/Postal Code
10595
Country
United States
Facility Name
Medical University of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Facility Name
Baptist Memorial Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38120
Country
United States
Facility Name
Houston Methodist Hospital
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Mayo Clinic Health System in Eau Claire
City
Eau Claire
State/Province
Wisconsin
ZIP/Postal Code
54703
Country
United States
Facility Name
Mayo Clinic Health System
City
La Crosse
State/Province
Wisconsin
ZIP/Postal Code
54601
Country
United States
Facility Name
Hôpital Raymond Poincaré
City
Garches
State/Province
Hauts De Seine
ZIP/Postal Code
92380
Country
France
Facility Name
Hôpital Henri Mondor
City
Créteil
State/Province
Val De Marne
ZIP/Postal Code
94000
Country
France
Facility Name
Hôpital Bicêtre
City
Le Kremlin-Bicêtre cedex
State/Province
Val De Marne
ZIP/Postal Code
94275
Country
France
Facility Name
Medical Hospital, Tokyo Medical and Dental University
City
Bunkyō-Ku
State/Province
Tokyo-To
ZIP/Postal Code
113-8519
Country
Japan
Facility Name
Jikei University Hospital
City
Minato-Ku
State/Province
Tokyo
ZIP/Postal Code
105-8471
Country
Japan
Facility Name
Tokyo Medical University Hospital
City
Shinjuku-Ku
State/Province
Tokyo
ZIP/Postal Code
160-0023
Country
Japan
Facility Name
Hospital Universitari de Bellvitge
City
L'Hospitalet De Llobregat
State/Province
Barcelona
ZIP/Postal Code
08907
Country
Spain
Facility Name
Hospital Universitari Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Clinic de Barcelona
City
Barcelona
ZIP/Postal Code
08036
Country
Spain
Facility Name
Hospital Universitario Ramon y Cajal
City
Madrid
ZIP/Postal Code
28034
Country
Spain
Facility Name
King's College Hospital
City
London
State/Province
Greater London
ZIP/Postal Code
SE5 9RS
Country
United Kingdom
Facility Name
Hammersmith Hospital
City
London
State/Province
Greater London
ZIP/Postal Code
W12 0HS
Country
United Kingdom
Facility Name
Royal Liverpool University Hospital
City
Liverpool
State/Province
Merseyside
ZIP/Postal Code
L7 8XP
Country
United Kingdom
Facility Name
Queen Elizabeth Hospital
City
Birmingham
State/Province
West Midlands
ZIP/Postal Code
B15 2TH
Country
United Kingdom
Facility Name
St James's University Hospital
City
Leeds
State/Province
West Yorkshire
ZIP/Postal Code
LS9 7TF
Country
United Kingdom
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
Citation
WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance, 28 January 2020.
Results Reference
background
PubMed Identifier
33826106
Citation
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.
Results Reference
result
PubMed Identifier
32660611
Citation
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.
Results Reference
result
PubMed Identifier
34473343
Citation
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.
Results Reference
derived
PubMed Identifier
32554923
Citation
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.
Results Reference
derived
Learn more about this trial
Efficacy and Safety Study of IV Ravulizumab in Patients With COVID-19 Severe Pneumonia
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