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

Acute Respiratory Distress Syndrome Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04369469
• Other study ID #: ALXN1210-COV-305
• Status: Terminated
• Phase: Phase 3
• Start date: May 10, 2020
• Est. completion date: April 8, 2021

Study information

• Verified date: May 2022
• Source: Alexion Pharmaceuticals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 202
• Est. completion date: April 8, 2021
• Est. primary completion date: February 8, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

Biological:
• Ravulizumab
Weight-based doses of ravulizumab were administered intravenously on Days 1, 5, 10, and 15.

Other:
• BSC
Participants received medications, therapies, and interventions per standard hospital treatment protocols.

Locations

Country	Name	City	State
France	Hôpital Henri Mondor	Créteil	Val De Marne
France	Hôpital Raymond Poincaré	Garches	Hauts De Seine
France	Hôpital Bicêtre	Le Kremlin-Bicêtre cedex	Val De Marne
Japan	Medical Hospital, Tokyo Medical and Dental University	Bunkyo-Ku	Tokyo-To
Japan	Jikei University Hospital	Minato-Ku	Tokyo
Japan	Tokyo Medical University Hospital	Shinjuku-Ku	Tokyo
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital Universitari Vall d'Hebron	Barcelona
Spain	Hospital Universitari de Bellvitge	L'Hospitalet De Llobregat	Barcelona
Spain	Hospital Universitario Ramon y Cajal	Madrid
United Kingdom	Queen Elizabeth Hospital	Birmingham	West Midlands
United Kingdom	St James's University Hospital	Leeds	West Yorkshire
United Kingdom	Royal Liverpool University Hospital	Liverpool	Merseyside
United Kingdom	Hammersmith Hospital	London	Greater London
United Kingdom	King's College Hospital	London	Greater London
United States	Baltimore VA Medical Center	Baltimore	Maryland
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	Henry Ford Hospital	Detroit	Michigan
United States	Mayo Clinic Health System in Eau Claire	Eau Claire	Wisconsin
United States	Houston Methodist Hospital	Houston	Texas
United States	Mayo Clinic Florida	Jacksonville	Florida
United States	University of Florida	Jacksonville	Florida
United States	Mayo Clinic Health System	La Crosse	Wisconsin
United States	Central Arkansas Veterans Healthcare System	Little Rock	Arkansas
United States	LAC/USC Health Center	Los Angeles	California
United States	Norton Healthcare	Louisville	Kentucky
United States	Mayo Clinic Health System	Mankato	Minnesota
United States	Baptist Memorial Hospital	Memphis	Tennessee
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	NYU Langone Health Center	New York	New York
United States	UC Irvine Medical Center	Orange	California
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Westchester Medical Center	Valhalla	New York
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals

Countries where clinical trial is conducted

United States,  France,  Japan,  Spain,  United Kingdom, 

References & Publications (3)

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 — View 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 Pneumon — View Citation

WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance, 28 January 2020.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29		Baseline, Day 29
Secondary	Change From Baseline In Terminal Complement Complex C5b-9 At Day 29		Baseline, Day 29