Clinical trial NCT04369469: 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
Overall status: TERMINATED
Phase: PHASE3
Conditions: 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
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-04-30
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29
timeFrame: Day 29
Secondary outcomes:
measure: Number Of Days Free Of Mechanical Ventilation At Day 29
timeFrame: Day 29
measure: Number of Days the Participants Were Alive and Not in ICU
timeFrame: Day 1 through Day 29
measure: Change From Baseline In Sequential Organ Failure Assessment (SOFA) At Day 29
timeFrame: Baseline, Day 29
measure: Change From Baseline In Peripheral Capillary Oxygen Saturation/Fraction Of Inspired Oxygen (SpO2/FiO2) At Day 29
timeFrame: Baseline, Day 29
measure: Number of Days the Participants Were Alive and Not in the Hospital
timeFrame: Day 1 through Day 29
measure: Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90
timeFrame: Up to Day 60 and Up to Day 90
measure: Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29
timeFrame: Day 1 and Day 29
measure: Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29
timeFrame: Baseline, Day 29
measure: Change From Baseline In Terminal Complement Complex C5b-9 At Day 29
timeFrame: Baseline, Day 29
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Central Arkansas Veterans Healthcare System
state: Arkansas
city: Los Angeles
country: United States
facility: LAC/USC Health Center
state: California
city: Orange
country: United States
facility: UC Irvine Medical Center
state: California
city: Washington
country: United States
facility: MedStar Georgetown University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Jacksonville
country: United States
facility: Mayo Clinic Florida
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Louisville
country: United States
facility: Norton Healthcare
state: Kentucky
city: Baltimore
country: United States
facility: Baltimore VA Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Mankato
country: United States
facility: Mayo Clinic Health System
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: NYU Langone Health Center
state: New York
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Valhalla
country: United States
facility: Westchester Medical Center
state: New York
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Memphis
country: United States
facility: Baptist Memorial Hospital
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Eau Claire
country: United States
facility: Mayo Clinic Health System in Eau Claire
state: Wisconsin
city: La Crosse
country: United States
facility: Mayo Clinic Health System
state: Wisconsin
city: Garches
country: France
facility: Hôpital Raymond Poincaré
state: Hauts De Seine
city: Créteil
country: France
facility: Hôpital Henri Mondor
state: Val De Marne
city: Le Kremlin-Bicêtre cedex
country: France
facility: Hôpital Bicêtre
state: Val De Marne
city: Bunkyō-Ku
country: Japan
facility: Medical Hospital, Tokyo Medical and Dental University
state: Tokyo-To
city: Minato-Ku
country: Japan
facility: Jikei University Hospital
state: Tokyo
city: Shinjuku-Ku
country: Japan
facility: Tokyo Medical University Hospital
state: Tokyo
city: L'Hospitalet De Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge
state: Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: London
country: United Kingdom
facility: King's College Hospital
state: Greater London
city: London
country: United Kingdom
facility: Hammersmith Hospital
state: Greater London
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
state: Merseyside
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
city: Leeds
country: United Kingdom
facility: St James's University Hospital
state: West Yorkshire
Study officials:
References:
citation: WHO. Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected. Interim guidance, 28 January 2020.
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.
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.
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.
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.