COVID-19 Severe Pneumonia, Acute Lung Injury, Acute Respiratory Distress Syndrome, Pneumonia, Viral
Conditions
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
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.
Interventions
BIOLOGICALRavulizumab
Weight-based doses of ravulizumab were administered intravenously on Days 1, 5, 10, and 15.
OTHERBSC
Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29 | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Days the Participants Were Alive and Not in ICU | Day 1 through Day 29 | 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, 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 | Baseline, 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 | Day 1 through Day 29 | The number of days that the participants were alive and not in the hospital from Day 1 through Day 29 are presented. |
| Number Of Days Free Of Mechanical Ventilation At Day 29 | 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. |
| Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29 | 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 | Baseline, Day 29 | — |
| Change From Baseline In Terminal Complement Complex C5b-9 At Day 29 | Baseline, Day 29 | — |
| Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | Up to Day 60 and 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. |
Countries
France, Japan, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Of the 210 participants screened, 8 (3.8%) participants were screen failures. A total of 202 participants were randomized and treated.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 - Ravulizumab + BSC Ravulizumab: Weight-based doses of ravulizumab were administered intravenously on Days 1, 5, 10, and 15. BSC: Participants received medications, therapies, and interventions per standard hospital treatment protocols. | 135 |
| Group 2 - BSC Alone Participants received medications, therapies, and interventions per standard hospital treatment protocols | 66 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Did Not Meet Inclusion/Exclusion Criteria | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Not Qualified due to History of Anaphylaxis | 1 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Unable to Provide Consent | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Group 2 - BSC Alone | Group 1 - Ravulizumab + BSC | Total |
|---|---|---|---|
| Age, Continuous | 63.5 years STANDARD_DEVIATION 12.4 | 63.2 years STANDARD_DEVIATION 13.23 | 63.3 years STANDARD_DEVIATION 12.93 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 6 participants | 9 participants | 15 participants |
| Race/Ethnicity, Customized Black or African American | 7 participants | 20 participants | 27 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 11 participants | 27 participants | 38 participants |
| Race/Ethnicity, Customized Missing/Unknown | 5 participants | 17 participants | 22 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 46 participants | 100 participants | 146 participants |
| Race/Ethnicity, Customized Not reported | 4 participants | 1 participants | 5 participants |
| Race/Ethnicity, Customized Not Reported | 2 participants | 4 participants | 6 participants |
| Race/Ethnicity, Customized Other | 5 participants | 13 participants | 18 participants |
| Race/Ethnicity, Customized White | 40 participants | 72 participants | 112 participants |
| Sex: Female, Male Female | 23 Participants | 39 Participants | 62 Participants |
| Sex: Female, Male Male | 43 Participants | 96 Participants | 139 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 55 / 135 | 25 / 66 |
| other Total, other adverse events | 97 / 127 | 49 / 67 |
| serious Total, serious adverse events | 79 / 127 | 38 / 67 |
Outcome results
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.
Time frame: Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1 - Ravulizumab + BSC | Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29 | 57.6 Percentage of participants |
| Group 2 - BSC Alone | Survival (Based On All-Cause Mortality) in Participants in the ITT Population At Day 29 | 59.7 Percentage of participants |
p-value: 0.605995% CI: [-0.1703, 0.1293]Mantel Haenszel
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.
Time frame: Baseline, Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Change From Baseline In Peripheral Capillary Oxygen Saturation/Fraction Of Inspired Oxygen (SpO2/FiO2) At Day 29 | 62.5 ratio | Standard Deviation 112.43 |
| Group 2 - BSC Alone | Change From Baseline In Peripheral Capillary Oxygen Saturation/Fraction Of Inspired Oxygen (SpO2/FiO2) At Day 29 | 134.0 ratio | Standard Deviation 104.35 |
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.
Time frame: Baseline, Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Change From Baseline In Sequential Organ Failure Assessment (SOFA) At Day 29 | -2.0 Units on a scale | Standard Deviation 6.25 |
| Group 2 - BSC Alone | Change From Baseline In Sequential Organ Failure Assessment (SOFA) At Day 29 | -4.5 Units on a scale | Standard Deviation 4.9 |
Secondary
Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29
Time frame: Baseline, Day 29
Population: PK/PD Population: participants in the ITT population with at least 1 postdose PK or PD result. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29 | -156.31 μg/mL | Standard Deviation 61.599 |
| Group 2 - BSC Alone | Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29 | 21.79 μg/mL | Standard Deviation 67.918 |
Secondary
Change From Baseline In Terminal Complement Complex C5b-9 At Day 29
Time frame: Baseline, Day 29
Population: PK/PD Population: participants in the ITT population with at least 1 postdose PK or PD result. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Change From Baseline In Terminal Complement Complex C5b-9 At Day 29 | -133.23 ug/L | Standard Deviation 202.07 |
| Group 2 - BSC Alone | Change From Baseline In Terminal Complement Complex C5b-9 At Day 29 | -277.21 ug/L | Standard Deviation 604.742 |
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.
Time frame: Up to Day 60 and Up to Day 90
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, Number Analyzed signifies those participants who were evaluable for the assessment at the specified time frame.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | Day 60 | 60 Participants |
| Group 1 - Ravulizumab + BSC | Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | Day 90 | 49 Participants |
| Group 2 - BSC Alone | Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | Day 60 | 29 Participants |
| Group 2 - BSC Alone | Estimated Number of Participants Alive At Up To Day 60 and At Up To Day 90 | Day 90 | 20 Participants |
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.
Time frame: Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Group 1 - Ravulizumab + BSC | Number Of Days Free Of Mechanical Ventilation At Day 29 | 6.79 Days |
| Group 2 - BSC Alone | Number Of Days Free Of Mechanical Ventilation At Day 29 | 6.81 Days |
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.
Time frame: Day 1 through Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Group 1 - Ravulizumab + BSC | Number of Days the Participants Were Alive and Not in ICU | 6.09 Days |
| Group 2 - BSC Alone | Number of Days the Participants Were Alive and Not in ICU | 6.71 Days |
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.
Time frame: Day 1 through Day 29
Population: The ITT Population consisted of all randomized participants. Participants were analyzed as randomized. Here, 'Number of Participants Analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Group 1 - Ravulizumab + BSC | Number of Days the Participants Were Alive and Not in the Hospital | 3.02 Days |
| Group 2 - BSC Alone | Number of Days the Participants Were Alive and Not in the Hospital | 3.47 Days |
Secondary
Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29
Results are reported in micrograms/milliliter (μg/mL).
Time frame: Day 1 and Day 29
Population: Pharmacokinetics/Pharmacodynamics (PK/PD) Population: participants in the ITT population with at least 1 postdose PK or PD result.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Group 1 - Ravulizumab + BSC | Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29 | Day 1 (predose) | 0.00 μg/mL | Standard Deviation 0 |
| Group 1 - Ravulizumab + BSC | Serum Ravulizumab Concentrations Prior to Dosing on Day 1 and Day 29 | Day 29 (predose) | 231.35 μg/mL | Standard Deviation 149.741 |