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

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT04369469
• Collaborator: (none)
• Enrollment: 202
• Locations: 39
• Arms: 2
• Actual Duration (Months): 10.9
• Patients Per Site: 5.2
• Patients Per Site Per Month: 0.5

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
COVID-19 Severe Pneumonia; Acute Lung Injury; Acute Respiratory Distress Syndrome; Pneumonia, Viral	Biological: Ravulizumab; Other: BSC	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 202 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 10, 2020
• Actual Primary Completion Date: Feb 8, 2021
• Actual Study Completion Date: Apr 8, 2021

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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).

8. Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29 [Baseline, Day 29]

9. Change From Baseline In Terminal Complement Complex C5b-9 At Day 29 [Baseline, Day 29]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

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.

1. Female participants who were breastfeeding or who have a positive pregnancy test result at Screening.

2. History of hypersensitivity to any ingredient contained in the study drug, including hypersensitivity to murine proteins.

3. 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.

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Alexion Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jun 9, 2020
• Statistical Analysis Plan - Jul 31, 2020

More Information

Publications

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

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT04369469
• Other Study ID Numbers: ALXN1210-COV-305
• First Posted: Apr 30, 2020
• Last Update Posted: May 24, 2022
• Last Verified: May 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alexion Pharmaceuticals: 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
• Additional relevant MeSH terms: COVID-19; Pneumonia; Pneumonia, Viral; Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury; Lung Injury; Syndrome; Ravulizumab

Study Results

Participant Flow

Pre-assignment Detail	Of the 210 participants screened, 8 (3.8%) participants were screen failures. A total of 202 participants were randomized and treated.

Arm/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols
Period Title: Overall Study
STARTED	135	67
Intent to Treat (ITT) Population	135	66
Pharmacokinetic (PK)	127	52
Safety Population	127	67
COMPLETED	125	58
NOT COMPLETED	10	9

Baseline Characteristics

Arm/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone	Total
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols	Total of all reporting groups
Overall Participants	135	66	201
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.2 (13.23)	63.5 (12.40)	63.3 (12.93)
Sex: Female, Male (Count of Participants)
Female	39 28.9%	23 34.8%	62 30.8%
Male	96 71.1%	43 65.2%	139 69.2%
Race/Ethnicity, Customized (participants) [Number]
Not Hispanic or Latino	100 74.1%	46 69.7%	146 72.6%
Hispanic or Latino	27 20%	11 16.7%	38 18.9%
Missing/Unknown	7 5.2%	5 7.6%	12 6%
Not reported	1 0.7%	4 6.1%	5 2.5%
Race/Ethnicity, Customized (participants) [Number]
White	72 53.3%	40 60.6%	112 55.7%
Black or African American	20 14.8%	7 10.6%	27 13.4%
Missing/Unknown	17 12.6%	5 7.6%	22 10.9%
Other	13 9.6%	5 7.6%	18 9%
Asian	9 6.7%	6 9.1%	15 7.5%
Not Reported	4 3%	2 3%	6 3%
American Indian or Alaska Native	1 0.7%	0 0%	1 0.5%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.5%	1 0.5%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

The ITT Population consisted of all randomized participants. Participants were analyzed as randomized.

Arm/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	135	66
Number [Percentage of participants]	57.6 42.7%	59.7 90.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Group 1 - Ravulizumab + BSC, Group 2 - BSC Alone
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6059
	Comments	One-sided Mantel-Haenszel test of the difference in two proportions stratified by intubated or not intubated on Day 1 and a family-wise Type I error of 0.025.
	Method	Mantel Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.0205
	Confidence Interval	(2-Sided) 95%; -0.1703 to 0.1293
	Parameter Dispersion	Type: Value:
	Estimation Comments	Two-sided 95% confidence interval using the Sato variance estimator, combined overall imputations.

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	129	62
Least Squares Mean (95% Confidence Interval) [Days]	6.79	6.81

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	129	62
Least Squares Mean (95% Confidence Interval) [Days]	6.09	6.71

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	42	17
Mean (Standard Deviation) [Units on a scale]	-2.0 (6.25)	-4.5 (4.90)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	38	17
Mean (Standard Deviation) [ratio]	62.5 (112.43)	134.0 (104.35)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	129	62
Least Squares Mean (95% Confidence Interval) [Days]	3.02	3.47

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	135	66
Day 60	60 44.4%	29 43.9%
Day 90	49 36.3%	20 30.3%

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Pharmacokinetics/Pharmacodynamics (PK/PD) Population: participants in the ITT population with at least 1 postdose PK or PD result.

Arm/Group Title	Group 1 - Ravulizumab + BSC
Arm/Group Description	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.
Measure Participants	126
Day 1 (predose)	0.00 (0.00)
Day 29 (predose)	231.35 (149.741)

9. Secondary Outcome

Title	Change From Baseline In Serum Free Complement Component 5 Concentrations At Day 29
Time Frame	Baseline, Day 29

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	43	14
Mean (Standard Deviation) [μg/mL]	-156.31 (61.599)	21.79 (67.918)

10. Secondary Outcome

Title	Change From Baseline In Terminal Complement Complex C5b-9 At Day 29
Time Frame	Baseline, Day 29

Outcome Measure Data

Analysis Population Description

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/Group Title	Group 1 - Ravulizumab + BSC	Group 2 - BSC Alone
Arm/Group Description	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.	Participants received medications, therapies, and interventions per standard hospital treatment protocols.
Measure Participants	43	14
Mean (Standard Deviation) [ug/L]	-133.23 (202.070)	-277.21 (604.742)

Adverse Events

Time Frame	Day 1 through Day 90
Adverse Event Reporting Description	Data for All-Cause Mortality was collected for the ITT Population (all randomized participants; participants were analyzed as randomized). Serious and Other (Not Including Serious) Adverse Events were collected for the Safety Population (all randomized participants who received at least 1 dose of study drug; participants were analyzed as treated).
Arm/Group Title	Group 1 - Ravulizumab + BSC		Group 2 - BSC Alone
Arm/Group Description	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.		Participants received medications, therapies, and interventions per standard hospital treatment protocols.
All Cause Mortality
	Group 1 - Ravulizumab + BSC		Group 2 - BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	55/135 (40.7%)		25/66 (37.9%)
Serious Adverse Events
	Group 1 - Ravulizumab + BSC		Group 2 - BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/127 (62.2%)		38/67 (56.7%)
Blood and lymphatic system disorders
Thrombocytopenia	2/127 (1.6%)	2	0/67 (0%)	0
Anaemia	1/127 (0.8%)	1	0/67 (0%)	0
Haemolytic anaemia	1/127 (0.8%)	1	0/67 (0%)	0
Leukocytosis	0/127 (0%)	0	1/67 (1.5%)	1
Microangiopathic haemolytic anaemia	1/127 (0.8%)	1	0/67 (0%)	0
Cardiac disorders
Cardiac arrest	4/127 (3.1%)	4	2/67 (3%)	2
Atrial fibrillation	1/127 (0.8%)	1	2/67 (3%)	2
Cardio-respiratory arrest	0/127 (0%)	0	2/67 (3%)	2
Pulseless electrical activity	1/127 (0.8%)	1	1/67 (1.5%)	1
Ventricular tachycardia	2/127 (1.6%)	2	0/67 (0%)	0
Acute myocardial infarction	0/127 (0%)	0	1/67 (1.5%)	1
Atrial flutter	0/127 (0%)	0	1/67 (1.5%)	1
Cardiac failure	1/127 (0.8%)	1	0/67 (0%)	0
Cardiogenic shock	0/127 (0%)	0	1/67 (1.5%)	1
Endocrine disorders
Hypothyroidism	0/127 (0%)	0	1/67 (1.5%)	1
Gastrointestinal disorders
Gastric haemorrhage	1/127 (0.8%)	1	0/67 (0%)	0
Gastrointestinal ischaemia	0/127 (0%)	0	1/67 (1.5%)	1
Oesophageal haemorrhage	1/127 (0.8%)	1	0/67 (0%)	0
General disorders
Multiple organ dysfunction syndrome	14/127 (11%)	14	6/67 (9%)	6
Condition aggravated	0/127 (0%)	0	1/67 (1.5%)	1
Oedema peripheral	0/127 (0%)	0	1/67 (1.5%)	1
Pyrexia	1/127 (0.8%)	1	0/67 (0%)	0
Hepatobiliary disorders
Ischaemic hepatitis	2/127 (1.6%)	2	0/67 (0%)	0
Hepatic failure	1/127 (0.8%)	1	0/67 (0%)	0
Liver injury	1/127 (0.8%)	1	0/67 (0%)	0
Infections and infestations
Septic shock	13/127 (10.2%)	15	3/67 (4.5%)	5
COVID-19 pneumonia	7/127 (5.5%)	7	0/67 (0%)	0
Pneumonia	4/127 (3.1%)	4	1/67 (1.5%)	1
Bacteraemia	2/127 (1.6%)	3	1/67 (1.5%)	1
Sepsis	3/127 (2.4%)	3	0/67 (0%)	0
Pneumonia bacterial	2/127 (1.6%)	2	0/67 (0%)	0
Staphylococcal bacteraemia	2/127 (1.6%)	2	0/67 (0%)	0
Systemic candida	2/127 (1.6%)	2	0/67 (0%)	0
Pneumonia pseudomonal	1/127 (0.8%)	2	0/67 (0%)	0
Bronchopulmonary aspergillosis	1/127 (0.8%)	1	0/67 (0%)	0
COVID-19	1/127 (0.8%)	1	0/67 (0%)	0
Candida infection	1/127 (0.8%)	1	0/67 (0%)	0
Clostridium difficile infection	0/127 (0%)	0	1/67 (1.5%)	1
Cryptococcosis	1/127 (0.8%)	1	0/67 (0%)	0
Cytomegalovirus viraemia	1/127 (0.8%)	1	0/67 (0%)	0
Device related infection	1/127 (0.8%)	1	0/67 (0%)	0
Enterobacter pneumonia	1/127 (0.8%)	1	0/67 (0%)	0
Escherichia bacteraemia	1/127 (0.8%)	1	0/67 (0%)	0
Fungal sepsis	1/127 (0.8%)	1	0/67 (0%)	0
Herpes simplex pneumonia	1/127 (0.8%)	1	0/67 (0%)	0
Klebsiella bacteraemia	1/127 (0.8%)	1	0/67 (0%)	0
Pneumonia pneumococcal	1/127 (0.8%)	1	0/67 (0%)	0
Pneumonia staphylococcal	1/127 (0.8%)	1	0/67 (0%)	0
Pseudomonal sepsis	1/127 (0.8%)	1	0/67 (0%)	0
Injury, poisoning and procedural complications
Head injury	1/127 (0.8%)	1	0/67 (0%)	0
Procedural hypotension	1/127 (0.8%)	1	0/67 (0%)	0
Vascular pseudoaneurysm	1/127 (0.8%)	1	0/67 (0%)	0
Investigations
Blood beta-D-glucan positive	0/127 (0%)	0	1/67 (1.5%)	1
Blood lactic acid increased	1/127 (0.8%)	1	0/67 (0%)	0
Fibrin D dimer increased	1/127 (0.8%)	1	0/67 (0%)	0
Oxygen saturation decreased	0/127 (0%)	0	1/67 (1.5%)	1
Transaminases increased	1/127 (0.8%)	1	0/67 (0%)	0
Metabolism and nutrition disorders
Metabolic acidosis	1/127 (0.8%)	1	0/67 (0%)	0
Musculoskeletal and connective tissue disorders
Haematoma muscle	1/127 (0.8%)	1	0/67 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer	1/127 (0.8%)	1	0/67 (0%)	0
Nervous system disorders
Cerebral infarction	2/127 (1.6%)	2	0/67 (0%)	0
Brain injury	1/127 (0.8%)	1	0/67 (0%)	0
Cerebrovascular accident	1/127 (0.8%)	1	0/67 (0%)	0
Encephalopathy	1/127 (0.8%)	1	0/67 (0%)	0
Haemorrhage intracranial	0/127 (0%)	0	1/67 (1.5%)	1
Intensive care unit acquired weakness	1/127 (0.8%)	1	0/67 (0%)	0
Renal and urinary disorders
Acute kidney injury	2/127 (1.6%)	2	2/67 (3%)	2
Renal failure	2/127 (1.6%)	2	2/67 (3%)	2
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	12/127 (9.4%)	12	5/67 (7.5%)	5
Acute respiratory failure	6/127 (4.7%)	6	4/67 (6%)	4
Respiratory failure	5/127 (3.9%)	5	5/67 (7.5%)	5
Hypoxia	4/127 (3.1%)	4	3/67 (4.5%)	3
Pneumothorax	4/127 (3.1%)	5	2/67 (3%)	2
Lung disorder	3/127 (2.4%)	3	1/67 (1.5%)	1
Respiratory acidosis	2/127 (1.6%)	2	1/67 (1.5%)	1
Pneumomediastinum	2/127 (1.6%)	2	0/67 (0%)	0
Pulmonary embolism	2/127 (1.6%)	2	0/67 (0%)	0
Haemothorax	1/127 (0.8%)	1	0/67 (0%)	0
Organizing pneumonia	1/127 (0.8%)	1	0/67 (0%)	0
Pulmonary haemorrhage	1/127 (0.8%)	1	0/67 (0%)	0
Respiratory distress	1/127 (0.8%)	1	0/67 (0%)	0
Stridor	1/127 (0.8%)	1	0/67 (0%)	0
Tracheal stenosis	1/127 (0.8%)	1	0/67 (0%)	0
Skin and subcutaneous tissue disorders
Subcutaneous emphysema	1/127 (0.8%)	1	0/67 (0%)	0
Vascular disorders
Hypotension	3/127 (2.4%)	4	0/67 (0%)	0
Shock hemorrhagic	1/127 (0.8%)	1	1/67 (1.5%)	1
Peripheral arterial occlusive disease	0/127 (0%)	0	1/67 (1.5%)	1
Other (Not Including Serious) Adverse Events
	Group 1 - Ravulizumab + BSC		Group 2 - BSC Alone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	97/127 (76.4%)		49/67 (73.1%)
Blood and lymphatic system disorders
Anaemia	13/127 (10.2%)	15	4/67 (6%)	5
Cardiac disorders
Atrial fibrillation	12/127 (9.4%)	12	5/67 (7.5%)	5
Bradycardia	6/127 (4.7%)	6	4/67 (6%)	4
Gastrointestinal disorders
Constipation	5/127 (3.9%)	5	5/67 (7.5%)	6
General disorders
Pyrexia	10/127 (7.9%)	12	6/67 (9%)	6
Infections and infestations
Pneumonia bacterial	7/127 (5.5%)	7	4/67 (6%)	4
Metabolism and nutrition disorders
Hyperkalaemia	8/127 (6.3%)	9	6/67 (9%)	6
Hypernatraemia	11/127 (8.7%)	11	3/67 (4.5%)	3
Renal and urinary disorders
Acute kidney injury	9/127 (7.1%)	10	5/67 (7.5%)	5
Respiratory, thoracic and mediastinal disorders
Lung disorder	1/127 (0.8%)	1	4/67 (6%)	6
Skin and subcutaneous tissue disorders
Decubitus ulcer	8/127 (6.3%)	9	4/67 (6%)	4
Vascular disorders
Hypotension	16/127 (12.6%)	18	8/67 (11.9%)	10
Deep vein thrombosis	14/127 (11%)	14	2/67 (3%)	2
Hypertension	9/127 (7.1%)	9	3/67 (4.5%)	3

Limitations/Caveats

Enrollment of participants was paused on 13-Jan-2021. At that time, 202 participants had been randomized. An interim analysis for efficacy and futility was conducted on data from the first 122 participants who completed the Primary Evaluation Period. The analysis showed that the study met the prespecified stopping criteria for futility. After review of all participant data, Alexion terminated the study on 01-Sep-2021.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.