ALXN1210 Versus Eculizumab in Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03056040
• Collaborator: (none)
• Enrollment: 195
• Locations: 49
• Arms: 2
• Actual Duration (Months): 58.1
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary purpose of this study was to assess the noninferiority of ravulizumab compared to eculizumab in adult participants with PNH who were clinically stable after having been treated with eculizumab for at least 6 months.

Condition or Disease	Intervention/Treatment	Phase
Paroxysmal Nocturnal Hemoglobinuria (PNH)	Biological: Ravulizumab; Biological: Eculizumab	Phase 3

Detailed Description

The study consisted of a 4-week Screening Period and a 26-week Randomized Treatment Period (Primary Evaluation Period). After completion of the Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 3 years.

The data presented is up to the Primary Completion date of the study and is for the Primary Evaluation Period. The results for the Extension Period will be reported after study completion.

Study Design

• Study Type: Interventional
• Actual Enrollment: 195 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
• Actual Study Start Date: Jun 5, 2017
• Actual Primary Completion Date: Mar 31, 2022
• Actual Study Completion Date: Apr 8, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ravulizumab On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 milligrams (mg). Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.	Biological: Ravulizumab; All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.; Other Names: ALXN1210 ULTOMIRIS
Active Comparator: Eculizumab Participants received 900 mg of eculizumab every 2 weeks (q2w) for 26 weeks. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.	Biological: Ravulizumab; All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.; Other Names: ALXN1210 ULTOMIRIS ; Biological: Eculizumab; All treatments were given as IV infusions. Participants received 900 mg of eculizumab q2w.

Outcome Measures

Primary Outcome Measures

1. Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183 [Baseline, Day 183]

   Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).

Secondary Outcome Measures

1. Percentage Of Participants With Breakthrough Hemolysis [Baseline through Day 183]

   Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 grams (g)/deciliter (dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the upper limit of normal (ULN).

2. Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores [Baseline, Day 183]

   FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.

3. Percentage Of Participants Who Achieved Transfusion Avoidance [Baseline through Day 183]

   Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through Day 183.

4. Percentage Of Participants With Stabilized Hemoglobin Levels [Baseline through Day 183]

   Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through Day 183.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female ≥18 years of age.

2. Treated with eculizumab for PNH for at least 6 months prior to Day 1.

3. Lactate dehydrogenase level ≤1.5 times the upper limit of normal (ULN) at screening.

4. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry.

5. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment.

6. Female participants of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab.

7. Willing and able to give written informed consent and comply with study visit schedule.

Exclusion Criteria:

1. History of bone marrow transplantation.

2. Body weight <40 kilograms at screening.

3. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation.

4. Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleeding, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, or coexisting chronic anemia unrelated to PNH).

5. Female participants who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1.

6. Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study treatment on Day 1 in this study or within 5 half-lives of that investigational product, whichever is greater.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Clinical Trial Site	Duarte	California	United States	91010
2	Clinical Trial Site	Los Angeles	California	United States	90033
3	Clinical Trial Site	Baltimore	Maryland	United States	21205
4	Clinical Trial Site	Detroit	Michigan	United States	48202
5	Clinical Trial Site	Bronx	New York	United States	10467
6	Clinical Trial Site	Canberra	Australian Capital Territory	Australia	2605
7	Clinical Trial Site	Kogarah	New South Wales	Australia	2217
8	Clinical Trial Site	Liverpool	New South Wales	Australia	2170
9	Clinical Trial Site	Woolloongabba	Queensland	Australia	4102
10	Clinical Trial Site	Parkville	Victoria	Australia	3050
11	Clinical Trial Site	Toronto	Ontario	Canada	M4N 3M5
12	Clinical Trial Site	Toronto	Ontario	Canada	M5G 2C4
13	Clinical Trial Site	Montréal	Quebec	Canada	H1T 2M4
14	Clinical Trial Site	Amiens		France	80054
15	Clinical Trial Site	Marseille		France	13273
16	Clinical Trial Site	Paris		France	75475
17	Clinical Trial Site	Pierre-Bénite		France	69495
18	Clinical Trial Site	Saint-Priest-en-Jarez		France	42271
19	Clinical Trial Site	Strasbourg		France	67091
20	Clinical Trial Site	Ulm	Baden Wuerttemberg	Germany	89081
21	Clinical Trial Site	Aachen	Nordrhein Westfalen	Germany	52074
22	Clinical Trial Site	Essen	Nordrhein Westfalen	Germany	45147
23	Clinical Trial Site	Firenze		Italy	50134
24	Clinical Trial Site	Milano		Italy	20122
25	Clinical Trial Site	Napoli		Italy	80131
26	Clinical Trial Site	Torino		Italy	10126
27	Clinical Trial Site	Vicenza		Italy	36100
28	Clinical Trial Site	Kanazawa-shi	Ishikawa	Japan	920-8641
29	Clinical Trial Site	Suwa	Nagano	Japan	392-8510
30	Clinical Trial Site	Suita-shi	Osaka	Japan	565-0871
31	Clinical Trial Site	Shinagawa-Ku	Tokyo	Japan	141-8625
32	Clinical Trial Site	Fukushima		Japan	960-1295
33	Clinical Trial Site	Daegu		Korea, Republic of	42415
34	Clinical Trial Site	Daejeon		Korea, Republic of	35015
35	Clinical Trial Site	Gyeonggi-do		Korea, Republic of	14584
36	Clinical Trial Site	Gyeonggi-do		Korea, Republic of	16247
37	Clinical Trial Site	Incheon		Korea, Republic of	21565
38	Clinical Trial Site	Seoul		Korea, Republic of	03080
39	Clinical Trial Site	Seoul		Korea, Republic of	03722
40	Clinical Trial Site	Seoul		Korea, Republic of	06351
41	Clinical Trial Site	Seoul		Korea, Republic of	06591
42	Clinical Trial Site	Maastricht		Netherlands	6229
43	Clinical Trial Site	Nijmegen		Netherlands	6525
44	Clinical Trial Site	Barcelona		Spain	08036
45	Clinical Trial Site	Madrid		Spain	28040
46	Clinical Trial Site	Majadahonda		Spain	28222
47	Clinical Trial Site	Airdrie		United Kingdom	ML6 9JS
48	Clinical Trial Site	Leeds		United Kingdom	LS9 7TF
49	Clinical Trial Site	London		United Kingdom	SE5 9RS

Sponsors and Collaborators

• Alexion Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Mar 1, 2019
• Statistical Analysis Plan - Dec 12, 2017

More Information

Publications

• Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Röth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. doi: 10.1182/blood-2018-09-876805. Epub 2018 Dec 3.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03056040
• Other Study ID Numbers: ALXN1210-PNH-302; 2016-002026-36
• First Posted: Feb 16, 2017
• Last Update Posted: Jul 21, 2022
• Last Verified: Jul 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hemoglobinuria; Hemoglobinuria, Paroxysmal; Eculizumab; Ravulizumab

Study Results

Participant Flow

Pre-assignment Detail	Participants were stratified into 1 of 2 groups based on their transfusion history. Stratified participants were randomly assigned in a 1:1 ratio to receive ravulizumab or eculizumab.

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.	Participants received 900 mg of eculizumab q2w for 26 weeks. After completion of the 26-week Primary Evaluation Period, participants had the opportunity to enter the Extension Period, wherein participants will receive weight-based doses of ravulizumab for up to 3 years.
Period Title: Primary Evaluation Period
STARTED	97	98
Received at Least 1 Dose of Study Drug	97	98
COMPLETED	96	95
NOT COMPLETED	1	3
Period Title: Primary Evaluation Period
STARTED	96	95
Received at Least 1 Dose of Ravulizumab	96	95
COMPLETED	0	0
NOT COMPLETED	96	95

Baseline Characteristics

Arm/Group Title	Ravulizumab	Eculizumab	Total
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.	Total of all reporting groups
Overall Participants	97	98	195
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.6 (14.41)	48.8 (13.97)	47.7 (14.19)
Sex: Female, Male (Count of Participants)
Female	47 48.5%	50 51%	97 49.7%
Male	50 51.5%	48 49%	98 50.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 3.1%	4 4.1%	7 3.6%
Not Hispanic or Latino	76 78.4%	77 78.6%	153 78.5%
Unknown or Not Reported	18 18.6%	17 17.3%	35 17.9%
Race/Ethnicity, Customized (Count of Participants)
White	50 51.5%	61 62.2%	111 56.9%
Asian	23 23.7%	19 19.4%	42 21.5%
Not Reported	13 13.4%	13 13.3%	26 13.3%
Black or African American	5 5.2%	3 3.1%	8 4.1%
Unknown	3 3.1%	1 1%	4 2.1%
Other	2 2.1%	1 1%	3 1.5%
Multiple	1 1%	0 0%	1 0.5%

Outcome Measures

1. Primary Outcome

Title	Percent Change In Lactate Dehydrogenase Levels From Baseline To Day 183
Description	Lactate dehydrogenase (LDH) is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria. A decrease in LDH indicates reduction (improvement) in hemolysis. Baseline was defined as the average of all available on-study assessments prior to the first study drug infusion. The percent change in LDH was analyzed using a mixed-effect model for repeated measures (MMRM) with the fixed, categorical effects of treatment, study visit, and study visit by treatment group interaction, as well as the continuous, fixed covariate of baseline LDH and the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1).
Time Frame	Baseline, Day 183

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.
Measure Participants	97	98
Least Squares Mean (95% Confidence Interval) [percent change]	-0.82	8.39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ravulizumab, Eculizumab
	Comments	Adjusting for a possible 10% dropout rate, a minimum of 192 participants were estimated to provide 90% power to demonstrate noninferiority of ravulizumab to eculizumab.
	Type of Statistical Test	Non-Inferiority
	Comments	A difference in percent change in LDH between the ravulizumab and eculizumab treatment groups at Day 183 along with a 2-sided 95% confidence interval (CI) was calculated. Noninferiority margin (NIM) was based on the upper bound of the 95% CI. NIM was 15%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-9.21
	Confidence Interval	(2-Sided) 95%; -18.84 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was estimated for ravulizumab - eculizumab.

2. Secondary Outcome

Title	Percentage Of Participants With Breakthrough Hemolysis
Description	Breakthrough hemolysis (BTH) was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia [hemoglobin <10 grams (g)/deciliter (dL)], major adverse vascular event [including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the upper limit of normal (ULN).
Time Frame	Baseline through Day 183

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.
Measure Participants	97	98
Number (95% Confidence Interval) [percentage of participants]	0.0 0%	5.1 5.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ravulizumab, Eculizumab
	Comments	A difference in the percentages of participants with BTH was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
	Type of Statistical Test	Non-Inferiority
	Comments	NIM was based on the upper bound of the 95% CI. NIM was 20%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-5.1
	Confidence Interval	(2-Sided) 95%; -18.99 to 8.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was estimated for ravulizumab - eculizumab.

3. Secondary Outcome

Title	Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores
Description	FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline was defined as the last non-missing assessment value prior to first study drug dose. Change in FACIT-Fatigue score from Baseline to Day 183 was analyzed using an MMRM with the fixed, categorical effects of treatment, the stratification randomization indicator of packed red blood cells transfusion history (yes/no within 12 months prior to Day 1), study visit, and study visit by treatment group interaction, as well as the continuous fixed covariate of Baseline FACIT-Fatigue score.
Time Frame	Baseline, Day 183

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.
Measure Participants	97	98
Least Squares Mean (95% Confidence Interval) [units on a scale]	2.01	0.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ravulizumab, Eculizumab
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	NIM was based on the lower bound of the 95% CI. NIM margin was -3.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95%; -0.21 to 3.15
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was estimated for ravulizumab - eculizumab.

4. Secondary Outcome

Title	Percentage Of Participants Who Achieved Transfusion Avoidance
Description	Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines (hemoglobin value of ≤9 g/dL with signs or symptoms of sufficient severity to warrant a transfusion, or a hemoglobin value of ≤7 g/dL regardless of presence of clinical signs or symptoms) through Day 183.
Time Frame	Baseline through Day 183

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.
Measure Participants	97	98
Number (95% Confidence Interval) [percentage of participants]	87.6 90.3%	82.7 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ravulizumab, Eculizumab
	Comments	A difference in the percentages of participants achieving transfusion avoidance was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug
	Type of Statistical Test	Non-Inferiority
	Comments	NIM was based on the lower bound of the 95% CI. NIM was -20%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	5.5
	Confidence Interval	(2-Sided) 95%; -4.27 to 15.68
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was estimated for ravulizumab - eculizumab.

5. Secondary Outcome

Title	Percentage Of Participants With Stabilized Hemoglobin Levels
Description	Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through Day 183.
Time Frame	Baseline through Day 183

Outcome Measure Data

Analysis Population Description

Full Analysis Set: All participants who received at least 1 dose of randomized treatment (ravulizumab or eculizumab).

Arm/Group Title	Ravulizumab	Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.	Participants received 900 mg of eculizumab q2w for 26 weeks.
Measure Participants	97	98
Number (95% Confidence Interval) [percentage of participants]	76.3 78.7%	75.5 77%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ravulizumab, Eculizumab
	Comments	A difference in the percentages of participants with stabilized hemoglobin was calculated between the ravulizumab and eculizumab treatment groups, along with a 95% CI for the difference using the stratified Newcombe CI method. The stratification factor observed was transfusion history within 1 year prior to first dose of study drug.
	Type of Statistical Test	Non-Inferiority
	Comments	NIM was based on the lower bound of the 95% CI. NIM was -20%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -10.41 to 13.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Treatment difference was estimated for ravulizumab - eculizumab.

Adverse Events

Time Frame	From Baseline (after first dose) to Day 183 (before dosing)
Adverse Event Reporting Description	Treatment-emergent adverse events (TEAEs) reported below include TEAEs that occurred during the Primary Evaluation Period, which was defined as events that started during or after the first infusion of study treatment up to before dosing on Day 183. Adverse events that occurred during or after dosing on Day 183 were considered as part of the Extension Period and were not reported.
Arm/Group Title	Ravulizumab		Eculizumab
Arm/Group Description	On Day 1, participants received weight-based doses of ravulizumab ranging from 2400 to 3000 mg. Thereafter, weight-based doses of ravulizumab ranging from 3000 to 3600 mg were administered on Days 15, 71, and 127.		Participants received 900 mg of eculizumab q2w for 26 weeks.
All Cause Mortality
	Ravulizumab		Eculizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/97 (0%)		0/98 (0%)
Serious Adverse Events
	Ravulizumab		Eculizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/97 (4.1%)		8/98 (8.2%)
Blood and lymphatic system disorders
Haemolysis	0/97 (0%)		2/98 (2%)
Cardiac disorders
Palpitations	0/97 (0%)		1/98 (1%)
Gastrointestinal disorders
Colitis	1/97 (1%)		0/98 (0%)
General disorders
Hyperthermia	1/97 (1%)		0/98 (0%)
Pyrexia	0/97 (0%)		3/98 (3.1%)
Hepatobiliary disorders
Cholelithiasis	0/97 (0%)		1/98 (1%)
Infections and infestations
Influenza	1/97 (1%)		0/98 (0%)
Lower respiratory tract infection	1/97 (1%)		0/98 (0%)
Pyelonephritis acute	0/97 (0%)		1/98 (1%)
Nervous system disorders
Epilepsy	1/97 (1%)		0/98 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/97 (1%)		0/98 (0%)
Other (Not Including Serious) Adverse Events
	Ravulizumab		Eculizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	84/97 (86.6%)		85/98 (86.7%)
Blood and lymphatic system disorders
Anaemia	6/97 (6.2%)		3/98 (3.1%)
Gastrointestinal disorders
Abdominal pain	6/97 (6.2%)		9/98 (9.2%)
Constipation	7/97 (7.2%)		5/98 (5.1%)
Diarrhoea	9/97 (9.3%)		7/98 (7.1%)
Nausea	8/97 (8.2%)		9/98 (9.2%)
Vomiting	6/97 (6.2%)		4/98 (4.1%)
General disorders
Chest pain	3/97 (3.1%)		9/98 (9.2%)
Fatigue	6/97 (6.2%)		6/98 (6.1%)
Influenza like illness	7/97 (7.2%)		8/98 (8.2%)
Pyrexia	9/97 (9.3%)		2/98 (2%)
Infections and infestations
Nasopharyngitis	21/97 (21.6%)		20/98 (20.4%)
Rhinitis	5/97 (5.2%)		4/98 (4.1%)
Upper respiratory tract infection	18/97 (18.6%)		10/98 (10.2%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	2/97 (2.1%)		5/98 (5.1%)
Pain in extremity	5/97 (5.2%)		4/98 (4.1%)
Nervous system disorders
Dizziness	3/97 (3.1%)		7/98 (7.1%)
Headache	26/97 (26.8%)		17/98 (17.3%)
Respiratory, thoracic and mediastinal disorders
Cough	5/97 (5.2%)		10/98 (10.2%)
Dyspnoea	0/97 (0%)		6/98 (6.1%)
Oropharyngeal pain	4/97 (4.1%)		9/98 (9.2%)

Limitations/Caveats

[Not Specified]

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.