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

Phase 3

Completed

• Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Interventions: Biological: Ravulizumab; Biological: Eculizumab

• Registration Number: NCT03056040
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

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.

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 4 years.

Study Timeline

• Study First Submitted: 2017-02-14
• Study First Submitted QC: 2017-02-14
• Study First Posted: 2017-02-16
• Study Start: 2017-05-17
• Results First Submitted: 2019-02-15
• Results First Submitted QC: 2019-03-19
• Results First Posted: 2019-03-21
• Primary Completion: 2022-02-21
• Study Completion: 2022-02-21
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-19
• Last Update Posted: 2024-12-27

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 197

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Eculizumab	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 4 years.
Ravulizumab	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 4 years.
Eculizumab	Ravulizumab	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 4 years.

Primary Outcome Measures

Name	Time	Method
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

Name	Time	Method
Number Of Participants With Breakthrough Hemolysis Through Day 183	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).
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.
Percentage Of Participants Who Achieved Transfusion Avoidance Through Day 183	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.
Percentage Of Participants With Stabilized Hemoglobin Levels Through Day 183	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.
Number Of Participants With Breakthrough Hemolysis Through End of Study	Baseline through end of study (up to 4 years)	BTH was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia \[hemoglobin \<10 g/dL\], major adverse vascular event \[including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2 times the ULN.
Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study	Baseline through end of study (up to 4 years)	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 the end of study.
Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study	Baseline through end of study (up to 4 years)	Stabilized hemoglobin was defined as avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline in the absence of transfusion through end of study.
Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study	Baseline, End of Study (up to 4 years)	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.

Trial Locations

Locations (1)

Research Site; 🇬🇧 London, United Kingdom