Ravulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab

Phase 3

Completed

• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Interventions: Combination Product: Ravulizumab OBDS; Biological: Ravulizumab

• Registration Number: NCT03748823
• Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary

The primary objective of this study is to evaluate pharmacokinetics (PK) of ravulizumab administered subcutaneously via an on-body delivery system (OBDS) compared with intravenously administered ravulizumab in adult participants with PNH who are clinically stable on eculizumab for at least 3 months prior to study entry.

Detailed Description

The study will consist of up to a 30-day Screening Period, a 10-week Randomized Treatment Period, and an Extension Period of up to 172 weeks.

Study Timeline

• Study First Submitted: 2018-11-19
• Study First Submitted QC: 2018-11-19
• Study First Posted: 2018-11-21
• Study Start: 2019-02-19
• Disposition First Submitted: 2021-01-11
• Primary Completion: 2021-02-02
• Results First Submitted: 2022-08-09
• Results First Submitted QC: 2022-10-10
• Disposition First Submitted QC: 2022-10-10
• Results First Posted: 2022-10-20
• Disposition First Posted: 2022-10-20
• Study Completion: 2023-08-31
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-01
• Last Update Posted: 2024-07-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 139

Inclusion Criteria

• Male or female ≥18 years of age
• Treated with eculizumab for PNH for at least 3 months prior to Day 1
• LDH level ≤1.5 × upper limit of normal (ULN) at screening
• PNH diagnosis confirmed by documented high-sensitivity flow cytometry.
• Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment.
• Body weight ≥40 to <100 kilogram (kg)
• 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.
• Willing and able to give written informed consent and comply with study visit schedule.

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Exclusion Criteria

• More than 1 LDH value > 2 × ULN within the 3 months prior to study entry
• History of bone marrow transplantation.
• History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the Investigator or Sponsor, would preclude participation.
• Unstable medical conditions (for example, myocardial ischemia, active gastrointestinal bleed, severe congestive heart failure, anticipated need for major surgery within 6 months of randomization, coexisting chronic anemia unrelated to PNH).
• Females who are pregnant, breastfeeding or who have a positive pregnancy test at screening or Day 1.
• Participation in another interventional clinical study or use of any experimental therapy within 30 days before initiation of study drug 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
Ravulizumab SC Treatment Group	Ravulizumab OBDS	In the Randomized Treatment Period, participants will receive an IV loading dose of ravulizumab on Day 1 followed by SC maintenance doses of ravulizumab administered via the ravulizumab OBDS on Day 15 and every week (qw) thereafter for a total of 10 weeks of study treatment. In the Extension Period, ravulizumab SC will be administered via the ravulizumab OBDS from Day 71 qw through Day 1274.
Ravulizumab SC Treatment Group	Ravulizumab	In the Randomized Treatment Period, participants will receive an IV loading dose of ravulizumab on Day 1 followed by SC maintenance doses of ravulizumab administered via the ravulizumab OBDS on Day 15 and every week (qw) thereafter for a total of 10 weeks of study treatment. In the Extension Period, ravulizumab SC will be administered via the ravulizumab OBDS from Day 71 qw through Day 1274.
Ravulizumab IV Treatment Group	Ravulizumab OBDS	In the Randomized Treatment Period, participants will receive an IV loading dose of ravulizumab on Day 1 followed by IV maintenance doses of ravulizumab on Day 15. In the Extension Period, ravulizumab SC will be administered via the ravulizumab OBDS from Day 71 qw through Day 1274.
Ravulizumab IV Treatment Group	Ravulizumab	In the Randomized Treatment Period, participants will receive an IV loading dose of ravulizumab on Day 1 followed by IV maintenance doses of ravulizumab on Day 15. In the Extension Period, ravulizumab SC will be administered via the ravulizumab OBDS from Day 71 qw through Day 1274.

Primary Outcome Measures

Name	Time	Method
Ctrough Serum Concentration of Ravulizumab	Predose at Day 71

Secondary Outcome Measures

Name	Time	Method
Ctrough Serum Concentration of Ravulizumab at Day 351	Predose at Day 351
Free Serum Complement Component 5 (C5) Concentrations at Day 71	Predose at Day 71
Free Serum Complement Component 5 (C5) Concentrations at Day 351	Predose at Day 351
Percent Change From Baseline in Lactate Dehydrogenase (LDH) Levels at Day 71	Baseline, Day 71	Baseline was defined as the last assessment prior to first study drug dose. LDH samples impacted by tabletop hemolysis were excluded from the analysis.
Percent Change From Baseline in LDH Levels at Day 351	Baseline, Day 351	SC baseline was defined as the last assessment prior to first dose of SC treatment. LDH samples impacted by tabletop hemolysis were excluded from the analysis.
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Subscale Version 4 Score at Day 71	Baseline, Day 71	FACIT-fatigue subscale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Items are scored on a 5 point Likert-type scale. Item scores ranged from 0 ("not at all") to 4 ("very much"). The total, summed score ranged from 0 to 52; lower scores indicating greater fatigue and higher score indicating better health-related quality of life. Baseline was defined as the last non-missing value prior to the first dose of study drug.
Change From Baseline in FACIT-Fatigue Scale Version 4 Score at Day 351	Baseline, Day 351	FACIT-fatigue subscale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days. Items are scored on a 5 point Likert-type scale. Item scores ranged from 0 ("not at all") to 4 ("very much"). The total, summed score ranged from 0 to 52; lower scores indicating greater fatigue and higher score indicating better health-related quality of life. Baseline was defined as the last non-missing value prior to the first dose of subcutaneous treatment.
Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 71	Baseline, Day 71	The Treatment Administration Satisfaction Questionnaire (TASQ) is a 19-item questionnaire that assesses treatment administration satisfaction across 5 domains: physical impact, psychological impact, impact on activities of daily living, convenience, and satisfaction. Each domain offers up to 5 response options; lower scores indicate a more positive response. Scoring is completed by summing each of the 5 domains. Total TASQ scores during the study ranged from 0 to 367, with a lower score indicating greater satisfaction with treatment administration.
Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 351	Baseline, Day 351	The Treatment Administration Satisfaction Questionnaire (TASQ) is a 19-item questionnaire that assesses treatment administration satisfaction across 5 domains: physical impact, psychological impact, impact on activities of daily living, convenience, and satisfaction. Each domain offers up to 5 response options; lower scores indicate a more positive response. Scoring is completed by summing each of the 5 domains. Total TASQ scores during the study ranged from 0 to 367, with a lower score indicating greater satisfaction with treatment administration.
Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 71	Baseline up to Day 71	Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \<10 grams/deciliter (g/dL)\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2\*upper limit of normal (ULN). Denominator for a percentage was participants with at least one post-baseline data for the period. For Through Day 71, only visits with data were used to assess breakthrough hemolysis.
Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 351	Baseline up to Day 351	Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath \[dyspnea\], anemia \[hemoglobin \<10 g/dL\], major adverse vascular event \[MAVE, including thrombosis\], dysphagia, or erectile dysfunction) in the presence of elevated LDH ≥2\*ULN. Denominator for a percentage was participants with at least one post-baseline data for the period.
Percentage of Participants Who Achieved Transfusion Avoidance up to Day 71	Baseline up to Day 71	Transfusion Avoidance was defined as participants who remained transfusion free and did not require a transfusion after the first dose of study drug through the period of interest. Percentages are based on participants with any post-baseline data for the period. For Through Day 71, only visits with data were used to assess transfusion avoidance.
Percentage of Participants Who Achieved Transfusion Avoidance up to Day 351	Baseline up to Day 351	Transfusion Avoidance was defined as participants who remained transfusion free and did not require a transfusion after the first dose of study drug through the period of interest. Denominator for a percentage was participants with at least one post-baseline data for the period.
Percentage of Participants Who Maintained Stabilized Hemoglobin (SHg) up to Day 71	Baseline up to Day 71	SHg was defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level from Baseline (defined as the last assessment prior to the first dose of the study drug) in the absence of transfusion to the end of the period of interest. Percentages were based on participants with at least one post-baseline data for the period. For Through Day 71, only visits with data were used to assess SHg.
Percentage of Participants Who Maintained SHg up to Day 351	Baseline up to Day 351	SHg was defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level from SC Baseline (defined as the last assessment prior to the first dose of SC treatment) in the absence of transfusion to the end of the period of interest. Denominator for a percentage was participants with at least one post-baseline data for the period. Visits were based on the number of days since first dose of SC treatment.

Trial Locations

Locations (1)

Research Site; 🇹🇷 Izmir, Turkey