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

Study Overview
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Brief Summary
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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 6 months.

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

Official Title
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A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab

Conditions
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Paroxysmal Nocturnal Hemoglobinuria

Intervention / Treatment
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* Combination Product: Ravulizumab OBDS
* Biological: Ravulizumab


Participation Criteria
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Eligibility Criteria
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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. Exclusion Criteria: LDH level ≤ 2 × upper limit of normal (ULN) within 3 months prior to Day 1 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ravulizumab SC Treatment Group<br>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. | Combination Product: Ravulizumab OBDS<br>* The ravulizumab OBDS is a biological-device combination product consisting of a prefilled cartridge containing ravulizumab SC and an on-body injector.<br>Biological: Ravulizumab<br>* Administered by IV infusion. Ravulizumab IV doses will be based on participant body weight.<br>* Other names: ALXN1210;|
| Active Comparator: Ravulizumab IV Treatment Group<br>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. | Combination Product: Ravulizumab OBDS<br>* The ravulizumab OBDS is a biological-device combination product consisting of a prefilled cartridge containing ravulizumab SC and an on-body injector.<br>Biological: Ravulizumab<br>* Administered by IV infusion. Ravulizumab IV doses will be based on participant body weight.<br>* Other names: ALXN1210;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ctrough Serum Concentration of Ravulizumab |  | Predose at Day 71 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 was defined as the last assessment prior to first study drug dose. Lactate dehydrogenase samples impacted by tabletop hemolysis were excluded from the analysis. | Baseline, Day 71 | 
| Percent Change From Baseline in Lactate Dehydrogenase Levels at Day 351 | Subcutaneous baseline was defined as the last assessment prior to first dose of subcutaneous treatment. Lactate dehydrogenase samples impacted by tabletop hemolysis were excluded from the analysis. | Baseline, Day 351 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Subscale Version 4 Score at 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; total scores range from 0 to 52 with 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. | Baseline, Day 71 | 
| Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Version 4 Score at Day 351 | FACIT-fatigue scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function over the preceding 7 days; total scores range from 0 to 52 with 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. | Baseline, Day 351 | 
| Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at 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. | Baseline, Day 71 | 
| Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at 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. | Baseline, Day 351 | 
| Percentage of Participants Who Experienced Breakthrough Hemolysis 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. | Baseline up to Day 71 | 
| Percentage of Participants Who Experienced Breakthrough Hemolysis 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. | Baseline up to Day 351 | 
| Percentage of Participants Who Achieved Transfusion Avoidance 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. | Baseline up to Day 71 | 
| Percentage of Participants Who Achieved Transfusion Avoidance 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. | Baseline up to Day 351 | 
| Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 71 | Stabilized hemoglobin (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. | Baseline up to Day 71 | 
| Percentage of Participants Who Maintained Stabilized Hemoglobin 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. | Baseline up to Day 351 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PNH