Back to resultsRavulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
Primary Purpose
Paroxysmal Nocturnal Hemoglobinuria
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Ravulizumab OBDS
Ravulizumab
Sponsored by
About this trial
This is an interventional treatment trial for Paroxysmal Nocturnal Hemoglobinuria focused on measuring PNH
Eligibility Criteria
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.
Sites / Locations
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Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Ravulizumab SC Treatment Group
Ravulizumab IV Treatment Group
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Ctrough Serum Concentration of Ravulizumab
Secondary Outcome Measures
Ctrough Serum Concentration of Ravulizumab at Day 351
Free Serum Complement Component 5 (C5) Concentrations at Day 71
Free Serum Complement Component 5 (C5) Concentrations 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03748823
Brief Title
Ravulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
October 2023
Overall Recruitment Status
Completed
Study Start Date
March 5, 2019 (Actual)
Primary Completion Date
April 14, 2020 (Actual)
Study Completion Date
August 31, 2023 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Alexion
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
No
5. Study Description
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 6 months.
Detailed Description
The study will consist of an up to 30 day Screening Period, a 10-week Randomized Treatment Period, and a 172-week Extension Period.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Paroxysmal Nocturnal Hemoglobinuria
Keywords
PNH
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
136 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Ravulizumab SC Treatment Group
Arm Type
Experimental
Arm Description
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.
Arm Title
Ravulizumab IV Treatment Group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Combination Product
Intervention Name(s)
Ravulizumab OBDS
Intervention Description
The ravulizumab OBDS is a biological-device combination product consisting of a prefilled cartridge containing ravulizumab SC and an on-body injector.
Intervention Type
Biological
Intervention Name(s)
Ravulizumab
Other Intervention Name(s)
ALXN1210
Intervention Description
Administered by IV infusion. Ravulizumab IV doses will be based on participant body weight.
Primary Outcome Measure Information:
Title
Ctrough Serum Concentration of Ravulizumab
Time Frame
Predose at Day 71
Secondary Outcome Measure Information:
Title
Ctrough Serum Concentration of Ravulizumab at Day 351
Time Frame
Predose at Day 351
Title
Free Serum Complement Component 5 (C5) Concentrations at Day 71
Time Frame
Predose at Day 71
Title
Free Serum Complement Component 5 (C5) Concentrations at Day 351
Time Frame
Predose at Day 351
Title
Percent Change From Baseline in Lactate Dehydrogenase (LDH) Levels at Day 71
Description
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.
Time Frame
Baseline, Day 71
Title
Percent Change From Baseline in Lactate Dehydrogenase Levels at Day 351
Description
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.
Time Frame
Baseline, Day 351
Title
Change From Baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Subscale Version 4 Score at Day 71
Description
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.
Time Frame
Baseline, Day 71
Title
Change From Baseline in Functional Assessment of Chronic Illness Therapy-Fatigue Scale Version 4 Score at Day 351
Description
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.
Time Frame
Baseline, Day 351
Title
Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 71
Description
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.
Time Frame
Baseline, Day 71
Title
Change From Baseline in Treatment Administration Satisfaction Questionnaire (TASQ) Score at Day 351
Description
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.
Time Frame
Baseline, Day 351
Title
Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 71
Description
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.
Time Frame
Baseline up to Day 71
Title
Percentage of Participants Who Experienced Breakthrough Hemolysis up to Day 351
Description
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.
Time Frame
Baseline up to Day 351
Title
Percentage of Participants Who Achieved Transfusion Avoidance up to Day 71
Description
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.
Time Frame
Baseline up to Day 71
Title
Percentage of Participants Who Achieved Transfusion Avoidance up to Day 351
Description
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.
Time Frame
Baseline up to Day 351
Title
Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 71
Description
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.
Time Frame
Baseline up to Day 71
Title
Percentage of Participants Who Maintained Stabilized Hemoglobin up to Day 351
Description
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.
Time Frame
Baseline up to Day 351
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Facility Information:
Facility Name
Clinical Trial Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90033
Country
United States
Facility Name
Clinical Trial Site
City
Liverpool
Country
Australia
Facility Name
Clinical Trial Site
City
Parkville
Country
Australia
Facility Name
Clinical Trial Site
City
Vienna
Country
Austria
Facility Name
Clinical Trial Site
City
Antwerpen
Country
Belgium
Facility Name
Clinical Trial Site
City
Brussels
Country
Belgium
Facility Name
Clinical Trial Site
City
Hasselt
Country
Belgium
Facility Name
Clinical Trial Site
City
Leuven
Country
Belgium
Facility Name
Clinical Trial Site
City
Botucatu
Country
Brazil
Facility Name
Clinical Trial Site
City
Ribeirão Preto
Country
Brazil
Facility Name
Clinical Trial Site
City
Rio De Janeiro
Country
Brazil
Facility Name
Clinical Trial Site
City
Salvador
Country
Brazil
Facility Name
Clinical Trial Site
City
São Paulo
Country
Brazil
Facility Name
Clinical Trial Site
City
Toronto
Country
Canada
Facility Name
Clinical Trial Site
City
Helsinki
Country
Finland
Facility Name
Clinical Trial Site
City
Amiens
Country
France
Facility Name
Clinical Trial Site
City
Brest
Country
France
Facility Name
Clinical Trial Site
City
Lille
Country
France
Facility Name
Clinical Trial Site
City
Montpellier
Country
France
Facility Name
Clinical Trial Site
City
Nantes
Country
France
Facility Name
Clinical Trial Site
City
Nice
Country
France
Facility Name
Clinical Trial Site
City
Paris
Country
France
Facility Name
Clinical Trial Site
City
Pessac
Country
France
Facility Name
Clinical Trial Site
City
Pierre-Bénite
Country
France
Facility Name
Clinical Trial Site
City
Poitiers
Country
France
Facility Name
Clinical Trial Site
City
Rennes
Country
France
Facility Name
Clinical Trial Site
City
Strasbourg
Country
France
Facility Name
Clinical Trial Site
City
Tours
Country
France
Facility Name
Clinical Trial Site
City
Catania
Country
Italy
Facility Name
Clinical Trial Site
City
Milano
Country
Italy
Facility Name
Clinical Trial Site
City
Roma
Country
Italy
Facility Name
Clinical Trial Site
City
Maastricht
Country
Netherlands
Facility Name
Clinical Trial Site
City
Ekaterinburg
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Moscow
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Saint Petersburg
Country
Russian Federation
Facility Name
Clinical Trial Site
City
Barcelona
Country
Spain
Facility Name
Clinical Trial Site
City
Donostia
Country
Spain
Facility Name
Clinical Trial Site
City
Las Palmas De Gran Canaria
Country
Spain
Facility Name
Clinical Trial Site
City
Madrid
Country
Spain
Facility Name
Clinical Trial Site
City
Majadahonda
Country
Spain
Facility Name
Clinical Trial Site
City
Sevilla
Country
Spain
Facility Name
Clinical Trial Site
City
Uppsala
Country
Sweden
Facility Name
Clinical Trial Site
City
Adana
Country
Turkey
Facility Name
Clinical Trial Site
City
Istanbul
Country
Turkey
Facility Name
Clinical Trial Site
City
İzmir
Country
Turkey
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
36272026
Citation
Yenerel MN, Sicre de Fontbrune F, Piatek C, Sahin F, Fureder W, Ortiz S, Ogawa M, Ozol-Godfrey A, Sierra JR, Szer J. Phase 3 Study of Subcutaneous Versus Intravenous Ravulizumab in Eculizumab-Experienced Adult Patients with PNH: Primary Analysis and 1-Year Follow-Up. Adv Ther. 2023 Jan;40(1):211-232. doi: 10.1007/s12325-022-02339-3. Epub 2022 Oct 22.
Results Reference
derived
Learn more about this trial
Ravulizumab Subcutaneous (SC) Versus Ravulizumab Intravenous (IV) in Adults With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab
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