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

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

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.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria
• Intervention / Treatment: Combination product: Ravulizumab OBDS; Biological: Ravulizumab

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 Type: Interventional
• Enrollment (Actual): 139
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Liverpool, Australia, 2170
    • Research Site
  • Parkville, Australia, 3050
    • Research Site
• Austria
  • Vienna, Austria, 1090
    • Research Site
• Belgium
  • Antwerpen, Belgium, 2020
    • Research Site
  • Bruxelles, Belgium, 1200
    • Research Site
  • Hasselt, Belgium, 3500
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
• Brazil
  • Botucatu, Brazil, 18618-970
    • Research Site
  • Ribeirão Preto, Brazil, 14049-901
    • Research Site
  • Rio De De Janeiro, Brazil, 20211030
    • Research Site
  • Salvador, Brazil, 40170010
    • Research Site
  • Sao Paulo, Brazil, 05403-000
    • Research Site
  • São Paulo, Brazil, 01308-050
    • Research Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Research Site
• Finland
  • Helsinki, Finland, 00029
    • Research Site
• France
  • Amiens, France, 80054
    • Research Site
  • Brest, France, 29609
    • Research Site
  • Lille, France, 59037
    • Research Site
  • Montpellier Cedex 5, France, 34090
    • Research Site
  • Nantes cedex 01, France, 44093
    • Research Site
  • Nice, France, 6200
    • Research Site
  • Paris, France, 75010
    • Research Site
  • Pessac, France, F-33604
    • Research Site
  • Pierre Benite Cedex, France, 69495
    • Research Site
  • Poitiers, France, 86021
    • Research Site
  • Rennes Cedex 9, France, 35033
    • Research Site
  • Strasbourg, France, 67098
    • Research Site
  • Tours, France, 37044
    • Research Site
• Italy
  • Catania, Italy, 95123
    • Research Site
  • Milano, Italy, 20122
    • Research Site
  • Roma, Italy, 00168
    • Research Site
  • Rome, Italy, 161
    • Research Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Research Site
• Russian Federation
  • Ekaterinburg, Russian Federation, 620102
    • Research Site
  • Moscow, Russian Federation, 125167
    • Research Site
  • Moscow, Russian Federation, 125284
    • Research Site
  • Saint-Petersburg, Russian Federation, 197089
    • Research Site
• Spain
  • Badalona, Spain, 8916
    • Research Site
  • Barcelona, Spain, 08036
    • Research Site
  • Donostia, Spain, 20014
    • Research Site
  • Las Palmas de Gran Canaria, Spain, 35020
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
  • Majadahonda, Spain, 28222
    • Research Site
  • Sevilla, Spain, 41013
    • Research Site
• Sweden
  • Uppsala, Sweden, 75185
    • Research Site
• Turkey
  • Adana, Turkey, 01330
    • Research Site
  • Istambul, Turkey, 34899
    • Research Site
  • Istanbul, Turkey, 34096
    • Research Site
  • Izmir, Turkey, 35100
    • Research Site
  • İstanbul, Turkey, 34093
    • Research Site
• United States
  • California
    • Los Angeles, California, United States, 90089
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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:

• 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2019
• Primary Completion (Actual): February 2, 2021
• Study Completion (Actual): August 31, 2023

Study Registration Dates

• First Submitted: November 19, 2018
• First Submitted That Met QC Criteria: November 19, 2018
• First Posted (Actual): November 21, 2018

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: July 1, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: PNH
• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Ravulizumab
• Other Study ID Numbers: ALXN1210-PNH-303; 2017-002370-39 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes