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

A Phase 3, Randomized, Open-Label, Active-Controlled Study of ALXN1210 Versus Eculizumab in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Currently Treated With Eculizumab

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.

Study Overview

• Status: Completed
• Conditions: Paroxysmal Nocturnal Hemoglobinuria (PNH)
• Intervention / Treatment: Biological: Ravulizumab; Biological: Eculizumab

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 3 years.

• Study Type: Interventional
• Enrollment (Actual): 195
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Australian Capital Territory
    • Canberra, Australian Capital Territory, Australia, 2605
      • Clinical Trial Site
  • New South Wales
    • Kogarah, New South Wales, Australia, 2217
      • Clinical Trial Site
    • Liverpool, New South Wales, Australia, 2170
      • Clinical Trial Site
  • Queensland
    • Woolloongabba, Queensland, Australia, 4102
      • Clinical Trial Site
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Clinical Trial Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M4N 3M5
      • Clinical Trial Site
    • Toronto, Ontario, Canada, M5G 2C4
      • Clinical Trial Site
  • Quebec
    • Montréal, Quebec, Canada, H1T 2M4
      • Clinical Trial Site
• France
  • Amiens, France, 80054
    • Clinical Trial Site
  • Marseille, France, 13273
    • Clinical Trial Site
  • Paris, France, 75475
    • Clinical Trial Site
  • Pierre-Bénite, France, 69495
    • Clinical Trial Site
  • Saint-Priest-en-Jarez, France, 42271
    • Clinical Trial Site
  • Strasbourg, France, 67091
    • Clinical Trial Site
• Germany
  • Baden Wuerttemberg
    • Ulm, Baden Wuerttemberg, Germany, 89081
      • Clinical Trial Site
  • Nordrhein Westfalen
    • Aachen, Nordrhein Westfalen, Germany, 52074
      • Clinical Trial Site
    • Essen, Nordrhein Westfalen, Germany, 45147
      • Clinical Trial Site
• Italy
  • Firenze, Italy, 50134
    • Clinical Trial Site
  • Milano, Italy, 20122
    • Clinical Trial Site
  • Napoli, Italy, 80131
    • Clinical Trial Site
  • Torino, Italy, 10126
    • Clinical Trial Site
  • Vicenza, Italy, 36100
    • Clinical Trial Site
• Japan
  • Fukushima, Japan, 960-1295
    • Clinical Trial Site
  • Ishikawa
    • Kanazawa-shi, Ishikawa, Japan, 920-8641
      • Clinical Trial Site
  • Nagano
    • Suwa, Nagano, Japan, 392-8510
      • Clinical Trial Site
  • Osaka
    • Suita-shi, Osaka, Japan, 565-0871
      • Clinical Trial Site
  • Tokyo
    • Shinagawa-Ku, Tokyo, Japan, 141-8625
      • Clinical Trial Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 42415
    • Clinical Trial Site
  • Daejeon, Korea, Republic of, 35015
    • Clinical Trial Site
  • Gyeonggi-do, Korea, Republic of, 14584
    • Clinical Trial Site
  • Gyeonggi-do, Korea, Republic of, 16247
    • Clinical Trial Site
  • Incheon, Korea, Republic of, 21565
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 03080
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 03722
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 06351
    • Clinical Trial Site
  • Seoul, Korea, Republic of, 06591
    • Clinical Trial Site
• Netherlands
  • Maastricht, Netherlands, 6229
    • Clinical Trial Site
  • Nijmegen, Netherlands, 6525
    • Clinical Trial Site
• Spain
  • Barcelona, Spain, 08036
    • Clinical Trial Site
  • Madrid, Spain, 28040
    • Clinical Trial Site
  • Majadahonda, Spain, 28222
    • Clinical Trial Site
• United Kingdom
  • Airdrie, United Kingdom, ML6 9JS
    • Clinical Trial Site
  • Leeds, United Kingdom, LS9 7TF
    • Clinical Trial Site
  • London, United Kingdom, SE5 9RS
    • Clinical Trial Site
• United States
  • California
    • Duarte, California, United States, 91010
      • Clinical Trial Site
    • Los Angeles, California, United States, 90033
      • Clinical Trial Site
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Clinical Trial Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Clinical Trial Site
  • New York
    • Bronx, New York, United States, 10467
      • Clinical Trial Site

Participation Criteria

Eligibility Criteria

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

Description

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.

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.

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; 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 3 years.	Biological: Ravulizumab; All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.; Other Names: ALXN1210; ULTOMIRIS
Active Comparator: 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 3 years.	Biological: Ravulizumab; All treatments were given as intravenous (IV) infusions. For participants weighing ≥40 to <60 kilograms (kg): 2400 mg was given as a single loading dose, followed by 3000 mg as maintenance dose. For participants weighing ≥60 to <100 kg: 2700 mg was given as a loading dose, followed by 3300 mg as maintenance dose. For participants weighing ≥100 kg: 3000 mg was given as a loading dose, followed by 3600 mg as maintenance dose.; Other Names: ALXN1210; ULTOMIRIS; Biological: Eculizumab; All treatments were given as IV infusions. Participants received 900 mg of eculizumab q2w.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change In Lactate Dehydrogenase Levels From Baseline To 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).	Baseline, Day 183

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline To Day 183 In Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue Scores	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.	Baseline, Day 183
Number Of Participants With Breakthrough Hemolysis 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).	Baseline through Day 183
Percentage Of Participants Who Achieved Transfusion Avoidance 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.	Baseline through Day 183
Percentage Of Participants With Stabilized Hemoglobin Levels 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.	Baseline through Day 183
Number Of Participants With Breakthrough Hemolysis Through End of Study	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.	Baseline through end of study (up to 5 years)
Change From Baseline To End of Study In FACIT-Fatigue Scores Through End of Study	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.	Baseline, End of Study (up to 5 years)
Percentage Of Participants Who Achieved Transfusion Avoidance Through End of Study	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.	Baseline through end of study (up to 5 years)
Percentage Of Participants With Stabilized Hemoglobin Levels Through End of Study	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.	Baseline through end of study (up to 5 years)

Collaborators and Investigators

• Sponsor: Alexion

Publications and helpful links

General Publications

• Schwartz CE, Stark RB, Borowiec K, Nolte S, Myren KJ. Norm-based comparison of the quality-of-life impact of ravulizumab and eculizumab in paroxysmal nocturnal hemoglobinuria. Orphanet J Rare Dis. 2021 Sep 15;16(1):389. doi: 10.1186/s13023-021-02016-8.
• Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, Gaya A, Lee JW, Gutierrez EO, Piatek CI, Szer J, Risitano A, Nakao S, Bachman E, Shafner L, Damokosh AI, Ortiz S, Roth A, Peffault de Latour R. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood. 2019 Feb 7;133(6):540-549. doi: 10.1182/blood-2018-09-876805. Epub 2018 Dec 3.
• Brodsky RA, Peffault de Latour R, Rottinghaus ST, Roth A, Risitano AM, Weitz IC, Hillmen P, Maciejewski JP, Szer J, Lee JW, Kulasekararaj AG, Volles L, Damokosh AI, Ortiz S, Shafner L, Liu P, Hill A, Schrezenmeier H. Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria. Haematologica. 2021 Jan 1;106(1):230-237. doi: 10.3324/haematol.2019.236877.
• Ishiyama K, Nakao S, Usuki K, Yonemura Y, Ikezoe T, Uchiyama M, Mori Y, Fukuda T, Okada M, Fujiwara SI, Noji H, Rottinghaus S, Aguzzi R, Yokosawa J, Nishimura JI, Kanakura Y, Okamoto S. Results from multinational phase 3 studies of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria: subgroup analysis of Japanese patients. Int J Hematol. 2020 Oct;112(4):466-476. doi: 10.1007/s12185-020-02934-6. Epub 2020 Aug 31.
• Kulasekararaj AG, Griffin M, Langemeijer S, Usuki K, Kulagin A, Ogawa M, Yu J, Mujeebuddin A, Nishimura JI, Lee JW, Peffault de Latour R; 301/302 Study Group. Long-term safety and efficacy of ravulizumab in patients with paroxysmal nocturnal hemoglobinuria: 2-year results from two pivotal phase 3 studies. Eur J Haematol. 2022 Sep;109(3):205-214. doi: 10.1111/ejh.13783. Epub 2022 Jun 16.
• Kulasekararaj AG, Hill A, Langemeijer S, Wells R, Gonzalez Fernandez FA, Gaya A, Ojeda Gutierrez E, Piatek CI, Mitchell L, Usuki K, Bosi A, Brodsky RA, Ogawa M, Yu J, Ortiz S, Roth A, Lee JW, Peffault de Latour R. One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab. Eur J Haematol. 2021 Mar;106(3):389-397. doi: 10.1111/ejh.13564. Epub 2021 Jan 3.
• Peffault de Latour R, Brodsky RA, Ortiz S, Risitano AM, Jang JH, Hillmen P, Kulagin AD, Kulasekararaj AG, Rottinghaus ST, Aguzzi R, Gao X, Wells RA, Szer J. Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies. Br J Haematol. 2020 Nov;191(3):476-485. doi: 10.1111/bjh.16711. Epub 2020 May 24.
• Schrezenmeier H, Kulasekararaj A, Mitchell L, Sicre de Fontbrune F, Devos T, Okamoto S, Wells R, Rottinghaus ST, Liu P, Ortiz S, Lee JW, Socie G. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naive to complement inhibitor therapy: open-label extension of a randomized study. Ther Adv Hematol. 2020 Oct 24;11:2040620720966137. doi: 10.1177/2040620720966137. eCollection 2020.
• Wietz IC, Kulagin A, Nakao S, Piatek CI, Szer J, Rottinghaus ST, Volles L, Damokosh AI, Aguzzi R, Larratt L, Risitano AM. A Phase 3 study of ravulizumab (ALXN1210) versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria naive to complement inhibitors: results of a subgroup analysis with patients stratified by baseline hemolysis level, transfusion history, and demographics. Blood. 2018;132 (Supplement 1):627. doi: 10.1182/blood-2018-99-110623

Study record dates

Study Major Dates

• Study Start (Actual): June 5, 2017
• Primary Completion (Actual): March 31, 2022
• Study Completion (Actual): April 8, 2022

Study Registration Dates

• First Submitted: February 14, 2017
• First Submitted That Met QC Criteria: February 14, 2017
• First Posted (Actual): February 16, 2017

Study Record Updates

• Last Update Posted (Actual): March 27, 2023
• Last Update Submitted That Met QC Criteria: February 23, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urologic Diseases; Urological Manifestations; Bone Marrow Diseases; Hematologic Diseases; Urination Disorders; Anemia; Proteinuria; Anemia, Hemolytic; Myelodysplastic Syndromes; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab; Ravulizumab
• Other Study ID Numbers: ALXN1210-PNH-302; 2016-002026-36 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No