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

Paroxysmal Nocturnal Hemoglobinuria (PNH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03056040
• Other study ID #: ALXN1210-PNH-302
• Secondary ID: 2016-002026-36
• Status: Completed
• Phase: Phase 3
• Start date: June 5, 2017
• Est. completion date: April 8, 2022

Study information

• Verified date: February 2023
• Source: Alexion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 195
• Est. completion date: April 8, 2022
• Est. primary completion date: March 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemoglobinuria
• Hemoglobinuria, Paroxysmal
• Paroxysmal Nocturnal Hemoglobinuria (PNH)

Intervention

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.
• Eculizumab
All treatments were given as IV infusions. Participants received 900 mg of eculizumab q2w.

Locations

Country	Name	City	State
Australia	Clinical Trial Site	Canberra	Australian Capital Territory
Australia	Clinical Trial Site	Kogarah	New South Wales
Australia	Clinical Trial Site	Liverpool	New South Wales
Australia	Clinical Trial Site	Parkville	Victoria
Australia	Clinical Trial Site	Woolloongabba	Queensland
Canada	Clinical Trial Site	Montréal	Quebec
Canada	Clinical Trial Site	Toronto	Ontario
Canada	Clinical Trial Site	Toronto	Ontario
France	Clinical Trial Site	Amiens
France	Clinical Trial Site	Marseille
France	Clinical Trial Site	Paris
France	Clinical Trial Site	Pierre-Bénite
France	Clinical Trial Site	Saint-Priest-en-Jarez
France	Clinical Trial Site	Strasbourg
Germany	Clinical Trial Site	Aachen	Nordrhein Westfalen
Germany	Clinical Trial Site	Essen	Nordrhein Westfalen
Germany	Clinical Trial Site	Ulm	Baden Wuerttemberg
Italy	Clinical Trial Site	Firenze
Italy	Clinical Trial Site	Milano
Italy	Clinical Trial Site	Napoli
Italy	Clinical Trial Site	Torino
Italy	Clinical Trial Site	Vicenza
Japan	Clinical Trial Site	Fukushima
Japan	Clinical Trial Site	Kanazawa-shi	Ishikawa
Japan	Clinical Trial Site	Shinagawa-Ku	Tokyo
Japan	Clinical Trial Site	Suita-shi	Osaka
Japan	Clinical Trial Site	Suwa	Nagano
Korea, Republic of	Clinical Trial Site	Daegu
Korea, Republic of	Clinical Trial Site	Daejeon
Korea, Republic of	Clinical Trial Site	Gyeonggi-do
Korea, Republic of	Clinical Trial Site	Gyeonggi-do
Korea, Republic of	Clinical Trial Site	Incheon
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Seoul
Netherlands	Clinical Trial Site	Maastricht
Netherlands	Clinical Trial Site	Nijmegen
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Madrid
Spain	Clinical Trial Site	Majadahonda
United Kingdom	Clinical Trial Site	Airdrie
United Kingdom	Clinical Trial Site	Leeds
United Kingdom	Clinical Trial Site	London
United States	Clinical Trial Site	Baltimore	Maryland
United States	Clinical Trial Site	Bronx	New York
United States	Clinical Trial Site	Detroit	Michigan
United States	Clinical Trial Site	Duarte	California
United States	Clinical Trial Site	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Alexion

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain,  United Kingdom, 

References & Publications (8)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)