ALXN1210 (Ravulizumab) Versus Eculizumab in Complement Inhibitor Treatment-Naïve Adult Participants With Paroxysmal Nocturnal Hemoglobinuria (PNH)

Paroxysmal Nocturnal Hemoglobinuria (PNH) Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02946463
• Other study ID #: ALXN1210-PNH-301
• Secondary ID: 2016-002025-11
• Status: Completed
• Phase: Phase 3
• Start date: December 12, 2016
• Est. completion date: February 28, 2023

Study information

• Verified date: April 2024
• Source: Alexion Pharmaceuticals, Inc.
• 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 had never been treated with a complement inhibitor (treatment-naïve).

Description:

The study consisted of a 4-week screening period and a 26-week randomized treatment period (Primary Evaluation Period). After completion of the 26-week Primary Evaluation Period, all participants had the opportunity to enter the Extension Period, wherein participants will receive ravulizumab for up to 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 272
• Est. completion date: February 28, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

Criteria For Patient Cohort Originally Enrolled in ALXN1210-PNH-301 Study: Inclusion Criteria: 1. Male or female =18 years of age. 2. PNH diagnosis confirmed by documented by high-sensitivity flow cytometry. 3. Presence of 1 or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 gram/deciliter), history of a major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cells (pRBC) transfusion due to PNH. 4. Lactate dehydrogenase (LDH) level =1.5 times the upper limit of normal at screening. 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. Treatment with a complement inhibitor at any time.

2. History of bone marrow transplantation. 3. Body weight <40 kg. 4. Females who are pregnant, breastfeeding, or who have a positive pregnancy test at screening or Day 1. 5. 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. 6. History of or ongoing major cardiac, pulmonary, renal, endocrine, or hepatic disease that, in the opinion of the investigator or sponsor, would preclude participation. 7. 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). Eligibility Criteria For Roll-over Cohort: 1. All participants regardless of age, who are currently receiving ALXN1210 IV in an ongoing ALXN1210 study in patients with PNH 2. Participants must be willing and able to give written informed consent and to comply with all Extension study visits and procedures, including the use of any data collection device(s) to directly record patient data 3. Females of childbearing potential and male patients with female partners of childbearing potential must use highly effective contraception continuing until at least 8 months after the last dose of ravulizumab.

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 kilogram (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 were administered induction doses of 600 mg followed by maintenance doses of 900 mg.

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Córdoba
Australia	Research Site	Perth
Austria	Research Site	Linz
Austria	Research Site	Vienna
Belgium	Research Site	Bruxelles
Belgium	Research Site	Hasselt
Belgium	Research Site	Leuven
Brazil	Research Site	Rio De Janeiro
Brazil	Research Site	Salvador
Brazil	Research Site	Sao Paulo
Brazil	Research Site	Sao Paulo
Canada	Research Site	Edmonton	Alberta
Canada	Research Site	Toronto	Ontario
Czechia	Research Site	Plzen
Czechia	Research Site	Prague
Estonia	Research Site	Tallinn
France	Research Site	Limoges
France	Research Site	MONTPELLIER Cedex 5
France	Research Site	Paris Cedex 10
France	Research Site	Pierre Benite
France	Research Site	Poitiers
France	Research Site	Rennes Cedex 9
Germany	Research Site	Aachen
Germany	Research Site	Essen
Germany	Research Site	Ulm
Italy	Research Site	Ascoli Piceno
Italy	Research Site	Firenze
Italy	Research Site	Milano
Italy	Research Site	Napoli
Italy	Research Site	Vicenza
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Bunkyo-ku
Japan	Research Site	Fukuoka-Shi
Japan	Research Site	Fukushima-shi
Japan	Research Site	Hamamatsu-shi
Japan	Research Site	Kanazawa-shi
Japan	Research Site	Kitakyusyu-shi
Japan	Research Site	Koshigaya-shi
Japan	Research Site	Kumamoto-shi
Japan	Research Site	Nagoya-shi
Japan	Research Site	Nishinomiya-shi
Japan	Research Site	Ogaki-shi
Japan	Research Site	Okayama-shi
Japan	Research Site	Okayama-shi
Japan	Research Site	Osakasayama-shi
Japan	Research Site	Sapporo-shi
Japan	Research Site	Shimotsuke-shi
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Shinjuku-ku
Japan	Research Site	Suita
Japan	Research Site	Tokorozawa-shi
Japan	Research Site	Tokyo
Japan	Research Site	Toyoake-shi
Japan	Research Site	Tsukuba-shi
Japan	Research Site	Wakayama-shi
Korea, Republic of	Research Site	Daejeon
Korea, Republic of	Research Site	Goyang-si
Korea, Republic of	Research Site	Incheon
Korea, Republic of	Research Site	Jeonju-si
Korea, Republic of	Research Site	JinJoo
Korea, Republic of	Research Site	Jung-gu
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Seoul
Korea, Republic of	Research Site	Songpa-gu
Korea, Republic of	Research Site	Suwon-si
Korea, Republic of	Research Site	Ulsan
Malaysia	Research Site	George
Malaysia	Research Site	Johor Bahru
Malaysia	Research Site	Kota Bharu
Malaysia	Research Site	Kota Bharu
Malaysia	Research Site	Kota Kinabalu
Malaysia	Research Site	Kuching
Malaysia	Research Site	Miri
Malaysia	Research Site	Sibu
Mexico	Research Site	Monterrey
Poland	Research Site	Gdansk
Poland	Research Site	Warszawa
Russian Federation	Research Site	Arkhangelsk
Russian Federation	Research Site	Barnaul
Russian Federation	Research Site	Irkutsk
Russian Federation	Research Site	Kirov
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Moscow
Russian Federation	Research Site	Murmansk
Russian Federation	Research Site	Novosibirsk
Russian Federation	Research Site	Omsk
Russian Federation	Research Site	Petrozavodsk
Russian Federation	Research Site	Rostov-on-Don
Russian Federation	Research Site	Saint-Petersburg
Russian Federation	Research Site	Saratov
Russian Federation	Research Site	St. Petersburg
Russian Federation	Research Site	Ufa
Serbia	Research Site	Belgrade
Singapore	Research Site	Singapore
Spain	Research Site	Madrid
Spain	Research Site	Majadahonda
Sweden	Research Site	Uppsala
Taiwan	Research Site	Changhua
Taiwan	Research Site	Hualien City
Taiwan	Research Site	Taichung
Taiwan	Research Site	Tainan
Taiwan	Research Site	Taipei
Thailand	Research Site	Bangkok
Thailand	Research Site	Bangkok
Thailand	Research Site	Songkhla
Turkey	Research Site	Eskisehir
United Kingdom	Research Site	Airdrie
United Kingdom	Research Site	Leeds
United Kingdom	Research Site	London
United States	Research Site	Fort Worth	Texas
United States	Research Site	Los Angeles	California
United States	Research Site	Whittier	California

Sponsors (1)

Lead Sponsor	Collaborator
Alexion Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  Czechia,  Estonia,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Mexico,  Poland,  Russian Federation,  Serbia,  Singapore,  Spain,  Sweden,  Taiwan,  Thailand,  Turkey,  United Kingdom, 

References & Publications (1)

Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Fureder W, Ptushkin V, Rottinghaus ST, Volles L, Shafner L, Aguzzi R, Pradhan R, Schrezenmeier H, Hill A. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539. doi: 10.1182/blood-2018-09-876136. Epub 2018 Dec 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion Of Participants With Normalization Of Lactate Dehydrogenase (LDH) Levels	LDH is an indicator of intravascular hemolysis that occurs in participants with paroxysmal nocturnal hemoglobinuria (PNH). A decrease in LDH from above the upper limit of normal (ULN) to below the ULN indicates reduction (improvement) in hemolysis. Normalization of LDH levels (LDH-N) was LDH levels less than or equal to 1 x ULN, from Day 29 through Day 183. The ULN for LDH is 246 U/L.	Day 29 through Day 183
Primary	Percentage Of Participants Who Achieved Transfusion Avoidance (TA)	Transfusion avoidance was defined as the percentage of participants who remained transfusion free and did not require a transfusion per protocol-specified guidelines through Day 183.	Baseline through Day 183
Secondary	Percentage Of Participants With Breakthrough Hemolysis (BTH)	Breakthrough hemolysis was defined as at least 1 new or worsening symptom or sign of intravascular hemolysis (fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin <10 gram/deciliter (g/dL)], major adverse vascular event [MAVE, including thrombosis], dysphagia, or erectile dysfunction) in the presence of elevated LDH =2 × ULN, after prior LDH reduction to <1.5 × ULN on therapy.	Baseline through Day 183
Secondary	Percent Change From Baseline In LDH Levels	Baseline is defined as the average of all available assessments of LDH levels prior to first study drug dose. Estimates are based on Mixed Model for Repeated Measures (MMRM) that includes treatment group, history of transfusion (as a categorical variable based on the stratification factor levels) and baseline LDH level (as a continuous variable), study visit and study visit by treatment group interaction. An unstructured covariance structure was used.	Baseline, Day 183
Secondary	Change From Baseline In Quality Of Life As Assessed By The Functional Assessment Of Chronic Illness Therapy (FACIT)-Fatigue	FACIT-Fatigue score ranges from 0 to 52, with a higher score indicating less fatigue. Baseline is defined as the last non-missing value prior to first dose of study drug. Estimates are based on MMRM that includes treatment group, the observed stratification randomization indicators (history of transfusion and LDH) and baseline FACIT-Fatigue level, study visit, and study visit by treatment group interaction. An unstructured covariance structure was used.	Baseline, Day 183
Secondary	Percentage Of Participants With Stabilized Hemoglobin Levels	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

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