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 20, 2016
• Est. completion date: February 28, 2023

Study information

• Verified date: April 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 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. This study is ongoing. The data presented is for the Primary Evaluation Period. The results for the Extension Period will be reported after study completion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 270
• Est. completion date: February 28, 2023
• Est. primary completion date: January 25, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years 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	Clinical Trial Site	Buenos Aires
Argentina	Clinical Trial Site	Buenos Aires
Argentina	Clinical Trial Site	Córdoba
Australia	Clinical Trial Site	Perth
Austria	Clinical Trial Site	Linz
Austria	Clinical Trial Site	Vienna
Belgium	Clinical Trial Site	Hasselt
Belgium	Clinical Trial Site	Leuven
Brazil	Clinical Trial Site	Belém
Brazil	Clinical Trial Site	Rio de Janeiro
Brazil	Clinical Trial Site	Salvador
Brazil	Clinical Trial Site	São Paulo
Brazil	Clinical Trial Site	São Paulo
Canada	Clinical Trial Site	Edmonton
Canada	Clinical Trial Site	Toronto
Czechia	Clinical Trial Site	Plzen
Czechia	Clinical Trial Site	Praha
Estonia	Clinical Trial Site	Tallinn
France	Clinical Trial Site	Limoges
France	Clinical Trial Site	Montpellier
France	Clinical Trial Site	Paris
France	Clinical Trial Site	Pierre-Bénite
France	Clinical Trial Site	Poitiers	Vienne
France	Clinical Trial Site	Rennes
Germany	Clinical Trial Site	Essen
Germany	Clinical Trial Site	Ulm
Italy	Clinical Trial Site	Ascoli Piceno
Italy	Clinical Trial Site	Firenze
Italy	Clinical Trial Site	Milano
Italy	Clinical Trial Site	Napoli
Italy	Clinical Trial Site	Vicenza
Japan	Clinical Trial Site	Bunkyo-Ku
Japan	Clinical Trial Site	Bunkyo-Ku
Japan	Clinical Trial Site	Fukuoka
Japan	Clinical Trial Site	Fukushima
Japan	Clinical Trial Site	Hamamatsu-shi
Japan	Clinical Trial Site	Kanazawa-shi
Japan	Clinical Trial Site	Koshigaya-shi
Japan	Clinical Trial Site	Kumamoto
Japan	Clinical Trial Site	Nishinomiya-shi
Japan	Clinical Trial Site	Ogaki-shi
Japan	Clinical Trial Site	Okayama-city
Japan	Clinical Trial Site	Okayama-shi
Japan	Clinical Trial Site	Osakasayama-shi
Japan	Clinical Trial Site	Sapporo
Japan	Clinical Trial Site	Shimotsuke-shi
Japan	Clinical Trial Site	Shinagawa-Ku
Japan	Clinical Trial Site	Shinjuku-Ku
Japan	Clinical Trial Site	Shinjuku-Ku
Japan	Clinical Trial Site	Suita-shi
Japan	Clinical Trial Site	Tokorozawa-shi
Japan	Clinical Trial Site	Toyoake-shi
Japan	Clinical Trial Site	Tsukuba
Japan	Clinical Trial Site	Wakayama-shi
Japan	Clinical Trial Site	Yokohama-City
Japan	Clinical Trial Site	Yokohama-City
Korea, Republic of	Clinical Trial Site	Anyang-si
Korea, Republic of	Clinical Trial Site	Busan
Korea, Republic of	Clinical Trial Site	Daegu
Korea, Republic of	Clinical Trial Site	Incheon
Korea, Republic of	Clinical Trial Site	Jeonju
Korea, Republic of	Clinical Trial Site	Jinju-si
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
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
Korea, Republic of	Clinical Trial Site	Seoul
Korea, Republic of	Clinical Trial Site	Suwon-si
Korea, Republic of	Clinical Trial Site	Suwon-si
Korea, Republic of	Clinical Trial Site	Ulsan
Malaysia	Clinical Trial Site	Ampang
Malaysia	Clinical Trial Site	Johor Bahru
Malaysia	Clinical Trial Site	Kota Bahru
Malaysia	Clinical Trial Site	Kota Bharu
Malaysia	Clinical Trial Site	Kota Bharu	Kelantan
Malaysia	Clinical Trial Site	Kota Kinabalu
Malaysia	Clinical Trial Site	Kubang Kerian
Malaysia	Clinical Trial Site	Kuching
Malaysia	Clinical Trial Site	Miri	Sarawak
Malaysia	Clinical Trial Site	Pulau Pinang
Malaysia	Clinical Trial Site	Sibu	Sarawak
Mexico	Clinical Trial Site	Monterrey
Poland	Clinical Trial Site	Gdansk
Poland	Clinical Trial Site	Warsaw
Russian Federation	Clinical Trial Site	Arkhangel'sk
Russian Federation	Clinical Trial Site	Barnaul
Russian Federation	Clinical Trial Site	Bryansk
Russian Federation	Clinical Trial Site	Irkutsk
Russian Federation	Clinical Trial Site	Kaluga
Russian Federation	Clinical Trial Site	Kirov
Russian Federation	Clinical Trial Site	Krasnodar
Russian Federation	Clinical Trial Site	Krasnoyarsk
Russian Federation	Clinical Trial Site	Krasnoyarsk
Russian Federation	Clinical Trial Site	Moscow
Russian Federation	Clinical Trial Site	Moscow
Russian Federation	Clinical Trial Site	Murmansk
Russian Federation	Clinical Trial Site	Nizhny Novgorod
Russian Federation	Clinical Trial Site	Novosibirsk
Russian Federation	Clinical Trial Site	Petrozavodsk
Russian Federation	Clinical Trial Site	Rostov-na-Donu
Russian Federation	Clinical Trial Site	Saint Petersburg
Russian Federation	Clinical Trial Site	Saratov
Russian Federation	Clinical Trial Site	Ufa
Singapore	Clinical Trial Site	Singapore
Spain	Clinical Trial Site	Barcelona
Spain	Clinical Trial Site	Madrid
Spain	Clinical Trial Site	Majadahonda
Sweden	Clinical Trial Site	Uppsala
Taiwan	Clinical Trial Site	Chang-hua
Taiwan	Clinical Trial Site	Hualien City
Taiwan	Clinical Trial Site	Kaohsiung
Taiwan	Clinical Trial Site	Taichung
Taiwan	Clinical Trial Site	Tainan
Taiwan	Clinical Trial Site	Taipei
Thailand	Clinical Trial Site	Bangkok
Thailand	Clinical Trial Site	Hat Yai
Thailand	Clinical Trial Site	Pathum Wan
Turkey	Clinical Trial Site	Eskisehir
United Kingdom	Clinical Trial Site	Leeds
United Kingdom	Clinical Trial Site	London
United States	Clinical Trial Site	Fort Worth	Texas
United States	Clinical Trial Site	Los Angeles	California
United States	Clinical Trial Site	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Alexion

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,  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 patients 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 Lactate Dehydrogenase (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