A Phase III, Randomized, Open-label, Active-controlled, Multicenter Study Evaluating the Efficacy and Safety of Crovalimab Versus Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Not Previously Treated With Complement Inhibitors
试验速览
- 阶段
- 3 期
- 状态
- 进行中（未招募）
- 入组人数
- 210
- 试验地点
- 94
- 主要终点
- Percentage of Participants With Transfusion Avoidance (TA)
研究概览
简要总结
A study designed to evaluate the non-inferiority of crovalimab compared with eculizumab in participants with PNH who have not been previously treated with complement inhibitor therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Body weight ≥ 40 kg at screening (pediatric participants with body weight < 40 kg)
- •Willingness and ability to comply with all study visits and procedures
- •Documented diagnosis of PNH, confirmed by high sensitivity flow cytometry
- •LDH level ≥ 2x ULN at screening (as per local assessment)
- •Vaccination against Neisseria meningitidis serotypes A, C, W, and Y< 3 years prior to initiation of study treatment; or, if not previously done, vaccination administered no later than one week after the first drug administration
- •Women of childbearing potential: agreement to remain abstinent or use contraception during the treatment period and for 10.5 months after the final dose of crovalimab or for 3 months after the final dose of eculizumab (or longer if required by the local product label)
排除标准
- •Current or previous treatment with a complement inhibitor
- •History of allogeneic bone marrow transplantation
- •History of Neisseria meningitidis infection within 6 months prior to screening and up to first study drug administration
- •History of myelodysplastic syndrome with Revised International Prognostic Scoring System (IPSS-R) prognostic risk categories of intermediate, high and very high
- •Pregnant or breastfeeding, or intending to become pregnant during the study, within 10.5 months after the final dose of crovalimab, or 3 months after the final dose of eculizumab (or longer if required by the local product label)
- •Participation in another interventional treatment study with an investigational agent or use of any experimental therapy within 28 days of screening or within 5 half-lives of that investigational product, whichever is greater
- •Concurrent disease, treatment, procedure or surgery, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose any additional risk for the participant, or would, in the opinion of the Investigator, preclude the participant's safe participation in and completion of the study
- •Splenectomy < 6 months before screening
- •Positive for Active Hepatitis B and C infection (HBV/HCV)
- •History of or ongoing cryoglobulinemia at screening
研究组 & 干预措施
Arm A (Crovalimab)
Crovalimab will be administered at an initial loading dose of 1000 milligrams (mg) (for participants with body weight between 40 and 100 kilograms [kg]) or 1500 mg (for participants with body weight ≥ 100 kg), as intravenous (IV) injection on Day 1 of Week 1 followed by four weekly subcutaneous (SC) injections of 340 mg starting on Day 2 of Week 1 and then once weekly (QW) at Weeks 2,3 and 4. Thereafter crovalimab will be administered, as SC injection, at a maintenance dose of 680 mg (for participants with body weight between 40 and 100 kg) or 1020 mg (for participants with body weight ≥ 100 kg) once every 4 weeks (Q4W) from Week 5 for a total of 24 weeks of study treatment. Participants may continue to receive crovalimab after 24 weeks of treatment up to maximum of 5 years.
干预措施: Crovalimab (Drug)
Arm B (Eculizumab)
Participants will receive loading dose of eculizumab 600 mg on Days 1, 8, 15, and 22, followed by maintenance dose of 900 mg on Day 29 and every 2 weeks (Q2W) thereafter until 24 weeks. Participants may switch to receive crovalimab after 24 weeks of eculizumab treatment.
干预措施: Crovalimab (Drug)
Arm B (Eculizumab)
Participants will receive loading dose of eculizumab 600 mg on Days 1, 8, 15, and 22, followed by maintenance dose of 900 mg on Day 29 and every 2 weeks (Q2W) thereafter until 24 weeks. Participants may switch to receive crovalimab after 24 weeks of eculizumab treatment.
干预措施: Eculizumab (Drug)
Arm C (Crovalimab) (Exploratory)
Participants with a body weight ≥ 5 to <12 kg will receive a loading series of crovalimab doses comprised of an IV dose on Day 1 of Week 1, followed by crovalimab SC dose on Day 2 Week 1. Maintenance doses will begin at Week 3 and will be administered Q2W, thereafter. Participants with a body weight ≥ 12 to < 20 kg and ≥ 20 kg will receive a loading series of crovalimab doses comprised of an IV dose on Day 1 of Week 1, followed by weekly crovalimab SC doses for 4 weeks at Week 1 (Day 2) and then at Weeks 2, 3, and 4. Maintenance doses will begin at Week 5 and will be administered Q2W thereafter, for participants with a body weight ≥ 12 to < 20 kg and Q4W thereafter, for participants with a body weight > 20 kg. After 24 weeks of crovalimab treatment, participants who derive benefit from the drug may continue to receive crovalimab.
干预措施: Crovalimab (Drug)
结局指标
主要结局
Percentage of Participants With Transfusion Avoidance (TA)
时间窗: Baseline to Week 25
TA is defined as participants who are packed red blood cell (pRBC) transfusion-free and do not require transfusion per protocol-specified guidelines. 95% Confidence Interval (CI) for percentage of participants with TA was calculated using the Wilson's method with continuity correction. Participants who withdrew before Week 25 were deemed to have had a transfusion. Percentages are rounded off to the nearest single decimal.
Percentage of Participants With Hemolysis Control Measured by LDH
时间窗: Week 5 to Week 25
A Generalized Estimating Equation (GEE) was used to estimate the population-average percentage of the participants with hemolysis control (measured by LDH ≤1.5 x upper limit of normal (ULN)) from Week 5 to Week 25 taking account of the intra-patient and inter-patient correlation between LDH control statuses across visits. Percentages are rounded off to the nearest single decimal.
次要结局
- Percentage of Participants With Adverse Events (AEs)(Up to 6 years)
- Percentage of Participants With AEs Leading to Study Drug Discontinuation(Up to 6 years)
- Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time(Up to 6 years)
- Percentage of Participants With Breakthrough Hemolysis (BTH)(Baseline to Week 25)
- Percentage of Participants With Stabilization of Hemoglobin(Baseline to Week 25)
- Change From Baseline in Fatigue Assessed by Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale(Baseline to Week 25)
- Percentage of Participants With Adverse Events (AEs)(Up to 6 years)
- Percentage of Participants With Injection-Site Reactions, Infusion-Related Reactions, Hypersensitivity and Infections (Including Meningococcal Meningitis)(Up to 6 years)
- Percentage of Participants With AEs Leading to Study Drug Discontinuation(Up to 6 years)
- Percentage of Participants With Clinical Manifestations of Drug-Target-Drug Complex (DTDC) Formation Amongst Participants Who Switched to Crovalimab Treatment From Eculizumab Treatment(Up to 6 years)
- Serum Concentrations of Crovalimab And Eculizumab Over Time(Up to 6 years)
- Percentage of Participants With Anti-Crovalimab Antibodies(Up to 6 years)
- Change in Pharmacodynamic (PD) Biomarkers Including Complement Activity (CH50) Over Time(Up to 6 years)
- Change Over Time in Free C5 Concentration in Crovalimab-Treated Participants(Up to 6 years)
- Observed Value in Reticulocyte Count (Count/Milliliters [mL])(Up to 6 years)
- Observed Value in Haptoglobin (Milligrams Per Deciliter [mg/dL])(Up to 6 years)
- Change From Baseline in Absolute Reticulocyte Count(Baseline, Day 1 Week 1, Week 2, 3, 4, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 and 25)
- Change From Baseline in Free Hemoglobin(Baseline, Week 2, 3, 4, 5, 9, 13, 17, 21, and 25)
- Change From Baseline in Haptoglobin(Baseline, Week 2, 3, 4, 5, 9, 13, 15, 17, 21, and 25)