A Randomized, Multicenter, Double-blind Clinical Trial Comparing Pharmacodynamic, Pharmacokinetic and Safety of a Biosimilar Eptacog Alfa (AryoSeven) and Novoseven®, in Patients With Hemophilia A or B With Inhibitors.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 48
- 试验地点
- 8
- 主要终点
- Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
研究概览
简要总结
The purpose of this multicentre, randomized, double-blinded, single dose, two-way cross-over study, is to compare the pharmacokinetics (PK) and pharmacodynamic (PD) of two different doses of the biosimilar eptacog alfa (activated) with Novoseven in 48 patients, adult and children (>12 years), not bleeding, with hemophilia A or B with inhibitors. Patients will be randomized to receive either a single dose of eptacog alfa biosimilar 90 μg/kg or 270 μg/kg and one single dose of NovoSeven 90 μg/kg or 270 μg/kg, or vice versa, with doses separated by a washout period. All patients will be followed 12 months and will receive biosimilar eptacog alfa, on demand, for every bleeding episode that should occur - or - for prophylaxis, with the aim of monitoring of inhibiting antibody formation, lack of efficacy and collection of safety data.
详细描述
Forty-eight patients enrolled, not bleeding, will be randomized to receive two injections separated by a washout period of 3 days (t1/2 = 2.3h). Patients are centrally registered and randomized to receive in a 2x2 cross-over setting either a single dose of two for the following products: A: AryoSeven 90 µg/kg and B: NovoSeven 90 µg/kg - or - C: AryoSeven 270 µg/kg and D: NovoSeven 270 µg/kg.
Patients will be hospitalized at the time of study medication administration and plasma sampling. Before any treatment, a blood sample will be obtained in all patients for testing for immunogenicity.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Blinding will be performed by an independent third party operator (nurse/pharmacist, unblinded), who will prepare undistinguishable syringes with patient's dosing and labelling.
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of congenital hemophilia A or B with inhibitors to FVIII or FIX titer >5 Bethesda Units (BU)
- •with > 2 episodes of bleeding/year requiring treatment with FVII infusions, non in bleeding status
- •male subjects
- •adult and children (>12 years)
- •written informed consent to the protocol to be eligible for the study. For minor patients, parent/legal guardian will provide consent and, when possible, patient assent will also be obtained. For compromised patients, their designated proxy must provide informed consent.
- •For the PK/PD phase, patients will be hospitalized at the time of study medication administration for plasma sampling (2 times during the study).
排除标准
- •Any other type of congenital or acquired coagulopathy, such as liver disease (hepatitis), vitamin k deficiency, uremia, malignancy.
- •Antibodies against Factor VII
- •Ongoing bleeding prophylaxis regimens with Novoseven or planned to occur during the trial
- •Patients who have received routine (prophylactic) treatment with rFVIIa in the period between screening visit (visit 1) and visit 2 of this study (first dose administration)
- •Platelet count less than 100.000 platelets/microliter (at screening visit)
- •Any clinical sign or known history of an arterial thrombotic event or deep venous- thrombosis or pulmonary embolism
- •HIV positive with current CD4+ count of less than 200/µL
- •Liver cirrhosis
- •Factor VIII/IX immune tolerance induction regimen planned to occur during the trial
- •Known hypersensitivity to the study medication
- •Parallel participation in another experimental drug trial.
- •Parallel participation in another marketed drug trial that may affect the primary endpoint of the study
结局指标
主要结局
Area under the plasma concentration time curve from time 0 to infinity, based on the last observed concentration (AUCinf)
时间窗: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection
Measurement of plasma level of factor VII clotting activity (FVII:C) determined by commercial Staclot® VIIa-recombinant tissue factor assay (Diagnostics Stago, France).
Treatment response to Thrombin Generation Assay (TGA), D-Dimer, F1.2 prothrombin fragments.
时间窗: Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection
Measurement of plasma levels based on standard methods recommended by the Subcommittee on the control of anticoagulation of the ISTH
次要结局
- Area under the plasma concentration-time curve from 0 to the last measurable time point (AUClast).(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- First order rate constant associated with the terminal (log-linear) portion of the curve (λz)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Volume of distribution (Vss)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Time of Cmax (tmax);(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Mean residence time (MRT)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Fraction of the total AUCinf that was derived by extrapolation beyond tlast (AUCextra)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Elimination half-life(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Maximum plasma concentration (Cmax)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Clearance and CL/Dose (CL)(Ten minutes prior to dose administration and at 10 minutes, 20 minutes, 1 hour, 3 hours, 5 hours, 8 hours, 12 hours, 24 hours and 30 hours after AryoSeven and NovoSeven injection)
- Immunogenicity(On plasma samples obtained at screening visit, before the second dose/second drug administration, and then every 3 months for a year)
- Adverse Events(Adverse events (AEs) will be monitored throughout the trial, from the first dose administered up to 12 months follow-up.)