A Phase 1, Prospective, Open Label, Two Period, Fixed Sequence, Dose-Escalation Study of the PK and Safety of BAX 826 (PSA-rFVIII) in Previously Treated Patients With Severe (FVIII <1%) Hemophilia A
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 40
- 试验地点
- 56
- 主要终点
- Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826
研究概览
简要总结
- To assess tolerability and safety of BAX 826 after a single infusion in previously treated patients (PTPs) with severe hemophilia A
- To determine the pharmacokinetic (PK) parameters of BAX 826 compared to ADVATE
- To evaluate immunogenicity of polysialic acid linked to Factor VIII (FVIII)
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Previously treated male participants aged 18 to 65 years (inclusive) at the time of screening
- •Diagnosis of severe hemophilia A (Factor VIII level <1%)
- •Previously treated with FVIII concentrates for ≥150 documented Exposure Days (EDs)
- •Karnofsky performance score of ≥60
- •Human immunodeficiency virus negative (HIV-); or HIV+ with stable disease
- •Hepatitis C virus negative (HCV-); or HCV+ with chronic stable hepatitis as assessed by the investigator
- •Able to understand and have provided written informed consent including signature on an informed consent form (ICF) approved by an ethics committee (EC)
- •Have provided written authorization for use and disclosure of protected health information
- •Agree to abide by the study schedule and to return for the required assessments
- •Willing and able to comply with the requirements of the protocol
排除标准
- •Detectable FVIII inhibitor at screening, with a titer ≥0.6 Bethesda Unit (BU)
- •Documented history of FVIII inhibitors with a titer ≥0.4 BU at any time prior to screening
- •Known clinical hypersensitivity towards mouse or hamster proteins or to polysialic acid (PSA)
- •Scheduled elective surgery during study participation
- •Severe chronic hepatic dysfunction
- •Severe renal impairment
- •Currently receiving, or has recently received (less than 3 months prior to study participation), or is scheduled to receive during the course of the study, other PSA-ylated drugs
- •Have received another investigational drug within 30 days prior to study entry and/or is scheduled to receive additional investigational drug during the course of the study in the context of another investigational drug study
- •Diagnosis of an inherited or acquired hemostatic defect other than hemophilia A
- •Currently receiving, or scheduled to receive during the course of the study, an immune-modulating drug other than antiretroviral chemotherapy
- •Has a clinically significant medical, psychiatric or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect the safety or compliance of the participant during the study
- •Is a family member or employee of the investigator
结局指标
主要结局
Serious AEs (SAEs) and Non-serious AEs Occurring After Infusion With BAX 826
时间窗: Up to 6 weeks ± 4 days post infusion with BAX826.
Serious Adverse Events and non-serious Adverse Events the occurred after infusion with BAX 826.
Immediate Tolerability (Vital Signs and Clinical Laboratory Assessments)
时间窗: Screening (Day -30 to -2); Advate Administration (Study Day 1) pre & postdose, and Day 4; Advate washout 96 hours to 4 weeks; BAX826 Administration Day 1 pre & postdose, Post BAX826 Day 4, 8, 14, and 23; and study termination visit, week 6 ± 4 days
Clinically significant results after treatment with investigational product that constitute an AE are counted. Vital signs include body temperature, respiratory rate, pulse rate, and blood pressure. Clinical laboratory results include: Hematology (hemoglobin, hematocrit, red blood cell count, white blood cell count with differential (i.e. basophils, eosinophils, lymphocytes, monocytes and neutrophils), international normalized ratio (INR), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), platelet count. Clinical Chemistry: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, gamma-glutamyltransferase (GGT), blood urea nitrogen (BUN), creatinine, glucose. Lipid panel: cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides
Immunogenicity: Inhibitory Antibodies to Factor VIII (FVIII)
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Inhibition of FVIII activity by antibodies binding to FVIII were measured using the Nijmegen modification of the Bethesda inhibitor assay.
Immunogenicity: Binding Antibodies to PSA-FVIII (ie BAX 826)
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Binding antibodies to PSA FVIII (ie BAX 826) IgG and IgM
Immunogenicity: Binding Antibodies to Factor VIII (FVIII)
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Binding antibodies to FVIII IgG and IgM
Immunogenicity: Anti-polysialic Acid (Anti-PSA) Antibodies
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Binding antibodies to PSA (IgG and IgM)
Immunogenicity: Anti-Chinese Hamster Ovary (Anti-CHO) Antibodies
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Binding antibodies to CHO
Immunogenicity: Human Anti-murine Antibodies (HAMA)
时间窗: Screening visit (Day -30 to -2); Advate Administration (Study Day 1) predose; ADVATE wash out period 96 hours to 4 weeks; BAX826 Administration Day 1 predose, and Post BAX826 Day 8; and study termination visit, week 6 ± 4 days
Binding antibodies HAMA (IgG)
次要结局
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to Infinity (AUC0-∞)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Terminal Half-life (t1/2)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Mean Residence Time (MRT)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Total Body Clearance (CL)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Incremental Recovery (IR)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Volume of Distribution at Steady State (Vss)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Maximum Plasma Concentration (Cmax)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Time to Maximum Concentration in Plasma (Tmax)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Area Under the Concentration-time Curve From Time 0 to the Last Quantifiable Time Point (AUC0-last)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 72 Hours (AUC0-72h)(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Pharmacokinetics: Area Under the Concentration-time Curve From 0 to 168 Hours (AUC0-168h) for BAX 826(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.)
- Comparison of Key Pharmacokinetic Parameters by Cohort(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, and 72 hours for both BAX 826 and ADVATE. BAX 826 will also include post-infusion at 96, 120, 144, and 168 hours.)
- Summary of Assessment of Dose Proportionality for BAX 826(Pre-infusion within 30 minutes; and post-infusion at 15 and 30 minutes, and 1, 3, 6, 9, 12, 24, 32, 48, 56, 72, 96, 120, 144, and 168 hours.)