Advate Antihemophilic Factor (Recombinant), Plasma/Albumin Free Method (ADVATE rAHF-PFM): A Phase 4 Study Comparing Two Prophylactic Regimens in Subjects With Severe or Moderately Severe Hemophilia A
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 82
- 主要终点
- Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens
研究概览
简要总结
The primary purpose of this randomized, two-arm parallel clinical study in 66 previously treated patients with severe or moderately severe hemophilia A is to compare the rate of bleeding episodes for standard prophylaxis (20-40 IU/kg every 48 ± 6 hours; actual dose determined by the investigator) with that of alternate prophylaxis (20-80 IU/kg every 72 + 6 hours; actual dose determined by Baxter utilizing an algorithm and the patient's pharmacokinetic data). The rates of bleeding episodes for the on-demand regimen and the prophylaxis regimens will also be compared for the cross-over portion of the study. Enrolled patients will be treated originally on demand for a period of 6 months and then they will be randomized into one of the prophylaxis arms. Prophylactic treatment will last for a period of 12 months +/- 2 weeks.
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
- 7 Years 至 65 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level <= 2% of normal, as tested at screening
- •The subject has a documented history of at least 150 exposure days to factor VIII concentrates (either plasma-derived or recombinant)
- •The subject is within 7 to 65 years of age
- •The subject has a Karnofsky performance score > (greater than) 60
- •The subject is human immunodeficiency virus negative (HIV-) or is HIV+ with a CD4 count >= 400 cells/mm³ (CD4 count determined at screening, if necessary)
- •The subject has been on a documented on-demand treatment regimen for at least 12 months immediately prior to enrollment
- •The subject has a documented history (e.g. in medical charts or dispensing information, or signed investigator statement) of at least 8 joint hemorrhages in the 12 months immediately prior to enrollment
- •The subject resides within the coverage area of the mobile compliance device; coverage area will be determined at screening
- •The subject or the subject's legally authorized representative has provided written informed consent
排除标准
- •The subject has a known hypersensitivity to factor VIII concentrates or mouse or hamster proteins
- •The subject has a history of factor VIII inhibitors with a titer >= 0.6 BU (by Bethesda or Nijmegen assay) at any time prior to screening
- •The subject has a detectable factor VIII inhibitor at screening, with a titer >= 0.4 BU (by Nijmegen Assay) in the central laboratory
- •The subject has severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) > 1.4, hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices.
- •The subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (e.g., qualitative platelet defect or von Willebrand's Disease)
- •The subject has been treated during the last sixty (60) days prior to or is being treated at screening/enrollment with an immunomodulating drug.
- •The subject has participated in another investigational study within thirty (30) days of enrollment
- •The subject has previously participated in a clinical study with rAHF-PFM
- •The subject's clinical condition may require a major surgery (defined as moderate to critical risk and perioperative blood loss ≥ 500 mL) during the period of the subject's participation in the study
- •The subject is female of childbearing potential with a positive pregnancy test
研究组 & 干预措施
1
Standard prophylaxis
干预措施: Antihemophilic factor, recombinant, manufactured protein-free (Drug)
2
PK-driven prophylaxis
干预措施: Antihemophilic factor, recombinant, manufactured protein-free (Drug)
结局指标
主要结局
Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens
时间窗: 12 months ±2 weeks
Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg.
Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens
时间窗: 12 months ±2 weeks
Participants were Randomized to Receive 1 of the 2 Following Prophylaxis Regimens (Study Part 2): 1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hour), exact regimen determined by investigator) 2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hour), exact regimen determined by sponsor) Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X' = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test.
次要结局
- Number of Participants With SAEs by Preferred MedDRA Term and Treatment Regimen(Throughout the study period (4 years and 5 months))
- Maximum Plasma Concentration (C-max)(Within 1 hour post-infusion)
- Volume of Distribution at Steady State(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Number of Participants Who Reported ≥1 AE Regardless of Relatedness to Investigational Product (IP)(Throughout study period (4 years and 5 months))
- Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens(On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks))
- Bleeding Episodes Treated With 1 to ≥4 Infusions(Throughout the study period (4 years and 5 months))
- Assessment of Hemostasis for Treatment of Bleeding Episodes(On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks))
- Total Area Under the Curve (AUC)(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Number of Participants Who Reported ≥1 AE Regardless of Relatedness to IP by Treatment Regimen(Throughout the study period (4 years and 5 months))
- AEs With Onset ≤1 Hour Following the End of an Infusion, Regardless of Relatedness(Throughout study period (4 years and 5 months))
- Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens(On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks))
- Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm(12 months ±2 weeks)
- Area Under the Curve(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Adjusted Incremental Recovery (IR)(30 minutes pre-infusion to 48 hours post-infusion)
- Terminal Half-life(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Weight-Adjusted Clearance(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens(On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks))
- Mean Residence Time(Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion)
- Factor VIII Inhibitor Development(Throughout study period (4 years and 5 months))
- Number of Participants With AEs Related to Investigational Product (IP)(Throughout study period (4 years and 5 months))
- Number of Participants With Severe SAEs and Severe Non-SAEs by Preferred MedDRA Term and Treatment Regimen(Throughout the study period (4 years and 5 months))
- Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS(Baseline)
- Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens(End of on-demand treatment period (6 months) and at study termination (approximately 18 months))
- HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period(End of on-demand treatment period (6 months) and at study termination (approximately 18 months))
- Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period(End of on-demand treatment period (6 months) and at study termination (approximately 18 months))
- Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period(End of on-demand treatment period (6 months) and at study termination (approximately 18 months))