Determination of Safety, Efficacy and Pharmacokinetics of GreenGene™ F in Previously Treated Patients 12 Years of Age or Older Diagnosed With Severe Hemophilia A
试验速览
- 阶段
- 3 期
- 入组人数
- 124
- 试验地点
- 61
- 主要终点
- Number of subject with development of inhibitors
研究概览
简要总结
The purpose of this study is to assess the safety, efficacy and pharmacokinetics of GreenGene™ F in subjects with severe hemophilia A previously treated (> 150 exposure days) with a Factor VIII concentrate and without presence or history of inhibitors to FVIII (Factor VIII).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female subjects age ≥ 12 years at the time of informed consent
- •Body weight ≥ 35 kg
- •Diagnosed with severe hemophilia A. All subjects must have severe hemophilia A with baseline FVIII <1% activity; <0.01 IU/mL
- •Have ≥ 150 previous exposure days to FVIII concentrates, as documented in the subject's medical records
- •Subjects included in the on-demand treatment cohort must have a verifiable record of at least three bleeding episodes per month on average in the last 6 months prior to enrollment
- •Negative assays for FVIII inhibitor at inclusion (<0.6BU Nijmegen assay)
- •Negative assays for FVIII inhibitor in subject files (<0.6BU Nijmegen assay) No history of positive inhibitor is allowed
- •Normal liver and kidney function.
- •Platelet count ≥ 100,000 μL
- •Normal prothrombin time or International Normalized Ratio (INR) < 1.5
- •Subjects receiving therapy for human immunodeficiency virus (HIV) or hepatitis must be on a stable treatment regimen
- •Subjects must be able to withhold FVIII infusions for approximately 72 h prior to each FVIII activity and inhibitor assay (96 h if participating in the PK sub study)
- •Absolute CD4 lymphocyte cell count ≥ 200 μL
- •Signed the written informed consent form or informed consent was obtained from the subject's legal guardian
- •Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [ß hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug
- •All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e. bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least one month before dosing)
- •Willing and able to comply with all aspects of the protocol
排除标准
- •Presence at Screening of FVIII inhibitor ≥ 0.6 BU as tested with the Nijmegen modification of the Bethesda assay in either central or local laboratory
- •History of FVIII inhibitor of ≥ 0.6 BU as measured using the Nijmegen modification of the Bethesda assay
- •History of FVIII inhibitor ≥ 1.0 BU if the subject has been tested routinely using the original Bethesda assay, or history of periods with low recovery and no response to Factor VIII treatment
- •Demonstrated an inability to respond to conventional doses of FVIII therapy
- •History of incremental recovery of Factor VIII <1.35% per IU/kg infused
- •Hematological disorders or blood coagulation diseases (e.g., idiopathic thrombocytopenic purpura, von Willebrand disease, etc.) other than hemophilia A
- •Laboratory or clinical evidence of portal vein hypertension including,(but not limited to, an INR > 1.4, the presence of splenomegaly and/or spider angiomata on physical examination and/or a history of esophageal hemorrhage or documented esophageal varices
- •Uncontrolled hypertension (diastolic blood pressure >100 mm Hg)
- •Hemoglobin < 10 g.dL
- •HIV disease symptoms regardless of presence of HIV antibodies
- •Routine administration (or planned routine administration during the course of the study), of immunosuppressive or immunomodulating drugs other than antiretroviral therapy (e.g., steroids, beta-interferon)
- •Severe renal dysfunction (creatinine > 2x upper limit of normal [ULN], total bilirubin > 2x the ULN)
- •Liver disease (alanine aminotransferase [ALT], aspartate aminotransferase [ AST] > 3x the ULN)
- •History of diabetes or other metabolic disease
- •History of hypersensitivity or serious adverse reaction to recombinant or plasma-derived FVIII concentrate
- •History of pretreatment prior to the administration of FVIII products (e.g., of antihistamines)
- •Regular use of antifibrinolytics or medications affecting platelet function
- •Hypersensitivity to hamster-or mouse derived proteins
- •Blood transfusions within 30 days of enrollment into the study
- •Current participation in another investigational drug or device study, or participated in a clinical study involving an investigational drug or device within 30 days of enrollment into the study
- •Unable or unwilling to cooperate with study procedures
研究组 & 干预措施
PK substudy
A cohort of 13-18 subjects will be included in the pharmacokinetic (PK) evaluation of GreenGene™ F and an approved recombinant Factor VIII product (Refacto AF); a minimum of 13 of these subjects will be re-evaluated at study end (50 exposure day).
干预措施: GreenGene™ F and an approved recombinant Factor VIII product (Biological)
Prophylaxis safety and efficacy substudy
Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding during prophylaxis over ≥ 50 exposure days.
干预措施: GreenGene™ F (Biological)
On-demand safety and efficacy substudy
Hemostatic efficacy of GreenGene™ F will be assessed by its effectiveness in controlling spontaneous or traumatic bleeding episodes and by the rate of breakthrough bleeding in a minimum of 10 on demand treated subjects during 50 exposure days.
干预措施: GreenGene™ F (Biological)
Surgical substudy
Peri-operative hemostatic control of GreenGene™ F in surgery or invasive procedures will be assessed in at least 10 surgeries, some of them major, in at least five subjects
干预措施: GreenGene™ F (Biological)
结局指标
主要结局
Number of subject with development of inhibitors
时间窗: evert 3 months, up to 18 months
Development of neutralizing antibodies (inhibitors) will be followed during the regular visits, average of 3 months.
次要结局
- Describe the PK profile of GreenGene™ F(Pre-dose, 0~48hours post-dose)