IMMUNE TOLERANCE INDUCTION, BY FACTOR VIII CONCENTRATE CONTAINING VON WILLEBRAND FACTOR, IN SEVERE OR MODERATE HAEMOPHILIA A PATIENTS WITH INHIBITORS
试验速览
- 阶段
- 4 期
- 入组人数
- 20
- 试验地点
- 4
- 主要终点
- Efficacy: evaluation of the success of IT induction
研究概览
简要总结
The purpose of this study is to assess the role of a FVIII/VWF complex concentrate (Emoclot) in successfully inducing immune tolerance (I.T.I.) in patients with Haemophilia A with inhibitors, including patients at high risk of failure.
详细描述
The development of factor VIII inhibitors occurs in approximately 30 to 40% of patients with severe Haemophilia A. The main negative clinical and cost consequence is the ineffectiveness of replacement therapy in patients with high-titer antibodies, who have a shorter life and greater morbidity than those who do not develop inhibitors. It is known from immunology that a regular and frequent exposure to the antigen of FVIII can induce tolerance of the immune system of the patient with inhibitors. This effect, called "immune tolerance induction" (ITI) is usually achieved after a prolonged exposure of the patient to FVIII, and is a common way of managing the condition of patients with inhibitors as well as the treatment of bleeding episodes with large amounts of hemostatic agents. In vitro and retrospective clinical studies suggest that FVIII/VWF complex concentrates may have less immunogenicity with respect to those plasma-derived concentrates purified with monoclonal antibodies (MABs), and recombinant DNA factor VIII concentrates (rFVIII), in both which the von Willebrand factor (VWF) is absent. Immune tolerance induction (ITI) showed to be effective in about 70% of Haemophiliacs with inhibitors. Poor prognosis factors have been identified by different registries: age ≥ 6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titer >10 BU at the start of ITI and previously failed ITI. The results of clinical studies suggest that complex concentrates of VWF/FVIII can be effective in ITI, even in patients at high risk of failure. To explain these findings, a role for VWF (i.e. prolonged antigen exposure) has been hypothesized.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 12 Years（Child）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Subjects (his/her parent/legal representative), must have given a written informed consent.
- •Male children: age <12 years.
- •Severe or moderate Haemophilia A (FVIII <2%).
- •High responders (clinical history of inhibitor peak > 5BU) or low-responders (clinical history of inhibitor peak < 5 BU) with potential bleedings, assessed by responsible physicians as not to be treated with high FVIII doses.
- •Any level of inhibitor at study enrollment.
- •Willingness and ability to participate in the study.
- •No other experimental treatments (involving or not FVIII concentrates).
排除标准
- •Any clinically relevant abnormality, in hematological, biochemical and urinary routine examinations, or any condition or treatment which in the investigator's opinion, makes the patient not eligible for the study.
- •Intolerance to active substances or to any of the excipients of FVIII / VWF concentrates.
- •Concomitant systemic treatment with immunosuppressive drugs.
研究组 & 干预措施
Plasma-derived FVIII/VWF concentrate
The drug will be delivered through intravenous slow infusion/injection. The starting dosage can vary between the minimum dosage of 50 IU/Kg 3 times a week up to a maximum of 200 IU/kg per day.
This starting dosage will be decided by the Principal Investigator according to patient's condition and other variables.
The initial dosage can be then adjusted on the base of response.
干预措施: Plasma-derived FVIII/VWF concentrate (Drug)
结局指标
主要结局
Efficacy: evaluation of the success of IT induction
时间窗: Up to33 months
Success:Inhibitor disappearance/reduction to \<0.6 BU/ml with FVIII activity recovery of at least ≥ 66% within 33 months of treatment ; Partial Success: inhibitor reduction to \<5 BU/ml with clinical response to FVIII treatment, not followed by an inhibitor increase to values \>5 BU/ml for a treatment period of 6 months on demand, or for 12 months of prophylactic treatment; No Response (Failure):Failure in relation to the above criteria defining complete response and partial response within 33 months, OR a reduction of the concentration of the inhibitor, less than 20%, compared to the peak of inhibitor in the IT, in every period of 6 months after the first 3 months of treatment. This implies that 9 months represents the minimum period of treatment and 33 months the maximum possible duration of ITI without success, OR patient withdrawal from the study for any reason.
次要结局
- Analysis of treatment compliance(Up to 33 months)
- Evaluation of the cost of therapy(Up to 33 months)
- Efficacy evaluation - IT persistence(Up to 33 months+ 12 months FU)
- Safety (adverse events)(Up to 33 months)
- Efficacy evaluation - Time to achieve ITI(Up to 33 months)
- Efficacy evaluation - FVIII genetic defect role in IT achievement(Up to 33 months)
- Efficacy evaluation - Role of an immediate IT to delayed IT in IT induction.(Up to 33 months)