Multi-centre, Oral Single Dose Experimental and Modelling Study to Evaluate the Pharmacokinetics of Deferiprone in Patients Aged From 1 Month to Less Than 6 Years of Age Affected by Transfusion-dependent Haemoglobinopathies.

Consorzio per Valutazioni Biologiche e Farmacologiche7 个研究点分布在 3 个国家目标入组 23 人开始时间: 2012年12月最近更新: 2017年1月11日

适应症

干预措施

试验速览

阶段: 2 期
状态: 已完成
发起方: Consorzio per Valutazioni Biologiche e Farmacologiche
入组人数: 23
试验地点: 7
主要终点: AUC (0-8h)

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Deferiprone (DFP) is the most extensively studied oral iron chelator to date. It has been authorised in Europe in 1999 for the treatment of iron overload in patients with beta-thalassaemia major when DFO is contraindicated or inadequate. Despite a wide experience of DFP there are limited experimental data available on DFP in children and no pharmacokinetic data in children under 6 years of age. On the basis of the existing data in adults and adolescent, in the DEEP-1 trial a pharmacokinetic bridging model was developed to support the dose selection in children aged less than 6 years affected by transfusion dependent haemoglobinopathies. The study consisted of two phases, namely an experimental phase, during which patients received a single dose and a modeling phase, during which PK data obtained after single dose in patients < 6 years of age were analysed in conjunction with historical PK data in adults and older children and adolescents. The model-based analysis of the data obtained after single dose enabled the assessment of the dosing regimen required for the purpose of accurate pharmacokinetic bridging. The ratio between the predicted systemic exposure parameters (AUC and Cmax) in the target population and reference group were used as basis for recommendation of the dose in the target population.

详细描述

Deferiprone (DFP) was investigated as therapy for children from 1 month to less than 6 years of age. The study was a multicenter randomised, single blind, and single dose PK study. The patients were randomised according to a stratification scheme in which three different dose levels were used.

Objectives: The primary objective of this study was to assess the pharmacokinetics of DFP in paediatric patients aged from 1 month to less than 6 years.

The secondary objectives of this study were:

To identify dose levels yielding deferiprone exposures comparable to adults and define the dose rationale in children aged from 1 month to less than 6 years.
To evaluate safety and tolerability of deferiprone after single dose administration in children aged from 1 month to less than 6 years.
To evaluate the effect of demographic covariates on DFP disposition and estimate the clearance distribution across the population.

Endpoints: The primary endpoints of the study were pharmacokinetic and included:

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
盲法: Single (Investigator)

入排标准

年龄范围: 1 Month 至 6 Years（Child）
性别: All
接受健康志愿者: 否

入选标准

•Patients in a chronic transfusional program who have received at least 150 ml/kg/year of packed red blood cells (corresponding approximately to 12 transfusions) and on current treatment with DFO, DFX, DFP; aged from 1 month to less than 6 years; or
•Patients naïve to any chelation treatment who have received not less than 150 ml/kg of packed red blood cells (corresponding to approximately 12 transfusions) and have ferritin levels > 800 ng/mL, aged from 1 month to less than 6 years; or
•Patients who meet the transfusion criteria (150 ml/kg/year corresponding approximately to 12 transfusions) and have known intolerance or contraindication to DFO
•And if all of the following criteria apply:
•Patients affected by any hereditary haemoglobinopathies requiring chronic transfusion therapy including but not limited to thalassaemia and sickle cell disease
•Written informed consent obtained from their legal guardian on the patient's behalf in accordance with the national legislations. According to his/her capability, patient's informed assent will be collected

排除标准

•Patient with known intolerance or contraindication to the trial treatment
•Patient with Hb levels less than 8g/dl (entry may be delayed until values return to normal)
•Patient with platelet count <100.000/mm3 or absolute neutrophil count <1.500/mm3 (entry may be delayed until values return to normal)
•Patient with evidence of abnormal liver function (ALT level >5 times the upper normal limit during six months preceding enrolment; entry may be delayed until values return to normal)
•iron overload from causes other than transfusional haemosiderosis
•severe heart dysfunction secondary to iron overload defined as the occurrence of heart failure or severe arrhythmia or as indicated by cardiac T2* lower than 10 ms, if recent MRI data is available,
•Patient with serum creatinine level above the upper normal limit at screening; entry may be delayed until values return to normal.
•Serological evidence of chronic hepatitis B (presence of HBe Ag, HBsAg, HBcAb-IgM, in the absence of HBsAb).
•History of significant medical or psychiatric disorder that may impair compliance with the requirements of the protocol.
•The patient has received another investigational drug within 30 days prior to this study.
•Patient with a pre-existing condition or any other surgical or medical condition which might significantly interfere with normal gastrointestinal and hepatic function that could alter the absorption, metabolism, and/or excretion of the study drug.
•Patient with a known history of HIV seropositivity.
•Fever and other signs/symptoms of infection in the 10 days before drug administration(treatment day)
•Concomitant use of other iron chelators or trivalent cation-dependent medicinal products such as aluminium-based antacids.
•Patient with a chronic condition that does not allow suspension of related treatment from starting of washout until drug is administered.

研究组 & 干预措施

Deferiprone, dose level 2

Experimental

single dose level of 16.7 mg/kg every 8 hours for a corresponding total daily dose of 50 mg/kg/day.

干预措施: Deferiprone, dose level 2 (Drug)

Deferiprone, dose level 3

Experimental

single dose level of 33.3 mg/kg every 8 hours for a corresponding total daily dose of 100 mg/kg/day.

干预措施: Deferiprone, dose level 3 (Drug)

Deferiprone, dose level 1

Experimental

single dose level of 8.3 mg/kg every 8 hours for a corresponding total daily dose of 25 mg/kg/day.

干预措施: Deferiprone, dose level 1 (Drug)