A Phase I/II Study to Evaluate the Safety and PK of iv Trappsol Cyclo (HP-β-CD) in Patients With Niemann-Pick Disease Type C NPC-1 and the Pharmacodynamic Effects of Treatment Upon Markers of Cholesterol Metabolism and Clinical Outcomes
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 5
- 主要终点
- To evaluate the plasma the Maximum Concentration (C max) of 3 doses of Trappsol by measurement of plasma levels
研究概览
简要总结
This research study is being conducted to find out whether Trappsol® Cyclo™, an experimental treatment for people with Niemann-Pick disease Type C1 (NPC-1) is safe at 3 different dose levels and what effects it has on people who have this condition. NPC-1 is caused by a defect in a protein which is important for the transport of fatty substances like cholesterol out of cells. Without this protein, fats build up in the cells ultimately leading to organ damage. The way in which this experimental treatment works is not fully understood but laboratory experiments have shown that it can potentially remove cholesterol build up from the cells in people who have NPC-1. Approximately 12 patients will be asked to take part in this research study for up to 56 weeks in total. recruitment is expected to take 9 months.Patients who take part will receive treatment by an intravenous infusion every two weeks. The study will look at what the body does to the drug as well as what the drug does to the body by taking and examining blood and urine samples. Samples of Cerebrospinal fluid (CSF) are also taken by lumbar puncture during and following the first treatment dose. Patients will also have their hearing tested, be asked questions by their doctor as well completing questionnaires to help assess any changes in their condition during treatment. Optional assessments patients can choose to take part in include liver biopsies, additional lumbar punctures for CSF.examinations to see if the drug is affecting these. This study is being sponsored and funded by CTD holdings INC. It is planned to be run in the UK, Italy, and Sweden.
详细描述
The planned study has been designed as a Phase I/II, double-blind, randomised, multi-centre, parallel group study based on information and data available from the administration of Trappsol Cyclo via compassionate/named patient use in patients with NPC-1, and data on other cyclodextrin products in the scientific literature.
The study is comprised of two stages. The primary objective of Stage 1 is to compare the plasma pharmacokinetics of three different doses of IV Trappsol Cyclo in the prevention /delay of NPC-1 progression.Secondary objectives include investigation of the Hydroxypropyl Beta Cyclodextrin (HP-β-CD) effect of three different doses of IV Trappsol Cyclo upon serum and lymphocytic markers of cholesterol metabolism (Stages 1 and 2) and evaluation of concentrations in the cerebrospinal fluid (CSF) following intravenous (IV) administration (Stage 1), evaluation of the impact of treatment upon measures of neurological function including ataxia, aphasia and saccadic eye movements, and the impact of treatment upon behavioural aspects of NPC-1 (Stage 2).
It is planned to recruit a total of 12 patients to the study. Patients will be randomised 1:1:1 to one of the three dose levels (1500 mg/kg, 2000 mg/kg or 2500 mg/kg; four patients per dose level). Treatment will be administered every two weeks by slow IV infusion at a concentration of 250 mg/mL over 8 hours. Patients completing Stage 1 of the study will continue into Stage 2 and receive treatment for 48 weeks. Patients who withdraw prior to completion of the initial pharmacokinetic (PK) and pharmacodynamics (PD) assessments will be replaced.
The design of the proposed study thus enables early assessment of biochemical markers of response but allows for a sufficient dosing duration to enable the effectiveness of Trappsol in NPC-1 to be assessed.
As miglustat is an approved treatment for NPC-1 in the EU, with an established efficacy and safety profile, it would be unethical to exclude patients receiving miglustat therapy from the study, given that the study itself will also be conducted at sites in Europe. However, it is planned to balance randomisation across the treatment groups for its use.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed diagnosis of NPC-1 defined as one of the following
- •Two NPC-1 mutations on genotyping
- •One NPC-1 mutation and positive filipin staining (current or prior)
- •Vertical supranuclear gaze palsy [VSNGP] plus either ≥ one NPC-1 mutation or positive filipin staining and no NPC-2 mutations
- •NIH NPC Severity Score <30 and with no more than 4 individual domains with a score ≥
- •Age range: 2 years upwards
- •Inclusion of the first three paediatric patients will be restricted to individuals aged ≥ 5 years. Once the first three paediatric patients have safely completed stage 1, study entry will be open to all ages ≥2 years as per the protocol
- •Negative pregnancy test for females of child bearing potential
- •Written, informed consent
排除标准
- •The presence of NPC-2 mutations on genotyping
- •Previous receipt of cyclodextrin therapy
- •Lanksy score < 50 if aged ≤16 or Karnofsky score < 40 if aged >
- •Inability to comply with the proposed protocol assessments
- •Concurrent treatment with any type of cholesterol lowering agents such as statins, fibrates, ezetimibe
- •Concurrent medical conditions representing a contraindication to any of the study medications
- •Stage 3 renal impairment or worse as indicated by eGFR< 60mL/min using the MDRD equation
- •Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or INR >
- •Involvement in another interventional clinical trial within the previous 6 months
- •Weight >100 kg
- •Females of childbearing potential who are not willing to use a method of highly effective contraception (hormonal contraception, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner, or true abstinence) during the study and the follow-up period. True abstinence can only be in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of a trial, and withdrawal are not acceptable methods of contraception.
- •Females who are breastfeeding
研究组 & 干预措施
Hydroxypropyl-beta-cyclodextrin IV 1500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
干预措施: Hydroxypropyl-beta-cyclodextrin (Drug)
Hydroxy-propyl-beta-cyclodextrin IV 2000 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
干预措施: Hydroxypropyl-beta-cyclodextrin (Drug)
Hydroxypropyl-beta-cyclodextrin IV 2500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
干预措施: Hydroxypropyl-beta-cyclodextrin (Drug)
结局指标
主要结局
To evaluate the plasma the Maximum Concentration (C max) of 3 doses of Trappsol by measurement of plasma levels
时间窗: 0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappsol and 0.5,1,2,4,8 & 12 h after the end of the infusion
To evaluate plasma PK of Trappsol by comparison of Maximum Concentration (Cmax ) of the three doses
To evaluate the elimination half-life of Trappsol by measurement of plasma levels
时间窗: 0,2,3,6 & 8h after the start of IV infusion of Trappsol and 0.5,1,2,4,8 &12h after the end of infusion
To evaluate the PK of Trappsol by comparison of the Elimination half-lives of three doses
To evaluate the Time to Maximum Concentration ( Tmax) of 3 doses of Trappsol by measurement of plasma levels
时间窗: 0,2,4,6,& 8h after the start of IV infusion of Trappsol and 0.5,1,2,4,6 &12h after the end of infusion
To evaluate the plasma PK of Trappsol by comparison of the Tmax of three doses
To evaluate the Volume of Distribution of Trappsol by measurement of plasma levels
时间窗: ),2,4,6 & 8 h after the start of the IV infusion of Trappsol and 0.5,1,2,4,8,&12 h after the end of the infusion
To evaluate the plasma PK of Trappsol by comparison of the Volume of Distribution of three doses
次要结局
- Markers of cholesterol metabolism(Screening,Days1,2,3,5,8,Weeks 2,4,8,10,12,14,16,18,20,24,28,32,36,40,44,48 and follow-up)
- CSF levels of HP-β-CD(Pre then 4,8,and 12h after the start of the initial infusion)
- Number of patients with treatment-related adverse events as assessed by CTCAE ( version 4.03)(Screening,Days1,2,3,4,6,8,Week 2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,36,38,40,42,44,46,48 and follow-up)
- Abdominal ultrasound(Baseline 12,24,36 and 48 weeks)
- The proportion of patients with a reduction from baseline in the NIH NPC severity scale(Baseline and 48weeks)
- Top evaluate the impact of treatment on ataxia(Screening, baseline and weeks 12,18,36 and 48)
- To evaluate the effect of treatment on fine motor skills(Screening, baseline and weeks 12,18,36 and 48)
- To evaluate the effect of treatment on saccadic eye movements(Screening, baseline and weeks 12,18,36 and 48)
- To evaluate cognitive impairment(Screening, baseline and weeks 12,18,36 and 48)