Clinical Trial: Study of Pharmacokinetics and Preliminary Efficacy in Patients With Niemann-Pick C1

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: 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 Cho

Brief Summary: 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.

Detailed Summary:

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
Sponsor: CTD Holdings, Inc.

Current Primary Outcome:

  • To evaluate the plasma the Maximum Concentration (C max) of 3 doses of Trappsol by measurement of plasma levels [ Time Frame: 0,2,4,6,& 8 hours (h) after the start of the IV infusion of Trappssol 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 Time to Maximum Concentration ( Tmax) of 3 doses of Trappsol by measurement of plasma levels [ Time Frame: 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 [ Time Frame: ),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
  • To evaluate the elimination half-life of Trappsol by measurement of plasma levels [ Time Frame: 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


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Markers of cholesterol metabolism [ Time Frame: 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 ]
    To investigate the effect of 3 different doses of intravenous Trappsol in patients upon serum and lymphocytic markers of cholesterol metabolism in patients with NPC-1
  • CSF levels of HP-β-CD [ Time Frame: Pre then 4,8,and 12h after the start of the initial infusion ]
    To evaluate HP-β-CD concentrations in CSF following intravenous administration of Trappsol in patients with NPC-1 to determine if the drug crosses the blood brain barrier
  • Number of patients with treatment-related adverse events as assessed by CTCAE ( version 4.03) [ Time Frame: 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 ]
    Events will be gathered by spontaneous reporting, clinical observation and laboratory tests including standard audiology tests and auditory evoked potential to assess hearing
  • Abdominal ultrasound [ Time Frame: Baseline 12,24,36 and 48 weeks ]
    Change from baseline in hepatic and splenic morphology
  • The proportion of patients with a reduction from baseline in the NIH NPC severity scale [ Time Frame: Baseline and 48weeks ]
    Reduction of one point in two or more domains
  • Top evaluate the impact of treatment on ataxia [ Time Frame: Screening, baseline and weeks 12,18,36 and 48 ]
    Ataxia will be rated using the Scale for the assessment and rating of ataxia (SARA)
  • To evaluate the effect of treatment on fine motor skills [ Time Frame: Screening, baseline and weeks 12,18,36 and 48 ]
    Motor skills will be assessed by the bead-threading test
  • To evaluate the effect of treatment on saccadic eye movements [ Time Frame: Screening, baseline and weeks 12,18,36 and 48 ]
    Changes in saccadic eye movements will be assessed by clinical observation.


Original Secondary Outcome: Same as current

Information By: CTD Holdings, Inc.

Dates:
Date Received: August 19, 2016
Date Started: March 20, 2017
Date Completion: December 2018
Last Updated: March 24, 2017
Last Verified: March 2017