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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by CTD Holdings, Inc.
Information provided by (Responsible Party):
CTD Holdings, Inc. Identifier:
First received: August 19, 2016
Last updated: March 24, 2017
Last verified: March 2017
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.

Condition Intervention Phase
Niemann-Pick Disease, Type C1
Drug: Hydroxypropyl-beta-cyclodextrin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
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 Cholesterol Metabolism and Clinical Outcomes

Resource links provided by NLM:

Further study details as provided by CTD Holdings, Inc.:

Primary Outcome Measures:
  • 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

Secondary Outcome Measures:
  • 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.

Other Outcome Measures:
  • Change from baseline in hepatic fractionated cholesterol [ Time Frame: Baseline , day 2 and 48weeks ]
    To investigate the impact of treatment on cholesterol handling by the liver

  • Exploratory measures of potential CSF Biomarkers [ Time Frame: Baseline, weeks 24and 48 ]
    To investigate the impact of treatment upon CSF markers of NPC-1 disease

Estimated Enrollment: 12
Actual Study Start Date: March 20, 2017
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: March 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Hydroxypropyl-beta-cyclodextrin IV 1500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
Drug: Hydroxypropyl-beta-cyclodextrin
Used in the treatment of Niemann-Pick C1
Other Name: Trappsol Cyclo
Active Comparator: Hydroxy-propyl-beta-cyclodextrin IV 2000 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
Drug: Hydroxypropyl-beta-cyclodextrin
Used in the treatment of Niemann-Pick C1
Other Name: Trappsol Cyclo
Active Comparator: Hydroxypropyl-beta-cyclodextrin IV 2500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8h every 2 weeks
Drug: Hydroxypropyl-beta-cyclodextrin
Used in the treatment of Niemann-Pick C1
Other Name: Trappsol Cyclo

Detailed Description:

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.

The maximum dose proposed for this study is below the maximum dose for which long term clinical data is available in 2 patients (2800 mg/kg weekly for 3-5 years). Although individual clinicians have not always utilised an escalating rate of infusion, the reports of infusion related reactions in three patients suggest that this is an appropriate clinical strategy to mitigate the risk of such events and is consistent with dosing administration for other therapeutic agents. In the proposed study, treatment will be administered less frequently than has been undertaken in compassionate use. This longer dosing interval is supported by nonclinical data comparing the metabolism of cholesterol in non-human species with that in man; although a once weekly dosing interval was initially studied in man based on data in the mouse, HP-β-CD cholesterol metabolism/turnover in the mouse is 13-fold higher than in man which, in NPC-1, likely translates into a 13-fold slower accumulation of cholesterol in human cells compared with those of the mouse.Therefore, it is theorised that, given the slower cholesterol metabolism in humans, the dosing interval could be much less frequent in man than in mouse; however, based on what is known about cholesterol metabolism in humans and the pharmacokinetic and pharmacodynamic effect of HP-β-CD in the mouse, a dosing interval of 2 weeks in man is likely to be well within the therapeutic dosing interval and also minimises the amount of infusions required to be administered.


Ages Eligible for Study:   2 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. 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
  2. NIH NPC Severity Score <30 and with no more than 4 individual domains with a score ≥ 3.
  3. Age range: 2 years upwards

    • Inclusion of the first six patients will be restricted to individuals aged ≥ 5 years. In the event that three patients aged >18 (i.e. adults) are recruited before the total recruitment has reached n=6, no more adults will be randomised to treatment until the first cohort of 6 patients is complete. Once the first six have safely completed stage 1, study entry will be open to all ages ≥2 years as per the protocol.
  4. Negative pregnancy test for females of child bearing potential
  5. Written, informed consent

Exclusion Criteria:

  1. The presence of NPC-2 mutations on genotyping
  2. Previous receipt of cyclodextrin therapy
  3. Lanksy score < 50 if aged ≤16 or Karnofsky score < 40 if aged > 16.
  4. Inability to comply with the proposed protocol assessments
  5. Concurrent treatment with any type of cholesterol lowering agents such as statins, fibrates, ezetimibe
  6. Concurrent medical conditions representing a contraindication to any of the study medications
  7. Stage 3 renal impairment or worse as indicated by eGFR< 60mL/min using the MDRD equation
  8. Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or INR >1. 8
  9. Involvement in another interventional clinical trial within the previous 6 months
  10. Weight >100 kg
  11. 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.
  12. Females who are breastfeeding

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02912793

Contact: Sharon Hrynkow, PhD
Contact: Bryan C Hurst, Mphil 0044 (0) 7881 780249

United Kingdom
Salford Royal Hospital Recruiting
Salford, Greater Manchester, United Kingdom, M6 8HD
Contact: Reena Sharma    44 (0) 161 789 7373   
Sponsors and Collaborators
CTD Holdings, Inc.
Principal Investigator: Reena Sharma, MB BS Salford Royal Foundation NHS Trust,
  More Information

Coussement W, Van Cauteren H, Vandenberghe J, et al. Toxicological profile of Hydroxypropyl-beta-cyclodextrin (HPBCD) in laboratory animals. In: Minutes of the Fifth International Symposium on cyclodextrins; 28-30 March 1990; Paris, France: Editions de Santé; 1990 p. 522-4.

Responsible Party: CTD Holdings, Inc. Identifier: NCT02912793     History of Changes
Other Study ID Numbers: CTD-TCNP-201
Study First Received: August 19, 2016
Last Updated: March 24, 2017
Individual Participant Data  
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Niemann-Pick Diseases
Niemann-Pick Disease, Type A
Niemann-Pick Disease, Type C
Pick Disease of the Brain
Aphasia, Primary Progressive
Frontotemporal Dementia
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Histiocytosis, Non-Langerhans-Cell
Lymphatic Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Frontotemporal Lobar Degeneration
Neurocognitive Disorders
Mental Disorders
Speech Disorders
Language Disorders processed this record on April 27, 2017