Study of the Pharmacokinetics of Trappsol and Effects on Potential Biomarkers of Niemann-Pick C1 (NPC1)
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ClinicalTrials.gov Identifier: NCT02939547 |
Recruitment Status :
Completed
First Posted : October 20, 2016
Last Update Posted : February 21, 2021
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Condition or disease | Intervention/treatment | Phase |
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Niemann-Pick Disease, Type C1 | Drug: Hydroxypropyl-beta-cyclodextrin | Phase 1 |
The planned study has been designed as a Phase I, 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 a screening phase of up to 4w a treatment phase of 12w and a 4w follow-up. The primary objective is to compare the plasma pharmacokinetics of single and multiple doses of two different levels of IV Trappsol Cyclo. Secondary objectives include investigation of the HP-β-CD effect of different doses of IV Trappsol Cyclo upon serum and lymphocytic markers of cholesterol metabolism and evaluation of Trappsol concentrations in the cerebrospinal fluid (CSF) following IV administration , evaluation of the impact of treatment upon measures of neurological function including ataxia, aphasia and saccadic eye movements, and the impact of treatment upon behavioral aspects of NPC-1.
It is planned to recruit a total of 12 patients to the study. Patients will be randomised 1:1 to one of the two dose levels (1500 mg/kg or 2500 mg/kg; six patients per dose level). Treatment will be administered every two weeks by slow IV infusion over 8 to 9 hours at different concentrations to achieve the proscribed dose levels. Patients will receive treatment for a total of 12 weeks. Patients who withdraw prior to completion of the initial pharmacokinetic and pharmacodynamic assessments will be replaced.
The design of the proposed study thus enables early assessment of potential biochemical markers of response but allows for a sufficient dosing duration to enable the short-term effectiveness of Trappsol in NPC to be assessed.
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 utilized 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, likely translates into a 13-fold slower accumulation of cholesterol in human cells compared with those of the mouse. Therefore, it is theorized 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 minimizes the amount of infusions required to be administered.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 13 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
Primary Purpose: | Basic Science |
Official Title: | A Phase I Study to Evaluate the Single and Multiple-dose Pharmacokinetics of Intravenous Trappsol Cyclo (HP-Beta-CD) in Patients With Niemann-Pick Disease Type C (NPC-1) and the Effects of Dosing Upon Biomarkers of NPC Disease |
Actual Study Start Date : | October 11, 2017 |
Actual Primary Completion Date : | February 10, 2020 |
Actual Study Completion Date : | February 10, 2020 |

Arm | Intervention/treatment |
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Active Comparator: Hydroxypropyl-beta-cyclodextrin IV 1500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8 - 9h every 2 weeks
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Drug: Hydroxypropyl-beta-cyclodextrin
Used in the treatment of Niemann-Pick Disease C1 ( NPC1)
Other Name: Hydroxypropyl-beta-cyclodextrin (HP-β-CD) |
Active Comparator: Hydroxypropyl-beta-cyclodextrin IV 2500 mg/kg
Hydroxypropyl-beta-cyclodextrin administered by slow IV infusion for 8 - 9h every 2 weeks
|
Drug: Hydroxypropyl-beta-cyclodextrin
Used in the treatment of Niemann-Pick Disease C1 ( NPC1)
Other Name: Hydroxypropyl-beta-cyclodextrin (HP-β-CD) |
- Maximum Concentration ( C max) of Trappsol in plasma from patients with Niemann-Pick disease Type C1 by measurement of plasma levels [ Time Frame: Pre- infusion then 2 ,4,6,8,8.5,9,10,11 12,16 and 20 hours after the start of the infusions at 1&12 w ]To compare the C max of Trappsol following 2 different dose levels of intravenous Trappsol in patients with NPC-1 disease following single and multiple doses
- Time to Maximum Concentration (T max) of Trappsol in plasma from patients with Niemann-Pick disease Type C1 by measurement of plasma levels [ Time Frame: Pre- infusion,2 ,4,6,8,8.5,9,10,11 12,16 and 20 hours after the start of the infusions at 1&12 w ]To compare the T max of Trappsol following 2 different dose levels of intravenous Trappsol in patients with NPC-1 disease following single and multiple doses
- Volume of Distribution of Trappsol in plasma from patients with Niemann-Pick disease Type C1 by measurement of plasma levels [ Time Frame: Pre- infusion,2 ,4,6,8,8.5,9,10,11 12,16 and 20 hours after the start of the infusions at 1&12 w ]To compare the Volume of Distribution of Trappsol following 2 different dose levels of intravenous Trappsol in patients with NPC-1 disease following single and multiple doses
- Elimination half-life (T1/2) of Trappsol in plasma from patients with Niemann-Pick disease Type C1 by measurement of plasma levels [ Time Frame: Pre- infusion,2 ,4,6,8,8.5,9,10,11 12,16 and 20 hours after the start of the infusions at 1&12 w ]To compare the T1/2 of Trappsol following 2 different doses.
- CSF levels of Trappsol [ Time Frame: Pre-infusion then 2,4,6,8,12 hours after the first infusion ( w1) and 8h after the start of the last infusion (W12) ]To evaluate HP-β-CD concentrations in CSF following 2 different dose levels of intravenous Trappsol in patients with NPC-1 disease following single and multiple doses
- Potential blood biomarkers of NPC1 [ Time Frame: Screening, baseline,then at 2,4,8,12 and 14 weeks ]To investigate the effect of 2 different doses of intravenous Trappsol upon peripheral blood biomarkers of NPC-1 disease
- Potential CSF biomarkers of NPC1 [ Time Frame: Baseline, then at 12 and 14 weeks ]To investigate the effect of 2 different doses of intravenous Trappsol upon biomarkers of NPC-1 disease in CSF
- Serum cholesterol precursors and metabolites [ Time Frame: Screening, baseline the Days1,3,,5,8,11 and 15 after the first infusion of Trappsol then at d2,3,5,8,11and 15 after the last infusion ( W12) ]To investigate the effect of 2 different doses of intravenous Trappsol in patients with NPC-1 disease upon serum and lymphocytic markers of cholesterol metabolism
- Fractionated cholesterol in hepatic tissue [ Time Frame: Baseline and 12 weeks ]To investigate the effect of 2 different doses of intravenous Trappsol in patients with NPC-1 disease upon fractionated cholesterol in hepatic tissue
- Splenic morphology assessed by qualitative change in ultrasound compared with baseline, NIH total and individual domain severity scores [ Time Frame: Baseline then 14 weeks ]To evaluate the effect of 2 different doses of Trappsol upon change in clinical manifestations of NPC-1 disease
- Hepatic morphology assessed by qualitative change in ultrasound compared with baseline, NIH total and individual domain severity scores [ Time Frame: Baseline then 14 weeks ]To evaluate the effect of 2 different doses of Trappsol upon change in clinical manifestations of NPC-1 disease
- Number of patients with treatment-related adverse events as graded by CTCAE criteria ( Version 4.03) [ Time Frame: Screening, baseline, days 1, 2-11, weeks 2,4,6,810,12,14 and 18 ]Events will be gathered by spontaneous reporting, clinical observation and laboratory tests including auditory tests and auditory evoked potentials to assess hearing
- Hepatic elasticity [ Time Frame: Baseline and 14weeks ]To investigate the effect of 2 different doses of intravenous Trappsol upon hepatic elasticity (measured by ultrasound scan) at 14 weeks (after 7 doses) in patients with NPC-1 disease
- Filipin signal intensity [ Time Frame: Baseline and 12weeks ]To investigate the effect of 2 different doses of intravenous Trappsol on filipin signal intensity (measured in cultured fibroblasts collected by skin biopsy) at 14 weeks (after 7 doses) in patients with NPC-1 disease

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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Confirmed diagnosis of NPC-1 defined as one of the following
- Two NPC-1 mutations on exome gene sequencing
- One NPC-1 mutation and positive filipin staining (current or prior)
- Vertical supranuclear gaze palsy [VSGP] 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 ≥ 3.
- Age range: 18 years upwards
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At least one systemic manifestation of NPC disease defined as one or more of
- Clinically detectable hepatomegaly and/or either ALT or AST outside the normal range for the study laboratory
- Clinically detectable splenomegaly
- Impaired respiratory function due to NPC or a history of pneumonia in the last 12 months
- Negative urine pregnancy test for females of child bearing potential
- Written, informed consent
Exclusion Criteria:
- The presence of NPC-2 mutations on exome gene sequencing
- Previous receipt of cyclodextrin therapy within 3 months of baseline
- Receipt of any of the following medications within 1 month of baseline: Coenzyme Q10, curcumin, cinnamon, fish oil supplements, high dose vitamin D (>500 milli-International unit (mIU)/day), acetyl leucine, or gingko biloba
- Concurrent treatment with any therapy indicated for the lowering of cholesterol such as statins, fibrates, ezetimibe
- Karnofsky score < 40
- Inability to comply with the proposed protocol assessments or any uncertainty about their ability to give meaningful, informed consent (legal guardian may give consent with patient assent)
- Concurrent medical conditions representing a contraindication to any of the study medications
- Grade 3 renal impairment or worse as indicated by eGFR< 60mL/min/1.73m2
- Clinical evidence of acute liver disease including symptoms of jaundice or right upper quadrant pain or INR >1.8
- Involvement in another interventional clinical trial within the previous 6 months from baseline
- Weight <40 kg or >100 kg
- Male patients and female patients of childbearing potential who are not willing to use appropriate birth control (i.e. double barrier birth control) from enrolment until the follow-up visit

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02939547
United States, California | |
UCSF Benioff Children's Hospital Oakland | |
Oakland, California, United States, 94609 | |
United States, New Jersey | |
Atlantic Health System/Morristown Medical Center | |
Morristown, New Jersey, United States, 07960 |
Principal Investigator: | Caroline Hastings, MD | Oakland CA |
Responsible Party: | Cyclo Therapeutics, Inc. |
ClinicalTrials.gov Identifier: | NCT02939547 |
Other Study ID Numbers: |
CTD-TCNPC-101 |
First Posted: | October 20, 2016 Key Record Dates |
Last Update Posted: | February 21, 2021 |
Last Verified: | February 2021 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Undecided |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
intravenous cyclodextrin compassionate Trappsol |
Pick Disease of the Brain Aphasia, Primary Progressive Frontotemporal Dementia Niemann-Pick Diseases Niemann-Pick Disease, Type A Niemann-Pick Disease, Type C Frontotemporal Lobar Degeneration Dementia Brain Diseases Central Nervous System Diseases Nervous System Diseases Neurocognitive Disorders Mental Disorders Aphasia Speech Disorders |
Language Disorders Communication Disorders Neurobehavioral Manifestations Neurologic Manifestations TDP-43 Proteinopathies Neurodegenerative Diseases Proteostasis Deficiencies Metabolic Diseases Sphingolipidoses Lysosomal Storage Diseases, Nervous System Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Histiocytosis, Non-Langerhans-Cell Histiocytosis Lymphatic Diseases |