- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01747135
Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease
Background:
- Hydroxypropyl beta cyclodextrin (HPBCD) is being tested for a disease called Niemann-Pick disease type C1 (NPC1). NPC1 is a genetic disorder that results in gradual loss of nervous system function. Cholesterol and other fats have trouble moving out of the brain cells, which makes the cells work poorly and leads to symptoms. There is no treatment currently approved in the US for NPC1. Researchers want to test if it is safe to use HPBCD for NPC1. They want to see if it can help brain cells process cholesterol better.
Objectives:
- To test the safety and effectiveness of HPBCD for NPC1.
Eligibility:
- Individuals between 2 and 25 years of age who have been diagnosed with NPC1 and who have not already received HPBCD in an attempt to treat NPC1.
Design:
- Participants will be screened with a physical exam and medical history. They will provide blood and urine samples for screening. They will also have neurological tests, including tests of hearing, speech and movement.
- Participants will have a lumbar puncture (also called a spinal tap) every month to deliver the drug to the spinal fluid that surrounds the brain. The length of the trial will be determined by the safety and efficacy information that is obtained.
- Treatment will be monitored with frequent blood and urine tests, cerebral spinal fluid tests, hearing and neurological exams.
Study Overview
Detailed Description
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Maryland
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Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center, 9000 Rockville Pike
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
INCLUSION CRITERIA:
- Aged greater than or equal to 2 and less than or equal to 25 years old at time of enrollment, either gender and any ethnicity.
Diagnosis of NPC1 based upon one of the following:
- Two NPC1 mutations;
- Positive filipin staining and at least one NPC1 mutation;
- Vertical supranuclear gaze palsy (VSNGP) in combination with either:
i. One NPC1 mutation, or
ii. Positive filipin staining and no Niemann-Pick Type 2 (NPC2) mutations.
- Patients with at least one neurological manifestation of NPC1. For example, but not limited to, hearing loss, vertical supranuclear gaze palsy, ataxia, dementia, dystonia, seizures, dysarthria, or dysphagia.
- Ability to travel to the National Institutes of Health Clinical Center (NIH CC) repeatedly for evaluation and follow-up.
- If taking miglustat, the patient must have been taking a constant dose of the medication for no less than 3 months prior to baseline evaluation and must be willing to maintain that dose level for the duration of the trial.
- Willing to discontinue all non-prescription supplements, with the exception of an age-appropriate multivitamin.
- Women of reproductive age must be willing to use an effective method of contraception for the duration of the trial.
Willing to participate in all aspects of trial design including serial blood and cerebrospinal fluid (CSF) collections.
EXCLUSION CRITERIA:
- Aged below 2 or above 25 years of age at enrollment in the trial.
- Subjects will be excluded if their weight would result in an endotoxin level that would exceed 0.2 EU/kg for either the saline or drug dosing.
- Severe manifestations of NPC1 that would interfere with the patient's ability to comply with the requirements of this protocol.
- Neurologically asymptomatic patients.
- Patients who have received any form of cyclodextrin in an attempt to treat NPC1. Treatment with another drug preparation for another medical indication that contains cyclodextrin as an excipient, will not exclude a patient.
- History of hypersensitivity reactions to cyclodextrin or components of the formulation.
- Pregnancy or breastfeeding at any time during the study.
- Patients with suspected infection of the CNS or any systemic infection.
- Spinal deformity that would impact the ability to perform a lumbar puncture
- Skin infection in the lumbar region
- Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500.
- Thrombocytopenia (a platelet count of less than 75,000 per cubic millimeter).
- Evidence of disturbed circulation of CSF.
- Contraindication for anesthesia.
- Prior use of anticoagulants or history/presence of a bleeding disorder with increased risk of clinical bleeding or an international normalized ratio (INR) greater than 2.
- Patients with clinical evidence of acute liver disease having symptoms of jaundice or right upper quadrant pain.
- Presence of anemia defined as two standard deviations below normal for age and gender.
- For subjects 18 years of age and older, the epidermal growth factor receptor (eGFR) is automatically calculated and reported by the NIH CC laboratory utilizing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Creatinine 2009 equation. We will exclude subjects greater than or equal to 18 years of age if eGFR is less than or equal to 60 mL/min/1.73 m2. For subjects < 18
12 years of age, we will utilize the national kidney disease education program (NKDEP) calculator (http://www.nkdep.nih.gov/lab-evaluation/gfr-calculators/children-conventional-unit.shtml). Results are reported as > 75 mL/min/1.73 m2 or lower. We will exclude subjects < 18 years of age if eGFR is less than or equal to 75 15 mL/min/1.73 m2
19. Hematuria on a single urinalysis, as defined by the American Urological Association (AUA) as five or more red blood cells per high-power field (or > 25/micro L) on microscopic evaluation of urinary sediment from a properly collected urinalysis specimen. The patient will not be excluded if 2 subsequent urine specimens are negative for hematuria as defined by the AUA.
20. Proteinuria (1+ protein on urinalysis) unless evaluated and classified as benign by patient s primary medical provider or by NIH nephrology consult or in the context of normal urine protein creatinine ratio and in the absence of clinical symptoms (edema, hypertension).
21. Active pulmonary disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation, pulmonary therapy, or requiring active suction.
22. Patients unable to complete a behavioral audiologic evaluation including pure-tone threshold assessment (500 Hz to 8000 Hz) to monitor for ototoxicity and for whom otoacoustic emissions (OAEs) cannot be reliably obtained at baseline.
23. Patients with ongoing seizures, that are not stable in frequency, type or duration over a 2 month period prior to enrollment, requiring change in dose of antiepileptic medication (other than adjustment for weight) over a 2 month period prior to enrollment, or requiring 3 or more antiepileptic medications to control seizures.
24. Patients, who in the opinion of the investigators are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Open label
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Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
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24-hydroxycholesterol Area under the curve
Time Frame: Days
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Days
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Secondary Outcome Measures
Outcome Measure |
Time Frame |
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Hearing loss.
Time Frame: Year
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Year
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Collaborators and Investigators
Publications and helpful links
General Publications
- Aqul A, Liu B, Ramirez CM, Pieper AA, Estill SJ, Burns DK, Liu B, Repa JJ, Turley SD, Dietschy JM. Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J Neurosci. 2011 Jun 22;31(25):9404-13. doi: 10.1523/JNEUROSCI.1317-11.2011.
- Brewster ME, Loftsson T. Cyclodextrins as pharmaceutical solubilizers. Adv Drug Deliv Rev. 2007 Jul 30;59(7):645-66. doi: 10.1016/j.addr.2007.05.012. Epub 2007 May 29.
- Chen FW, Li C, Ioannou YA. Cyclodextrin induces calcium-dependent lysosomal exocytosis. PLoS One. 2010 Nov 29;5(11):e15054. doi: 10.1371/journal.pone.0015054.
- Boenzi S, Catesini G, Sacchetti E, Tagliaferri F, Dionisi-Vici C, Deodato F. Comprehensive-targeted lipidomic analysis in Niemann-Pick C disease. Mol Genet Metab. 2021 Dec;134(4):337-343. doi: 10.1016/j.ymgme.2021.11.005. Epub 2021 Nov 16.
- Farmer CA, Thurm A, Farhat N, Bianconi S, Keener LA, Porter FD. Long-Term Neuropsychological Outcomes from an Open-Label Phase I/IIa Trial of 2-Hydroxypropyl-beta-Cyclodextrins (VTS-270) in Niemann-Pick Disease, Type C1. CNS Drugs. 2019 Jul;33(7):677-683. doi: 10.1007/s40263-019-00642-2.
Helpful Links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Mental Disorders
- Metabolic Diseases
- Brain Diseases
- Central Nervous System Diseases
- Nervous System Diseases
- Lymphatic Diseases
- Neurologic Manifestations
- Neurobehavioral Manifestations
- Neurocognitive Disorders
- Genetic Diseases, Inborn
- Neurodegenerative Diseases
- TDP-43 Proteinopathies
- Proteostasis Deficiencies
- Metabolism, Inborn Errors
- Lysosomal Storage Diseases
- Lipid Metabolism Disorders
- Dementia
- Brain Diseases, Metabolic
- Brain Diseases, Metabolic, Inborn
- Language Disorders
- Communication Disorders
- Sphingolipidoses
- Lysosomal Storage Diseases, Nervous System
- Lipidoses
- Lipid Metabolism, Inborn Errors
- Speech Disorders
- Frontotemporal Lobar Degeneration
- Aphasia
- Histiocytosis, Non-Langerhans-Cell
- Histiocytosis
- Frontotemporal Dementia
- Aphasia, Primary Progressive
- Pick Disease of the Brain
- Niemann-Pick Diseases
- Niemann-Pick Disease, Type A
- Niemann-Pick Disease, Type C
- Molecular Mechanisms of Pharmacological Action
- Sequestering Agents
- Betadex
Other Study ID Numbers
- 130001
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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