CompletedPhase 1/2

Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1

United States12 participantsStarted 2014-04-25

Plain-language summary

Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. The causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead to progressive accumulation of unesterified cholesterol and other lipids in the central nervous system (CNS). Vorinostat is a histone deacetylase inhibitor that has been shown in vivo to increase mutant NPC1 protein levels and to reverse cellular accumulation of unesterified cholesterol. Vorinostat has been labeled by the FDA for treatment of cutaneous T-cell lymphoma. In this Phase I, non-randomized, open-label, single-center study, we plan to study whether Vorinostat can be repurposed to treat patients with NPC1. Our primary objective is to determine the safety and tolerability of Vorinostat in NPC1 disease. Our secondary objectives will be to determine biochemical efficacy of Vorinostat to increase expression of NPC1 protein and normalize lipid and protein biomarkers. This study will enroll up to 12 NPC1 patients and test the safety of two dose levels (200 and 400 mg). Drug will be administered on a 3 days on/4 days off schedule for 3 months at each dose level. Patients will be evaluated at the NIH Clinical Center at 0, 3 and 6 months. Safety will be assessed by adverse events (AEs), clinical laboratory tests and physical examinations. Biochemical efficacy will be assessed by measurement of serum and cerebral spinal fluid biomarkers. Clinical efficacy will be evaluated by audiologic testing, assessment ataxia, and swallowing studies.

Who can participate

Age range18 Years – 60 Years

SexALL

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Inclusion criteria

✓. Aged greater than or equal to 18 and less than or equal to 60 years old at time of enrollment, either gender, and any ethnicity.
✓. Diagnosis of NPC1 based upon one of the following:
✓. 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.
✓. A patient s cultured skin fibroblasts when treated with 10 M Vorinostat must exhibit a reduction in the filipin lysosomal storage organelle ratio equivalent to 75% of the response measured in NPC1 positive control fibroblasts.
✓. Ability to travel to the NIH Clinical Center 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 three 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.

Exclusion criteria

What they're measuring

Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1

Timeframe: 3 months

Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1

Timeframe: 3 months

Trial details

NCT IDNCT02124083

SponsorEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Sponsor typeNIH

Study typeINTERVENTIONAL

Primary completion2016-12-13

Results submitted2017-12-12

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