Neimann-Pick DiseasePhase 1/2NCT02124083
Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1
A Phase 1/2 study testing Vorinostat in people with Neimann-Pick Disease, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Neimann-Pick Disease
- What is being tested?
- Vorinostat
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Apr 2014to 13 Dec 2016
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
None listed.
Who cannot join
- Aged below 18 or above 60 years of age at enrollment in the trial.
- 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 or an HDACi in an attempt to treat NPC1.
- History of hypersensitivity reactions to Vorinostat or components of the formulation.
- Pregnancy or breastfeeding at any time during the study.
Show all 24Show fewer
- Patients with suspected infection of the CNS or any systemic infection.
- Neutropenia, defined as an absolute neutrophil count (ANC) of less than 1,500 per microliter.
- Thrombocytopenia defined as a platelet count less than 75,000 per microliter, or a history of greater than or equal to grade 2 thrombocytopenia (50,000-75,000 platelets/microliter).
- Prior use of anticoagulants or history/presence of a bleeding disorder.
- Hepatic laboratory parameters (aspartate aminotransferase (AST), alanine aminotransferase, (ALT)) greater than four-times upper limit of normal.
- Presence of anemia defined as two standard deviations below normal for age and gender.
- Serum creatinine level greater than 1.5 times the upper limit of normal.
- Hematuria (greater than15 RBC/mcL or positive hemoglobin). This exclusion criteria will not apply to a female currently menstruating who has no history of renal disease or other evidence of renal impairment (eg hypertension, serum creatinine above upper limit of normal, history of renal disease). Urinalyis will be repeated after menses has ended and drug discontinued if hematuria persists. Efforts will be made to avoid menses in scheduling the initial admission.
- Proteinuria (1+ protein on urinalysis) Patient will not be excluded if urine protein/creatinine ratio is normal or if classified as benign by either patient's primary medical provider or upon obtaining a nephrology consult.
- Serum potassium or Magnesium outside of the normal laboratory range prior to initiation of vorinostat therapy.
- Diabetes or a fasting glucose greater than 106 mg/dl.
- Active pulmonary disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation, pulmonary therapy, or requiring active suction.
- Patients with uncontrolled seizures per either of the criteria below.
- Unstable frequency, type or duration of seizures. Quantified by a seizure log over the two months prior to enrollment.
- Patients requiring antiepileptic medication changes (other than dose adjustments for weight) in the two months prior to enrollment, or requiring three or more antiepileptic medications to control seizures.
- Use of another HDAC inhibitor or compounds with established HDAC inhibitory activity, including valproic acid, unless discontinued at least 2 months prior to enrollment.
- History of a thromboembolic event (such as DVT or Pulmonary embolism).
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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.
Read the detailed description
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.
- Conditions
- Neimann-Pick Disease
- Being tested
- Vorinostat
- Keywords
- Niemann Pick Disease, Type C1, Phase I, Phase 2, Vorinostat
- Medical subject headings
- Niemann-Pick Disease, Type A, Niemann-Pick Disease, Type C
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VorinostatDrug
Histone deactylase inhibitor
| Study group | Role | What they receive |
|---|---|---|
| Vorinostat | Experimental | Trial participants were treated with Vorinostat (3 days on/4 days off regimen) to limit toxicity. Subjects were initially dosed with 200 mg (two 100 mg capsules) by mouth daily for three months, followed by dose escalation to 400 mg (four 100 mg capsules) by mouth daily for three months. Receives: Drug: Vorinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1
The number of Niemann-Pick Disease, type C1 patients completing 3 month 200 mg phase
Measured: 3 months
Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1
The number of Niemann-Pick Disease, type C1 patients completing 3 month 400 mg phase
Measured: 3 months
Secondary outcomes (4)
Biochemical Efficacy as Measured by Serum Cathepsin D
Serum concentration of Cathepsin D. Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling. Cathepsin D normal range = 220-515 ng/ml.
Measured: 6 months
Biochemical Efficacy as Measured by Serum Cathepsin D
Serum concentration of Cathepsin D. Cathepsin D is an aspartyl protease involved in protein catabolism and tissue remodeling. Cathepsin D normal range = 220-515 ng/ml.
Measured: Baseline
Biochemical Efficacy as Measured by Serum LGALS3
Serum concentration of LGALS3 (galectin-3). Galectin-3 is a carbohydrate-binding lectin whose expression is associated with inflammatory cells including macrophages, neutrophils, and mast cells. LGALS3 normal range = 1.4-5.3 ng/ml.
Measured: 6 months
Biochemical Efficacy as Measured by Serum LGALS3
Serum concentration of LGALS3 (galectin-3). Galectin-3 is a carbohydrate-binding lectin whose expression is associated with inflammatory cells including macrophages, neutrophils, and mast cells. LGALS3 normal range = 1.4-5.3 ng/ml.
Measured: Baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Apr 2014 (estimated)
- Study start25 Apr 2014
- Primary completion13 Dec 2016
- Study completion13 Dec 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Neimann-Pick DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Forbes D Porter, M.D., Principal investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02124083
- Sponsor's protocol ID
- 140102
- Other IDs
- 14-CH-0102
- Status last verified
- 13 Jan 2018
- First submitted
- 25 Apr 2014
- Last updated
- 22 Feb 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Vanier MT. Niemann-Pick diseases. Handb Clin Neurol. 2013;113:1717-21. doi: 10.1016/B978-0-444-59565-2.00041-1.
PubMed 23622394Ory DS. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):331-9. doi: 10.1016/s1388-1981(00)00158-x. No abstract available.
PubMed 11111100Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F. The adult form of Niemann-Pick disease type C. Brain. 2007 Jan;130(Pt 1):120-33. doi: 10.1093/brain/awl260. Epub 2006 Sep 26.
PubMed 17003072Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.
PubMed 34389161
Study at a glance
From the registry record, last updated by the sponsor on 22 Feb 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1/2 Study of Vorinostat Therapy in Niemann-Pick Disease, Type C1
- ClinicalTrials.gov ID
- NCT02124083
- Acronym / sponsor ID
- 140102
- Conditions
- Neimann-Pick Disease
- Keywords
- Niemann Pick Disease, Type C1, Phase I, Phase 2, Vorinostat
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
- Collaborators
- Washington University School of Medicine, Weill Medical College of Cornell University
- Study start
- 25 Apr 2014
- Primary completion
- 13 Dec 2016 (actual)
- Study completion
- 13 Dec 2016 (actual)
- First posted
- 28 Apr 2014 (estimated)
- Results
- Posted 22 Feb 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Vorinostat | Experimental | Drug: VorinostatTrial participants were treated with Vorinostat (3 days on/4 days off regimen) to limit toxicity. Subjects were initially dosed with 200 mg (two 100 mg capsules) by mouth daily for three months, followed by dose escalation to 400 mg (four 100 mg capsules) by mouth daily for three months. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (0 listed)
Key exclusion criteria (24 listed)
- Aged below 18 or above 60 years of age at enrollment in the trial.
- 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 or an HDACi in an attempt to treat NPC1.
- History of hypersensitivity reactions to Vorinostat or components of the formulation.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VorinostatHistone deactylase inhibitor | Drug | Vorinostat |
Primary outcome
Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1
Time frame: 3 months
The number of Niemann-Pick Disease, type C1 patients completing 3 month 200 mg phase
Number of Participants With Tolerabilty of 400 mg Vorinostat in Niemann-Pick Disease, Type C1
Time frame: 3 months
The number of Niemann-Pick Disease, type C1 patients completing 3 month 400 mg phase
4 secondary outcomes
Biochemical Efficacy as Measured by Serum Cathepsin D
Time frame: 6 months
Biochemical Efficacy as Measured by Serum Cathepsin D
Time frame: Baseline
Biochemical Efficacy as Measured by Serum LGALS3
Time frame: 6 months
Biochemical Efficacy as Measured by Serum LGALS3
Time frame: Baseline
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Feb 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23622394Vanier MT. Niemann-Pick diseases. Handb Clin Neurol. 2013;113:1717-21. doi: 10.1016/B978-0-444-59565-2.00041-1.
- Background: PubMed 11111100Ory DS. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta. 2000 Dec 15;1529(1-3):331-9. doi: 10.1016/s1388-1981(00)00158-x. No abstract available.
- Background: PubMed 17003072Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F. The adult form of Niemann-Pick disease type C. Brain. 2007 Jan;130(Pt 1):120-33. doi: 10.1093/brain/awl260. Epub 2006 Sep 26.
- Derived from this study: PubMed 34389161Garcia AA, Koperniku A, Ferreira JCB, Mochly-Rosen D. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. Trends Pharmacol Sci. 2021 Oct;42(10):829-844. doi: 10.1016/j.tips.2021.07.002. Epub 2021 Aug 10.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Forbes D Porter, M.D. principal investigator
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Vorinostat in people with Neimann-Pick Disease, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 0 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Feb 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 22 Feb 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Tolerabilty of 200 mg Vorinostat in Niemann-Pick Disease, Type C1 (time frame: 3 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02124083, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Feb 2018.