Biomarker Validation for Niemann-Pick Disease, Type C: Safety and Efficacy of N-Acetyl Cysteine

NCT00975689 | Completed Phase 1 Results DMC

• 2 other identifiers: 09018509-CH-0185
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Niemann-Pick disease type C (NPC) is a genetic disorder that results in progressive loss of nervous system function by affecting the membranes of nerve cells. There is no known cure for NPC.
• N-acetyl cysteine (NAC) is a drug that has been approved by the Food and Drug Administration to use either orally or IV for the treatment of acetaminophen (Tylenol) poisoning or as an aerosol to reduce the stickiness of mucous in patients with cystic fibrosis. In the body, NAC is converted to an amino acid called cysteine, which cells can convert to a chemical called glutathione. Glutathione is important in helping cells deal with oxidative stress. Based on a number of experiments in cells, mice and patients with NPC, we believe that oxidative stress is increased in NPC. If we can increase glutathione levels, we may be able to decrease the oxidative stress. Objectives: \- To test the safety and effectiveness of N-acetyl cysteine to treat Niemann-Pick disease (type C). Eligibility: \- Individuals at least 1 year of age who have been diagnosed with NPC. Design:
• Patients entering this study will be seen at the National Institutes of Health Clinical Center four times during the 20 weeks of the study. These admissions will occur at the start of the study and at weeks 8, 12, and 20. The first NIH visit will last 2 days, and the other visits will last 1 day.
• Patients will participate in a two-stage study: a period of 8 weeks receiving NAC and a second period of 8 weeks when receiving a placebo (a pill without NAC). Every patient participating in this study will receive NAC during one of the two time periods.
• The two treatment periods will be separated by a wash-out period, 4 weeks when patients will receive neither NAC nor placebo. Patients will also have a 4-week wash-out period at the beginning of the study. Most physician-prescribed medications, such as seizure medications, will be allowed.
• During each visit, examinations, procedures, and tests will be done, including blood and urine samples.

Conditions

Niemann-Pick Disease, Type C

Keywords

Niemann-Pick Disease, Type C; Biomarkers; N-Acetyl Cysteine; Oxidized Cholesterol; Neurodegeneration; NPC

Outcome Measures

Primary Outcomes (1)

• Oxysterol Levels

  Six months

Interventions

N-Acetyl Cysteine DRUG

900mg effervescent tablet; Dosed as 15 mg/kg/day (maximum dose 900 mg per day) for one week, advanced to 30 mg/kg/day (maximum dose 1800 mg per day) for the second week, and then advanced to 60 mg/kg/day (maximum dose 2700 mg) for the remainder of the trial (6 additional weeks).

Eligibility Criteria

• Age: 12 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may not qualify if:

• All patients with an established diagnosis of NPC will be considered for this study. The diagnosis may be based upon either molecular or biochemical testing.
• Diagnosis of NPC by cellular assay or molecular testing.
• Twelve months of age or older and weight greater than 10 kg.
• Patient must be able to take the study medication orally or per gastrostomy tube.
• Patients will be excluded if they cannot travel to the NIH because of their medical condition or are too ill to be cared for at home.
• Patients will be excluded if they are unable to tolerate the study procedures.
• Patients will be excluded if they are pregnant (a negative urine pregnancy test will be required for any menstruating female before participation in this study and at each NIH Clinical Center admission). If sexually active, contraception must be used for the duration of the study.
• Patients will be excluded if they have had prior allergic or hypersensitivity symptoms associated with NAC use.
• Patients will be excluded from the study if they are unwilling to discontinue the following drugs and supplements for the duration of the study.
• a. All dietary supplements
• b. Any antioxidant supplement other than prescribed by the study. This will include dietary juices or drinks being marketed as a source of antioxidants
• c. CoQ10 supplements
• d. Any over-the-counter medication being used on a daily basis for which there is not a defined clinical reason
• e. NAC use
• Physician prescribed medications will be reviewed on a case-by-case basis. Patients may be excluded if medical therapies could interfere with the study endpoints. Except for carbamazepine, seizure control medications will be allowed. Patients will be excluded if taking carbamazepine or nitroglycerin.

Sponsors & Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): lead
• University of Oxford: collaborator
• Washington University School of Medicine: collaborator
• National Human Genome Research Institute (NHGRI): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81. doi: 10.1034/j.1399-0004.2003.00147.x.

  PMID: 12974729 BACKGROUND

• Carstea ED, Morris JA, Coleman KG, Loftus SK, Zhang D, Cummings C, Gu J, Rosenfeld MA, Pavan WJ, Krizman DB, Nagle J, Polymeropoulos MH, Sturley SL, Ioannou YA, Higgins ME, Comly M, Cooney A, Brown A, Kaneski CR, Blanchette-Mackie EJ, Dwyer NK, Neufeld EB, Chang TY, Liscum L, Strauss JF 3rd, Ohno K, Zeigler M, Carmi R, Sokol J, Markie D, O'Neill RR, van Diggelen OP, Elleder M, Patterson MC, Brady RO, Vanier MT, Pentchev PG, Tagle DA. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science. 1997 Jul 11;277(5323):228-31. doi: 10.1126/science.277.5323.228.

  PMID: 9211849 BACKGROUND

• Naureckiene S, Sleat DE, Lackland H, Fensom A, Vanier MT, Wattiaux R, Jadot M, Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000 Dec 22;290(5500):2298-301. doi: 10.1126/science.290.5500.2298.

  PMID: 11125141 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Niemann-Pick Disease, Type C; Nerve Degeneration

Interventions

Acetylcysteine

Condition Hierarchy (Ancestors)

Niemann-Pick Diseases; Sphingolipidoses; 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; Histiocytosis; Lymphatic Diseases; Hemic and Lymphatic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Results Point of Contact

• Title: Dr. Forbes D Porter, Senior Investigator
• Organization: National Institute of Child Health and Human Development; NIH

fdporter@mail.nih.gov

(301) 435-4432

Study Officials

• Forbes D Porter, M.D.

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

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 10, 2009
• First Posted: September 11, 2009
• Study Start: August 1, 2009
• Primary Completion: November 1, 2010
• Study Completion: November 1, 2010
• Last Updated: May 6, 2013
• Results First Posted: July 12, 2012

Record last verified: 2013-04

Locations

US (1)