Protocol Number: 09-CH-0185

Title:

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

Number:

09-CH-0185

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.

Sponsoring Institute:

National Institute of Child Health and Human Development (NICHD)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION AND EXCLUSION CRITERIA:

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.

INCLUSION CRITERIA:

1. Diagnosis of NPC by cellular assay or molecular testing.

2. Twelve months of age or older and weight greater than 10 kg.

3. Patient must be able to take the study medication orally or per gastrostomy tube.

EXCLUSION CRITERIA:

1. 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.

2. Patients will be excluded if they are unable to tolerate the study procedures.

3. 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.

4. Patients will be excluded if they have had prior allergic or hypersensitivity symptoms associated with NAC use.

5. 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

6. 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.

7. Over-the-counter medications use on a daily basis will be reviewed on a case-by-case basis. Patients may be excluded if medical therapies could interfere with the study endpoints.

8. Patients will be excluded if they have an uncontrolled seizure disorder.

9. Patients on miglustat at the start of the study will be excluded if the dose of miglustat cannot be held constant for the duration of the study. The miglustat dose must have been constant for two months prior to the baseline NIH evaluation. Patients will be withdrawn if they initiate miglustat use after entering the study.

10. Patient who are at risk for gastric hemorrhage (preexisting esophageal varices or peptic ulcer disease).

11. Patients on a sodium restricted diet for medical reasons.

12. The following laboratory test abnormalities will exclude patients from the study:

--a. AST or ALT elevated greater than 4-fold upper limit of normal. Note: NPC patients frequently have transaminase levels 2-3 fold above normal.

--b. Anemia defined as two standard deviations below normal for age and gender.

--c. Platelet count less than 75,000.

--d. Elevated serum creatine level

--e. Hematuria or proteinuria

Special Instructions:

Currently Not Provided

Keywords:

Niemann-Pick Disease, Type C

Biomarkers

N-Acetyl Cysteine

Oxidized Cholesterol

Neurodegeneration

NPC

Recruitment Keyword(s):

None

Condition(s):

Niemann-Pick Disease, Type C

Investigational Drug(s):

N-Acetyl Cysteine

Investigational Device(s):

None

Intervention(s):

Drug: N-acetyl cysteine

Supporting Site:

NICHD, NHGRI, Washington University Mount Sinai School of Medicine, Oxford University, Ara Parseghian Medical Research Foundation

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Vanier MT, Millat G. Niemann-Pick disease type C. Clin Genet. 2003 Oct;64(4):269-81.

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.

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.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Clinical Research Informatics, CC.

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