Niemann-Pick Disease, Type CPhase 1/2NCT00975689

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

A Phase 1/2 study testing N-Acetyl Cysteine in people with Niemann-Pick Disease, Type C, run by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 12 months and older
Conditions the study is for: Niemann-Pick Disease, Type C
What is being tested?: N-Acetyl Cysteine
Type of treatment: Pill or oral medicine
How many people: 35 participants
Where: 1 siteUnited States
Study dates: Aug 2009to Nov 2010
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 12 months and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

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.

Who cannot join

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

Show all 22Show fewer

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.
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.
Patients will be excluded if they have an uncontrolled seizure disorder.
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.
Patient who are at risk for gastric hemorrhage (preexisting esophageal varices or peptic ulcer disease).
Patients on a sodium restricted diet for medical reasons.
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

Trial locations and contacts

1 site in 1 country.

United States1 site

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892

Other trials in United States

About this study

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.

Read the detailed description

Niemann-Pick Disease, type C (NPC) is an autosomal recessive lysosomal storage disease with progressive neurodegeneration. It is characterized by intracellular accumulation of cholesterol and glycosphingolipids. The age of onset is variable with cases manifesting from infancy to adulthood. Classically, initial neurological symptoms are observed in early to late childhood. Symptoms and signs of NPC include prolonged neonatal jaundice, splenomegaly, and various neurological manifestations, especially ataxia, dysmetria, dysarthria, vertical supranuclear gaze palsy and cognitive decline. Currently there are no approved therapies for NPC. A recent controlled study and a series of case reports suggest some efficacy for miglustat. Miglustat inhibits the biosynthesis of glycosphingolipids. The pathophysiological processes contributing to neurodegeneration in NPC have been intensively studied in NPC mouse models. Potential pathological processes include toxic effects of cholesterol or glycosphingolipid accumulation, deficient oxysterol production, peroxisomal dysfunction, mitochondrial dysfunction, perturbed intracellular calcium homeostasis, inflammation, induction of apoptosis, deficient neurosteroid synthesis, and increased oxidative stress. The degree to which each of these pathological processes contributes to the pathology of NPC is not known; however, the multiple processes involved suggest that combinatorial therapy addressing various aspects of this disorder will be necessary. A major impediment to the development of clinical trials for NPC has been the prior lack of outcome measures. Identifying biomarkers was a major goal of our NPC natural history trial (06-CH-0186). We now have identified multiple biochemical abnormalities in our cohort of patients that may prove useful as biomarkers in a therapeutic trial. The next step is to attempt to validate these potential biomarkers in a therapeutic trial. Thus in this protocol we plan to evaluate the safety and efficacy of N-acetylcysteine to improve a group of biomarkers related to increased oxidative stress.

The goals of this protocol are:

To validate the use of biomarkers in a therapeutic trial for NPC.
To evaluate the safety of N-acetylcysteine in NPC patients.
To evaluate the efficacy of N-acetylcysteine to improve biomarkers associated with increased oxidative stress in NPC patients.

Conditions: Niemann-Pick Disease, Type C
Being tested: N-Acetyl Cysteine
Keywords: Niemann-Pick Disease, Type C, Biomarkers, N-Acetyl Cysteine, Oxidized Cholesterol, Neurodegeneration, NPC
Medical subject headings: Niemann-Pick Disease, Type C, Nerve Degeneration

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

N-Acetyl CysteineDrug
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).

What is being measured

The primary outcome is the main question the study is designed to answer.

Oxysterol Levels
Measured: Six months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Aug 2009Nov 2010

First posted11 Sep 2009 (estimated)
Study startAug 2009
Primary completionNov 2010
Study completionNov 2010

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 (3)Papers the sponsor has linked to this study.
Other trials for Niemann-Pick Disease, Type CStudies 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: Randomised
Intervention model: Crossover
Masking: Triple blind
Who is masked: Participant, Care provider, Investigator
Enrolment: 35 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00975689
Sponsor's protocol ID: 090185
Other IDs: 09-CH-0185
Status last verified: Apr 2013
First submitted: 10 Sep 2009
Last updated: 6 May 2013
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes

Publications

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.
PubMed 12974729
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.
PubMed 9211849
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.
PubMed 11125141

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Niemann-Pick Disease, Type C trials

Study at a glance

From the registry record, last updated by the sponsor on 6 May 2013. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Biomarker Validation for Niemann-Pick Disease, Type C: Safety and Efficacy of N-Acetyl Cysteine
ClinicalTrials.gov ID: NCT00975689
Acronym / sponsor ID: 090185
Conditions: Niemann-Pick Disease, Type C
Keywords: Niemann-Pick Disease, Type C, Biomarkers, N-Acetyl Cysteine, Oxidized Cholesterol, Neurodegeneration, NPC
Phase: Phase 1/2
Study type: Interventional
Recruitment status: Completed
Enrolment: 35 participants (actual)
Lead sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)US National Institutes of Health
Collaborators: University of Oxford, Washington University School of Medicine, National Human Genome Research Institute (NHGRI)
Study start: Aug 2009
Primary completion: Nov 2010 (actual)
Study completion: Nov 2010 (actual)
First posted: 11 Sep 2009 (estimated)
Results: Posted 12 Jul 2012

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

Detailed description

The goals of this protocol are:

To validate the use of biomarkers in a therapeutic trial for NPC.
To evaluate the safety of N-acetylcysteine in NPC patients.
To evaluate the efficacy of N-acetylcysteine to improve biomarkers associated with increased oxidative stress in NPC patients.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Triple blind (participant, care provider, investigator)

Who may qualify

Ages: 12 months and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (4 listed)

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.

Key exclusion criteria (22 listed)

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.

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
N-Acetyl Cysteine900mg 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).	Drug	–

Primary outcome

Oxysterol Levels
Time frame: Six months

Results and safety

Results posted to the registry on 12 Jul 2012, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Placebo Phase A/NAC Phase B	17	15
NAC Phase A/Placebo Phase B	18	15

Primary outcome: Oxysterol Levels

Time frame: Six months. Mean (Standard Error). Unit: ng/mL

Measure	NAC Phase n = 30	Placebo Phase n = 30
Value	28.09 (2.152)	27.64 (2.045)

Population analysed: Every patient in the trial received the study drug as well as the placebo.

Adverse events

Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo Phase A/NAC Phase B	3 of 17 (17.6%)	0 of 17 (0%)	Not reported
NAC Phase A/Placebo Phase B	5 of 18 (27.8%)	0 of 18 (0%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 May 2013.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 12974729Vanier 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.
Background: PubMed 9211849Carstea 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.
Background: PubMed 11125141Naureckiene 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.
NIH Clinical Center Detailed Web PageLink provided by the sponsor.

Related trials for Niemann-Pick Disease, Type C

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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?

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 4 inclusion and 22 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 6 May 2013. 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 12 Jul 2012). 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?

Oxysterol Levels (time frame: Six months). 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 NCT00975689, which also lists 3 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 6 May 2013.