Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis

NCT00028262 | Completed Phase 4 Results DMC

• 2 other identifiers: 01008601-CH-0086
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine the effectiveness of a drug called Cystagon in treating infantile neuronal ceroid lipofuscinosis (INCL), a progressive neurological disease affecting children. At around 11 to 13 months of age, patients develop slowed head growth, mild brain atrophy (wasting), electroencephalographic (EEG) changes and retinal deterioration, with symptoms worsening over time. The disease results from an enzyme deficiency that causes fatty compounds called ceroid to accumulate in cells. In laboratory experiments, Cystagon has helped remove ceroid from cells of patients with INCL. Children with INCL between 6 months and 3 years of age may be eligible for this study. Participants take Cystagon daily by mouth every 6 hours. They are admitted to the NIH Clinical Center for a 4- to 5-day period every 6 months for the following tests and evaluations:

• Review of medical history, including a detailed record of seizures, physical examination, blood tests and clinical photographs. For the initial baseline studies, examinations may also be scheduled with pediatric neurology, ophthalmology and anesthesia services.
• Magnetic resonance imaging (MRI) of the brain MRI uses a powerful magnet, radio waves, and computers to provide detailed images of the brain without the use of X-rays. The patient lies on a table that slides inside a donut-shaped machine containing a magnetic field. The child requires general anesthesia for the procedure.
• Electroretinogram (ERG) measures the function of the retina, the light-sensitive tissue in the back of the eye. To record the flash ERG, a special contact lens is placed on the eye s surface and the eye is stimulated with flashes of light. Infants and very young children require general anesthesia for the procedure.
• Visual evoked potential (VEP) measures the function of the visual pathway from the eye to the brain. To record the VEP, five electrodes are placed on the scalp and the eye is stimulated with flashes of light. Infants and very young children must be anesthetized for the procedure.
• Electroencephalogram (EEG) measures brain electrical activity, using electrodes placed on the scalp. The test is useful in defining seizures. The child may need to be sedated to keep still during the test.
• Skin biopsy A small piece of skin is removed (usually from the upper arm or shoulder) under local anesthetic to grow cells in the laboratory. This procedure is done at the start of the study and is repeated after 1 year if therapy results are promising. Children s condition may improve, stabilize or worsen during this study. Life may be prolonged without significant improvement in quality. The information gained from the study may help scientists develop more potent drugs to treat INCL.

Conditions

Infantile Neronal Ceroid Lipofuscinosis

Keywords

Palmitoyl-Protein Thioesterase; Lysosomes; Batten Disease; Encephalopathy; Progressive Neurodegeneration; CLN 1; Infantile Neuronal Ceroid Lipofuscinosis; Cystagon

Outcome Measures

Primary Outcomes (1)

• Change in Cellular Granular Osmiophilic Deposits (GRODs) in Electron Micrographs of Peripheral White Blood Cells.

  The GRODs in peripheral white blood cells from all patients before and during treatment were analyzed by transmission electron microscopy (TEM) at 30000xmagnification. Two investigators working independently of each other identified and counted the GRODs and the results were averaged.

  10 years

Study Arms (1)

Drug: Cystagon and N-acetylcysteine

EXPERIMENTAL

Drug: Cystagon

Interventions

Cystagon DRUG

Drug: Cystagon and N-acetylcysteine

Eligibility Criteria

• Age: 6 Months - 3 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may not qualify if:

• Only patients between 6 months and 3 years of age will be admitted in this study. Parents or caregivers of patients recruited to the study will be provided with a copy of the protocol and the consent form to review prior to their coming to the NIH. They will be encouraged to call either Dr. Levin or Dr. Mukherjee to discuss any questions they may have concerning the protocol prior to enrollment in the study.
• The proposed age range (6 mo to 3 yrs) was chosen because these children are expected to have a mild to moderate neurological deficiency but are well enough to be cared for at home by the family. Therefore, these patients should not require extensive medical or nursing care during their stay at the Clinical Center. Moreover, the patients are locally cared for by neurologists and pediatricians on a regular basis, and such care will continue when the patients return home.
• In our initial protocol we restricted the admission of patients that carried two lethal mutations in the PPT1 gene. The purpose of including only those patients who carry specific PPT1 mutations
• (L10X, R151X, R164X, W296X, R122W, c.169insA and E184K) was to establish that the beneficial effects of the combination therapy because a patients who had any two of these mutations manifested the most severe disease phenotype. Because of the uniform manifestation of the disease it was easier to determine any beneficial effects of the combination drug therapy.
• Subsequently, our protocol was approved for treatment of INCL patients with any two mutations in the PPT1 gene. Our protocol has been previously amended to include all INCL patients regardless of the PPT1 mutations they carry.
• Patients with intractable seizures that cannot be controlled by two or fewer antiepileptic medications will not be accepted for this study. Patients who cannot take nourishment orally or who are in a vegetative state will not be enrolled in this study even if the 6 months to 3 year age criterion is met.
• Both male and female patients are eligible for enrollment in this study.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 1988;10(2):80-3. doi: 10.1016/s0387-7604(88)80075-5.

  PMID: 3291628 BACKGROUND

• Rider JA, Rider DL. Batten disease: past, present, and future. Am J Med Genet Suppl. 1988;5:21-6. doi: 10.1002/ajmg.1320310606.

  PMID: 3146319 BACKGROUND

• Rapola J, Haltia M. Cytoplasmic inclusions in the vermiform appendix and skeletal muscle in two types of so-called neuronal ceroid-lipofuscinosis. Brain. 1973 Dec;96(4):833-40. doi: 10.1093/brain/96.4.833. No abstract available.

  PMID: 4359377 BACKGROUND

• Zhang Z, Butler JD, Levin SW, Wisniewski KE, Brooks SS, Mukherjee AB. Lysosomal ceroid depletion by drugs: therapeutic implications for a hereditary neurodegenerative disease of childhood. Nat Med. 2001 Apr;7(4):478-84. doi: 10.1038/86554.

  PMID: 11283676 BACKGROUND

• Levin SW, Baker EH, Zein WM, Zhang Z, Quezado ZM, Miao N, Gropman A, Griffin KJ, Bianconi S, Chandra G, Khan OI, Caruso RC, Liu A, Mukherjee AB. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol. 2014 Aug;13(8):777-87. doi: 10.1016/S1474-4422(14)70142-5. Epub 2014 Jul 2.

  PMID: 24997880 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Ceroid lipofuscinosis, neuronal 1, infantile; Neuronal Ceroid-Lipofuscinoses; Brain Diseases

Interventions

Cysteamine

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Central Nervous System Diseases

Intervention Hierarchy (Ancestors)

Mercaptoethylamines; Ethylamines; Amines; Organic Chemicals; Sulfhydryl Compounds; Sulfur Compounds

Results Point of Contact

• Title: Dr. Anil Mukherjee
• Organization: National Institute of Child Health and Human Development

mukherja@exchange.nih.gov

+1 301 496 7213

Study Officials

• Anil B Mukherjee, 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 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2001
• First Posted: December 18, 2001
• Study Start: February 1, 2001
• Primary Completion: November 1, 2013
• Study Completion: November 1, 2013
• Last Updated: October 27, 2016
• Results First Posted: January 21, 2015

Record last verified: 2016-09

Locations

US (1)