Infantile Neronal Ceroid Lipofuscinosis Clinical Trial
Official title:
A Combination Therapy With Cystagon and N-Acetylcysteine for INCL Patients
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.
| Status | Completed |
| Enrollment | 10 |
| Est. completion date | November 2013 |
| Est. primary completion date | November 2013 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 6 Months to 3 Years |
| Eligibility |
- INCLUSION and EXCLUSION CRITERIA: 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. The rigid age exclusion criteria will be used because the majority of INCL patients have more frequent seizures, complete retinal blindness and significant cerebral atrophy beyond 3 years of age. Dr. Santavuori (one of our consultants who is now deceased), who had the most extensive experience with these patients, believed that the neurological degeneration after age 2 might not be reversible. While Dr. Santavuori s speculation is well taken, we feel that since to date there has not been any effective treatment to slow the progression of neuronal death in INCL, and since our preliminary results show that Cystagon slows the progression of neurodegeneration, we feel that a combination of Cystagon plus N-Ac with its anti-apoptotic and neuro-protective effects may show some added benefits over Cystagon therapy alone. 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. |
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United States | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland |
| Lead Sponsor | Collaborator |
|---|---|
| Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
United States,
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 — View Citation
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. — View Citation
Rider JA, Rider DL. Batten disease: past, present, and future. Am J Med Genet Suppl. 1988;5:21-6. — View Citation
Santavuori P. Neuronal ceroid-lipofuscinoses in childhood. Brain Dev. 1988;10(2):80-3. Review. — View Citation
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. — View Citation
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | 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 | No |