Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis

NCT ID: NCT00028262

Last Updated: 2016-10-27

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-02-28
• Study Completion Date: 2013-11-30

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.

Detailed Description

Neuronal ceroid lipofuscinoses (NCLs), commonly known as Batten disease, represent a group of the most common (1 in 12,500) heritable neurodegenerative storage disorders of childhood. Mutations of at least 8 different genes are responsible for various forms of NCL. The infantile form of NCL or INCL is the most severe disease. It is caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 is a lysosomal enzyme that cleaves thioester linkages in S-acylated proteins and its deficiency leads to abnormal lysosomal accumulation of fattyacylated- proteins (ceroids) leading to INCL pathogenesis. Since thioester linkages are labile, drugs with nucleophilic property are likely to mimic PPT1 and may have therapeutic potential for INCL. We previously reported that cysteamine, phosphocysteamine, cysteamine bitartrate (cystagon) and N-acetylcysteine disrupt thioester linkages in a model PPT1-substrate, C(14) palmitoyl-CoA, releasing C(14) palmitic acid. The results of our laboratory studies have shown that cysteamine mediates the depletion of intracellular ceroid deposits and prevents their reaccumulation. For the last 9 years, we have been conducting a clinical trial to determine whether a combination of Cystagon (Cysteamine bitartrate) and N-acetylcysteine (mucomyst) is beneficial for INCL patients. In parallel with these studies, using an animal model of INCL we found that this combination therapy reduces oxidative stress caused by high levels of reactive oxygen species (ROS) in the brain of mice lacking the PPT1 enzyme. To date, we have admitted a total of 10 patients (5 females and 5 males) to this protocol; however, one male patient was lost to follow-up. Thus, we have treated 9 patients (5 females and 4 males) and these patients showed no adverse reactions to these drugs except for one patient who initially had mild gastrointestinal discomfort which went away when cystagon was stopped and restarted from the lowest dose and this mild adverse effect did not recur. Compared with the published natural history of INCL, our preliminary results show that although several parameters of disease progression are slowed due to the treatment it does not completely arrest the neurodegenerative process. We are currently analyzing all the data gathered so far and a manuscript describing the results will be prepared for submission to a peer-reviewed journal.

Conditions

Infantile Neronal Ceroid Lipofuscinosis

Keywords

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Drug: Cystagon and N-acetylcysteine

Group Type: EXPERIMENTAL

Cystagon

Intervention Type: DRUG

Interventions

Cystagon

Intervention Type: DRUG

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 3 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Anil B Mukherjee, M.D.

Role: PRINCIPAL_INVESTIGATOR

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

Locations

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, United States

Countries

United States

References

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

Reference Type: BACKGROUND

PMID: 3291628 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 3146319 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 4359377 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11283676 (View on PubMed)

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.

Reference Type: RESULT

PMID: 24997880 (View on PubMed)

Related Links

http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2001-CH-0086.html

NIH Clinical Center Detailed Web Page

Other Identifiers

01-CH-0086

Identifier Type: -

Identifier Source: secondary_id

010086

Identifier Type: -

Identifier Source: org_study_id