Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis
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|ClinicalTrials.gov Identifier: NCT00028262|
Recruitment Status : Completed
First Posted : December 18, 2001
Results First Posted : January 21, 2015
Last Update Posted : October 27, 2016
|First Submitted Date ICMJE||December 17, 2001|
|First Posted Date ICMJE||December 18, 2001|
|Results First Submitted Date||January 9, 2015|
|Results First Posted Date||January 21, 2015|
|Last Update Posted Date||October 27, 2016|
|Start Date ICMJE||February 2001|
|Primary Completion Date||November 2013 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Change in Cellular Granular Osmiophilic Deposits (GRODs) in Electron Micrographs of Peripheral White Blood Cells. [ Time Frame: 10 years ]
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.
|Original Primary Outcome Measures ICMJE||Not Provided|
|Change History||Complete list of historical versions of study NCT00028262 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Cystagon to Treat Infantile Neuronal Ceroid Lipofuscinosis|
|Official Title ICMJE||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:
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.|
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Infantile Neronal Ceroid Lipofuscinosis|
|Intervention ICMJE||Drug: Cystagon|
|Study Arms||Experimental: Drug: Cystagon and N-acetylcysteine
Intervention: Drug: Cystagon
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||November 2013|
|Primary Completion Date||November 2013 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
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.
|Ages||6 Months to 3 Years (Child)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT00028262|
|Other Study ID Numbers ICMJE||010086
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||National Institutes of Health Clinical Center (CC) ( Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) )|
|Study Sponsor ICMJE||Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)|
|Collaborators ICMJE||Not Provided|
|PRS Account||National Institutes of Health Clinical Center (CC)|
|Verification Date||September 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP