Gaucher disease is an inherited functional deficiency of glucocerebrosidase (beta-glucosidase) which leads to glycolipid accumulation in various tissues. OGT 918 is a reversible inhibitor of glucosylceramide synthase, a key enzyme in the synthesis of glycolipids, and has shown beneficial effects in a clinical study in type 1 Gaucher disease. The primary objective of this clinical trial is to evaluate OGT 918 as a treatment for neuronopathic Gaucher disease by assessing changes in saccadic eye movement velocity. Other markers of the disease will also be assessed, including neurological and pulmonary involvement. Secondary objectives are to assess the clinical safety and tolerability of OGT 918 therapy. Up to 30 patients, recruited from the National Institutes Health, Bethesda, USA and the Institute of Child Health, London, U.K. will be randomized to OGT 918 or no treatment in a 2:1 ratio for the 12 month study period. Patients will be clinically diagnosed with neuronopathic Gaucher disease, 12 years of age or older, on a stable dose of enzyme replacement therapy (ERT) for at least 6 months and be able to swallow capsules. Randomization will be stratified based on whether or not the patient has undergone a splenectomy. All patients will follow an identical visit schedule. Patients aged 12 years or over randomized to receive OGT 918 will commence treatment at a dose of 200 mg (2 x 100 mg capsules) OGT 918 three times daily. As some patients may experience initial gastrointestinal intolerance this dose may be modified, however the aim will be to maintain patients at the highest tolerable dose in order to achieve the most clinical benefit. Data analysis is planned, comparing OGT 918 to the no treatment group, when all patients have completed 12 months of the study. The study will be extended, up to a total of 12 additional months, to collect safety and efficacy data. The length of the extension study will be dependent on the results of the final analysis. All patients completing the main study, including those initially randomized to the no treatment group, will be able to participate in the extension study unless there are safety issues to prohibit this. All patients in the extension study will receive OGT 918. Disease activity assessments will be conducted as indicated in the study flow charts. For a complete description of all study assessments, please refer to Section 7 of the main protocol. Where possible, study assessments will be blinded. The effect of OGT 918 on the electro-oculographic characteristics of saccadic activity, specifically the amplitude/velocity characteristics (main sequence), will be the primary outcome variable. Saccadic velocity-amplitude relationship is decreased in neuronopathic Gaucher patients. This study will assess whether OGT 918 therapy is capable of improving or stopping any further deterioration of this ocular function.
- INCLUSION CRITERIA: Patients with neuronopathic Gaucher disease, confirmed by clinical diagnosis, who if receiving enzyme replacement therapy have been stable on enzyme replacement therapy for at least 6 months or have successfully undergone a bone marrow transplant at least one year prior to study entry. Patients who are at least 4 years old and can swallow a capsule. EXCLUSION CRITERIA: Patients younger than 18 years who are unable to give informed assent and/or whose legal guardian is unable to provide informed consent. Patients aged 18 and over who cannot provide informed consent and/or whose legal guardian is unable to provide witnessed informed consent. Fertile patients, who at the time of the study could be sexually active, and who do not agree to use adequate contraception throughout the study and for three months after cessation of OGT 918 treatment. Patients who cannot tolerate the study procedures or who are unable to travel to the study center as required by this protocol. Patients currently undergoing therapy with other investigational agents or patients taking drugs or food supplements which may interfere with gastrointestinal absorption or motility. Patients suffering from clinically significant diarrhea (greater than 3 liquid stools per day for greater than 7 days) without definable cause within 3 months of the Screening Visit, or who have a history of significant gastrointestinal disorders. Patients with an intercurrent medical condition that would render them unsuitable for the study e.g. HIV, hepatitis infection. Patients who in the opinion of the investigator (for whatever reason) are thought to be unsuitable for the study. Patients with an adjusted Creatinine Clearance of less than 70 ml/min/1.73m(2) (CrCl less than 70).