A Phase 3, Randomized, Multi-Center, Multi-National, Double-Blind Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Once Daily versus Twice Daily Dosing of Genz-112638 in Patients with Gaucher Disease Type 1 who have Demonstrated Clinical Stability on a Twice Daily Dose of Genz-112638.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 234
- 试验地点
- 1
- 主要终点
- The primary outcome of the study is to measure the number of randomized patients who remain stable after treatment with Genz-112638 for both dosing regimens (BID full dose, QD full dose) separately
研究概览
简要总结
Background: Gaucher disease is an autosomal recessive lysosomal glycolipid storage disease that results from a deficiency of acid â-glucosidase. The major natural substrate for this enzyme is glucosylceramide (GL-1), an intermediate metabolite in the synthesis and catabolism of more complex glycosphingolipids. Gaucher disease is characterized by lysosomal accumulation of GL-1 due to impaired GL-1 hydrolysis secondary to the deficiency of the enzyme acid â-glucosidase. In patients with Gaucher disease, different tissues show increases in GL-1 concentration, leading to the main manifestations of the disease: Anemia, thrombocytopenia, hepatosplenomegaly, skeletal disease, and neurological disease. The hallmark of Gaucher disease is the presence of lipid-engorged cells derived from the monocyte/macrophage system (Gaucher cell), which show a characteristic histological appearance and are distributed in tissues where macrophages reside (i.e., liver, spleen, lung, and bone marrow). It is believed that the storage material within these Gaucher cells of visceral tissues originates from phagocytosis of the blood cells, while in neurons of the brain, the storage material is believed to originate from endogenous synthesis.
The approach under development is the use of substrate reduction using Genz-112638, which acts by partially inhibiting the enzyme GL-1 synthase. The goal of this approach is to reduce the synthesis of the accumulated GL-1 (substrate reduction therapy) to a level where the residual enzyme activity of the mutant acid â-glucosidase, the enzyme deficient in Gaucher disease, can degrade GL-1, thus preventing storage of GL-1.
Study Design: This is a Phase 3, randomized, multi-center, multi-national, double-blind study to evaluate the efficacy, safety, and PK of QD versus BID Genz-112638 in male and female patients with Gaucher disease type 1 who have demonstrated clinical stability on BID dosing of Genz-112638.
研究设计
- 研究类型
- Interventional
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •The patient is greater than or equal to 18 years of age.
- •The patient has a diagnosis of Gaucher disease type 1 confirmed by a documented deficiency of acid Beta-glucosidase activity by enzyme assay.
- •The patient has any of the following abnormalities at the time of Screening: -Hemoglobin level greater than ot equal to 9 g/dL (mean of 2 measurements); -Platelet count greater than ot equal to 70,000/mm3 (mean of 2 measurements); -Spleen volume less than or equal to 25 multiples of normal (MN); -Liver volume less than or equal to 2.0 MN.
- •The patient consents to provide a blood sample for genotyping for Gaucher disease and for cytochrome P4502D6 (CYP2D6) to categorize the patients predicted rate of metabolism, if these genotyping results are not already available for the patient.
排除标准
- •The patient received pharmacological chaperones or miglustat within 6 months prior to administration of the first dose of Genz-112638 in this study.
- •The patient has had a partial or total splenectomy within 3 years prior to administration of the first dose of Genz-112638 in this study.
- •The patient has any evidence of neurologic disorder (e.g., peripheral neuropathy, tremor, seizures, Parkinsonism or cognitive impairment) or pulmonary involvement (e.g., pulmonary hypertension) as related to Gaucher disease.
- •The patient is transfusion-dependent.
- •The patient has a documented deficiency of iron, vitamin B-12, or folate that requires treatment not yet initiated or, if initiated, the patient has not been stable under treatment for at least 3 months prior to administration of the first dose of Genz-112638 in this study.
- •The patient has documented prior esophageal varices or liver infarction or current liver enzymes (alanine transaminase [ALT]/aspartate aminotransferase [AST]) or total bilirubin greater than 2 times the upper limit of normal (ULN), unless the patient has a diagnosis of Gilbert Syndrome.
- •The patient has any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (including hypokalaemia or hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that, in the opinion of the Investigator, may preclude participation in the study.
- •The patient is known to have any of the following: Clinically significant coronary artery disease including history of myocardial infarction [MI] or ongoing signs or symptoms consistent with cardiac ischemia or heart failure; or clinically significant arrhythmias or conduction defect such as 2nd or 3rd degree atrioventricular (AV) block, complete bundle branch block, prolonged QTc interval, or sustained ventricular tachycardia (VT).
结局指标
主要结局
The primary outcome of the study is to measure the number of randomized patients who remain stable after treatment with Genz-112638 for both dosing regimens (BID full dose, QD full dose) separately
时间窗: Week 52
次要结局
- The secondary outcome would be the see the Improvement in Hemoglobin level,(and platelet count,)