Tay-Sachs disease Sandhoff disease MedDRA version: 23.0 Level: LLT Classification code 10043147 Term: Tay-Sachs disease System Organ Class: 10010331 - Congenital, familial and genetic disorders MedDRA version: 23.0 Level: LLT Classification code 10081314 Term: Sandhoff disease System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Sponsors
Genzyme Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Primary population and adult secondary population: age = 18 years - Juvenile/adolescent secondary population: 2 = age =65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by ß-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes and/or is without clinical features - For primary population and participants with juvenile/adolescent late onset GM2 gangliosidosis and GM1 gangliosidosis, the participant cannot understand and perform all age-appropriate study assessments with the exception of 25FWT and PROs. - Relevant medical disorders that would compromise his/her safety - Documented diagnosis of hepatitis B, C, human immunodeficiency virus 1 or 2 - World Health Organization (WHO) grade > 2 cortical cataract or a grade > 2 posterior subcapsular cataract; patients with nuclear cataracts will be accepted - Participant who requires invasive ventilatory support - Current treatment by anticoagulants, cataractogenic medications or any medications that may worsen the vision of patient with cataract - Previous treatment with substrate reduction therapy (SRT) within 3 months prior to study enrollment, strong or moderate inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives prior to enrollment. This also includes the consumption of grapefruit, grapefruit juice or grapefruit products within 72hrs prior to starting investigational medicinal product (IMP) administration. - Current participation in another study - Use of investigational medicinal product (IMP) within 3 months or 5 half-lives prior to enrollment, whichever is longer, before study enrollment (for N-acetyl-leucine, within 5 half-lives before study enrollment). - Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total bilirubin > 2 x the upper limite of normal (ULN) at the time of screening unless the participant has the diagnosis of Gilbert syndrome and maintains a level of bilirubin < 5 mg/dl and direct bilirubin < 20% (1 mg/dl) of total bilirubin level - Renal insufficiency is defined by estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at the screening visit
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: - Primary population: To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period - Secondary population: To assess PD response (plasma and CSF GL-1 biomarker and disease specific biomarkers) of venglustat when administered once daily over a 104-week period ;Secondary Objective: Primary population (adult participants with late-onset GM2 gangliosidosis): - To assess the PD of daily oral dosing of venglustat and the effect of venglustat on selected performance test and scale over a 104-week period. - To determine the safety and tolerability of venglustat when administered orally once daily over a 104-week period - To assess the pharmacokinetics (PK) of venglustat in plasma and cerebrospinal fluid (CSF) Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosidosis): - To assess the effect of venglustat on selected performance tests and scale over a 104-week period - To determine the safety and tolerability of venglustat when administered once daily over a 104-week period - To assess the PK of venglustat in plasma and CSF - To assess the acceptability and palatability of the venglustat tablet ;Primary end point(s): 1 - Change in cerebrospinal fluid (CSF) GM2 biomarker ; Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population 2 - Change in the 9-hole pegboard test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population 3 - Assessment of pharmacodynamic (PD) response in plasma and CSF: - GL-1, GM1 biomarkers ; Concentration of GL-1 biomarker with pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population - GL-1, GM2 biomarkers ; Concentration of GL-1 with GM2 for GM2 gangliosidosis in secondary population - GL-1, GM2, GM3 biomarkers ; Concentration of GL-1 with GM2, GM3 for siali | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1 - Safety/tolerability: Adverse events ; Number of patients with adverse events 2 - Assessment of pharmacokinetic (PK) parameters in plasma: Cmax ; Maximum venglustat concentration (Cmax) 3 - Assessment of PK parameters in plasma: tmax ; Time to maximum venglustat concentration (tmax) 4 - Assessment of PK parameters in plasma: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h) 5 - Assessment of PK parameters in plasma: plasma concentrations;Plasma venglustat concentration 6 - Assessment of PK parameters :CSF venglustat; CSF venglustat concentration 7 - Change in 25-foot walk test (FWT) ; Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline) 8 - Absolute change in CSF GM2 biomarker 9 - Change in Friedreich's Ataxia Rating Scale (FARS) ; Change in FARS score from baseline to Week 104 10 - Change in 9-hole peg test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population 11 - Acceptability and palatability assessments;Timepoint(s) of evaluation of this end point: 1, 5, 7,8,9,10,11 : From baseline to Week 104 6: Week 104 2,3,4: From baseline up to Week 12 | — |
Countries
Argentina, Austria, Brazil, Czechia, Czech Republic, France, Germany, Italy, Japan, Portugal, Russian Federation, Spain, Türkiye, United Kingdom, United States
Outcome results
None listed