E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Tay-Sachs disease
Sandhoff disease |
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E.1.1.1 | Medical condition in easily understood language |
Tay-Sachs disease
Sandhoff disease |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10043147 |
E.1.2 | Term | Tay-Sachs disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10081314 |
E.1.2 | Term | Sandhoff disease |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- 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
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E.2.2 | Secondary objectives of the trial |
Primary population (adult participants with late-onset GM2 gangliosidosis):
- To assess 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
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Primary population and adult secondary population: age ≥ 18 years
- Juvenile/adolescent secondary population: 2 ≥ age < 18 years with weight ≥ 10 kg
- Participants with a diagnosis of late onset GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) caused by genetic β-hexosaminidase deficiency resulting from mutations in the HEXA or HEXB genes (primary population only); a secondary population will enroll patients with diagnosis of juvenile/adolescent GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile adult galactosialidosis
- For primary population, the participant has the ability to perform the 9-HPT at the screening visit in < = 240 seconds for the 2 consecutive trials of the dominant hand and the 2 consecutive trials of the nondominant hand.
- Participants with a history of seizures well controlled by medication other than strong or moderate inducer or inhibitor of CYP3A4
- Participant is cooperative, able to ingest oral medication, willing to travel to a study site (if applicable), and able to comply with all aspects of the study, including all assessments, according to the Investigator's judgement
- Signed written informed assent/consent
- Contraception for sexually active male participants or female patient; not pregnant or breastfeeding |
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E.4 | Principal exclusion criteria |
- Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by β-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.
- 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
- 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 limit 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 |
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E.5 End points |
E.5.1 | 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 sialidosis in secondary population
- GL-1, GM1, GM3 biomarkers ; Concentration of GL-1 with GM1, GM3 for galactosialidosis in secondary population
- GL-1 biomarker ; Concentration of GL-1 for saposin C deficiency in secondary population |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3 : From baseline to Week 104 |
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E.5.2 | 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)
Assessment of PK parameters in plasma: tmax ; Time to maximum venglustat concentration (tmax)
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)
3 - Assessment of PK parameters in CSF: Cmax ; Maximum venglustat concentration (Cmax)
Assessment of PK parameters in CSF: tmax ; Time to maximum venglustat concentration (tmax)
Assessment of PK parameters in CSF: AUC0-24h ; Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
4 - Change in 25-foot walk test (FWT) ; Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
5 - Change in Friedreich's Ataxia Rating Scale (FARS) ; Change in FARS score from baseline to Week 104
6 - Change in 9-hole peg test (9-HPT) ; Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 3, 4, 5, 6 : From baseline to Week 104 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
For secondary population: open-label treatment with venglustat only |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Austria |
Brazil |
Czechia |
France |
Germany |
Italy |
Japan |
Portugal |
Russian Federation |
Spain |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 14 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 14 |