A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, pharmacodynamics, pharmacokinetics, and safety of venglustat in late onset GM2

JRCT ID: jRCT2021200023

Registered date:09/10/2020

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Tay-Sachs Disease, Sandhoff Disease
• Date of first enrollment: 27/10/2020
• Target sample size: 77
• Countries of recruitment: Spain,Japan,United States,Japan,Brazil,Japan,Russian Federation,Japan,United Kingdom,Japan,Argentina,Japan,Austria,Japan,Czechia,Japan,Germany,Japan,Italy,Japan,Portugal,Japan,Turkey,Japan,France,Japan
• Study type: Interventional

Intervention(s)

Drug: venglustat GZ402671
- Pharmaceutical form: tablet
- Route of administration: oral
Drug: placebo
- Pharmaceutical form: tablet
- Route of administration: oral

Outcome(s)

Primary Outcome

1. Change in cerebrospinal fluid (CSF) GM2 biomarker [ Time Frame: From baseline to Week 104 ], Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population
2. Change in the 9-hole pegboard test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population
3. Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
4. Assessment of PD response in plasma: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population
5. Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population
6. Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population
7. Assessment of PD response in plasma: GL-1 biomarker [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 for saposin C deficiency in secondary population
8. Assessment of PD response in CSF: GL-1, GM1 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
9. Assessment of PD response in CSF: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population
10. Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population
11. Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population
12. Assessment of PD response in CSF: GL-1 biomarker [ Time Frame: From baseline to Week 104 ], Concentration of GL-1 for saposin C deficiency in secondary population

Secondary Outcome

1. Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ], Number of patients with adverse events
2. Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline to Week 12 ], Maximum venglustat concentration (Cmax)
3. Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline to Week 12 ], Time to maximum venglustat concentration (tmax)
4. Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline to Week 12 ], Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
5. Assessment of PK parameters in CSF: Cmax [ Time Frame: Week 104 ], Maximum venglustat concentration (Cmax)
6. Assessment of PK parameters in CSF: tmax [ Time Frame: Week 104 ], Time to maximum venglustat concentration (tmax)
7. Assessment of PK parameters in CSF: AUC0-24h [ Time Frame: Week 104 ], Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
8. Change in 25-foot walk test (FWT) [ Time Frame: From baseline to Week 104 ], Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
9. Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS) [ Time Frame: From baseline to Week 104 ], Change in the neurological examination of the FARS score from baseline to Week 104
10. Change in 9-hole peg test (9-HPT) [ Time Frame: From baseline to Week 104 ], Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population

Key inclusion & exclusion criteria

• Age minimum: >= 2age old
• Age maximum: Not applicable
• Gender: Both

Include 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 beta-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; no sperm donating for male participant

Exclude criteria

- Participant has clinical features of Tay-Sachs or Sandhoff disease, not caused by beta-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 25-foot walk test (25FWT) and patient-reported outcome (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, 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/1.73m^2 at the screening visit

Related Information

• Primary Sponsor: Tanaka Tomoyuki
• Secondary ID(s): NCT04221451,2019-002375-34