A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2 (AMETHIST)

Investigating the Effects of an Investigational Medication on GM2 Gangliosidosis, a Rare Nervous System Disorder

Not Recruiting
2 years or above
All
Phase 3
75 participants needed

Study Overview

Primary Objectives:

Primary population (adult participants with late-onset GM2 gangliosidosis): To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period

Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosialidosis): 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 Objectives:

Primary population:

  • 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:

  • 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

Study Details

The total duration is up to approximately 223 weeks, including a 60-day screening period, a 104-week primary analysis treatment period, a 104-week open-label extension treatment period and a 6-week post-treatment safety observation period.

Eligibility Criteria

You may be eligible for this study if you meet the following criteria:

  • Conditions: Tay-Sachs Disease, Sandhoff Disease
  • Age: 2 years or above
  • Gender: All

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; no sperm donating for male participant

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 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, 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

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Updated on 25 Mar 2025. Study ID: NCT04221451

This study investigates the effects of an investigational medication on people with late-onset GM2 gangliosidosis, a rare genetic disorder that affects the nervous system. The study is designed to see how the medication works in the body and how it affects certain health markers over a 104-week period. Participants will include adults with late-onset GM2 gangliosidosis, as well as individuals with similar conditions such as GM1 gangliosidosis and other related disorders.

Participants will take the investigational medication orally every day. The study will evaluate the safety and effects of the medication by checking how it is absorbed in the blood and cerebrospinal fluid (CSF). The study will also involve performance tests to see how participants respond to the medication. The procedures will include regular health assessments to monitor any changes in condition or side effects.

  • Who can participate: Adults 18 years and older with late-onset GM2 gangliosidosis and related conditions can participate. Children and adolescents aged 2 to 17 weighing at least 10 kg are also eligible, provided they can take oral medication and complete study assessments.
  • Study details: Participants will take an oral dose of the investigational medication daily, with regular health checks and performance tests to monitor safety and effects. The study, lasting 223 weeks, includes a placebo group for comparison.
  • Study timelines: The study will last 223 weeks.