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

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Genzyme

Status and phase

Active, not recruiting
Phase 3

Conditions

Tay-Sachs Disease
Sandhoff Disease

Treatments

Drug: venglustat GZ402671
Drug: placebo

Study type

Interventional

Funder types

Industry

Identifiers

NCT04221451
EFC15299
U1111-1197-7905 (Other Identifier)
2019-002375-34

Details and patient eligibility

About

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

Full description

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.

Enrollment

75 patients

Sex

All

Ages

2+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

75 participants in 2 patient groups, including a placebo group

GZ402671
Experimental group
Description:
Primary population: participant will receive venglustat dose once daily during the primary analysis period (104 weeks) and the open-label extension period (104 weeks). Secondary population: participant will receive venglustat at various doses once daily during the primary analysis period open-label (104 weeks) and the open-label extension period (104 weeks).
Treatment:
Drug: venglustat GZ402671
Placebo
Placebo Comparator group
Description:
Primary population: participants will receive placebo once daily during the primary analysis period (104 weeks) and will receive venglustat dose once daily during the open-label extension period (104 weeks).
Treatment:
Drug: placebo

Trial contacts and locations

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Data sourced from clinicaltrials.gov

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