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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| ClinicalTrials.gov Identifier: NCT04221451 |
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Recruitment Status :
Active, not recruiting
First Posted : January 9, 2020
Last Update Posted : November 4, 2022
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Sponsor:
Genzyme, a Sanofi Company
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
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Brief Summary:
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 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
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Tay-Sachs Disease Sandhoff Disease | Drug: venglustat GZ402671 Drug: placebo | Phase 3 |
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 74 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Treatment |
| Official Title: | A Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Venglustat in Late-onset GM2 Gangliosidosis (Tay-Sachs Disease and Sandhoff Disease) Together With a Separate Basket for Juvenile/Adolescent Late-onset GM2 Gangliosidosis and Ultra-rare Diseases Within the Same and Similar Glucosylceramide-based Sphingolipid Pathway |
| Actual Study Start Date : | June 29, 2020 |
| Estimated Primary Completion Date : | February 25, 2024 |
| Estimated Study Completion Date : | February 25, 2026 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Tay-Sachs disease
Sandhoff disease
GM2-gangliosidosis, AB variant
MedlinePlus related topics:
Tay-Sachs Disease
| Arm | Intervention/treatment |
|---|---|
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Experimental: GZ402671
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). |
Drug: venglustat GZ402671
Pharmaceutical form: tablet Route of administration: oral |
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Placebo Comparator: Placebo
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).
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Drug: placebo
Pharmaceutical form: tablet Route of administration: oral |
Primary Outcome Measures :
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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 Measures :
- Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ]Number of patients with adverse events
- Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline up to Week 12 ]Maximum venglustat concentration (Cmax)
- Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline up to Week 12 ]Time to maximum venglustat concentration (tmax)
- Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline up to Week 12 ]Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
- Assessment of PK parameters in plasma: plasma concentrations [ Time Frame: From baseline up to Week 104 ]Plasma venglustat concentration
- Assessment of PK parameters: CSF venglustat concentration [ Time Frame: Week 104 ]CSF venglustat concentration
- 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)
- 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
- 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
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| Ages Eligible for Study: | 2 Years and older (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221451
Locations
Show 24 study locations
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
| Study Director: | Clinical Sciences & Operations | Sanofi |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | Genzyme, a Sanofi Company |
| ClinicalTrials.gov Identifier: | NCT04221451 |
| Other Study ID Numbers: |
EFC15299 2019-002375-34 U1111-1197-7905 ( Other Identifier: UTN ) |
| First Posted: | January 9, 2020 Key Record Dates |
| Last Update Posted: | November 4, 2022 |
| Last Verified: | November 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Tay-Sachs Disease Gangliosidoses, GM2 Gangliosidoses Sandhoff Disease Sphingolipidoses Lysosomal Storage Diseases, Nervous System Brain Diseases, Metabolic, Inborn Brain Diseases, Metabolic Brain Diseases Central Nervous System Diseases Nervous System Diseases |
Metabolism, Inborn Errors Genetic Diseases, Inborn Lipidoses Lipid Metabolism, Inborn Errors Lysosomal Storage Diseases Metabolic Diseases Lipid Metabolism Disorders Venglustat Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |