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 |
Recruitment Status :
Recruiting
First Posted : January 9, 2020
Last Update Posted : March 29, 2021
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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) |
Estimated Enrollment : | 62 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 : | November 2023 |
Estimated Study Completion Date : | November 2023 |

Arm | Intervention/treatment |
---|---|
Experimental: GZ402671
Primary population: participant will receive venglustat dose 1 once daily during 104 weeks. Secondary population: participant will receive venglustat at various doses once daily during 104 weeks (open label period). |
Drug: venglustat GZ402671
Pharmaceutical form: tablet Route of administration: oral |
Placebo Comparator: Placebo
Primary population: participants will receive placebo once daily during 104 weeks.
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Drug: placebo
Pharmaceutical form: tablet Route of administration: oral |
- 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
- 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 to Week 110 ]Maximum venglustat concentration (Cmax)
- Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline to Week 110 ]Time to maximum venglustat concentration (tmax)
- Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline to Week 110 ]Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
- Assessment of PK parameters in CSF: Cmax [ Time Frame: Week 104 ]Maximum venglustat concentration (Cmax)
- Assessment of PK parameters in CSF: tmax [ Time Frame: Week 104 ]Time to maximum venglustat concentration (tmax)
- 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)
- 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 |
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
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, 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.

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
Contact: Trial Transparency email recommended (Toll free number for US & Canada) | 800-633-1610 ext option 6 | Contact-US@sanofi.com |
United States, California | |
Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004 | Recruiting |
Los Angeles, California, United States, 90095 | |
Contact: Aaron Fisher 310-206-8153 | |
Principal Investigator: Susan Perlman, MD | |
United States, Maryland | |
NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005 | Recruiting |
Bethesda, Maryland, United States, 20892-1205 | |
Contact: Andrea Ashton 240-274-8168 | |
Principal Investigator: Cynthia Tift, MD | |
United States, Massachusetts | |
Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002 | Recruiting |
Boston, Massachusetts, United States, 02114 | |
Contact: Daniel Kelly Clinical Research Coordinator 617-724-6374 | |
Principal Investigator: Florian Eichler, MD | |
United States, New York | |
NYU Langone - 550 First Avenue-Investigational site number 8400001 | Recruiting |
New York, New York, United States, 10016 | |
Contact 929-455-5108 | |
Principal Investigator: Heather LAU, MD | |
Brazil | |
Hospital de Clinicas de Porto Alegre _investigational site number 0760001 | Recruiting |
Porto Alegre, Brazil, 90035-903 | |
Contact: Diane Pedrini 55 51 3359-6341 dianebpedrini@gmail.com | |
Principal Investigator: Roberto Giugliani, MD PhD | |
Czechia | |
Investigational Site Number 2030001 | Recruiting |
Praha 2, Czechia, 12808 | |
Germany | |
Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001 | Recruiting |
Gießen, Germany, 35389 | |
Contact: Katharina Biesgen 49 641 98556848 Katharina.Biesgen@uk-gm.de | |
Principal Investigator: Andreas Hahn, Prof. | |
Japan | |
Investigational Site Number 3920001 | Recruiting |
Akita-Shi, Japan | |
Russian Federation | |
Investigational Site Number 6430001 | Recruiting |
Moscow, Russian Federation, 125367 | |
Spain | |
Investigational Site Number 7240001 | Recruiting |
Esplugues De Llobregat, Spain, 08950 | |
Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004 | Recruiting |
Hospitalet De Llobregat, Spain, 08907 | |
Contact: Elena Fabra efabra@bellvitgehospital.cat | |
Principal Investigator: Jordi Gascon Bayarri, MD | |
Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002 | Recruiting |
Santiago De Compostela, Spain, 15706 | |
Contact: Sofía Gouveia sofia.bsg@gmail.com | |
Principal Investigator: Maria Couce Pico, MD | |
United Kingdom | |
Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001 | Recruiting |
Cambridge, United Kingdom, CB2 0QQ | |
Contact: Liz Morris 01223274634 liz.morris@addenbrookes.nhs.uk | |
Principal Investigator: Timothy Cox, Prof. | |
Manchester University NHS Foundation Trust St Marys Hospital Manchester Royal Infirmary Oxford Road_investigational site number 8260003 | Not yet recruiting |
Manchester, United Kingdom, M13 9WL | |
Principal Investigator: Simon Jones, MD | |
Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002 | Not yet recruiting |
Salford, United Kingdom, M6 8HD | |
Contact: Marie Meehan 00441612064851 Marie.Meehan@srft.nhs.uk | |
Principal Investigator: Ana Jovanovic, MD |
Study Director: | Clinical Sciences & Operations | Sanofi |
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: | March 29, 2021 |
Last Verified: | March 2021 |
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://www.clinicalstudydatarequest.com/ |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Tay-Sachs Disease Sandhoff Disease Gangliosidoses, GM2 Gangliosidoses 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 |