Tay-Sachs DiseasePhase 3AMETHISTNCT04221451
A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2
A Phase 3 study testing venglustat GZ402671 in people with Tay-Sachs Disease and Sandhoff Disease, run by Genzyme, a Sanofi Company at 23 sites in 13 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 2 years and olderHealthy volunteers can take part
- Conditions the study is for
- Tay-Sachs Disease, Sandhoff Disease
- What is being tested?
- venglustat GZ402671
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 75 participants
- Where
- 23 sitesin 13 countries
- Study dates
- 29 Jun 2020to 26 Dec 2024
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- 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 locations and contacts
23 sites in 13 countries.
23 sites in 13 countries
United States5 sites
Emory Genetics - Investigational site number 8400006
Atlanta, Georgia, 30322
NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005
Bethesda, Maryland, 20892
Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002
Boston, Massachusetts, 02114
Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004
Los Angeles, California, 90095
NYU Langone - 550 First Avenue-Investigational site number 8400001
New York, New York, 10016
Spain3 sites
Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001
Esplugues de Llobregat, Catalunya [Cataluña], 08950
Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004
L'Hospitalet de Llobregat, Barcelona [Barcelona], 08907
Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002
Santiago de Compostela, Galicia [Galicia], 15706
United Kingdom3 sites
Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001
Cambridge, Cambridgeshire, CB2 OQQ
Investigational Site Number : 8260003
Manchester, M13 9WL
Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002
Salford, M6 8HD
Argentina2 sites
Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001
Córdoba, X5004FHP
Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002
Pilar, Buenos Aires, B1629ODT
Japan2 sites
Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001
Akita, Akita, 010-1495
Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002
Sendai, Miyagi, 983-8512
Brazil1 site
Hospital de Clinicas de Porto Alegre _investigational site number 0760001
Porto Alegre, Rio Grande do Sul, 90035 003
Czechia1 site
Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001
Prague, 12808
France1 site
APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001
Paris, 75013
Germany1 site
Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001
Giessen, 35390
Portugal1 site
Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002
Lisbon, 1649-035
Russia1 site
Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001
Moscow, 125367
Turkey (Türkiye)1 site
Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001
Ankara, 06500
About this study
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
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
Read more
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
Read the detailed 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.
- Conditions
- Tay-Sachs Disease, Sandhoff Disease
- Being tested
- venglustat GZ402671, placebo
- Medical subject headings
- Tay-Sachs Disease, Sandhoff Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
venglustat GZ402671Drug
Pharmaceutical form: tablet
Route of administration: oral
placeboDrug
Pharmaceutical form: tablet
Route of administration: oral
| Study group | Role | What they receive |
|---|---|---|
| GZ402671 | Experimental | 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). Receives: Drug: venglustat GZ402671 |
| Placebo | Placebo comparator | 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). Receives: Drug: placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104
Lumbar puncture was performed for obtaining CSF samples at specified timepoints to assess the presence of GM2 biomarker in PP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: PP: Annualized Rate of Change From Baseline in the 9-HPT to Week 104
9-HPT is a test of upper extremity (arm and hand) function.Participant is seated at table with small, shallow container holding pegs and block containing 9 empty holes.On start command when stopwatch is started,participant picks up 9 pegs one at a time as quickly as possible, puts them in 9 holes and once they are in holes, removes them again as quickly as possible one at a time,replacing them into shallow container. Both dominant and non-dominant hands are tested twice (2 consecutive trials of dominant hand followed immediately by 2 consecutive trials of non-dominant hand).Total time (ranging up to 300 seconds):averaged, converted to reciprocals which were averaged and back-transformed to obtain global 9-HPT.Higher value on 9-HPT is indicative of higher disability.Mean annualized rate of change in 9-HPT was obtained from exponential transformation of mean slope of log-transformed 9-HPT.Baseline: last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF Biomarkers (Glucosylceramide [GL-1] and GM2) to Week 104 in Juvenile/Adolescent Late-onset GM2 Gangliosidosis Participants
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM2 biomarkers in juvenile/adolescent late-onset GM2 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 and GM1 Biomarkers to Week 104 in GM1 Gangliosidosis Participants
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM1 biomarkers in GM1 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM2 and Monosialodihexosylganglioside (GM3) Biomarkers to Week 104 in Sialidosis Type 1 Participant
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM2 and GM3 biomarkers in sialidosis type 1 participant of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on sialidosis type 1 participant from secondary PD population (all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD).
Measured: Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM1 and GM3 Biomarkers to Week 104 in Juvenile/Adult Galactosialidosis Participants
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM1 and GM3 biomarkers in juvenile/adult galactosialidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on juvenile/adult galactosialidosis participant from secondary PD population which included all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD.
Measured: Baseline (Day 1) and Week 104
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 Biomarker to Week 104 in Saposin C Deficiency Participants
Plasma and CSF samples were planned to be collected at specified timepoints to assess the presence of GL-1 biomarkers in saposin C deficiency participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) to Week 104
Secondary outcomes (12)
PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104
Lumbar puncture was performed for obtaining CSF samples at specified timepoints to assess the presence of GM2 biomarker in PP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104
The 25FWT is a quantitative mobility and leg function performance test based on a timed 25-foot walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly and safely as possible for 2 trials (can use assistive devices). The time is calculated from the initiation of the instruction to start and ends when the participant has reached the 25-foot mark. The amount of time (in seconds) to walk 25 feet is recorded (ranging up to 180 seconds). The 25FWT score is defined as the average of 2 trials. A higher value on the 25FWT is indicative of higher disability. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
Measured: Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104
The FARS-neuro includes 23 items and is composed of 4 sections that assesses different neurological faculties: bulbar activity (4 items), upper limb coordination (5 items assessed right and left side), lower limb coordination (2 items assessed right and left side), peripheral nervous system (5 items assessed right and left side) and upright stability (7 items). Total score is calculated as the sum of scores on items of this section and ranges from 0 to 117; mean is presented. Higher value indicates higher disability. Baseline=last available value before or equal to first dose of study drug date in PAP. PP: primary efficacy population: all randomized participants with diagnosis of late-onset GM2 gangliosidosis aged >=18 years. SP: secondary efficacy population: all enrolled participants with diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1, or juvenile/adult galactosialidosis.
Measured: Baseline (Day 1) and Week 104
PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAE were AEs that developed, worsened or became serious during the TE period.
Measured: From first dose of study drug (Day 1) up to end of PAP, 104 weeks
PAP: PP: Plasma Venglustat Concentration
Plasma samples were collected at specified timepoints to obtain venglustat concentrations for PP in PAP.
Measured: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Plasma Venglustat Concentration
Plasma samples were collected at specified timepoints to obtain venglustat concentration for SP in PAP. Data is presented by dose level for all diseases combined for SP in PAP.
Measured: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: CSF Venglustat Concentration
CSF samples were collected via lumbar puncture at Week 104 to obtain venglustat concentrations for PP and SP in PAP. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.
Measured: Week 104
PAP: PP and SP: Maximum Plasma Concentration Observed (Cmax) of Venglustat
Plasma samples were collected at specified timepoints to obtain Cmax of venglustat. The mean of Cmax, irrespective of the timepoint where the patient-individual Cmax value was observed is presented as opposed to endpoint 13 wherein mean of plasma venglustat concentration at each specified timepoint is presented. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.
Measured: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Time to Reach Maximum Plasma Concentration (Tmax) of Venglustat
Plasma samples were collected at specified timepoints to obtain tmax of venglustat. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.
Measured: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Area Under the Plasma Concentration Versus Time Curve Calculated Over a Predefined Time Period 0 to 24 Hours (AUC0-24) of Venglustat
Plasma samples were collected at specified timepoints to obtain AUC0-24 of venglustat. For SP: data is presented by dose level for all diseases combined. Only those participants with data collected at specified timepoints are reported.
Measured: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Percent Change From Baseline in the 9-HPT to Week 104
9-HPT is a test of upper extremity (arm and hand) function.Participant is seated at table with small, shallow container holding pegs \& block containing 9 empty holes.On start command (stopwatch started),participant picks up 9 pegs one at a time as quickly as possible, puts them in 9 holes \& once they are in holes, removes them again as quickly as possible one at a time,replacing them into shallow container,2 consecutive trials of dominant hand followed immediately by 2 consecutive trials of non-dominant hand.Total time (ranging up to 300 seconds):averaged, converted to reciprocals which were averaged and back-transformed to obtain global 9-HPT.Higher value indicates higher disability.Baseline: last available value before or equal to first dose of study drug date in PAP.Secondary efficacy population:all enrolled participants with diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis,GM1 gangliosidosis,saposin C deficiency,sialidosis type 1 or juvenile/adult galactosialidosis.
Measured: Baseline (Day 1) and Week 104
PAP: SP: Number of Participants With >=80% Compliance as Per Method of Intake
For the secondary pediatric population, the acceptability and palatability of venglustat tablets was assessed through the route of venglustat administration collected in the electronic case report form and study drug compliance throughout PAP. The assessment was based on tablet always swallowed as whole or chewed and swallowed at least once. Number of participants with >=80% compliance for each is presented here.
Measured: Baseline (Day 1) to Week 104
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2020
- Study start29 Jun 2020
- Primary completion26 Dec 2024
- Study completion26 Dec 2024
Why it stopped: Discontinued based on the absence of positive trends on clinical endpoints.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Tay-Sachs DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 75 participants (actual)
Sponsor and investigators
- Lead sponsor
- Genzyme, a Sanofi Company
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Sciences & Operations, Study director, Sanofi
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04221451
- Sponsor's protocol ID
- EFC15299
- Other IDs
- U1111-1197-7905, EFC15299, 2019-002375-34, 2019
- Acronym
- AMETHIST
- Status last verified
- Jan 2026
- First submitted
- 6 Jan 2020
- Last updated
- 28 Jan 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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
Publications
Nicoli ER, Annunziata I, d'Azzo A, Platt FM, Tifft CJ, Stepien KM. GM1 Gangliosidosis-A Mini-Review. Front Genet. 2021 Sep 3;12:734878. doi: 10.3389/fgene.2021.734878. eCollection 2021.
PubMed 34539759
Study at a glance
From the registry record, last updated by the sponsor on 28 Jan 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04221451
- Acronym / sponsor ID
- AMETHIST / EFC15299
- Conditions
- Tay-Sachs Disease, Sandhoff Disease
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Discontinued based on the absence of positive trends on clinical endpoints.
- Enrolment
- 75 participants (actual)
- Lead sponsor
- Genzyme, a Sanofi CompanyIndustry (pharma, biotech, devices)
- Study start
- 29 Jun 2020 (actual)
- Primary completion
- 26 Dec 2024 (actual)
- Study completion
- 26 Dec 2024 (actual)
- First posted
- 9 Jan 2020 (actual)
- Results
- Posted 28 Jan 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| GZ402671 | Experimental | Drug: venglustat GZ402671Primary 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). |
| Placebo | Placebo comparator | Drug: placeboPrimary 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). |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| venglustat GZ402671Pharmaceutical form: tablet Route of administration: oral | Drug | GZ402671 |
| placeboPharmaceutical form: tablet Route of administration: oral | Drug | Placebo |
Primary outcome
PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104
Time frame: Baseline (Day 1) and Week 104
Lumbar puncture was performed for obtaining CSF samples at specified timepoints to assess the presence of GM2 biomarker in PP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
PAP: PP: Annualized Rate of Change From Baseline in the 9-HPT to Week 104
Time frame: Baseline (Day 1) and Week 104
9-HPT is a test of upper extremity (arm and hand) function.Participant is seated at table with small, shallow container holding pegs and block containing 9 empty holes.On start command when stopwatch is started,participant picks up 9 pegs one at a time as quickly as possible, puts them in 9 holes and once they are in holes, removes them again as quickly as possible one at a time,replacing them into shallow container. Both dominant and non-dominant hands are tested twice (2 consecutive trials of dominant hand followed immediately by 2 consecutive trials of non-dominant hand).Total time (ranging up to 300 seconds):averaged, converted to reciprocals which were averaged and back-transformed to obtain global 9-HPT.Higher value on 9-HPT is indicative of higher disability.Mean annualized rate of change in 9-HPT was obtained from exponential transformation of mean slope of log-transformed 9-HPT.Baseline: last available value before or equal to the first dose of study drug date in the PAP.
PAP: SP: Percent Change From Baseline in Plasma and CSF Biomarkers (Glucosylceramide [GL-1] and GM2) to Week 104 in Juvenile/Adolescent Late-onset GM2 Gangliosidosis Participants
Time frame: Baseline (Day 1) and Week 104
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM2 biomarkers in juvenile/adolescent late-onset GM2 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 and GM1 Biomarkers to Week 104 in GM1 Gangliosidosis Participants
Time frame: Baseline (Day 1) and Week 104
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1 and GM1 biomarkers in GM1 gangliosidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM2 and Monosialodihexosylganglioside (GM3) Biomarkers to Week 104 in Sialidosis Type 1 Participant
Time frame: Baseline (Day 1) and Week 104
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM2 and GM3 biomarkers in sialidosis type 1 participant of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on sialidosis type 1 participant from secondary PD population (all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD).
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM1 and GM3 Biomarkers to Week 104 in Juvenile/Adult Galactosialidosis Participants
Time frame: Baseline (Day 1) and Week 104
Plasma and CSF samples were collected at specified timepoints to assess the presence of GL-1, GM1 and GM3 biomarkers in juvenile/adult galactosialidosis participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP. Analysis was planned to be performed on juvenile/adult galactosialidosis participant from secondary PD population which included all enrolled participants with this clinical diagnosis who received at least 1 dose of study drug and who had baseline and post-baseline assessments of PD.
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 Biomarker to Week 104 in Saposin C Deficiency Participants
Time frame: Baseline (Day 1) to Week 104
Plasma and CSF samples were planned to be collected at specified timepoints to assess the presence of GL-1 biomarkers in saposin C deficiency participants of SP in PAP. The baseline value was defined as the last available value before or equal to the first dose of study drug date in the PAP.
12 secondary outcomes
PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104
Time frame: Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104
Time frame: Baseline (Day 1) and Week 104
PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104
Time frame: Baseline (Day 1) and Week 104
PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Time frame: From first dose of study drug (Day 1) up to end of PAP, 104 weeks
PAP: PP: Plasma Venglustat Concentration
Time frame: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Plasma Venglustat Concentration
Time frame: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: CSF Venglustat Concentration
Time frame: Week 104
PAP: PP and SP: Maximum Plasma Concentration Observed (Cmax) of Venglustat
Time frame: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Time to Reach Maximum Plasma Concentration (Tmax) of Venglustat
Time frame: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: PP and SP: Area Under the Plasma Concentration Versus Time Curve Calculated Over a Predefined Time Period 0 to 24 Hours (AUC0-24) of Venglustat
Time frame: Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12
PAP: SP: Percent Change From Baseline in the 9-HPT to Week 104
Time frame: Baseline (Day 1) and Week 104
PAP: SP: Number of Participants With >=80% Compliance as Per Method of Intake
Time frame: Baseline (Day 1) to Week 104
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jan 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 34539759Nicoli ER, Annunziata I, d'Azzo A, Platt FM, Tifft CJ, Stepien KM. GM1 Gangliosidosis-A Mini-Review. Front Genet. 2021 Sep 3;12:734878. doi: 10.3389/fgene.2021.734878. eCollection 2021.
- EFC15299 Plain Language Results SummaryLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Sciences & Operations study director
Sanofi
23 sites in 13 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing venglustat GZ402671 in people with Tay-Sachs Disease and Sandhoff Disease, run by Genzyme, a Sanofi Company at 23 sites in 13 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 28 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 23 sites in United States, Spain, United Kingdom, Argentina, Japan and 8 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 28 Jan 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104 (time frame: Baseline (Day 1) and Week 104). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04221451, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Jan 2026.