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

NCT04221451 — Phase 3, Terminated, 75 participants, Genzyme, a Sanofi Company

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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

Registry	NCT04221451, acronym AMETHIST
Status	Terminated - Discontinued based on the absence of positive trends on clinical endpoints.
Phase	Phase 3
Study type	Interventional; randomized, parallel, masking: quadruple, treatment
Enrollment	75 (Actual)
Sponsor	Genzyme, a Sanofi Company (Industry)
Conditions	Tay-Sachs Disease, Sandhoff Disease
Interventions	venglustat GZ402671, placebo (Drug)
Dates	start 2020-06-29, primary completion 2024-12-26, completion 2024-12-26, first posted 2020-01-09, last updated 2026-01-28
Locations	23 sites in United States, Argentina, Brazil, Czechia, France, Germany, Italy, Japan and 5 more countries

-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 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

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+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.

+Arms and interventions

Arm	Type	Interventions	Description
GZ402671	Experimental	Drug: venglustat 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).
Placebo	Placebo comparator	Drug: 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).

venglustat GZ402671 (Drug): Pharmaceutical form: tablet Route of administration: oral
placebo (Drug): Pharmaceutical form: tablet Route of administration: oral

+Outcome measures

Primary outcomes

PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104 [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 [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 [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 [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 [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 [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 [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.

Secondary outcomes

PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104 [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 and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104 [Baseline (Day 1) and 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.
PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104 [Baseline (Day 1) and 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.
PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [From first dose of study drug (Day 1) up to end of PAP, 104 weeks]: 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.
PAP: PP: Plasma Venglustat Concentration [Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12]: Plasma samples were collected at specified timepoints to obtain venglustat concentrations for PP in PAP.
PAP: SP: Plasma Venglustat Concentration [Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12]: 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.
PAP: PP and SP: CSF Venglustat Concentration [Week 104]: 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.
PAP: PP and SP: Maximum Plasma Concentration Observed (Cmax) of Venglustat [Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12]: 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.
PAP: PP and SP: Time to Reach Maximum Plasma Concentration (Tmax) of Venglustat [Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12]: 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.
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 [Pre-dose (0 hour) and 0.5, 3, 8, 12 and 24 hours post-dose at Week 12]: 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.
PAP: SP: Percent Change From Baseline in the 9-HPT to Week 104 [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 \& 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.
PAP: SP: Number of Participants With >=80% Compliance as Per Method of Intake [Baseline (Day 1) to Week 104]: 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.

+Eligibility

Sex: All, ages: 2 Years to any, accepts healthy volunteers

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.

+Posted results

Participant flow

Milestone	PAP: PP: Placebo	PAP: PP: Venglustat	PAP: SP: Venglustat
Started	19	40	16
Completed	17	35	14
Not completed	2	5	2

Outcome results

PAP: PP: Percent Change From Baseline in CSF GM2 Biomarker to Week 104 (Primary), Mean, percent change: PAP: PP: Placebo -11.33 +/- 4.23; PAP: PP: Venglustat -47.57 +/- 3.04 (p <0.0001)
PAP: PP: Annualized Rate of Change From Baseline in the 9-HPT to Week 104 (Primary), Mean, percent per year: PAP: PP: Placebo 0.95 +/- 1.92; PAP: PP: Venglustat 2.49 +/- 1.35 (p 0.7435)
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 (Primary), Mean, percent change: PAP: SP: Venglustat -82.35 +/- 9.94
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 and GM1 Biomarkers to Week 104 in GM1 Gangliosidosis Participants (Primary), Mean, percent change: PAP: SP: Venglustat 17.42 +/- 188.41
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 (Primary), Mean, percent change: PAP: SP: Venglustat NA
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1, GM1 and GM3 Biomarkers to Week 104 in Juvenile/Adult Galactosialidosis Participants (Primary), Mean, percent change: PAP: SP: Venglustat NA
PAP: SP: Percent Change From Baseline in Plasma and CSF GL-1 Biomarker to Week 104 in Saposin C Deficiency Participants (Primary)
PAP: PP: Absolute Change From Baseline in CSF GM2 Biomarker to Week 104 (Secondary), Mean, ng/mL: PAP: PP: Placebo -17.64 +/- 2.36; PAP: PP: Venglustat -32.83 +/- 1.70
PAP: PP and SP: Change From Baseline in 25-foot Walk Test (25FWT) to Week 104 (Secondary), Mean, seconds: PAP: PP: Placebo 1.4 +/- 4.2; PAP: PP: Venglustat 8.9 +/- 31.0; PAP: SP: Venglustat
PAP: PP and SP: Change From Baseline in the Neurological Examination of the Friedreich's Ataxia Rating Scale (FARS) (FARS-neuro) to Week 104 (Secondary), Mean, score on a scale: PAP: PP: Placebo 0.4 +/- 6.0; PAP: PP: Venglustat -1.0 +/- 8.5; PAP: SP: Venglustat
PAP: PP and SP: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) (Secondary), Count of participants, Participants: PAP: PP: Placebo 19; PAP: PP: Venglustat 40; PAP: SP: Venglustat 14
PAP: PP: Plasma Venglustat Concentration (Secondary), Mean, ng/mL: PAP: PP: Venglustat 112 +/- 43.7
PAP: SP: Plasma Venglustat Concentration (Secondary), Mean, ng/mL: PAP: SP: Venglustat 56.4
PAP: PP and SP: CSF Venglustat Concentration (Secondary), Mean, ng/mL: PAP: PP: Venglustat 5.64 +/- 2.05; PAP: SP: Venglustat
PAP: PP and SP: Maximum Plasma Concentration Observed (Cmax) of Venglustat (Secondary), Mean, ng/mL: PAP: PP: Venglustat 188 +/- 60.8; PAP: SP: Venglustat
PAP: PP and SP: Time to Reach Maximum Plasma Concentration (Tmax) of Venglustat (Secondary), Median, hour: PAP: PP: Venglustat 3.00 (2.77 to 7.05); PAP: SP: Venglustat
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 (Secondary), Mean, hour*ng/mL: PAP: PP: Venglustat 3230 +/- 1110; PAP: SP: Venglustat
PAP: SP: Percent Change From Baseline in the 9-HPT to Week 104 (Secondary), Mean, percent change: PAP: SP: Venglustat -1.2 +/- 24.5
PAP: SP: Number of Participants With >=80% Compliance as Per Method of Intake (Secondary), Count of participants, Participants: PAP: SP: Venglustat 8

Adverse events

Time frame: Adverse events:From first dose of study drug (Day 1) up to 104 weeks (PAP) and from 104 weeks up to 6 weeks post last drug in OLE, maximum duration 200 weeks due to study termination. Deaths were collected from first dose of study drug (Day 1) up to end of follow-up, maximum 200 weeks due to study termination.

Arm	Deaths	Serious adverse events	Other adverse events
PAP: PP: Placebo	0/19 (0.0%)	4/19 (21.1%)	19/19 (100.0%)
PAP: PP: Venglustat	0/40 (0.0%)	8/40 (20.0%)	38/40 (95.0%)
PAP: SP: Venglustat	1/16 (6.3%)	6/16 (37.5%)	14/16 (87.5%)
OLE: PP: Delayed Venglustat	1/16 (6.3%)	4/16 (25.0%)	11/16 (68.8%)
OLE: PP: Early Venglustat	0/34 (0.0%)	2/34 (5.9%)	19/34 (55.9%)
OLE: SP: Venglustat	0/14 (0.0%)	2/14 (14.3%)	9/14 (64.3%)

Serious adverse events by term

Term	Organ system	PAP: PP: Placebo	PAP: PP: Venglustat	PAP: SP: Venglustat	OLE: PP: Delayed Venglustat	OLE: PP: Early Venglustat	OLE: SP: Venglustat
Burn Infection	Infections and infestations	0/19	1/40	0/16	0/16	0/34	0/14
Cellulitis	Infections and infestations	0/19	1/40	0/16	0/16	0/34	0/14
Cystitis	Infections and infestations	0/19	1/40	0/16	0/16	0/34	0/14
Infected Bite	Infections and infestations	0/19	0/40	0/16	0/16	0/34	1/14
Respiratory Tract Infection Viral	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Sepsis	Infections and infestations	0/19	1/40	0/16	0/16	0/34	0/14
Upper Respiratory Tract Infection	Infections and infestations	0/19	0/40	0/16	0/16	0/34	1/14
Urinary Tract Infection	Infections and infestations	0/19	2/40	0/16	0/16	0/34	0/14
Hypophagia	Metabolism and nutrition disorders	1/19	0/40	0/16	0/16	0/34	0/14
Acute Psychosis	Psychiatric disorders	0/19	0/40	1/16	0/16	0/34	0/14
Completed Suicide	Psychiatric disorders	0/19	0/40	0/16	1/16	0/34	0/14
Mania	Psychiatric disorders	1/19	0/40	0/16	0/16	1/34	0/14
Persecutory Delusion	Psychiatric disorders	1/19	0/40	0/16	0/16	0/34	0/14
Suicidal Ideation	Psychiatric disorders	0/19	0/40	0/16	1/16	0/34	0/14
Dyskinesia	Nervous system disorders	0/19	0/40	1/16	0/16	0/34	0/14
Respiratory Failure	Respiratory, thoracic and mediastinal disorders	0/19	0/40	1/16	0/16	0/34	0/14
Dysphagia	Gastrointestinal disorders	0/19	0/40	1/16	1/16	0/34	0/14
Faecaloma	Gastrointestinal disorders	1/19	0/40	0/16	0/16	0/34	0/14
Oesophageal Achalasia	Gastrointestinal disorders	1/19	0/40	0/16	0/16	0/34	0/14
Vomiting	Gastrointestinal disorders	0/19	0/40	1/16	0/16	0/34	0/14
Cholelithiasis	Hepatobiliary disorders	0/19	1/40	0/16	0/16	0/34	0/14
Hepatic Mass	Hepatobiliary disorders	0/19	0/40	0/16	1/16	0/34	0/14
Intervertebral Disc Protrusion	Musculoskeletal and connective tissue disorders	0/19	0/40	0/16	0/16	1/34	0/14
Urinary Retention	Renal and urinary disorders	1/19	0/40	0/16	0/16	0/34	0/14
Ankle Fracture	Injury, poisoning and procedural complications	0/19	1/40	0/16	0/16	0/34	0/14
Femur Fracture	Injury, poisoning and procedural complications	0/19	0/40	1/16	0/16	0/34	0/14
Hip Fracture	Injury, poisoning and procedural complications	0/19	1/40	0/16	0/16	0/34	0/14
Post Lumbar Puncture Syndrome	Injury, poisoning and procedural complications	1/19	0/40	0/16	0/16	0/34	0/14
Tibia Fracture	Injury, poisoning and procedural complications	0/19	2/40	0/16	1/16	0/34	0/14

Other adverse events by term

Term	Organ system	PAP: PP: Placebo	PAP: PP: Venglustat	PAP: SP: Venglustat	OLE: PP: Delayed Venglustat	OLE: PP: Early Venglustat	OLE: SP: Venglustat
Bacterial Infection	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Bacterial Vaginosis	Infections and infestations	0/19	0/40	0/16	0/16	0/34	1/14
Breast Abscess	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Bronchiolitis	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Bronchitis	Infections and infestations	0/19	1/40	0/16	0/16	0/34	1/14
Covid-19	Infections and infestations	3/19	13/40	7/16	2/16	2/34	1/14
Conjunctivitis	Infections and infestations	2/19	1/40	1/16	0/16	0/34	0/14
Enterobiasis	Infections and infestations	0/19	0/40	1/16	0/16	0/34	1/14
Fungal Foot Infection	Infections and infestations	1/19	0/40	0/16	0/16	0/34	0/14
Gastroenteritis	Infections and infestations	1/19	0/40	2/16	0/16	0/34	0/14
Helicobacter Gastritis	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Herpes Zoster	Infections and infestations	0/19	0/40	0/16	1/16	0/34	0/14
Hordeolum	Infections and infestations	0/19	0/40	0/16	1/16	0/34	0/14
Infected Bite	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Influenza	Infections and infestations	2/19	3/40	2/16	0/16	0/34	0/14
Kidney Infection	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Localised Infection	Infections and infestations	0/19	1/40	0/16	1/16	0/34	0/14
Nasopharyngitis	Infections and infestations	1/19	1/40	5/16	2/16	1/34	1/14
Oral Infection	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Otitis Media	Infections and infestations	0/19	0/40	1/16	0/16	1/34	0/14
Perichondritis	Infections and infestations	0/19	0/40	0/16	1/16	0/34	0/14
Pharyngotonsillitis	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Pneumonia	Infections and infestations	0/19	0/40	1/16	0/16	3/34	0/14
Respiratory Tract Infection	Infections and infestations	0/19	4/40	1/16	0/16	0/34	0/14
Sinusitis	Infections and infestations	0/19	2/40	0/16	1/16	0/34	0/14
Skin Infection	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Upper Respiratory Tract Infection	Infections and infestations	1/19	1/40	1/16	0/16	0/34	0/14
Urinary Tract Infection	Infections and infestations	1/19	6/40	2/16	0/16	3/34	2/14
Urinary Tract Infection Bacterial	Infections and infestations	1/19	0/40	0/16	0/16	0/34	0/14
Vulvovaginal Candidiasis	Infections and infestations	0/19	0/40	1/16	0/16	0/34	0/14
Vulvovaginal Mycotic Infection	Infections and infestations	0/19	0/40	0/16	0/16	0/34	1/14
Drug Hypersensitivity	Immune system disorders	0/19	0/40	1/16	0/16	0/34	0/14
Seasonal Allergy	Immune system disorders	0/19	0/40	0/16	0/16	0/34	1/14
Cachexia	Metabolism and nutrition disorders	0/19	0/40	1/16	0/16	0/34	0/14
Decreased Appetite	Metabolism and nutrition disorders	1/19	0/40	0/16	1/16	1/34	0/14
Iron Deficiency	Metabolism and nutrition disorders	0/19	0/40	0/16	1/16	0/34	0/14
Vitamin D Deficiency	Metabolism and nutrition disorders	0/19	3/40	0/16	0/16	1/34	0/14
Anxiety	Psychiatric disorders	2/19	4/40	0/16	0/16	0/34	1/14
Apathy	Psychiatric disorders	1/19	0/40	0/16	0/16	0/34	0/14
Depression	Psychiatric disorders	1/19	2/40	1/16	0/16	1/34	1/14
Disorientation	Psychiatric disorders	0/19	0/40	0/16	1/16	0/34	0/14
Emotional Disorder	Psychiatric disorders	0/19	0/40	0/16	1/16	0/34	0/14
Grief Reaction	Psychiatric disorders	1/19	1/40	0/16	0/16	0/34	0/14
Insomnia	Psychiatric disorders	0/19	0/40	1/16	0/16	0/34	0/14
Irritability	Psychiatric disorders	0/19	0/40	1/16	0/16	2/34	0/14
Mania	Psychiatric disorders	0/19	0/40	0/16	1/16	0/34	0/14
Ataxia	Nervous system disorders	1/19	0/40	0/16	0/16	0/34	0/14
Balance Disorder	Nervous system disorders	0/19	2/40	0/16	1/16	1/34	0/14
Disturbance In Attention	Nervous system disorders	0/19	2/40	0/16	0/16	2/34	0/14
Dizziness	Nervous system disorders	1/19	3/40	2/16	1/16	0/34	0/14
Headache	Nervous system disorders	4/19	10/40	4/16	2/16	3/34	1/14
Hypoaesthesia	Nervous system disorders	1/19	1/40	0/16	0/16	0/34	0/14
Hyporeflexia	Nervous system disorders	1/19	0/40	0/16	0/16	0/34	0/14
Hypotonia	Nervous system disorders	1/19	0/40	0/16	0/16	0/34	0/14
Loss Of Consciousness	Nervous system disorders	0/19	0/40	1/16	0/16	0/34	0/14
Myasthenia Gravis	Nervous system disorders	1/19	0/40	0/16	0/16	0/34	0/14
Myoclonus	Nervous system disorders	0/19	0/40	1/16	0/16	0/34	0/14
Paraesthesia	Nervous system disorders	2/19	3/40	0/16	0/16	0/34	0/14
Seizure	Nervous system disorders	0/19	0/40	1/16	0/16	0/34	0/14
Speech Disorder	Nervous system disorders	0/19	0/40	2/16	0/16	0/34	0/14

103 more terms not shown.

Limitations and caveats: The study was early terminated based on the absence of positive trends on clinical endpoints; there were no safety concerns. For sialidosis type 1 and juvenile/adult galactosialidosis, due to the rarity of the disease and the specificity of the endpoint, reporting individual-level data would risk compromising participant privacy and confidentiality.

+Locations (23)

Facility	City	Country
Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004	Los Angeles, California	United States
Emory Genetics - Investigational site number 8400006	Atlanta, Georgia	United States
NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005	Bethesda, Maryland	United States
Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002	Boston, Massachusetts	United States
NYU Langone - 550 First Avenue-Investigational site number 8400001	New York, New York	United States
Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002	Pilar, Buenos Aires	Argentina
Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001	Córdoba	Argentina
Hospital de Clinicas de Porto Alegre _investigational site number 0760001	Porto Alegre, Rio Grande do Sul	Brazil
Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001	Prague	Czechia
APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001	Paris	France
Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001	Giessen	Germany
Investigational Site Number : 3800001	Milan	Italy
Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001	Akita, Akita	Japan
Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002	Sendai, Miyagi	Japan
Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002	Lisbon	Portugal
Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001	Moscow	Russia
Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004	L'Hospitalet de Llobregat, Barcelona [Barcelona]	Spain
Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001	Esplugues de Llobregat, Catalunya [Cataluña]	Spain
Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002	Santiago de Compostela, Galicia [Galicia]	Spain
Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001	Ankara	Turkey (Türkiye)
Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001	Cambridge, Cambridgeshire	United Kingdom
Investigational Site Number : 8260003	Manchester	United Kingdom
Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002	Salford	United Kingdom

+Publications

Results publication: 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. PMID 34539759

+Study documents

Study Protocol (PDF, 2023-08-16)
Statistical Analysis Plan (PDF, 2023-08-03)

+Investigators

Clinical Sciences & Operations, Study director, Sanofi

+Funding

NIH grants: 2019