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

Sandhoff Disease Clinical Trial

— AMETHIST  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04221451
• Other study ID #: EFC15299
• Secondary ID: U1111-1197-79052
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: June 29, 2020
• Est. completion date: February 25, 2026

Study information

• Verified date: January 2024
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 75
• Est. completion date: February 25, 2026
• Est. primary completion date: January 18, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years and older

Eligibility

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 ß-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 ß-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.

Related Conditions & MeSH terms

• Sandhoff Disease
• Tay-Sachs Disease

Intervention

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

Locations

Country	Name	City	State
Argentina	Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001	Córdoba
Argentina	Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002	Pilar	Buenos Aires
Brazil	Hospital de Clinicas de Porto Alegre _investigational site number 0760001	Porto Alegre	Rio Grande Do Sul
Czechia	Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001	Praha 2
France	APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001	Paris
Germany	Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001	Gießen
Italy	Investigational Site Number : 3800001	Milano
Japan	Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001	Akita-shi	Akita
Japan	Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002	Sendai-shi	Miyagi
Portugal	Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002	Lisboa
Russian Federation	Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001	Moscow
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 Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004	Hospitalet de Llobregat	Barcelona [Barcelona]
Spain	Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002	Santiago de Compostela	Galicia [Galicia]
Turkey	Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001	Ankara
United Kingdom	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 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	Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004	Los Angeles	California
United States	NYU Langone - 550 First Avenue-Investigational site number 8400001	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Czechia,  France,  Germany,  Italy,  Japan,  Portugal,  Russian Federation,  Spain,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in cerebrospinal fluid (CSF) GM2 biomarker	Percent change in CSF GM2 biomarker from baseline to Week 104 in primary population	From baseline to Week 104
Primary	Change in the 9-hole pegboard test (9-HPT)	Annualized rate of change in the 9-HPT from baseline to Week 104 in primary population	From baseline to Week 104
Primary	Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers	Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in plasma: GL-1, GM2 biomarkers	Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers	Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers	Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in plasma: GL-1 biomarker	Concentration of GL-1 for saposin C deficiency in secondary population	From baseline to Week 104
Primary	Assessment of PD response in CSF: GL-1, GM1 biomarkers	Concentration of GL-1 biomarker and pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in CSF: GL-1, GM2 biomarkers	Concentration of GL-1 and GM2 for GM2 gangliosidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers	Concentration of GL-1 and GM2, GM3 for sialidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers	Concentration of GL-1 and GM1, GM3 for galactosialidosis in secondary population	From baseline to Week 104
Primary	Assessment of PD response in CSF: GL-1 biomarker	Concentration of GL-1 for saposin C deficiency in secondary population	From baseline to Week 104
Secondary	Safety/tolerability: Adverse events	Number of patients with adverse events	From baseline to Week 104
Secondary	Assessment of pharmacokinetic (PK) parameters in plasma: Cmax	Maximum venglustat concentration (Cmax)	From baseline up to Week 12
Secondary	Assessment of PK parameters in plasma: tmax	Time to maximum venglustat concentration (tmax)	From baseline up to Week 12
Secondary	Assessment of PK parameters in plasma: AUC0-24h	Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)	From baseline up to Week 12
Secondary	Assessment of PK parameters in plasma: plasma concentrations	Plasma venglustat concentration	From baseline up to Week 104
Secondary	Assessment of PK parameters: CSF venglustat concentration	CSF venglustat concentration	Week 104
Secondary	Change in 25-foot walk test (FWT)	Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)	From baseline to Week 104
Secondary	Absolute change in CSF GM2 biomarker		From baseline to Week 104
Secondary	Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS)	Change in the neurological examination of the FARS score from baseline to Week 104	From baseline to Week 104
Secondary	Change in 9-hole peg test (9-HPT)	Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population	From baseline to Week 104
Secondary	Acceptability assessment	Venglustat tablets acceptability will be assessed through the route of venglustat administration collected in the eCRF and study intervention compliance	From baseline to Week 104