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

Sponsor

Genzyme, a Sanofi Company (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT04221451

Collaborator

(none)

Enrollment

Locations

Arms

67.9

Anticipated Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Primary Objectives:

Primary population (adult participants with late-onset GM2 gangliosidosis): To assess the efficacy and pharmacodynamics (PD) of daily oral dosing of venglustat when administered over a 104-week period

Secondary population (participants with juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, saposin C deficiency, sialidosis type 1 or juvenile/adult galactosialidosis): To assess PD response (plasma and CSF GL-1 biomarker and disease specific biomarkers) of venglustat when administered once daily over a 104-week period

Secondary Objectives:

Primary population:

To assess the effect of venglustat on selected performance test and scale over a 104-week period
To determine the safety and tolerability of venglustat when administered orally once daily over a 104-week period
To assess the pharmacokinetics (PK) of venglustat in plasma and cerebrospinal fluid (CSF)

Secondary population:

To assess the effect of venglustat on selected performance tests and scale over a 104-week period
To determine the safety and tolerability of venglustat when administered once daily over a 104-week period
To assess the PK of venglustat in plasma and CSF

Condition or Disease	Intervention/Treatment	Phase
Tay-Sachs Disease Sandhoff Disease	Drug: venglustat GZ402671 Drug: placebo	Phase 3

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

Study Type:

Interventional

Actual Enrollment :

74 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability of Venglustat in Late-onset GM2 Gangliosidosis (Tay-Sachs Disease and Sandhoff Disease) Together With a Separate Basket for Juvenile/Adolescent Late-onset GM2 Gangliosidosis and Ultra-rare Diseases Within the Same and Similar Glucosylceramide-based Sphingolipid Pathway

Actual Study Start Date :

Jun 29, 2020

Anticipated Primary Completion Date :

Feb 25, 2026

Anticipated Study Completion Date :

Feb 25, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GZ402671 Primary population: participant will receive venglustat dose once daily during the primary analysis period (104 weeks) and the open-label extension period (104 weeks). Secondary population: participant will receive venglustat at various doses once daily during the primary analysis period open-label (104 weeks) and the open-label extension period (104 weeks).	Drug: venglustat GZ402671 Pharmaceutical form: tablet Route of administration: oral
Placebo Comparator: Placebo Primary population: participants will receive placebo once daily during the primary analysis period (104 weeks) and will receive venglustat dose once daily during the open-label extension period (104 weeks).	Drug: placebo Pharmaceutical form: tablet Route of administration: oral

Arm

Intervention/Treatment

Experimental: GZ402671

Primary population: participant will receive venglustat dose once daily during the primary analysis period (104 weeks) and the open-label extension period (104 weeks). Secondary population: participant will receive venglustat at various doses once daily during the primary analysis period open-label (104 weeks) and the open-label extension period (104 weeks).

Drug: venglustat GZ402671

Pharmaceutical form: tablet Route of administration: oral

Placebo Comparator: Placebo

Primary population: participants will receive placebo once daily during the primary analysis period (104 weeks) and will receive venglustat dose once daily during the open-label extension period (104 weeks).

Drug: placebo

Pharmaceutical form: tablet Route of administration: oral

Outcome Measures

Primary Outcome Measures

Change in cerebrospinal fluid (CSF) GM2 biomarker [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) [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 [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 [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 [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 [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 [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 [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 [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 [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 [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 [From baseline to Week 104]
Concentration of GL-1 for saposin C deficiency in secondary population

Secondary Outcome Measures

Safety/tolerability: Adverse events [From baseline to Week 104]
Number of patients with adverse events
Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [From baseline up to Week 12]
Maximum venglustat concentration (Cmax)
Assessment of PK parameters in plasma: tmax [From baseline up to Week 12]
Time to maximum venglustat concentration (tmax)
Assessment of PK parameters in plasma: AUC0-24h [From baseline up to Week 12]
Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
Assessment of PK parameters in plasma: plasma concentrations [From baseline up to Week 104]
Plasma venglustat concentration
Assessment of PK parameters: CSF venglustat concentration [Week 104]
CSF venglustat concentration
Change in 25-foot walk test (FWT) [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) [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) [From baseline to Week 104]
Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years and Older

Sexes Eligible for Study:

All

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004	Los Angeles	California	United States	90095
2	Emory Genetics - Investigational site number 8400006	Atlanta	Georgia	United States	30322
3	NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005	Bethesda	Maryland	United States	20892-1205
4	Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002	Boston	Massachusetts	United States	02114
5	NYU Langone - 550 First Avenue-Investigational site number 8400001	New York	New York	United States	10016
6	Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002	Buenos Aires		Argentina	B1629AHJ
7	Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001	Córdoba		Argentina	X5004FHP
8	AKH Wien_Universitätsklinik für Innere Medizin III Klinische Abteilung für Endokrinologie & Stoffwechsel Währinger Gürtel 18-20_investigational site number 0400001	Wien		Austria	1090
9	Hospital de Clinicas de Porto Alegre _investigational site number 0760001	Porto Alegre		Brazil	90035-903
10	Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001	Praha 2		Czechia	12808
11	APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001	Paris		France	Cedex 13-75651
12	Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001	Gießen		Germany	35389
13	Investigational Site Number 3800001	Milano		Italy	20133
14	Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001	Akita-Shi		Japan	010-1495
15	Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002	Sendai		Japan	983-8512
16	Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002	Lisboa		Portugal	1649-035
17	Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001	Moscow		Russian Federation	125367
18	Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001	Esplugues De Llobregat		Spain	08950
19	Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004	Hospitalet De Llobregat		Spain	08907
20	Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002	Santiago De Compostela		Spain	15706
21	Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001	Ankara		Turkey	06500
22	Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001	Cambridge		United Kingdom	CB2 0QQ
23	Investigational Site Number 8260003	Manchester		United Kingdom	M13 9WL
24	Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002	Salford		United Kingdom	M6 8HD

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Genzyme, a Sanofi Company

ClinicalTrials.gov Identifier:

NCT04221451

Other Study ID Numbers:

EFC15299
2019-002375-34
U1111-1197-7905

First Posted:

Jan 9, 2020

Last Update Posted:

Jul 8, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Additional relevant MeSH terms:

Tay-Sachs Disease

Sandhoff Disease

Study Results

No Results Posted as of Jul 8, 2022