Clinical trial NCT04221451: A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Tay-Sachs Disease
Sandhoff Disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2020-01-09
Enrollment: 75
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in cerebrospinal fluid (CSF) GM2 biomarker
timeFrame: From baseline to Week 104
measure: Change in the 9-hole pegboard test (9-HPT)
timeFrame: From baseline to Week 104
measure: Assessment of pharmacodynamic (PD) response in plasma: GL-1, GM1 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in plasma: GL-1, GM2 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in plasma: GL-1 biomarker
timeFrame: From baseline to Week 104
measure: Assessment of PD response in CSF: GL-1, GM1 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in CSF: GL-1, GM2 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers
timeFrame: From baseline to Week 104
measure: Assessment of PD response in CSF: GL-1 biomarker
timeFrame: From baseline to Week 104
Secondary outcomes:
measure: Safety/tolerability: Adverse events
timeFrame: From baseline to Week 104
measure: Assessment of pharmacokinetic (PK) parameters in plasma: Cmax
timeFrame: From baseline up to Week 12
measure: Assessment of PK parameters in plasma: tmax
timeFrame: From baseline up to Week 12
measure: Assessment of PK parameters in plasma: AUC0-24h
timeFrame: From baseline up to Week 12
measure: Assessment of PK parameters in plasma: plasma concentrations
timeFrame: From baseline up to Week 104
measure: Assessment of PK parameters: CSF venglustat concentration
timeFrame: Week 104
measure: Change in 25-foot walk test (FWT)
timeFrame: From baseline to Week 104
measure: Absolute change in CSF GM2 biomarker
timeFrame: From baseline to Week 104
measure: Change in the neurological examination of the Friedreich's Ataxia Rating Scale (FARS)
timeFrame: From baseline to Week 104
measure: Change in 9-hole peg test (9-HPT)
timeFrame: From baseline to Week 104
measure: Acceptability assessment
timeFrame: From baseline to Week 104
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004
state: California
city: Atlanta
country: United States
facility: Emory Genetics - Investigational site number 8400006
state: Georgia
city: Bethesda
country: United States
facility: NIH National Human Genome Research Institute - 10 Center Dr - Bldg. 10 CRC3-2551 MSC 1205 - Investigational site number 8400005
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002
state: Massachusetts
city: New York
country: United States
facility: NYU Langone - 550 First Avenue-Investigational site number 8400001
state: New York
city: Pilar
country: Argentina
facility: Hospital Universitario Austral Pilar, Buenos Aires_Unidad de Investigación Clínica_investigational site number 0320002
state: Buenos Aires
city: Córdoba
country: Argentina
facility: Clínica Universitaria Reina Fabiola Córdoba_investigational site number 0320001
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre _investigational site number 0760001
state: Rio Grande Do Sul
city: Praha 2
country: Czechia
facility: Vseobecna Fakultni Nemocnice V Praze Metabolicke centrum U Nemocnice 2_investigational site number 2030001
city: Paris
country: France
facility: APHP - Centre Hospitalier la Pitié Salpetrière, Service de Neurologie, 47-83 Boulevard De l'Hôpital_Investigational site number 2500001
city: Gießen
country: Germany
facility: Universitätsklinikum der Justus-Liebig-Universität Gießen Zentrum für Kinderheilkunde und Jugendmedizin Feulgenstraße 10-12_investigational site number 2760001
city: Milano
country: Italy
facility: Investigational Site Number : 3800001
city: Akita-shi
country: Japan
facility: Japanese Red Cross Akita Hospital 222-1 Nawashirosawa, Kamikitatesaruta_investigational site number 3920001
state: Akita
city: Sendai-shi
country: Japan
facility: Tohoku Medical and Pharmaceutical University Hospital_investigation site number 3920002
state: Miyagi
city: Lisboa
country: Portugal
facility: Centro Hospitalar Universitário Lisboa Norte- Hospital Santa Maria Avenida Professor Egas Moniz_investigational site number 6200002
city: Moscow
country: Russian Federation
facility: Research Center Of Neurology 80, Volokolamskoye shosse_investigational site number 6430001
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitari de Bellvitge. Feixa Llarga, S / N_investigational site number 7240004
state: Barcelona [Barcelona]
city: Esplugues de Llobregat
country: Spain
facility: Hospital Maternoinfantil Sant Joan de Déu Paseo de Sant Joan de Déu, 2_investigational site number 7240001
state: Catalunya [Cataluña]
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago-CHUS. Travesia de Chopuana, s/n_investigational site number 7240002
state: Galicia [Galicia]
city: Ankara
country: Turkey
facility: Gazi Universitesi Tip Fakultesi Emniyet Street Mevlana Blv Besevler Yenimahalle_investigational site number 7920001
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust Addenbrookes Hospital Hills Road_investigational site number 8260001
state: Cambridgeshire
city: Manchester
country: United Kingdom
facility: Investigational Site Number : 8260003
city: Salford
country: United Kingdom
facility: Salford Royal NHS Foundation Trust Salford Royal Hospital Stott Lane_investigational site number 8260002
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.