Sandhoff Disease, Tay-Sachs Disease
Conditions
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.
Interventions
Pharmaceutical form: tablet Route of administration: oral
DRUGplacebo
Pharmaceutical form: tablet Route of administration: oral
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Argentina, Brazil, Czechia, France, Germany, Italy, Japan, Portugal, Russia, Spain, Turkey (Türkiye), United Kingdom, United States
Contacts
STUDY_DIRECTORClinical Sciences & Operations
Sanofi
Participant flow
Recruitment details
This study consisted of 2 periods: primary analysis period (PAP) & open-label extension (OLE) period. In PAP, primary population (PP) was randomized in a 2:1 ratio to receive either venglustat or placebo in double-blind manner. Secondary population (SP) received OL venglustat. Post completion of PAP, eligible participants entered OLE in which all participants received OL venglustat. The study was early terminated based on absence of positive trends on clinical endpoints; no safety concerns.
Pre-assignment details
In PAP, 59 participants in the PP (adult participants with diagnosis of late-onset disialotetrahexosylganglioside \[GM2\] gangliosidosis) and 16 participants in the SP (juvenile/adolescent participants with diagnosis of late-onset GM2 gangliosidosis, monosialotetrahexosylganglioside \[GM1\] gangliosidosis, saposin C deficiency, sialidosis type 1, or juvenile/adult galactosialidosis) were treated. Randomization for PP was stratified on participant's ability to walk at baseline visit (yes/no).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 12.4 years STANDARD_DEVIATION 7.3 |
| Clinical diagnosis of SP GM1 gangliosidosis | 7 Participants |
| Clinical diagnosis of SP Juvenile/adolescent GM2 gangliosidosis | 7 Participants |
| Clinical diagnosis of SP Juvenile/adult galactosialidosis | 1 Participants |
| Clinical diagnosis of SP Saposin C deficiency | 0 Participants |
| Clinical diagnosis of SP Sialidosis type 1 | 1 Participants |
| PP: 9-hole peg Test (9-HPT) | 45.89 seconds STANDARD_DEVIATION 34.65 |
| PP: Cerebrospinal fluid (CSF) GM2 biomarker | 63.00 nanogram/milliliter (ng/mL) STANDARD_DEVIATION 36.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 40 | 1 / 16 | 1 / 16 | 0 / 34 | 0 / 14 |
| other Total, other adverse events | 19 / 19 | 38 / 40 | 14 / 16 | 11 / 16 | 19 / 34 | 9 / 14 |
| serious Total, serious adverse events | 4 / 19 | 8 / 40 | 6 / 16 | 4 / 16 | 2 / 34 | 2 / 14 |
Outcome results
None listed