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

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ClinicalTrials.gov Identifier: NCT04221451
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : March 29, 2021
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

Tracking Information
First Submitted Date  ICMJE January 6, 2020
First Posted Date  ICMJE January 9, 2020
Last Update Posted Date March 29, 2021
Actual Study Start Date  ICMJE June 29, 2020
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 5, 2020)
  • Change in cerebrospinal fluid (CSF) GM2 biomarker [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 for saposin C deficiency in secondary population
Original Primary Outcome Measures  ICMJE
 (submitted: January 6, 2020)
  • Change in cerebrospinal fluid (CSF) GM2 biomarker [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 biomarker with pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
  • Assessment of PD response in plasma: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM2 for GM2 gangliosidosis in secondary population
  • Assessment of PD response in plasma: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM2, GM3 for sialidosis in secondary population
  • Assessment of PD response in plasma: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM1, GM3 for galactosialidosis in secondary population
  • Assessment of PD response in plasma: GL-1 biomarker [ Time Frame: 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 [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 biomarker with pathway specific biomarker GM1 for GM1 gangliosidosis in secondary population
  • Assessment of PD response in CSF: GL-1, GM2 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM2 for GM2 gangliosidosis in secondary population
  • Assessment of PD response in CSF: GL-1, GM2, GM3 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM2, GM3 for sialidosis in secondary population
  • Assessment of PD response in CSF: GL-1, GM1, GM3 biomarkers [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 with GM1, GM3 for galactosialidosis in secondary population
  • Assessment of PD response in CSF: GL-1 biomarker [ Time Frame: From baseline to Week 104 ]
    Concentration of GL-1 for saposin C deficiency in secondary population
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 5, 2020)
  • Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ]
    Number of patients with adverse events
  • Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline to Week 110 ]
    Maximum venglustat concentration (Cmax)
  • Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline to Week 110 ]
    Time to maximum venglustat concentration (tmax)
  • Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline to Week 110 ]
    Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
  • Assessment of PK parameters in CSF: Cmax [ Time Frame: Week 104 ]
    Maximum venglustat concentration (Cmax)
  • Assessment of PK parameters in CSF: tmax [ Time Frame: Week 104 ]
    Time to maximum venglustat concentration (tmax)
  • Assessment of PK parameters in CSF: AUC0-24h [ Time Frame: Week 104 ]
    Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
  • Change in 25-foot walk test (FWT) [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: From baseline to Week 104 ]
    Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population
Original Secondary Outcome Measures  ICMJE
 (submitted: January 6, 2020)
  • Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ]
    Number of patients with adverse events
  • Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline to Week 104 ]
    Maximum venglustat concentration (Cmax)
  • Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline to Week 104 ]
    Time to maximum venglustat concentration (tmax)
  • Assessment of PK parameters in plasma: AUC0-24h [ Time Frame: From baseline to Week 104 ]
    Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
  • Assessment of PK parameters in CSF: Cmax [ Time Frame: From baseline to Week 104 ]
    Maximum venglustat concentration (Cmax)
  • Assessment of PK parameters in CSF: tmax [ Time Frame: From baseline to Week 104 ]
    Time to maximum venglustat concentration (tmax)
  • Assessment of PK parameters in CSF: AUC0-24h [ Time Frame: From baseline to Week 104 ]
    Concentration versus time curve calculated using the trapezoidal method from time 0 to 24 hours (AUC0-24h)
  • Change in 25-foot walk test (FWT) [ Time Frame: From baseline to Week 104 ]
    Change in timed 25-FWT from baseline to Week 104 (in patients able to walk at baseline)
  • Change in Friedreich's Ataxia Rating Scale (FARS) [ Time Frame: From baseline to Week 104 ]
    Change in FARS score from baseline to Week 104
  • Change in 9-hole peg test (9-HPT) [ Time Frame: From baseline to Week 104 ]
    Annualized rate of change in the 9-HPT from baseline to Week 104 in secondary population
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, and Safety of Venglustat in Late-onset GM2
Official Title  ICMJE 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
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
Detailed Description The total duration is up to approximately 119 weeks, including a 60-day screening period, a 104-week treatment period, and a 6-week post-treatment safety observation period.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Tay-Sachs Disease Sandhoff Disease
Intervention  ICMJE
  • Drug: venglustat GZ402671

    Pharmaceutical form: tablet

    Route of administration: oral

  • Drug: placebo

    Pharmaceutical form: tablet

    Route of administration: oral

Study Arms  ICMJE
  • Experimental: GZ402671

    Primary population: participant will receive venglustat dose 1 once daily during 104 weeks.

    Secondary population: participant will receive venglustat at various doses once daily during 104 weeks (open label period).

    Intervention: Drug: venglustat GZ402671
  • Placebo Comparator: Placebo
    Primary population: participants will receive placebo once daily during 104 weeks.
    Intervention: Drug: placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: January 6, 2020)
62
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2023
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

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.
  • 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
  • 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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 2 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com
Listed Location Countries  ICMJE Brazil,   Czechia,   Germany,   Japan,   Russian Federation,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04221451
Other Study ID Numbers  ICMJE EFC15299
2019-002375-34
U1111-1197-7905 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/
Responsible Party Sanofi ( Genzyme, a Sanofi Company )
Study Sponsor  ICMJE Genzyme, a Sanofi Company
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP