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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04221451
Recruitment Status : Recruiting
First Posted : January 9, 2020
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )

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 119 weeks, including a 60-day screening period, a 104-week treatment period, and a 6-week post-treatment safety observation period.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 62 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 : June 29, 2020
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023


Arm Intervention/treatment
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).

Drug: venglustat GZ402671

Pharmaceutical form: tablet

Route of administration: oral


Placebo Comparator: Placebo
Primary population: participants will receive placebo once daily during 104 weeks.
Drug: placebo

Pharmaceutical form: tablet

Route of administration: oral





Primary Outcome Measures :
  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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


Secondary Outcome Measures :
  1. Safety/tolerability: Adverse events [ Time Frame: From baseline to Week 104 ]
    Number of patients with adverse events

  2. Assessment of pharmacokinetic (PK) parameters in plasma: Cmax [ Time Frame: From baseline to Week 110 ]
    Maximum venglustat concentration (Cmax)

  3. Assessment of PK parameters in plasma: tmax [ Time Frame: From baseline to Week 110 ]
    Time to maximum venglustat concentration (tmax)

  4. 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)

  5. Assessment of PK parameters in CSF: Cmax [ Time Frame: Week 104 ]
    Maximum venglustat concentration (Cmax)

  6. Assessment of PK parameters in CSF: tmax [ Time Frame: Week 104 ]
    Time to maximum venglustat concentration (tmax)

  7. 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)

  8. 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)

  9. 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

  10. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04221451


Contacts
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Contact: Trial Transparency email recommended (Toll free number for US & Canada) 800-633-1610 ext option 6 Contact-US@sanofi.com

Locations
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United States, California
Ataxia Center and HD Center of Excellence, 300 UCLA Med Plaza, Suite B200 - Investigational site number 8400004 Recruiting
Los Angeles, California, United States, 90095
Contact: Aaron Fisher    310-206-8153      
Principal Investigator: Susan Perlman, MD         
United States, Massachusetts
Massachusetts General Hospital - Charles River Plaza 175 Cambridge St. Ste 340 - Investigational site number 8400002 Recruiting
Boston, Massachusetts, United States, 02114
Contact: Daniel Kelly, Clinical Research Coordinator    617-724-6374      
Principal Investigator: Florian Eichler, MD         
United States, New York
NYU Langone - 550 First Avenue - Investigational site number 8400001 Recruiting
New York, New York, United States, 10016
Contact    929-455-5108      
Principal Investigator: Heather LAU, MD         
Brazil
Investigational Site Number 0760001 Recruiting
Porto Alegre, Brazil, 90035 003
Germany
Investigational Site Number 2760001 Recruiting
Gießen, Germany, 35390
Japan
Investigational Site Number 3920001 Recruiting
Akita-Shi, Japan
Russian Federation
Investigational Site Number 6430001 Recruiting
Moscow, Russian Federation, 125367
Spain
Investigational Site Number 7240002 Recruiting
A Coruña, Spain, 15706
Investigational Site Number 7240001 Recruiting
Barcelona, Spain, 08950
Investigational Site Number 7240004 Recruiting
Hospitalet De Llobregat, Spain, 08907
United Kingdom
Investigational Site Number 8260001 Recruiting
Cambridge, United Kingdom, CB2 OQQ
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
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Study Director: Clinical Sciences & Operations Sanofi
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Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT04221451    
Other Study ID Numbers: EFC15299
2019-002375-34
U1111-1197-7905 ( Other Identifier: UTN )
First Posted: January 9, 2020    Key Record Dates
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
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/

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Gangliosidoses, GM2
Tay-Sachs Disease
Sandhoff Disease
Gangliosidoses
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders