A Study to Evaluate the Effect of Venglustat Tablets on Left Ventricular Mass Index in Male and Female Adult Participants With Fabry Disease (CARAT)

A Randomized, Open-label, Parallel-group, 18-month Phase 3 Study to Evaluate the Effect of Venglustat Compared With Usual Standard of Care on Left Ventricular Mass Index in Participants With Fabry Disease and Left Ventricular Hypertrophy

This is an 18-month, multicenter, randomized, active-control, parallel-group Phase 3 study, in which participants will be randomized to venglustat versus standard of care therapy (agalsidase alfa, agalsidase beta, or migalastat) to evaluate the effect of venglustat on left ventricular mass index (LVMI) in adult participants with Fabry disease and left ventricular hypertrophy.

• Study visits will take place approximately every 3 to 6 months
• Participants who complete the randomized period may continue to the long-term extension (LTE) to receive venglustat for up to additional 34 months with the total study duration up to 4.4 years maximum.

Study Overview

• Status: Recruiting
• Conditions: Fabry Disease
• Intervention / Treatment: Drug: Venglustat (GZ402671); Drug: Agalsidase alfa; Drug: Agalsidase beta (GZ419828); Drug: Migalastat

Detailed Description

Randomized period: the total duration will be up to approximately of 20 months (1 month screening 18 months of treatment and a possible follow-up period of 1 month if no participation in the long-term extension period)

Long-term extension period: the total duration will be from minimum 19 months (18 months of treatment and 1 month of follow-up period) to maximum 35 months (34 months of treatment and 1 month of follow-up period). The maximum total study duration is approximately 4.4 years

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Trial Transparency email recommended (Toll free for US & Canada); Phone Number: option 6 800-633-1610; Email: Contact-US@sanofi.com

Study Locations

• Austria
  • Graz, Austria, 8036
    • Recruiting
    • Investigational Site Number : 0400001
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Recruiting
      • Investigational Site Number : 1240006
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Recruiting
      • Investigational Site Number : 1240002
• China
  • Beijing, China, 100034
    • Recruiting
    • Investigational Site Number : 1560002
  • Beijing, China, 100044
    • Recruiting
    • Investigational Site Number : 1560005
  • Chengdu, China, 610041
    • Recruiting
    • Investigational Site Number : 1560001
  • Shanghai, China, 200025
    • Recruiting
    • Investigational Site Number : 1560003
• Czechia
  • Praha 2, Czechia, 12808
    • Recruiting
    • Investigational Site Number : 2030001
• Denmark
  • Copenhagen, Denmark
    • Recruiting
    • Investigational Site Number : 2080001
• France
  • Garches, France, 92380
    • Recruiting
    • Investigational Site Number : 2500001
• Germany
  • Berlin, Germany, 10117
    • Recruiting
    • Investigational Site Number : 2760003
  • Hochheim am Main, Germany, 65239
    • Recruiting
    • Investigational Site Number : 2760004
  • Würzburg, Germany, 97080
    • Recruiting
    • Investigational Site Number : 2760001
• Greece
  • Athens, Greece, 11527
    • Recruiting
    • Investigational Site Number : 3000002
  • Athens, Greece, 12462
    • Recruiting
    • Investigational Site Number : 3000003
  • Heraklion, Greece, 71500
    • Recruiting
    • Investigational Site Number : 3000001
• Italy
  • Napoli, Italy, 80131
    • Recruiting
    • Investigational Site Number : 3800002
  • Napoli, Italy, 80131
    • Recruiting
    • Investigational Site Number : 3800003
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Recruiting
      • Investigational Site Number : 3800001
• Japan
  • Fukuoka
    • Fukuoka-shi, Fukuoka, Japan, 814-0180
      • Recruiting
      • Investigational Site Number : 3920004
  • Kagoshima
    • Kagoshima-shi, Kagoshima, Japan, 890-8520
      • Completed
      • Investigational Site Number : 3920003
  • Kanagawa
    • Kawasaki-shi, Kanagawa, Japan, 215-0026
      • Recruiting
      • Investigational Site Number : 3920005
  • Miyagi
    • Sendai-shi, Miyagi, Japan, 980-8574
      • Recruiting
      • Investigational Site Number : 3920002
  • Tokyo
    • Minato-ku, Tokyo, Japan, 105-8471
      • Recruiting
      • Investigational Site Number : 3920001
• Korea, Republic of
  • Gyeongsangnam-do
    • Yangsan-si, Gyeongsangnam-do, Korea, Republic of
      • Recruiting
      • Investigational Site Number : 4100002
  • Seoul-teukbyeolsi
    • Seoul, Seoul-teukbyeolsi, Korea, Republic of, 03722
      • Recruiting
      • Investigational Site Number : 4100001
• Netherlands
  • Amsterdam, Netherlands, 1105AZ
    • Recruiting
    • Investigational Site Number : 5280001
• Norway
  • Bergen, Norway, 5021
    • Recruiting
    • Investigational Site Number : 5780001
• Poland
  • Krakow, Poland, 31-202
    • Recruiting
    • Investigational Site Number : 6160001
• Spain
  • Alicante, Spain, 03010
    • Recruiting
    • Investigational Site Number : 7240003
  • Vigo, Spain, 36312
    • Recruiting
    • Investigational Site Number : 7240001
  • Madrid, Comunidad De
    • Madrid / Madrid, Madrid, Comunidad De, Spain, 28007
      • Recruiting
      • Investigational Site Number : 7240002
• Taiwan
  • Taichung, Taiwan, 407
    • Recruiting
    • Investigational Site Number : 1580003
  • Taipei 104, Taiwan, 104
    • Recruiting
    • Investigational Site Number : 1580001
• Turkey
  • Ankara, Turkey, 06500
    • Recruiting
    • Investigational Site Number : 7920001
  • Istanbul, Turkey, 34303
    • Recruiting
    • Investigational Site Number : 7920002
  • Kocaeli, Turkey, 41380
    • Recruiting
    • Investigational Site Number : 7920003
• United Kingdom
  • London, City Of
    • London, London, City Of, United Kingdom, NW3 2QG
      • Recruiting
      • Investigational Site Number : 8260001
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-2110
      • Recruiting
      • University of Alabama at Birmingham (UAB) - The Kirklin Clin Site Number : 8400010
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Recruiting
      • Emory Clinic Site Number : 8400009
  • New York
    • Hawthorne, New York, United States, 10532
      • Recruiting
      • Maryam Banikazemi, MD Site Number : 8400001
  • Virginia
    • Fairfax, Virginia, United States, 22030
      • Recruiting
      • Lysosomal and Rare Disorders Research and Treatment Center, Inc Site Number : 8400004

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female participants aged 18 to 65 with previously confirmed diagnosis of Fabry disease and a history of clinical symptoms of Fabry disease.
• Participants may be receiving treatment with agalsidase alfa, agalsidase beta, or migalastat, or may be untreated.
• Left ventricular hypertrophy.
• Contraception for male or female participants: not pregnant or breastfeeding; no sperm donating for male participant.
• A signed informed consent must be provided prior to any study-related procedures.

Exclusion Criteria:

• History of transient ischemic attack, stroke, myocardial infarction, heart failure, major cardiovascular surgery or kidney transplantation.
• History of seizures currently requiring treatment.
• Underlying medical condition that may cause or contribute to left ventricular hypertrophy.
• Asymmetric hypertrophy by cardiac MRI at screening if considered by central reader to be not related to Fabry disease.
• Advanced cardiac fibrosis, defined as significant late gadolinium enhancement affecting 3 or more segments involving >50% of myocardial thickness on screening cardiac MRI.
• History of clinically significant cardiac arrhythmia. Atrial fibrillation that is well controlled on a stable medical regimen for at least 12 months is not an exclusion if the CHA2DS2-VASc score is 0 for males or 1 for females.
• Estimated glomerular filtration rate <45 mL/min/1.73m2.
• Presence of severe depression as measured by Beck's Depression Inventory (BDI)-II >28 and/or a history of an untreated, unstable major affective disorder within 1 year of the screening visit.
• Patients with hepatitis C, HIV, or hepatitis B infection.
• Positive SARS-CoV-2 virus test within 2 weeks of enrollment, or COVID-19 requiring hospitalization within 6 months of enrollment.
• History of drug and/or alcohol abuse.
• Moderate to severe hepatic impairment.
• History of or active hepatobiliary disease.
• Liver enzymes (alanine aminotransferase/aspartate aminotransferase) or total bilirubin >2 times the upper limit of normal.
• Strong or moderate inducers or inhibitors of cytochrome P450 CYP3A4 within 14 days or 5 half-lives, whichever is longer, prior to randomization.
• Known contraindication to undergoing MRI or known hypersensitivity to gadolinium-based contrast agents.

The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Venglustat; Participants will receive venglustat once daily, orally	Drug: Venglustat (GZ402671); Tablet; Oral
Active Comparator: Standard of Care Therapy; Participants will receive a locally approved Fabry therapy at the standard dose and schedule (in accordance with the locally approved prescribing information)	Drug: Agalsidase alfa; Concentrate for solution for infusion; IV infusion; Other Names: Replagal®; Drug: Agalsidase beta (GZ419828); Powder for concentrate for solution for infusion; IV infusion; Other Names: Fabrazyme®; Drug: Migalastat; Hard capsules; Oral; Other Names: Galafold®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Slope of left ventricular mass index as measured by cardiac magnetic resonance imaging (MRI) (central reading)	from baseline to 18 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Slope of estimated glomerular filtration rate (eGFR) as assessed by the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine equation	from baseline to 18 months
Change in T1 relaxation time, measured by cardiac MRI (central reading)	from baseline to 18 months
Change in global longitudinal strain, measured by echocardiography (central reading)	from baseline to 18 months
Number of participants with adverse event (AE) and serious adverse event (SAE)	from baseline to 18 months
Change in Beck Depression Inventory-II (BDI-II) score	from baseline to 18 months
Plasma venglustat concentrations at prespecified visits over the study duration	from baseline to 18 months
Percent Change in tiredness component of FD-PRO	from baseline to 18 months
Percent Change in swelling in lower extremities component of FD-PRO	from baseline to 18 months
Change in the lens clarity by ophthalmological examination	from baseline to 18 months

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Study Director: Clinical Sciences & Operations Clinical Sciences and Operations, Sanofi

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2022
• Primary Completion (Estimated): December 29, 2025
• Study Completion (Estimated): July 15, 2027

Study Registration Dates

• First Submitted: March 4, 2022
• First Submitted That Met QC Criteria: March 4, 2022
• First Posted (Actual): March 15, 2022

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 14, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Cerebral Small Vessel Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Fabry Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Venglustat
• Other Study ID Numbers: EFC16158; U1111-1266-5068 (Registry Identifier: ICTRP); 2021-002320-20 (EudraCT Number); 2023-509715-91 (Registry Identifier: CTIS)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No