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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: Venglustat (GZ402671)
* Drug: Agalsidase alfa
* Drug: Agalsidase beta (GZ419828)
* Drug: Migalastat


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venglustat<br>Participants will receive venglustat once daily, orally | Drug: Venglustat (GZ402671)<br>* Tablet; Oral<br>|
| Active Comparator: Standard of Care Therapy<br>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<br>* Concentrate for solution for infusion; IV infusion<br>* Other names: Replagal®;Drug: Agalsidase beta (GZ419828)<br>* Powder for concentrate for solution for infusion; IV infusion<br>* Other names: Fabrazyme®;Drug: Migalastat<br>* Hard capsules; Oral<br>* Other names: Galafold®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 | Measure Description | 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 | 
| 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 | 
| 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 | 
| Change in the lens clarity by ophthalmological examination |  | from baseline to 18 months | 
| Plasma venglustat concentrations at prespecified visits over the study duration |  | from baseline to 18 months |