A Study to Evaluate the Effect of Venglustat Tablets on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease

Study Overview
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Brief Summary
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This is a 12-month, parallel treatment, Phase 3, double-blind, randomized, placebo controlled study to evaluate the effect of venglustat on neuropathic and abdominal pain symptoms of Fabry disease in participants ≥16 years of age with Fabry disease who are treatment-naïve or untreated for at least 6 months. Study visits will take place approximately every 3 months. The double-blind period will be followed by an open-label extension (OLE) during which participants who have completed the double-blind period will be treated with venglustat for up to an additional 12 months.

Detailed Description
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Double blind period: the total duration will be up to approximately of 14 months (1 month of screening 12 month of treatment period, and a possible follow-up period of 1 month if no participation in the open label extension period) Open-label extension period: the total duration will be approximately of 31 months (12 month of OLE treatment, additional OLE treatment until a common study end of treatment date (CSEOTD, approximately 18 months), and 1 month of follow-up period)

Official Title
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A Randomized, Double-blind, Placebo-controlled, 12-month Phase 3 Study to Evaluate the Effect of Venglustat on Neuropathic and Abdominal Pain in Male and Female Participants ≥16 Years of Age With Fabry Disease Who Are Treatment-naïve or Untreated for at Least 6 Months

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: Venglustat (GZ402671)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female adult patients 16 year of age or older, who have had a previously confirmed diagnosis of Fabry disease and a history of clinical symptoms of Fabry disease Patients who are treatment-naïve or without prior treatment with an approved or experimental therapy for Fabry disease within at least 6 months prior to screening. Average score of ≥3 (0=no symptom, 10=symptom as bad as you can imagine) on the participant-defined most-bothersome symptom (among neuropathic pain in upper extremities, neuropathic pain in lower extremities, or abdominal pain), as measured by the Fabry Disease Patient-Reported Outcome (FD-PRO) at screening. Contraception (with double contraception methods) for male and female participants; not pregnant or breastfeeding for female participants; no sperm donation for male participants. Weight ≥30 Kg A signed informed consent must be provided prior to any study-related procedures. Exclusion Criteria: Any manifestations of Fabry disease that preclude placebo administration. History of transient ischemic attack, stroke, myocardial infarction, heart failure, evidence of left ventricular hypertrophy and/or cardiac fibrosis, major cardiovascular surgery, or kidney transplantation. 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. Patients with hepatitis C, HIV, or hepatitis B infection. Neuropathic pain in upper or lower extremities, or abdominal pain not related to Fabry disease. History of seizures currently requiring treatment. Uncontrolled hypertension over the past 12 months prior to screening, or systolic BP >=150 or diastolic BP >=100 at screening. Estimated glomerular filtration rate <60 mL/min/1.73m². Urine protein to creatinine ratio >= 1 g/g at screening. 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. Positive SARS-CoV-2 virus test within 2 weeks of enrollment, or COVID 19 requiring hospitalization within 6 months of enrollment. Moderate to severe hepatic impairment. History of drug and/or alcohol abuse. History of or active hepatobiliary disease. Liver enzymes (alanine aminotransferase (ALT)/aspartate aminotransferase (AST)) or total bilirubin >2 times the upper limit of normal (ULN). Initiation of chronic treatment for pain, or change in pain medication regimen, within 3 months prior to randomization. Strong or moderate inducers or inhibitors of cytochrome P450 3A within 14 days or 5 half-lives, whichever is longer, prior to randomization. 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: 16 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Venglustat<br>Participant will receive venglustat dose once daily up to 12 months | Drug: Venglustat (GZ402671)<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>|
| Placebo Comparator: Placebo<br>Participants will receive placebo once daily up to 12 months | Drug: Placebo<br>* Pharmaceutical form: Tablet Route of administration: Oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change from baseline at 6 months in the most bothersome symptom of 3 Fabry Disease Patient-Reported Outcome (FD-PRO) items (neuropathic pain in upper extremities, neuropathic pain in lower extremities, and abdominal pain) |  | From baseline to 6 months | 
| Percent change from baseline at 12 months in the most bothersome symptom of 3 Fabry Disease Patient-Reported Outcome (FD-PRO) items (neuropathic pain in upper extremities, neuropathic pain in lower extremities, and abdominal pain) |  | From baseline to 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent change in plasma globotriaosylsphingosine (lyso-GL-3) |  | From baseline to 6 month and 12 months | 
| Frequency of rescue pain medication use | Number of days with use of rescue pain medications during the 6-month treatment period, divided by duration of the 6-month treatment period and multiplied by 100. The same definition will be used for the 12-month period. | From baseline to 6 months and 12 months | 
| Change in the percentage of days with at least 1 stool reflecting diarrhea (Bristol Stool Form Scale [BSFS] Type 6 or 7) |  | From baseline to 6 month and 12 months | 
| Percent change in tiredness component of FD-PRO |  | From baseline to 6 month and 12 months | 
| Proportion of responders in neuropathic or abdominal pain, as assessed by FD-PRO | Response is defined as at least a 30% decrease from baseline in the most bothersome of 3 FD-PRO items between neuropathic pain in upper extremities, neuropathic pain in lower extremities, and abdominal pain | At 6 months and 12 months | 
| Number of participants with adverse event (AE) and serious adverse event (SAE) |  | From baseline to 6 month and 12 months | 
| Change in the lens clarity (new or worsening lens opacities) by ophthalmological examination (by slit lamp exam at Visit 2 and Visit 6) |  | From baseline to 12 months | 
| Change in Beck Depression Inventory-II (BDI-II) score |  | From baseline to 6 month and 12 months | 
| Plasma venglustat concentrations at prespecified visits over the study duration |  | From baseline to 6 month and 12 months | 
| Maximum venglustat plasma concentration (Cmax) |  | From baseline to 6 month and 12 months | 
| Time to maximum venglustat plasma concentration (tmax) |  | From baseline to 6 month and 12 months | 
| Area under the venglustat plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) |  | From baseline to 6 month and 12 months |