A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients

Multicenter, Randomized, Double-blind, Placebo-controlled Two Stage Study to Characterize the Efficacy, Safety, Tolerability and Pharmacokinetics of GZ/SAR402671 in Patients at Risk of Rapidly Progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD)

Primary Objective:

To determine the effect of venglustat on the rate of total kidney volume (TKV) growth (Stage 1) and estimated glomerular filtration rate (eGFR) decline in participants at risk of rapidly progressive Autosomal Dominant Polycystic Kidney Disease (ADPKD) (Stage 2).

Secondary Objectives:

• To determine the effect of venglustat on the rate of renal function decline (Stage 1) and on the rate of TKV growth (Stage 2).
• To evaluate the pharmacokinetics (PK) of venglustat in ADPKD participants (Stages 1 and 2).
• To determine the effect of venglustat on pain and fatigue, based on participant reported diary (Stages 1 and 2).
• Safety/tolerability objectives:
• To characterize the safety profile of venglustat (Stages 1 and 2).
• To evaluate the effect of venglustat on mood using Beck Depression Inventory II (BDI-II) (Stages 1 and 2).
• To evaluate the effect of venglustat on the lens by ophthalmological examination (Stages 1 and 2).

Study duration per participant was 26 months (maximal) that included a screening period of 15 days, run-in period of 2 weeks, a 24-month treatment period, and a follow-up 30 days after final dose of investigational medicinal product (IMP).

Inclusion criteria:

• Male or female adult with ADPKD with age at the time the consent was signed:

  1. between 18 to 50 years (both inclusive) for participants from Stage 1.
  2. between 18 to 50 years (both inclusive) for participants from Stage 2 with eGFR between 45 and 89.9 milliliters per minute per 1.73 meter square (mL/min/1.73 m^2) during screening period.*
  3. between 18 to 55 years (both inclusive) for participants from Stage 2 with eGFR between 30 and 44.9 mL/min/1.73 m^2 during screening period.*

• Diagnosis of ADPKD in participants with a family history would be based on unified Pei criteria. In the absence of a family history, the diagnosis would be based on the presence of renal cysts bilaterally, totaling at least 20, in the absence of findings suggestive of other cystic renal diseases.

• Mayo Imaging Classification of ADPKD Class 1C, 1D or 1E**

  **Total kidney volume (TKV) had confirmed by a central reader prior to Visit 3.

• Estimated glomerular filtration rate between 45 to 89.9 mL/min/1.73 m^2 during screening period* (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) for Stage 1.

• Estimated glomerular filtration rate between 30 to 89.9 mL/min/1.73 m^2 during screening period* (CKD-EPI equation) for Stage 2.

  *Eligibility would be confirmed by eGFR value from one of the two first pre-randomization eGFR measurements.

• Stable treatment regimen of antihypertensive therapy for at least 30 days prior to the screening visit for hypertensive participant.

• Able to read, comprehend, and respond to the study questionnaires.

• Participant had given voluntary written informed consent before performance of any study related procedures not part of standard medical care.

• Participant had no access to tolvaptan at the time of study start or tolvaptan was not indicated for treatment of participant according to treating physician (participant does not meet recommended criteria for treatment, refuses to initiate or does not tolerate treatment with tolvaptan).

• The participants, if female of childbearing potential, must have had a negative blood pregnancy test (β-human chorionic gonadotropin [β-hCG]) at the screening visit and a negative urine pregnancy test at the baseline visit.

• Female participants of childbearing potential and male participants must have had agreed to practice true abstinence in line with their preferred and usual lifestyle or to use double-contraceptive methods (including a highly effective method of contraception for female participants of childbearing potential) for the entire duration of the study and for at least 6 weeks for females and 90 days for males following their last dose of study drug.

Exclusion criteria:

• Systolic blood pressure greater than (>) 160 millimeters of Mercury (mmHg) at Run-in and Baseline visits.
• Administration within 3 months prior to the screening visit of tolvaptan or other Polycystic Kidney Disease-modifying agents (somatostatin analogues).
• Participation in another investigational interventional study or use of IMP, within 3 months or 5 half lives, whichever was longer, before randomization.
• The participant had a positive result of any of the following tests: hepatitis B surface antigen (HBsAg), anti-hepatitis C virus (anti HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti HIV1 and anti HIV2 Ab). Participants with a positive hepatitis B surface antibody (HBsAb) test were eligible if other criteria were met (i.e., negative tests for: HBsAg, hepatitis B core antibody [HBcAb]). Participants immune due to natural infection (positive hepatitis B surface antibody (HBsAb), negative hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody [HBcAb]) were eligible if they had negative hepatitis B vaccine (HBV) deoxyribonucleic acid (DNA) test.
• A history of drug and/or alcohol abuse within the past year prior to the screening visit. A history of alcohol dependence within the 5 years prior to the screening visit.
• The participant was scheduled for in-patient hospitalization including elective surgery, during the study.
• The participant had a clinically significant, uncontrolled medical condition that, in the opinion of the investigator, would put the safety of the participant at risk through participation, or which would affect the efficacy or safety analysis if the condition exacerbated during the study, or that might significantly interfere with study compliance, including all prescribed evaluations and follow-up activities.
• The participants, in the opinion of the investigator, was unable to adhere to the requirements of the study or unable to undergo study assessments (e.g., had contraindications to pupillary dilation or unable to undergo magnetic resonance imaging (MRI) [For example: participant's weight exceeds weight capacity of the MRI, ferromagnetic metal prostheses, aneurysm clips, severe claustrophobia, large abdominal/back tattoos, etc.]).
• Any country-related specific regulation that would prevent the participant from entering the study.
• The participants did not adhere to treatment (less than [<] 70 percent [%] compliance rate) in the run-in.
• The participant had, according to World Health Organization (WHO) Grading, a cortical cataract greater than or equal to (>=)one-quarter of the lens circumference (Grade cortical cataract-2 [COR-2]) or a posterior subcapsular cataract >=2 millimeter (Grade posterior subcapsular cataract-2 [PSC-2]). Participant with nuclear cataracts would not be excluded.
• The participant was then receiving potentially cataractogenic medications, including a chronic regimen (more frequently than every 2 weeks) of any route of corticosteroids (including medium and high potency topical steroids) or any medication that might cause cataract, according to the Prescribing Information.
• The participant had received strong or moderate inducers or inhibitors of CYP3A4 within 14 days or 5 half-lives, whichever was longer, prior to randomization. This also included the consumption of grapefruit, grapefruit juice, or grapefruit containing products within 72 hours of starting venglustat administration.
• The participant was pregnant, or lactating.
• Liver enzymes (alanine aminotransferase /aspartate aminotransferase ) or total bilirubin >2 times the upper limit of normal unless the participant had the diagnosis of Gilbert syndrome. Participants with the Gilbert syndrome should have had no additional symptoms or signs which suggested hepatobiliary disease and serum total bilirubin level no more than 3 milligrams per deciliter (mg/dL) (51 [micromoles per Liter] mcmol/L) with conjugated bilirubin less than 20% of the total bilirubin fraction.
• Presence of severe depression as measured by Beck Depression Inventory-II (BDI-II) >28 and/or a history of a major affective disorder within 1 year of the screening visit.
• Known hypersensitivity to venglustat or any component of the excipients.

The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.