A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients
A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients
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 patients 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 Autosomal Dominant Polycystic
 Kidney Disease patients (Stages 1 and 2).

 -  To determine the effect of venglustat on pain and fatigue, based on patient reported
 diary (Stages 1 and 2).

 -  Safety/tolerability objective:

 -  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 is 26 months (maximal) per stage, including 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 Autosomal Dominant Polycystic Kidney Disease (ADPKD) with
 age at the time the consent is signed:

 1. between 18 to 50 years (both inclusive) for patients from Stage 1

 2. between 18 to 50 years (both inclusive) for patients from Stage 2 with eGFR
 between 45 and 89.9 mL/min/1.73 m2 during screening period*

 3. between 18 to 55 years (both inclusive) for patients from Stage 2 with eGFR
 between 30 and 44.9 mL/min/1.73 m2 during screening period.*

 -  Diagnosis of AKPKD in patients with a family history will be based on unified Pei
 criteria. In the absence of a family history, the diagnosis will 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) must be confirmed by a central reader prior to Visit 3.

 -  Estimated glomerular filtration rate between 45 to 89.9 mL/min/1.73 m2 during
 screening period* (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) for
 Stage 1.

 -  Estimated glomerular filtration rate between 30 to 89.9 mL/min/1.73 m2 during
 screening period* (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) for
 Stage 2.

 *Eligibility will 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 patient.

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

 -  Patient has given voluntary written informed consent before performance of any study
 related procedures not part of standard medical care.

 -  Patient does not have access to tolvaptan at the time of study start or tolvaptan is
 not indicated for treatment of patient according to treating physician (patient does
 not meet recommended criteria for treatment, refuses to initiate or does not tolerate
 treatment with tolvaptan).

 -  The patient, if female of childbearing potential, must have 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 patients of childbearing potential and male patients must agree 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 >160 mm Hg 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).

 -  Current participation in another investigational interventional study or use of
 investigational medicinal product (IMP), within 3 months or 5 half lives, whichever is
 longer, before randomization.

 -  The patient has 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). Patients with
 a positive hepatitis B surface antibody (HBsAb) test are eligible if other criteria
 are met (ie, negative tests for: HBsAg, hepatitis B core antibody [HBcAb]). Patients
 immune due to natural infection (positive hepatitis B surface antigen (HBsAb),
 negative hepatitis B surface antibody (HBsAg) and positive hepatitis B core antibody
 [HBcAb]) are eligible if they have negative HBV 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 patient is scheduled for in-patient hospitalization including elective surgery,
 during the study.

 -  The patient has a clinically significant, uncontrolled medical condition that, in the
 opinion of the investigator, would put the safety of the subject at risk through
 participation, or which would affect the efficacy or safety analysis if the condition
 exacerbated during the study, or that may significantly interfere with study
 compliance, including all prescribed evaluations and follow-up activities.

 -  The patient, in the opinion of the investigator, is unable to adhere to the
 requirements of the study or unable to undergo study assessments (eg, has
 contraindications to pupillary dilation or unable to undergo magnetic resonance
 imaging (MRI) [For example: patient'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 patient from entering
 the study.

 -  The patients did not adhere to treatment (<70% compliance rate) in the run-in.

 -  The patient has, according to World Health Organization (WHO) Grading, a cortical
 cataract >one-quarter of the lens circumference (Grade cortical cataract-2 [COR-2]) or
 a posterior subcapsular cataract >2 mm (Grade posterior subcapsular cataract-2
 [PSC-2]). Patients with nuclear cataracts will not be excluded.

 -  The patient is currently 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 may cause
 cataract, according to the Prescribing Information.

 -  The patient has received strong or moderate inducers or inhibitors of CYP3A4 within 14
 days or 5 half-lives, whichever is longer, prior to randomization. This also includes
 the consumption of grapefruit, grapefruit juice, or grapefruit containing products
 within 72 hours of starting venglustat administration.

 -  The patient is pregnant, or lactating.

 -  Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or
 total bilirubin >2 times the upper limit of normal unless the patient has the
 diagnosis of Gilbert syndrome. Patients with the Gilbert syndrome should have no
 additional symptoms or signs which suggest hepatobiliary disease and serum total
 bilirubin level no more than 3mg/dl (51 μmol/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 is not intended to contain all considerations relevant to a patient's
 potential participation in a clinical trial.