臨床研究等提出・公開システム

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)

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

478

A total of 201 participants were randomized in placebo group, 78 participants in 8 mg venglustat group and 199 participants in 15 mg venglustat group. Of these, 200 participants in placebo group and all participants in 8 mg and 15 mg venglustat group were exposed to IMP. Twelve (6.0%) participants in placebo group, 10 participants (12.8%) in 8 mg venglustat group, and 12 participants (6.0%) in 15 mg venglustat group completed the study treatment. Sixteen (8.0%) participants in placebo group, 12 participants (15.4%) in 8 mg venglustat group and 16 participants (8.0%) in 15 mg venglustat group completed the study.

Stage 1 Enrolled: 236 participants Treated: 236 participants Completed: 34 participants Discontinued: 202 participants Stage 2 Enrolled: 242 participants Treated: 241 participants Completed: 0 participants Discontinued: 242 participants

There were 128 participants (64.0%) in placebo group, 65 participants (83.3%) in 8 mg venglustat group and 143 participants (71.9%) in 15 mg venglustat group with any treatment-emergent adverse event (TEAE) reported during the study. There were 14 participants (7.0%) in placebo group, 15 participants (19.2%) in 8 mg venglustat group and 26 participants (13.1%) in 15 mg venglustat group who experienced treatmentemergent SAEs. There were no TEAEs leading to death in this study. Three participants (1.5%) in placebo group, 2 participants (2.6%) in 8 mg venglustat group and 6 participants (3.0%) in 15 mg venglustat group experienced TEAE leading to permanent study intervention discontinuation. Eleven participants (5.5%) in placebo group, 6 participants (7.7%) in 8 mg venglustat group and 14 participants (7.0%) in 15 mg venglustat group experienced TE Adverse event of special interest (AESI).

The primary endpoint in Stage 1 was annualized rate of change in TKV based on MRI from baseline to 18 months. The annualized rate of change in TKV was 6.35% per year (95% CI: 5.10 to 7.62) in placebo group, 7.71% per year (95% CI: 6.46 to 8.98) in 8 mg venglustat group and 6.38% per year (95% CI: 5.11 to 7.66) in 15 mg venglustat group. The two-sided p-value of 8 mg venglustat group versus placebo was 0.1367 and 15 mg venglustat group versus placebo was 0.9812. The primary efficacy endpoint in combined Stage 1 and Stage 2 was annualized rate of change in eGFR (CKD-EPI equation) from baseline to 24 months. The annualized rate of change in eGFR estimate (SE) was -2.40 (0.46) mL/min/1.73m^2/year in placebo group, -4.82 (0.50) mL/min/1.73m^2/year in 8 mg venglustat group and -4.89 (0.46) mL/min/1.73m^2/year in 15 mg venglustat group. The two-sided p-value when placebo was compared with 8 mg venglustat group was 0.0005 and with 15 mg venglustat group was 0.0002.

The incidence of all TEAEs was similar in placebo group, 8 mg venglustat group, and 15 mg venglustat group in the Stage 1 safety population, as well as similar in placebo group and 15 mg venglustat group in the extended combined Stage 1 and Stage 2 safety population; however, there were significantly more treatment-emergent SAEs reported in 15 mg venglustat group than in placebo group. There were no deaths reported during the study period. As determined from Stage 1 of the study, following venglustat 8 mg or 15 mg QD oral administration, steady state appeared to have been achieved on or before 1 month (assessed from pre-dose concentrations, Ctrough), with an accumulation of approximately 3-fold (assessed from post-dose concentrations). In general, venglustat plasma exposure (Ctrough) at steady state increased in a close to dose proportional manner. Venglustat PK in Stage 2 of the study was consistent with that observed in Stage 1. Following venglustat 15 mg QD dose, the mean (SD) pre-dose concentrations (Ctrough) ranged from 103.9 (50.2) ng/mL - 120.3 (73.1) ng/mL in Stage 1 and 109.3 (60.7) ng/mL at 1 month in Stage 2. As determined from Stage 1 of the study, following venglustat 8 mg or 15 mg QD oral administration, steady state was achieved on or before 1 month (assessed from pre-dose concentrations, Ctrough), with an accumulation of approximately 3-fold (assessed from postdose concentrations). In general, venglustat plasma exposure (Ctrough) at steady state increased in a close to dose proportional manner with an increase in dose from 8 to 15 mg. Venglustat PK in Stage 2 of the study was consistent with that observed in Stage 1. Following venglustat 15 mg QD dose, the mean (SD) pre-dose (Ctrough) concentrations ranged from 103.9 (50.2) ng/mL- 120.3 (73.1) ng/mL in Stage 1 and 109.3 (60.7) ng/mL at 1 month in Stage 2.

The interim analysis for futility using Stage 1 data of this study met the prespecified stopping rule based on the primary endpoint (annualized rate of change in TKV). Based on this prespecified criteria and recommendation from the Data Monitoring Committee, study EFC15392 was terminated. Termination decision was due to a lack of efficacy in the ADPKD population and not related to safety findings with venglustat.

Yes

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

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp@sanofi.com

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp@sanofi.com

completed

Jan. 31, 2019

Interventional

Allocation: Randomized, Masking: Double blind, Design: Parallel

treatment purpose

2-3

- Male or female adult with Autosomal Dominant Polycystic Kidney Disease (ADPKD) with an age at the time the consent is signed:
a) between 18 and 50 years (both inclusive) for patients in Stage 1
b) between 18 and 50 years (both inclusive) for patients in Stage 2 with an estimated glomerular filtration rate (eGFR) between 45 and 89.9 mL/min/1.73 m2 during screening period*
c) between 18 and 55 years (both inclusive) for patients in Stage 2 with eGFR between 30 and 44.9 mL/min/1.73 m2 during screening period*
Diagnosis of ADPKD 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

- eGFR between 45 and 89.9 mL/min/1.73 m2 during screening period* (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) for Stage 1.
eGFR between 30 and 89.9 mL/min/1.73 m2 during screening period* (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 [beta-human chorionic gonadotropin (beta-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 patients 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.

- 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 antibody [HBsAb], negative hepatitis B surface antigen [HBsAg], and positive hepatitis B core antibody [HBcAb]) are eligible if they a 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 patient 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 umol/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.

Both

Polycystic kidney, autosomal dominant

investigational material(s)
Generic name etc : GZ402671
INN of investigational material : venglustat
Therapeutic category code : 251 Agents affecting urinary organs
Dosage and Administration for Investigational material : once daily for 24 months

control material(s)
Generic name etc : Placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : once daily for 24 months

efficacy
Rate of change in total kidney volume (TKV) [Time Frame: From baseline to 18 months]
Annualized rate of change in total kidney volume (TKV) based on magnetic resonance imaging (MRI) from baseline to 18 months (Stage 1)
efficacy
Rate of change in eGFR [Time Frame: From baseline to 24 months]
Annualized rate of change in estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) from baseline to 24 months (Stage 2)

efficacy
Rate of change in eGFR [Time Frame: From baseline to 18 months]
Annualized rate of change in eGFR (CKD-EPI equation) from baseline to 18 months (Stage 1)
efficacy
Rate of change in TKV [Time Frame: From baseline to 18 months]
Annualized rate of change in TKV based on MRI from baseline to 18 months (Stage 2)
efficacy
Change in pain [Time Frame: Stage 1: From baseline to 18 months; Stage 2: From baseline to 24 months]
Change in Brief Pain Inventory (BPI) - Item 3 from the daily symptom diary.
efficacy
Change in fatigue [Time Frame: Stage 1: From baseline to 18 months; Stage 2: From baseline to 24 months]
Change in Brief Fatigue Inventory (BFI) - Item 3 from the daily symptom diary.

safety
Number of adverse events [Time Frame: From baseline to end of treatment +30 days]
Number of adverse events (Stages 1 and 2)
pharmacokinetics
Assessment of plasma concentration of venglustat [Time Frame: Stage 1: Day 1, Months 1, 6, and 18; Stage 2: Months 6 and 24]
Assessment of single time-point plasma concentration (Stages 1 and 2)
safety
Change in lens clarity [Time Frame: From baseline to end of treatment +30 days]
Change in the lens clarity from baseline by ophthalmological examination (Stages 1 and 2)
safety
Change in score of Beck Depression Inventory-II (BDI-II) [Time Frame: From baseline to end of treatment +30 days]
Change in score of BDI-II (Stages 1 and 2)

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Oct. 17, 2018