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

NCT03523728 | Terminated Phase 2 Results DMC FDA Drug

• 3 other identifiers: EFC153922017-004084-12U1111-1202-0775
• Study Type: interventional
• Target: 478
• Locations: 22 countries
• Sites: 93

Brief Summary

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).

Conditions

Polycystic Kidney, Autosomal Dominant

Outcome Measures

Primary Outcomes (2)

• Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Stage 1

  Total kidney volume is a measure for assessing disease progression in participants with ADPKD, a prognostic biomarker of renal function decline and progression to end-stage renal disease. Kidney volume was assessed using magnetic resonance imaging (MRI). The annualized slope of change in TKV (in percentage \[%\] per year) in each treatment group was obtained from the back-transformation of the mean slope of log10-transformed TKV obtained from the linear mixed effect model. The model included fix effects of treatment (venglustat 15 mg, venglustat 8 mg or placebo), mayo imaging classification (as per randomization stratification factor: class 1C versus 1D versus 1E), time (as continuous variable in years), treatment \* time interaction and mayo imaging classification \* time interaction and included random intercept and slope.

  From Baseline to Month 18

• Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) From Baseline to Month 24: Combined Stage 1 and Stage 2

  An eGFR was used to measure level of kidney function and determine the stage of kidney disease in ADPKD participants. Baseline eGFR was defined for each participant as the average of eGFR values assessed prior or equal to first dose of study drug or randomization for participants randomized and not exposed. Annualized rate of change in eGFR in each treatment group was obtained from the linear mixed effect model including the fixed categorical effects of treatment group (venglustat 15 mg, venglustat 8 mg or placebo), mayo imaging classification (as per interactive response technology \[IRT\]: 1C, 1D, 1E), time (as continuous variable in years), treatment-by-time, mayo imaging classification-by-time, and included random intercept and slope.

  From Baseline to Month 24

Secondary Outcomes (18)

• Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 24: Stage 1

  From Baseline to Month 24

• Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Combined Stage 1 and Stage 2

  From Baseline to Month 18

• Change in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1

  From Baseline to Month 18

• Change in Pain Severity as Measured by Brief Pain Inventory-Short Form (BPI-SF)-Item 3 Scale Score From Baseline to Month 24: Combined Stage 1 and Stage 2

  From Baseline to Month 24

• Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1

  From Baseline to Month 18

Study Arms (5)

Stage 1- Placebo

PLACEBO COMPARATOR

Participants from Stage 1 were randomized to receive 2 capsules of placebo matched to venglustat once daily for treatment period of 24 months.

Drug: Placebo

Stage 1- Venglustat 8 mg

EXPERIMENTAL

Participants from Stage 1 were randomized to receive venglustat 8 milligrams (mg) (i.e., 2 capsules of 4 mg) once daily for treatment period of 24 months.

Drug: Venglustat

Stage 1- Venglustat 15 mg

EXPERIMENTAL

Participants from Stage 1 were randomized to receive 1 capsule of venglustat 15 mg and 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.

Drug: Venglustat; Drug: Placebo

Stage 2- Placebo

PLACEBO COMPARATOR

Participants from Stage 2 were randomized to receive 1 capsule of placebo matched to venglustat once daily for treatment period of 24 months.

Drug: Placebo

Stage 2- Venglustat 15 mg

EXPERIMENTAL

Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.

Drug: Venglustat

Interventions

Venglustat DRUG

Pharmaceutical form: capsule; Route of administration: oral

Also known as: GZ402671

Stage 1- Venglustat 15 mg; Stage 1- Venglustat 8 mg; Stage 2- Venglustat 15 mg

Placebo DRUG

Pharmaceutical form: capsule; Route of administration: oral

Stage 1- Placebo; Stage 1- Venglustat 15 mg; Stage 2- Placebo

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Male or female adult with ADPKD with age at the time the consent was signed:
• between 18 to 50 years (both inclusive) for participants from Stage 1.
• 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.\*
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (95)

Investigational Site Number 8400002

Birmingham, Alabama, 35294, United States

Location

Investigational Site Number 8400017

Los Angeles, California, 90024, United States

Location

Investigational Site Number 8400001

San Francisco, California, 94143, United States

Location

Investigational Site Number 8400008

Aurora, Colorado, 80045, United States

Location

Investigational Site Number 8400010

New Haven, Connecticut, 06510, United States

Location

Investigational Site Number 8400004

Atlanta, Georgia, 30322, United States

Location

Investigational Site Number 8400007

Chicago, Illinois, 60637, United States

Location

Investigational Site Number 8400014

Iowa City, Iowa, 52242, United States

Location

Investigational Site Number 8400003

Kansas City, Kansas, 66103, United States

Location

Investigational Site Number 8400021

Baltimore, Maryland, 21201, United States

Location

Investigational Site Number 8400016

Boston, Massachusetts, 02111, United States

Location

Investigational Site Number 8400020

Rochester, Minnesota, 55905, United States

Location

Investigational Site Number 8400027

Kansas City, Missouri, 64111, United States

Location

Investigational Site Number 8400011

Philadelphia, Pennsylvania, 19104, United States

Location

Investigational Site Number 8400015

San Antonio, Texas, 78215, United States

Location

Investigational Site Number 8400019

Morgantown, West Virginia, 26506, United States

Location

Investigational Site Number 8400005

Madison, Wisconsin, 53792, United States

Location

Investigational Site Number 8400006

Milwaukee, Wisconsin, 53226, United States

Location

Investigational Site Number 0320001

Buenos Aires, C1429BWN, Argentina

Location

Investigational Site Number 0320003

Santa Fe, S3000EPV, Argentina

Location

Investigational Site Number 0360002

Herston, 4029, Australia

Location

Investigational Site Number 0360003

Nedlands, 6009, Australia

Location

Investigational Site Number 0360001

Westmead, 2145, Australia

Location

Investigational Site Number 0400001

Graz, 8036, Austria

Location

Investigational Site Number 0400004

Vienna, 1090, Austria

Location

Investigational Site Number 0560001

Brussels, 1200, Belgium

Location

Investigational Site Number 0560002

Leuven, 3000, Belgium

Location

Investigational Site Number 1240002

Edmonton, T6G 2B7, Canada

Location

Investigational Site Number 1240003

Montreal, H2W 1R7, Canada

Location

Investigational Site Number 1240001

Toronto, M5G 2N2, Canada

Location

Investigational Site Number 1560005

Beijing, 100853, China

Location

Investigational Site Number 1560004

Chengdu, 610041, China

Location

Investigational Site Number 1560009

Guangzhou, 510080, China

Location

Investigational Site Number 1560006

Hangzhou, 310003, China

Location

Investigational Site Number 1560002

Hefei, 230022, China

Location

Investigational Site Number 1560007

Nanjing, 210009, China

Location

Investigational Site Number 1560008

Nanjing, 210029, China

Location

Investigational Site Number 1560001

Shanghai, 200003, China

Location

Investigational Site Number 1560003

Shenyang, 110004, China

Location

Investigational Site Number 2030001

Prague, 12808, Czechia

Location

Investigational Site Number 2030002

Prague, 14021, Czechia

Location

Investigational Site Number 2080001

Copenhagen, 2100, Denmark

Location

Investigational Site Number 2080002

Roskilde, 4000, Denmark

Location

Investigational Site Number 2500004

Bordeaux, 33076, France

Location

Investigational Site Number 2500003

Brest, 29609, France

Location

Investigational Site Number 2500002

Paris, 75015, France

Location

Investigational Site Number 2500001

Toulouse, 31403, France

Location

Investigational Site Number 2760001

Berlin, 10117, Germany

Location

Investigational Site Number 2760003

Cologne, 50937, Germany

Location

Investigational Site Number 2760002

Dresden, 01307, Germany

Location

Investigational Site Number 2760010

Dresden, 01307, Germany

Location

Investigational Site Number 2760007

Düsseldorf, 40210, Germany

Location

Investigational Site Number 2760009

Essen, 45122, Germany

Location

Investigational Site Number 2760005

Hanover, 30625, Germany

Location

Investigational Site Number 2760011

Leipzig, 04103, Germany

Location

Investigational Site Number 2760012

Mainz, 55131, Germany

Location

Investigational Site Number 2760004

München, 81675, Germany

Location

Investigational Site Number 3760003

Ashdod, 7747629, Israel

Location

Investigational Site Number 3760002

Rehovot, 76100, Israel

Location

Investigational Site Number 3800001

Brescia, 25123, Italy

Location

Investigational Site Number 3800002

Milan, 20132, Italy

Location

Investigational Site Number 3800003

Napoli, 80131, Italy

Location

Investigational Site Number 3920002

Bunkyō City, Japan

Location

Investigational Site Number 3920005

Kamakura-Shi, Japan

Location

Investigational Site Number 3920006

Kawasaki-Shi, Japan

Location

Investigational Site Number 3920010

Kyoto, Japan

Location

Investigational Site Number 3920009

Nagoya, Japan

Location

Investigational Site Number 3920003

Niigata, Japan

Location

Investigational Site Number 3920007

Osaka, Japan

Location

Investigational Site Number 3920001

Sapporo, Japan

Location

Investigational Site Number 3920004

Shinjuku-Ku, Japan

Location

Investigational Site Number 3920008

Toyoake-Shi, Japan

Location

Investigational Site Number 5280003

Amsterdam, 1105AZ, Netherlands

Location

Investigational Site Number 5280001

Groningen, 9713 GZ, Netherlands

Location

Investigational Site Number 5280002

Nijmegen, 6525 GA, Netherlands

Location

Investigational Site Number 6160001

Lodz, 92-213, Poland

Location

Investigational Site Number 6160003

Warsaw, 04-141, Poland

Location

Investigational Site Number 6160002

Wroclaw, 50-556, Poland

Location

Investigational Site Number 6200004

Almada, 2801-951, Portugal

Location

Investigational Site Number 6200005

Carnaxide, 2790-134, Portugal

Location

Investigational Site Number 6200001

Loures, 2674-514, Portugal

Location

Investigational Site Number 6420002

Bucharest, 022328, Romania

Location

Investigational Site Number 6420004

Oradea, 410469, Romania

Location

Investigational Site Number 6420001

Timișoara, 300723, Romania

Location

Investigational Site Number 4100001

Seoul, 03080, South Korea

Location

Investigational Site Number 4100002

Seoul, 07061, South Korea

Location

Investigational Site Number 7240003

Barcelona, 08003, Spain

Location

Investigational Site Number 7240001

Barcelona, 08025, Spain

Location

Investigational Site Number 7240002

Madrid, 28040, Spain

Location

Investigational Site Number 1580001

Taichung, 40447, Taiwan

Location

Investigational Site Number 1580002

Taipei, 10043, Taiwan

Location

Investigational Site Number 7920001

Istanbul, Turkey (Türkiye)

Location

Investigational Site Number 7920002

Kayseri, 38039, Turkey (Türkiye)

Location

Investigational Site Number 7920003

Kocaeli, 41380, Turkey (Türkiye)

Location

Investigational Site Number 8260001

Sheffield, S5 7AU, United Kingdom

Location

Related Publications (3)

• Gansevoort RT, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong ACM, Pei YPC, Torres VE, Modur V, Antonshchuk I, Perrone RD. Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: Primary Results of a Double-Blind, Placebo-Controlled, Phase 2/3 Randomized Clinical Trial. Am J Kidney Dis. 2023 May;81(5):517-527.e1. doi: 10.1053/j.ajkd.2022.10.016. Epub 2022 Dec 17.

  PMID: 36535535 RESULT

• St Pierre K, Cashmore BA, Bolignano D, Zoccali C, Ruospo M, Craig JC, Strippoli GF, Mallett AJ, Green SC, Tunnicliffe DJ. Interventions for preventing the progression of autosomal dominant polycystic kidney disease. Cochrane Database Syst Rev. 2024 Oct 2;10(10):CD010294. doi: 10.1002/14651858.CD010294.pub3.

  PMID: 39356039 DERIVED

• Perrone RD, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong ACM, Pei YPC, Torres VE, Modur V, Gansevoort RT. The STAGED-PKD 2-Stage Adaptive Study With a Patient Enrichment Strategy and Treatment Effect Modeling for Improved Study Design Efficiency in Patients With ADPKD. Kidney Med. 2022 Aug 27;4(10):100538. doi: 10.1016/j.xkme.2022.100538. eCollection 2022 Oct.

  PMID: 36204243 DERIVED

MeSH Terms

Conditions

Polycystic Kidney, Autosomal Dominant

Interventions

venglustat

Condition Hierarchy (Ancestors)

Polycystic Kidney Diseases; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Ciliopathies; Genetic Diseases, Inborn

Limitations and Caveats

Following decision to discontinue EFC15392 based on the futility analysis, the two-steps analysis initially planned were not applicable, therefore only the final analysis of all safety endpoints (laboratory, vital sign, ECG, physical examination, BDI-II, and lens opacity) were performed on extended combined Stage 1 and Stage 2 safety population only.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 1, 2018
• First Posted: May 14, 2018
• Study Start: October 4, 2018
• Primary Completion: August 3, 2021
• Study Completion: August 3, 2021
• Last Updated: February 3, 2023
• Results First Posted: November 9, 2022

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share

Locations

PL (3); AR (2); PT (3); DE (10); RO (3); ES (3); GB (1); BE (2); DK (2); TW (2); TU (3); US (18); IL (2); CA (3); CN (9); NL (3); KR (2); AU (3); CZ (2); IT (3); FR (4); JP (10)