Clinical trial NCT03523728: A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Polycystic Kidney, Autosomal Dominant
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2018-05-14
Enrollment: 478
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Stage 1
timeFrame: From Baseline to Month 18
measure: 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
timeFrame: From Baseline to Month 24
Secondary outcomes:
measure: Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 24: Stage 1
timeFrame: From Baseline to Month 24
measure: Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Combined Stage 1 and Stage 2
timeFrame: From Baseline to Month 18
measure: 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
timeFrame: From Baseline to Month 18
measure: 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
timeFrame: From Baseline to Month 24
measure: Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1
timeFrame: From Baseline to Month 18
measure: Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 24: Combined Stage 1 and Stage 2
timeFrame: From Baseline to Month 24
measure: Pharmacokinetics: Plasma Concentration of Venglustat: Stage 1
timeFrame: Day 1: 3 hours Post-Dose, Month 1: Pre-Dose and 3 hours Post-Dose, Month 6: Pre-Dose, Month 18: Pre-Dose
measure: Pharmacokinetics: Plasma Concentration of Venglustat: Stage 2
timeFrame: Month 1: Pre-dose and 3 hours Post-dose
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Stage 1
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Hematology: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Clinical Chemistry: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Potentially and Clinically Significant Abnormalities: Urinalysis: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Potentially and Clinically Significant Abnormalities: Vital Signs: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
measure: Number of Participants With Physical Examination Abnormalities: Combined Stage 1 and Stage 2
timeFrame: Baseline, Month 18, Month 24
measure: Change From Baseline in Beck Depression Inventory-II (BDI-II) Score: Combined Stage 1 and Stage 2
timeFrame: Baseline, Months 3, 6, 9, 12, 15, 18, 21, and 24, Last on-treatment value up to last IMP + 1 day (anytime during the maximum duration of 25 months)
measure: Number of Participants With Worsening Lens Opacity From Baseline During the Treatment-emergent Period: Combined Stage 1 and Stage 2
timeFrame: From the first IMP administration up to the last IMP administration in EFC15392 study + 30 days (i.e., up to 25 months) or up to the first visit in LTS15823 study, whichever comes earlier
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Investigational Site Number 8400002
state: Alabama
city: Los Angeles
country: United States
facility: Investigational Site Number 8400017
state: California
city: San Francisco
country: United States
facility: Investigational Site Number 8400001
state: California
city: Aurora
country: United States
facility: Investigational Site Number 8400008
state: Colorado
city: New Haven
country: United States
facility: Investigational Site Number 8400010
state: Connecticut
city: Atlanta
country: United States
facility: Investigational Site Number 8400004
state: Georgia
city: Chicago
country: United States
facility: Investigational Site Number 8400007
state: Illinois
city: Iowa City
country: United States
facility: Investigational Site Number 8400014
state: Iowa
city: Kansas City
country: United States
facility: Investigational Site Number 8400003
state: Kansas
city: Baltimore
country: United States
facility: Investigational Site Number 8400021
state: Maryland
city: Boston
country: United States
facility: Investigational Site Number 8400016
state: Massachusetts
city: Rochester
country: United States
facility: Investigational Site Number 8400020
state: Minnesota
city: Kansas City
country: United States
facility: Investigational Site Number 8400027
state: Missouri
city: Philadelphia
country: United States
facility: Investigational Site Number 8400011
state: Pennsylvania
city: San Antonio
country: United States
facility: Investigational Site Number 8400015
state: Texas
city: Morgantown
country: United States
facility: Investigational Site Number 8400019
state: West Virginia
city: Madison
country: United States
facility: Investigational Site Number 8400005
state: Wisconsin
city: Milwaukee
country: United States
facility: Investigational Site Number 8400006
state: Wisconsin
city: Buenos Aires
country: Argentina
facility: Investigational Site Number 0320001
city: Santa Fe
country: Argentina
facility: Investigational Site Number 0320003
city: Herston
country: Australia
facility: Investigational Site Number 0360002
city: Nedlands
country: Australia
facility: Investigational Site Number 0360003
city: Westmead
country: Australia
facility: Investigational Site Number 0360001
city: Graz
country: Austria
facility: Investigational Site Number 0400001
city: Wien
country: Austria
facility: Investigational Site Number 0400004
city: Bruxelles
country: Belgium
facility: Investigational Site Number 0560001
city: Leuven
country: Belgium
facility: Investigational Site Number 0560002
city: Edmonton
country: Canada
facility: Investigational Site Number 1240002
city: Montreal
country: Canada
facility: Investigational Site Number 1240003
city: Toronto
country: Canada
facility: Investigational Site Number 1240001
city: Beijing
country: China
facility: Investigational Site Number 1560005
city: Chengdu
country: China
facility: Investigational Site Number 1560004
city: Guangzhou
country: China
facility: Investigational Site Number 1560009
city: Hangzhou
country: China
facility: Investigational Site Number 1560006
city: Hefei
country: China
facility: Investigational Site Number 1560002
city: Nanjing
country: China
facility: Investigational Site Number 1560007
city: Nanjing
country: China
facility: Investigational Site Number 1560008
city: Shanghai
country: China
facility: Investigational Site Number 1560001
city: Shenyang
country: China
facility: Investigational Site Number 1560003
city: Praha 2
country: Czechia
facility: Investigational Site Number 2030001
city: Praha 4
country: Czechia
facility: Investigational Site Number 2030002
city: Copenhagen
country: Denmark
facility: Investigational Site Number 2080001
city: Roskilde
country: Denmark
facility: Investigational Site Number 2080002
city: Bordeaux
country: France
facility: Investigational Site Number 2500004
city: Brest
country: France
facility: Investigational Site Number 2500003
city: Paris
country: France
facility: Investigational Site Number 2500002
city: Toulouse
country: France
facility: Investigational Site Number 2500001
city: Berlin
country: Germany
facility: Investigational Site Number 2760001
city: Dresden
country: Germany
facility: Investigational Site Number 2760002
city: Dresden
country: Germany
facility: Investigational Site Number 2760010
city: Düsseldorf
country: Germany
facility: Investigational Site Number 2760007
city: Essen
country: Germany
facility: Investigational Site Number 2760009
city: Hannover
country: Germany
facility: Investigational Site Number 2760005
city: Köln
country: Germany
facility: Investigational Site Number 2760003
city: Leipzig
country: Germany
facility: Investigational Site Number 2760011
city: Mainz
country: Germany
facility: Investigational Site Number 2760012
city: München
country: Germany
facility: Investigational Site Number 2760004
city: Ashdod
country: Israel
facility: Investigational Site Number 3760003
city: Reẖovot
country: Israel
facility: Investigational Site Number 3760002
city: Brescia
country: Italy
facility: Investigational Site Number 3800001
city: Milano
country: Italy
facility: Investigational Site Number 3800002
city: Napoli
country: Italy
facility: Investigational Site Number 3800003
city: Bunkyo-Ku
country: Japan
facility: Investigational Site Number 3920002
city: Kamakura-Shi
country: Japan
facility: Investigational Site Number 3920005
city: Kawasaki-Shi
country: Japan
facility: Investigational Site Number 3920006
city: Kyoto-Shi
country: Japan
facility: Investigational Site Number 3920010
city: Nagoya-Shi
country: Japan
facility: Investigational Site Number 3920009
city: Niigata-Shi
country: Japan
facility: Investigational Site Number 3920003
city: Osaka-Shi
country: Japan
facility: Investigational Site Number 3920007
city: Sapporo-Shi
country: Japan
facility: Investigational Site Number 3920001
city: Shinjuku-Ku
country: Japan
facility: Investigational Site Number 3920004
city: Toyoake-Shi
country: Japan
facility: Investigational Site Number 3920008
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 4100001
city: Seoul
country: Korea, Republic of
facility: Investigational Site Number 4100002
city: Amsterdam
country: Netherlands
facility: Investigational Site Number 5280003
city: Groningen
country: Netherlands
facility: Investigational Site Number 5280001
city: Nijmegen
country: Netherlands
facility: Investigational Site Number 5280002
city: Warszawa
country: Poland
facility: Investigational Site Number 6160003
city: Wrocław
country: Poland
facility: Investigational Site Number 6160002
city: Łódź
country: Poland
facility: Investigational Site Number 6160001
city: Almada
country: Portugal
facility: Investigational Site Number 6200004
city: Carnaxide
country: Portugal
facility: Investigational Site Number 6200005
city: Loures
country: Portugal
facility: Investigational Site Number 6200001
city: Bucuresti
country: Romania
facility: Investigational Site Number 6420002
city: Oradea
country: Romania
facility: Investigational Site Number 6420004
city: Timisoara
country: Romania
facility: Investigational Site Number 6420001
city: Barcelona
country: Spain
facility: Investigational Site Number 7240003
city: Barcelona
country: Spain
facility: Investigational Site Number 7240001
city: Madrid
country: Spain
facility: Investigational Site Number 7240002
city: Taichung
country: Taiwan
facility: Investigational Site Number 1580001
city: Taipei
country: Taiwan
facility: Investigational Site Number 1580002
city: Istanbul
country: Turkey
facility: Investigational Site Number 7920001
city: Kayseri
country: Turkey
facility: Investigational Site Number 7920002
city: Kocaeli
country: Turkey
facility: Investigational Site Number 7920003
city: Sheffield
country: United Kingdom
facility: Investigational Site Number 8260001
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.