A Medical Research Study Designed to Determine if Venglustat Can be a Future Treatment for ADPKD Patients (STAGED-PKD)

• ClinicalTrials.gov Identifier: NCT03523728
• Recruitment Status: Terminated
• First Posted: May 14, 2018
• Results First Posted: November 9, 2022
• Last Update Posted: February 3, 2023
• Sponsor: Genzyme, a Sanofi Company
• Information provided by (Responsible Party): Sanofi ( Genzyme, a Sanofi Company )

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Polycystic Kidney, Autosomal Dominant	Drug: Venglustat; Drug: Placebo	Phase 2; Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 478 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: October 4, 2018
• Actual Primary Completion Date: August 3, 2021
• Actual Study Completion Date: August 3, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Stage 1- Placebo; 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; Pharmaceutical form: capsule; Route of administration: oral
Experimental: Stage 1- Venglustat 8 mg; 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; Pharmaceutical form: capsule; Route of administration: oral; Other Name: GZ402671
Experimental: Stage 1- Venglustat 15 mg; 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; Pharmaceutical form: capsule; Route of administration: oral; Other Name: GZ402671; Drug: Placebo; Pharmaceutical form: capsule; Route of administration: oral
Placebo Comparator: Stage 2- Placebo; 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; Pharmaceutical form: capsule; Route of administration: oral
Experimental: Stage 2- Venglustat 15 mg; Participants from Stage 2 were randomized to receive 1 capsule of venglustat 15 mg once daily for treatment period of 24 months.	Drug: Venglustat; Pharmaceutical form: capsule; Route of administration: oral; Other Name: GZ402671

Outcome Measures

Primary Outcome Measures :

1. Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Stage 1 [ Time Frame: From Baseline to Month 18 ]
   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.
2. 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 [ Time Frame: From Baseline to Month 24 ]
   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.

Secondary Outcome Measures :

1. Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 24: Stage 1 [ Time Frame: From Baseline to Month 24 ]
   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 was obtained from the linear mixed effect model including the fixed categorical effects of treatment group, mayo imaging classification (as per IRT), time (as continuous variable in years), treatment-by-time, mayo imaging classification-by-time, and included random intercept and slope. Due to early termination of study for futility, the two-steps analysis initially planned was not applicable, then the annualized rate of change from baseline in eGFR in Stage 1 population were assessed using all data available up to database lock (i.e., including Month 24 assessment). As this is a slope, it allowed to have more data and to reduce variability.
2. Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Combined Stage 1 and Stage 2 [ Time Frame: From Baseline to Month 18 ]
   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 MRI. The annualized slope of change in TKV (in % 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.
3. 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 [ Time Frame: From Baseline to Month 18 ]
   The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a numeric rating scale (NRS) to assess pain severity and pain interference in the past 24 hours and the past week. BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The NRS ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicates greater intensity of pain. Least-squares (LS) means, and standard errors (SE) were estimated from mixed-effect model with repeated measures (MMRM) analysis.
4. 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 [ Time Frame: From Baseline to Month 24 ]
   The BPI-SF is a validated, self-administered questionnaire designed to measure a participant's perceived level of pain. The BPI-SF consisted of 15 items that use a NRS to assess pain severity and pain interference in the past 24 hours and the past week. BPI-SF Item 3 asks participants to "Please rate your pain by marking the box beside the number that best describes your pain at its worst in the past 24 hours." The NRS ranged from 0 (no pain) to 10 (worst imaginable pain), where higher scores indicate greater intensity of pain. LS means and SE were estimated from MMRM analysis.
5. Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1 [ Time Frame: From Baseline to Month 18 ]
   The BFI-SF is a 10-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 10-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to 'Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. The NRS ranged from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. LS means and SE were estimated from MMRM analysis.
6. 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 [ Time Frame: From Baseline to Month 24 ]
   The BFI-SF is a 10-item, validated, self-administered questionnaire that was originally developed to assess fatigue severity. The 10-items were measured on a 0-10 scale, with 0 being 'does not interfere' and 10 being 'completely interferes.' BFI - Item 3 asks participants to "Please rate your fatigue (weariness, tiredness) by circling the one number that best describes your worst level of fatigue during the past 24 hours. The NRS ranged from 0 (no fatigue) to 10 (worst imaginable fatigue). Higher global scores were associated with more severe fatigue. LS means and SE were estimated from MMRM analysis.
7. Pharmacokinetics: Plasma Concentration of Venglustat: Stage 1 [ Time Frame: Day 1: 3 hours Post-Dose, Month 1: Pre-Dose and 3 hours Post-Dose, Month 6: Pre-Dose, Month 18: Pre-Dose ]
   Venglustat plasma concentrations was determined using a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.
8. Pharmacokinetics: Plasma Concentration of Venglustat: Stage 2 [ Time Frame: Month 1: Pre-dose and 3 hours Post-dose ]
   Venglustat plasma concentrations was determined using a validated LC-MS/MS method. Data for this outcome measure was not planned to be collected and analyzed for placebo arm.
9. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Stage 1 [ Time Frame: 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 ]
   An adverse event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. A serious adverse event (SAE) was any untoward medical occurrence that at any dose: results in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed, worsened or became serious during the treatment-emergent (TE) period (defined as the time from the first investigational medicinal product [IMP] administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier).
10. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. SAE was any untoward medical occurrence that at any dose: results in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, or was a medically important event. TEAEs were AEs that developed, worsened or became serious during the TE period (defined as the time from the first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier).
11. Number of Participants With Potentially Clinically Significant Abnormalities: Hematology: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Criteria for potentially clinically significant abnormalities: Hemoglobin: less than or equal to (<=) 115 grams per liter (g/L) [Male]; <=95 g/L [Female]; greater than or equal to (>=) 185 g/L [Male]; >=165 g/L [Female]; Decrease from baseline >=20 g/L; Hematocrit: <=0.37 volume/volume (v/v) [Male]; <=0.32 v/v [Female]; >=0.55 v/v [Male]; >=0.5 v/v [Female]; Erythrocyte (red blood cells [RBC]): >=6*10^12 per liter (/L); Platelet: less than (<) 100*10^9/L; >=700*10^9/L; Leukocyte (white blood cells [WBC]): <3*10^9/L [Non-Black]; <2*10^9/L [Black], >=16*10^9/L; Neutrophils: <1.5*10^9/L [Non-Black]; <1*10^9/L [Black]; Lymphocytes: greater than (>) 4*10^9/L, Monocytes: >0.7*10^9/L; Basophils: >0.1*10^9/L; and Eosinophils: >0.5*10^9/L or >upper limit of normal (ULN) (if ULN >=0.5*10^9/L).
12. Number of Participants With Potentially Clinically Significant Abnormalities: Clinical Chemistry: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 millimoles per liter (mmol/L) and <lower limit of normal (LLN): >=11.1 mmol/L (unfasted); >=7 mmol/L (fasted); Albumin:<=25 g/L; Sodium: <=129 mmol/L; >=160 mmol/L; Potassium: <3 mmol/L; >=5.5 mmol/L; Chloride: <80 mmol/L, >115 mmol/L; Creatinine: >=150 micro millimoles per liter (mcmol/L) (Adults); >=30% change from Baseline; >=100% change from Baseline, Urea Nitrogen: >=17 mmol/L; Alanine Aminotransferase (ALT): >3 ULN; Aspartate Aminotransferase (AST): >3 ULN; Alkaline Phosphatase: >1.5 ULN; Total Bilirubin: >1.5 ULN, >2 ULN; ALT >3 ULN and Bilirubin >2 ULN; and Direct Bilirubin >35% Bilirubin and Bilirubin >1.5 ULN.
13. Number of Participants With Potentially and Clinically Significant Abnormalities: Urinalysis: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Criteria for potentially clinically significant abnormalities: Urine pH: <=4.6 and >=8.
14. Number of Participants With Potentially and Clinically Significant Abnormalities: Vital Signs: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Criteria for potentially clinically significant abnormalities: Sitting Systolic Blood Pressure: <=95 millimeters of Mercury (mmHg) and decrease from Baseline >=20 mmHg; >=160 mmHg and increase from Baseline >=20 mmHg; Sitting Diastolic Blood Pressure: <=45 mmHg and decrease from Baseline >=10 mmHg, >=110 mmHg and increase from Baseline >=10 mmHg; Sitting Heart Rate: <=50 beats/minute and decrease from Baseline >=20 beats/minute; >=120 beats/minute and increase from Baseline >=20 beats/minute; and Weight: >=5% decrease from Baseline; >=5% increase from Baseline.
15. Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Criteria for potentially clinically significant abnormalities: Heart Rate: <50 beats/minute; <50 beats/minute and decrease from Baseline >=20 beats/minute; <40 beats/minute; <40 beats/minute and decrease from Baseline >=20 beats/min; <30 beats/minute; >90 beats/minute; >90 beats/minute and increase from Baseline >=20 beats/minute; >100 beats/minute; >100 beats/minute and increase from Baseline >=20 beats/minute; >120 beats/minute; >120 beats/minute, increase from Baseline >=20 beats/minute; PR Interval: >200 milliseconds (msec); >200 msec and increase from Baseline >=25%; >220 msec, >240 msec; QRS Interval: >110 msec; >110 msec and increase from Baseline >=25%; >120 msec; >120 msec and increase from Baseline >=25%; QT Interval: >500 msec; QT corrected for heart rate (QTc) Bazett: >450 msec; >480 msec; increase from Baseline (30-60) msec; increase from Baseline >60 msec; QTc Fridericia: >450 msec; >480 msec; increase from Baseline (30-60) msec and increase from Baseline > 60 msec.
16. Number of Participants With Physical Examination Abnormalities: Combined Stage 1 and Stage 2 [ Time Frame: Baseline, Month 18, Month 24 ]
    Physical examination included: Head, Heart, Lung, Abdomen, Musculo/Skeletal, Skin, and Mental Status. Abnormality in physical examination was based on investigator's discretion. Results are based on the treatment emergent period which was defined as time from the first IMP administration up to the last IMP administration in EFC15392 study + 30 days or up to the first visit in LTS15823 study, whichever comes earlier.
17. Change From Baseline in Beck Depression Inventory-II (BDI-II) Score: Combined Stage 1 and Stage 2 [ Time Frame: 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) ]
    The Beck Depression Inventory-II (BDI-II) is a 21-item questionnaire used to assess depression. Most items are rated on a 4-point scale from 0 to 3, and a few items are rated on a 7-point scale. Individual item scores are added to get a total BDI-II score from 0 to 63. The higher the total score, the more severe the depression, and the lower the total score, the less severe the depression.
18. Number of Participants With Worsening Lens Opacity From Baseline During the Treatment-emergent Period: Combined Stage 1 and Stage 2 [ Time Frame: 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 ]
    Worsening of lens opacity classification system (LOCS) III score or World Health Organization (WHO) grade in nuclear opacification, cortical opacification and posterior subcapsular opacification were assessed for 'Any eye', 'Unilateral' and 'Bilateral' separately. A participant could be counted in all the 3 categories. In each category, the worst case was taken into account. To be evaluable for 'Any', a participant had to have at least one eye evaluable, whereas, for 'Unilateral' and 'Bilateral', a participant had to have both eyes evaluable. Therefore, the sum of 'Unilateral' + 'Bilateral' is not necessarily equal to 'Any' in the below table. The difference observed in 'Nuclear Opacification' in 15 mg group, comes from that 1 participant who had Unilateral worsening at a given visit and a Bilateral worsening at another visit. Therefore, this participant was counted as 'Unilateral', 'Bilateral' and counted only once in 'Any'. Results are based on the TE period.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 55 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, Alabama

Investigational Site Number 8400002

Birmingham, Alabama, United States, 35294

United States, California

Investigational Site Number 8400017

Los Angeles, California, United States, 90024

Investigational Site Number 8400001

San Francisco, California, United States, 94143

United States, Colorado

Investigational Site Number 8400008

Aurora, Colorado, United States, 80045

United States, Connecticut

Investigational Site Number 8400010

New Haven, Connecticut, United States, 06510

United States, Georgia

Investigational Site Number 8400004

Atlanta, Georgia, United States, 30322

United States, Illinois

Investigational Site Number 8400007

Chicago, Illinois, United States, 60637

United States, Iowa

Investigational Site Number 8400014

Iowa City, Iowa, United States, 52242

United States, Kansas

Investigational Site Number 8400003

Kansas City, Kansas, United States, 66103

United States, Maryland

Investigational Site Number 8400021

Baltimore, Maryland, United States, 21201

United States, Massachusetts

Investigational Site Number 8400016

Boston, Massachusetts, United States, 02111

United States, Minnesota

Investigational Site Number 8400020

Rochester, Minnesota, United States, 55905

United States, Missouri

Investigational Site Number 8400027

Kansas City, Missouri, United States, 64111

United States, Pennsylvania

Investigational Site Number 8400011

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Investigational Site Number 8400015

San Antonio, Texas, United States, 78215

United States, West Virginia

Investigational Site Number 8400019

Morgantown, West Virginia, United States, 26506

United States, Wisconsin

Investigational Site Number 8400005

Madison, Wisconsin, United States, 53792

Investigational Site Number 8400006

Milwaukee, Wisconsin, United States, 53226

Argentina

Investigational Site Number 0320001

Buenos Aires, Argentina, C1429BWN

Investigational Site Number 0320003

Santa Fe, Argentina, S3000EPV

Australia

Investigational Site Number 0360002

Herston, Australia, 4029

Investigational Site Number 0360003

Nedlands, Australia, 6009

Investigational Site Number 0360001

Westmead, Australia, 2145

Austria

Investigational Site Number 0400001

Graz, Austria, 8036

Investigational Site Number 0400004

Wien, Austria, 1090

Belgium

Investigational Site Number 0560001

Bruxelles, Belgium, 1200

Investigational Site Number 0560002

Leuven, Belgium, 3000

Canada

Investigational Site Number 1240002

Edmonton, Canada, T6G 2B7

Investigational Site Number 1240003

Montreal, Canada, H2W 1R7

Investigational Site Number 1240001

Toronto, Canada, M5G 2N2

China

Investigational Site Number 1560005

Beijing, China, 100853

Investigational Site Number 1560004

Chengdu, China, 610041

Investigational Site Number 1560009

Guangzhou, China, 510080

Investigational Site Number 1560006

Hangzhou, China, 310003

Investigational Site Number 1560002

Hefei, China, 230022

Investigational Site Number 1560007

Nanjing, China, 210009

Investigational Site Number 1560008

Nanjing, China, 210029

Investigational Site Number 1560001

Shanghai, China, 200003

Investigational Site Number 1560003

Shenyang, China, 110004

Czechia

Investigational Site Number 2030001

Praha 2, Czechia, 12808

Investigational Site Number 2030002

Praha 4, Czechia, 14021

Denmark

Investigational Site Number 2080001

Copenhagen, Denmark, 2100

Investigational Site Number 2080002

Roskilde, Denmark, 4000

France

Investigational Site Number 2500004

Bordeaux, France, 33076

Investigational Site Number 2500003

Brest, France, 29609

Investigational Site Number 2500002

Paris, France, 75015

Investigational Site Number 2500001

Toulouse, France, 31403

Germany

Investigational Site Number 2760001

Berlin, Germany, 10117

Investigational Site Number 2760002

Dresden, Germany, 01307

Investigational Site Number 2760010

Dresden, Germany, 01307

Investigational Site Number 2760007

Düsseldorf, Germany, 40210

Investigational Site Number 2760009

Essen, Germany, 45122

Investigational Site Number 2760005

Hannover, Germany, 30625

Investigational Site Number 2760003

Köln, Germany, 50937

Investigational Site Number 2760011

Leipzig, Germany, 04103

Investigational Site Number 2760012

Mainz, Germany, 55131

Investigational Site Number 2760004

München, Germany, 81675

Israel

Investigational Site Number 3760003

Ashdod, Israel, 7747629

Investigational Site Number 3760002

Reẖovot, Israel, 76100

Italy

Investigational Site Number 3800001

Brescia, Italy, 25123

Investigational Site Number 3800002

Milano, Italy, 20132

Investigational Site Number 3800003

Napoli, Italy, 80131

Japan

Investigational Site Number 3920002

Bunkyo-Ku, Japan

Investigational Site Number 3920005

Kamakura-Shi, Japan

Investigational Site Number 3920006

Kawasaki-Shi, Japan

Investigational Site Number 3920010

Kyoto-Shi, Japan

Investigational Site Number 3920009

Nagoya-Shi, Japan

Investigational Site Number 3920003

Niigata-Shi, Japan

Investigational Site Number 3920007

Osaka-Shi, Japan

Investigational Site Number 3920001

Sapporo-Shi, Japan

Investigational Site Number 3920004

Shinjuku-Ku, Japan

Investigational Site Number 3920008

Toyoake-Shi, Japan

Korea, Republic of

Investigational Site Number 4100001

Seoul, Korea, Republic of, 03080

Investigational Site Number 4100002

Seoul, Korea, Republic of, 07061

Netherlands

Investigational Site Number 5280003

Amsterdam, Netherlands, 1105AZ

Investigational Site Number 5280001

Groningen, Netherlands, 9713 GZ

Investigational Site Number 5280002

Nijmegen, Netherlands, 6525 GA

Poland

Investigational Site Number 6160003

Warszawa, Poland, 04-141

Investigational Site Number 6160002

Wrocław, Poland, 50-556

Investigational Site Number 6160001

Łódź, Poland, 92-213

Portugal

Investigational Site Number 6200004

Almada, Portugal, 2801-951

Investigational Site Number 6200005

Carnaxide, Portugal, 2790-134

Investigational Site Number 6200001

Loures, Portugal, 2674-514

Romania

Investigational Site Number 6420002

Bucuresti, Romania, 022328

Investigational Site Number 6420004

Oradea, Romania, 410469

Investigational Site Number 6420001

Timisoara, Romania, 300723

Spain

Investigational Site Number 7240003

Barcelona, Spain, 08003

Investigational Site Number 7240001

Barcelona, Spain, 08025

Investigational Site Number 7240002

Madrid, Spain, 28040

Taiwan

Investigational Site Number 1580001

Taichung, Taiwan, 40447

Investigational Site Number 1580002

Taipei, Taiwan, 10043

Turkey

Investigational Site Number 7920001

Istanbul, Turkey

Investigational Site Number 7920002

Kayseri, Turkey, 38039

Investigational Site Number 7920003

Kocaeli, Turkey, 41380

United Kingdom

Investigational Site Number 8260001

Sheffield, United Kingdom, S5 7AU

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

  Study Documents (Full-Text)

Documents provided by Sanofi ( Genzyme, a Sanofi Company ):

Study Protocol  [PDF] April 19, 2021

Statistical Analysis Plan  [PDF] June 22, 2021

More Information

Additional Information:

For more information in Germany/Austria, please click here 

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03523728
• Other Study ID Numbers: EFC15392; 2017-004084-12 ( EudraCT Number ); U1111-1202-0775 ( Other Identifier: UTN )
• First Posted: May 14, 2018
• Results First Posted: November 9, 2022
• Last Update Posted: February 3, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Polycystic Kidney Diseases; Polycystic Kidney, Autosomal Dominant; Congenital Abnormalities; Kidney Diseases, Cystic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Abnormalities, Multiple; Ciliopathies; Genetic Diseases, Inborn; Venglustat; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action