Congenital Cystic Kidney Disease
Conditions
Brief summary
Primary Objective: -To determine the effect of early versus delayed treatment with venglustat on the total kidney volume (TKV) in participants at risk of rapidly progressive autosomal dominant polycystic kidney disease (ADPKD). Secondary Objective: * To determine the effect of early versus delayed treatment with venglustat on the renal function (estimated glomerular filtration rate \[eGFR\] \[Chronic Kidney Disease Epidemiology Collaboration {CKD-EPI} equation\]). * To characterize the safety profile of venglustat. * To evaluate the effect of venglustat on the lens by ophthalmological examination. * To evaluate the effect of venglustat on mood using Beck Depression Inventory-II (BDI-II).
Detailed description
The planned study duration per participant was 25.5 months (maximal). Screening period (when applicable): up to 2 weeks. Core treatment period: 24 months. Follow-up: 30 days after final dose of the investigational medicinal product (IMP) (venglustat).
Interventions
Pharmaceutical form: capsule Route of administration: oral
Sponsors
Sanofi
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
: * Male or female adult with ADPKD who had completed the treatment period in Stage 1 or Stage 2 of Study EFC15392 (NCT03523728). * The participants who had an eGFR \>30 mL/min/1.73 m\^2: 1. Measured at Visit 11 of the EFC15392 study for participant enrolled in the LTS15823 study at the time of Visit 12 (Month 24; end-of treatment visit) of the EFC15392 study. 2. Measured at Screening visit for participant enrolled in the LTS15823 study not concomitantly to the Visit 12 (Month 24; end-of treatment visit) of the EFC15392 study. * Contraceptive used by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 1. Male participants who agreed to practice true abstinence in line with their preferred and usual lifestyle or to use double-contraceptive methods for the entire duration of the study and for at least 90 days following their last dose of IMP. 2. Female participants who had a negative urine pregnancy test at the Baseline visit and 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 the entire duration of the study and for at least 6 weeks following their last dose of IMP. * Capable of giving signed informed consent before performance of any study related procedures not part of standard medical care. * Able to read, comprehend, and respond to the study questionnaires.
Exclusion criteria
* For participants who had lag phase between the end of the EFC15392 study and Screening visit (Visit 0) in the LTS15823 study. * The participant had a new 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. * A history of drug abuse and/or alcohol abuse or alcohol dependence during the lag phase between the end of the EFC15392 study and Screening visit (Visit 0) in the LTS15823 study when applicable. * Administration of tolvaptan or other polycystic kidney disease-modifying agents (somatostatin analogues) within 3 months prior to the Screening visit (Visit 0) in the LTS15823 study when applicable. * The participant was 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 participant had received strong or moderate inducers or inhibitors of CYP3A4 within 14 days or 5 half lives, whichever was longer, prior to the Baseline visit (including consumption of grapefruit-containing products within 72 hours of starting venglustat administration). * Participation in another investigational interventional study or use of IMP, within 3 months or 5 half-lives, whichever was longer, before the Baseline visit (Visit 1) except participation in the EFC15392 study when applicable. * 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 had no additional symptoms or signs which suggest hepatobiliary disease and serum total bilirubin level no more than 3 milligrams per decilitre (mg/dL) (51 micromoles per litre \[μmol/L\]) with conjugated bilirubin less than 20 percent (%) of the total bilirubin fraction. For participants with or without lag phase between the end of EFC15392 study and entry into LTS15823 study: * The participant was pregnant or lactating. * Presence of severe depression as measured by BDI-II \>28 at Visit 1 (for participants enrolled in the LTS15823 study at the time of the end of treatment visit of the EFC15392 study) or at Visit 0 (for participants enrolled in the LTS15823 study after the end-of-treatment visit of the EFC15392 study). * Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Total Kidney Volume (TKV) | From the EFC15392 study Baseline to 24 months of open-label extension study LTS15823 | Total kidney volume is a measure of disease progression in the ADPKD participants. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Due to the early termination of study LTS15823 and low enrollment numbers, efficacy analysis was not performed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From the Baseline in Estimated Glomerular Filtration Rate (eGFR) as Assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) | From the EFC15392 study Baseline to 24 months of open-label extension study LTS15823 | eGFR is a measure of kidney function assessed through blood/serum. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Due to the early termination of study LTS15823 and low enrollment numbers, efficacy analysis was not performed. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the first administration of the IMP in LTS15823 study up to the last IMP administration in LTS15823 study + 30 days (i.e., up to approximately 20 weeks) | Adverse event (AE) was defined as any untoward medical occurrence in participant who received investigational medicinal product (IMP) and did not necessarily have a causal relationship with treatment. All reported AEs were TEAEs that developed/worsened during 'TEAE period' (defined as the time from the first administration of the IMP in LTS15823 study up to the last IMP administration + 30 days). A SAEs was defined as any AE that at any dose results in: death; is life threatening; requires initial or prolonged inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via an authorized medicinal product; is a medically important event. |
| Change From Baseline in Lens Clarity During the Open-label Extension Treatment-emergent Period of LTS15823 Study | Baseline (EFC15392 study Baseline); from first administration of IMP up to last administration of IMP of open-label extension study LTS15823 + 30 days (i.e., up to approximately 20 weeks), in comparison to the EFC15392 study Baseline | Change from EFC15392 study Baseline in the lens clarity was assessed by ophthalmological examination with World Health Organization (WHO) simplified cataract grading system during the open label extension treatment-emergent period of LTS15823 study. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Baseline was defined as the values from EFC15392 study Baseline. |
| Effect on Mood With Change From Baseline in Beck Depression Inventory (BDI-II) Score During the Open-label Extension Treatment-emergent Period of LTS15823 Study | Baseline (EFC15392 study Baseline); from first IMP administration up to 3 months in study LTS15823, in comparison to the EFC15392 study Baseline | BDI-II was a validated self-reported instrument of 21 questions which were each scored on a Likert scale of 0 to 3. Total score was calculated as sum of all scores of 21 questions. Total scores ranged from 0 (minimal depression) to 63 (severe depression), with higher score totals indicating more severe depression symptoms (0 to 13: indicates minimal depression;14 to 19: indicates mild depression; 20 to 28: indicates moderate depression; and 29 to 63: indicates severe depression). A negative change from baseline indicated an improvement. Baseline was defined as the values from EFC15392 study Baseline. |
Countries
Australia, Belgium, Germany, Japan, Netherlands, South Korea, Spain, United States
Participant flow
Recruitment details
The study was conducted at 11 centers in 8 countries. A total of 24 participants were enrolled in the study between 09 February 2021 and 13 July 2021. Out of which, 23 participants were treated.
Pre-assignment details
Participants at risk of rapidly progressive autosomal dominant polycystic kidney disease (ADPKD) who had previously completed Stage 1 of Study EFC15392 (NCT: NCT03523728) were enrolled in this study.
Participants by arm
| Arm | Count |
|---|---|
| Venglustat 15mg Participants enrolled in open-label Venglustat 15 mg once daily orally. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Enrolled but not treated | 1 |
| Overall Study | Study terminated by sponsor | 23 |
Baseline characteristics
| Characteristic | Venglustat 15mg |
|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 4.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 12 Participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 23 |
| other Total, other adverse events | 0 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
Percent Change in Total Kidney Volume (TKV)
Total kidney volume is a measure of disease progression in the ADPKD participants. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Due to the early termination of study LTS15823 and low enrollment numbers, efficacy analysis was not performed.
Time frame: From the EFC15392 study Baseline to 24 months of open-label extension study LTS15823
Population: For study LTS15823, due to low number of enrollments as compared to the planned numbers and very limited data available post-baseline (only 2 participants reached the planned Month 3 visit), the analysis was carried out only on the available safety and tolerability data. Due to early termination of the study, no efficacy data was available at Month 24 hence the efficacy analysis was not performed.
Secondary
Change From Baseline in Lens Clarity During the Open-label Extension Treatment-emergent Period of LTS15823 Study
Change from EFC15392 study Baseline in the lens clarity was assessed by ophthalmological examination with World Health Organization (WHO) simplified cataract grading system during the open label extension treatment-emergent period of LTS15823 study. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Baseline was defined as the values from EFC15392 study Baseline.
Time frame: Baseline (EFC15392 study Baseline); from first administration of IMP up to last administration of IMP of open-label extension study LTS15823 + 30 days (i.e., up to approximately 20 weeks), in comparison to the EFC15392 study Baseline
Population: For study LTS15823, due to early termination of the study, no ophthalmological data was collected at the planned visits as per protocol and thus the planned analysis was not performed.
Secondary
Change From the Baseline in Estimated Glomerular Filtration Rate (eGFR) as Assessed by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
eGFR is a measure of kidney function assessed through blood/serum. Study LTS15823 was terminated prematurely by the Sponsor following a decision to terminate the parent study EFC15392 (NCT03523728). Study EFC15392 was terminated based on the results of the planned prespecified futility analysis performed for this study. Termination decision was due to a lack of efficacy in the ADPKD population and not linked to safety findings with venglustat. Due to the early termination of study LTS15823 and low enrollment numbers, efficacy analysis was not performed.
Time frame: From the EFC15392 study Baseline to 24 months of open-label extension study LTS15823
Population: For study LTS15823, due to low number of enrollments as compared to the planned numbers and very limited data available post-baseline (only 2 participants reached the planned Month 3 visit), the analysis was carried out only on the available safety and tolerability data. Due to early termination of the study, no efficacy data was available at Month 24 hence the efficacy analysis was not performed.
Secondary
Effect on Mood With Change From Baseline in Beck Depression Inventory (BDI-II) Score During the Open-label Extension Treatment-emergent Period of LTS15823 Study
BDI-II was a validated self-reported instrument of 21 questions which were each scored on a Likert scale of 0 to 3. Total score was calculated as sum of all scores of 21 questions. Total scores ranged from 0 (minimal depression) to 63 (severe depression), with higher score totals indicating more severe depression symptoms (0 to 13: indicates minimal depression;14 to 19: indicates mild depression; 20 to 28: indicates moderate depression; and 29 to 63: indicates severe depression). A negative change from baseline indicated an improvement. Baseline was defined as the values from EFC15392 study Baseline.
Time frame: Baseline (EFC15392 study Baseline); from first IMP administration up to 3 months in study LTS15823, in comparison to the EFC15392 study Baseline
Population: Analysis was performed on long-term extension safety population. BDI score was collected for 16 participants at Baseline and up to 3 months at the end of trial visit i.e., within 30 days after last dose of study drug following the decision for early termination of the study. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Venglustat 15mg | Effect on Mood With Change From Baseline in Beck Depression Inventory (BDI-II) Score During the Open-label Extension Treatment-emergent Period of LTS15823 Study | Baseline | 2.188 score on a scale | Standard Deviation 4.086 |
| Venglustat 15mg | Effect on Mood With Change From Baseline in Beck Depression Inventory (BDI-II) Score During the Open-label Extension Treatment-emergent Period of LTS15823 Study | Change from Baseline | -0.875 score on a scale | Standard Deviation 4.455 |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Adverse event (AE) was defined as any untoward medical occurrence in participant who received investigational medicinal product (IMP) and did not necessarily have a causal relationship with treatment. All reported AEs were TEAEs that developed/worsened during 'TEAE period' (defined as the time from the first administration of the IMP in LTS15823 study up to the last IMP administration + 30 days). A SAEs was defined as any AE that at any dose results in: death; is life threatening; requires initial or prolonged inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is a suspected transmission of any infectious agent via an authorized medicinal product; is a medically important event.
Time frame: From the first administration of the IMP in LTS15823 study up to the last IMP administration in LTS15823 study + 30 days (i.e., up to approximately 20 weeks)
Population: Analysis was performed on Long-term extension safety population which included all participants who had received at least one dose of study medication.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Venglustat 15mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Any TEAEs | 2 Participants |
| Venglustat 15mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 1 Participants |