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

Polycystic Kidney, Autosomal Dominant Clinical Trial

— STAGED-PKD  

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03523728
• Other study ID #: EFC15392
• Secondary ID: 2017-004084-12U1
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: October 4, 2018
• Est. completion date: August 3, 2021

Study information

• Verified date: February 2023
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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).

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 478
• Est. completion date: August 3, 2021
• Est. primary completion date: August 3, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 (ß-human chorionic gonadotropin [ß-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.

Related Conditions & MeSH terms

• Polycystic Kidney Diseases
• Polycystic Kidney, Autosomal Dominant

Intervention

Drug:
• Venglustat
Pharmaceutical form: capsule; Route of administration: oral
• Placebo
Pharmaceutical form: capsule; Route of administration: oral

Locations

Country	Name	City	State
Argentina	Investigational Site Number 0320001	Buenos Aires
Argentina	Investigational Site Number 0320003	Santa Fe
Australia	Investigational Site Number 0360002	Herston
Australia	Investigational Site Number 0360003	Nedlands
Australia	Investigational Site Number 0360001	Westmead
Austria	Investigational Site Number 0400001	Graz
Austria	Investigational Site Number 0400004	Wien
Belgium	Investigational Site Number 0560001	Bruxelles
Belgium	Investigational Site Number 0560002	Leuven
Canada	Investigational Site Number 1240002	Edmonton
Canada	Investigational Site Number 1240003	Montreal
Canada	Investigational Site Number 1240001	Toronto
China	Investigational Site Number 1560005	Beijing
China	Investigational Site Number 1560004	Chengdu
China	Investigational Site Number 1560009	Guangzhou
China	Investigational Site Number 1560006	Hangzhou
China	Investigational Site Number 1560002	Hefei
China	Investigational Site Number 1560007	Nanjing
China	Investigational Site Number 1560008	Nanjing
China	Investigational Site Number 1560001	Shanghai
China	Investigational Site Number 1560003	Shenyang
Czechia	Investigational Site Number 2030001	Praha 2
Czechia	Investigational Site Number 2030002	Praha 4
Denmark	Investigational Site Number 2080001	Copenhagen
Denmark	Investigational Site Number 2080002	Roskilde
France	Investigational Site Number 2500004	Bordeaux
France	Investigational Site Number 2500003	Brest
France	Investigational Site Number 2500002	Paris
France	Investigational Site Number 2500001	Toulouse
Germany	Investigational Site Number 2760001	Berlin
Germany	Investigational Site Number 2760002	Dresden
Germany	Investigational Site Number 2760010	Dresden
Germany	Investigational Site Number 2760007	Düsseldorf
Germany	Investigational Site Number 2760009	Essen
Germany	Investigational Site Number 2760005	Hannover
Germany	Investigational Site Number 2760003	Köln
Germany	Investigational Site Number 2760011	Leipzig
Germany	Investigational Site Number 2760012	Mainz
Germany	Investigational Site Number 2760004	München
Israel	Investigational Site Number 3760003	Ashdod
Israel	Investigational Site Number 3760002	Re?ovot
Italy	Investigational Site Number 3800001	Brescia
Italy	Investigational Site Number 3800002	Milano
Italy	Investigational Site Number 3800003	Napoli
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
Korea, Republic of	Investigational Site Number 4100001	Seoul
Korea, Republic of	Investigational Site Number 4100002	Seoul
Netherlands	Investigational Site Number 5280003	Amsterdam
Netherlands	Investigational Site Number 5280001	Groningen
Netherlands	Investigational Site Number 5280002	Nijmegen
Poland	Investigational Site Number 6160001	Lódz
Poland	Investigational Site Number 6160003	Warszawa
Poland	Investigational Site Number 6160002	Wroclaw
Portugal	Investigational Site Number 6200004	Almada
Portugal	Investigational Site Number 6200005	Carnaxide
Portugal	Investigational Site Number 6200001	Loures
Romania	Investigational Site Number 6420002	Bucuresti
Romania	Investigational Site Number 6420004	Oradea
Romania	Investigational Site Number 6420001	Timisoara
Spain	Investigational Site Number 7240001	Barcelona
Spain	Investigational Site Number 7240003	Barcelona
Spain	Investigational Site Number 7240002	Madrid
Taiwan	Investigational Site Number 1580001	Taichung
Taiwan	Investigational Site Number 1580002	Taipei
Turkey	Investigational Site Number 7920001	Istanbul
Turkey	Investigational Site Number 7920002	Kayseri
Turkey	Investigational Site Number 7920003	Kocaeli
United Kingdom	Investigational Site Number 8260001	Sheffield
United States	Investigational Site Number 8400004	Atlanta	Georgia
United States	Investigational Site Number 8400008	Aurora	Colorado
United States	Investigational Site Number 8400021	Baltimore	Maryland
United States	Investigational Site Number 8400002	Birmingham	Alabama
United States	Investigational Site Number 8400016	Boston	Massachusetts
United States	Investigational Site Number 8400007	Chicago	Illinois
United States	Investigational Site Number 8400014	Iowa City	Iowa
United States	Investigational Site Number 8400003	Kansas City	Kansas
United States	Investigational Site Number 8400027	Kansas City	Missouri
United States	Investigational Site Number 8400017	Los Angeles	California
United States	Investigational Site Number 8400005	Madison	Wisconsin
United States	Investigational Site Number 8400006	Milwaukee	Wisconsin
United States	Investigational Site Number 8400019	Morgantown	West Virginia
United States	Investigational Site Number 8400010	New Haven	Connecticut
United States	Investigational Site Number 8400011	Philadelphia	Pennsylvania
United States	Investigational Site Number 8400020	Rochester	Minnesota
United States	Investigational Site Number 8400015	San Antonio	Texas
United States	Investigational Site Number 8400001	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Israel,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Poland,  Portugal,  Romania,  Spain,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (1)

Gansevoort RT, Hariri A, Minini P, Ahn C, Chapman AB, Horie S, Knebelmann B, Mrug M, Ong AC, Pei YP, Torres VE, Modur V, Antonshchuk I, Perrone RD. Venglustat, a Novel Glucosylceramide Synthase Inhibitor, in Patients at Risk of Rapidly Progressing ADPKD: — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Annualized Rate of Change in Estimated Glomerular Filtration Rate (eGFR) From Baseline to Month 24: Stage 1	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.	From Baseline to Month 24
Secondary	Annualized Slope of Change in Total Kidney Volume (TKV) From Baseline to Month 18: Combined Stage 1 and Stage 2	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.	From Baseline to Month 18
Secondary	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	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.	From Baseline to Month 18
Secondary	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	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.	From Baseline to Month 24
Secondary	Change in Fatigue Severity as Measured by Brief Fatigue Inventory (BFI-SF)-Item 3 Scale Score From Baseline to Month 18: Stage 1	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.	From Baseline to Month 18
Secondary	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	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.	From Baseline to Month 24
Secondary	Pharmacokinetics: Plasma Concentration of Venglustat: Stage 1	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.	Day 1: 3 hours Post-Dose, Month 1: Pre-Dose and 3 hours Post-Dose, Month 6: Pre-Dose, Month 18: Pre-Dose
Secondary	Pharmacokinetics: Plasma Concentration of Venglustat: Stage 2	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.	Month 1: Pre-dose and 3 hours Post-dose
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Stage 1	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).	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
Secondary	Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs): Combined Stage 1 and Stage 2	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).	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
Secondary	Number of Participants With Potentially Clinically Significant Abnormalities: Hematology: Combined Stage 1 and Stage 2	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).	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
Secondary	Number of Participants With Potentially Clinically Significant Abnormalities: Clinical Chemistry: Combined Stage 1 and Stage 2	Criteria for potentially clinically significant abnormalities: Glucose: <=3.9 millimoles per liter (mmol/L) and	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
Secondary	Number of Participants With Potentially and Clinically Significant Abnormalities: Urinalysis: Combined Stage 1 and Stage 2	Criteria for potentially clinically significant abnormalities: Urine pH: <=4.6 and >=8.	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
Secondary	Number of Participants With Potentially and Clinically Significant Abnormalities: Vital Signs: Combined Stage 1 and Stage 2	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.	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
Secondary	Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram: Combined Stage 1 and Stage 2	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.	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
Secondary	Number of Participants With Physical Examination Abnormalities: Combined Stage 1 and Stage 2	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.	Baseline, Month 18, Month 24
Secondary	Change From Baseline in Beck Depression Inventory-II (BDI-II) Score: Combined Stage 1 and Stage 2	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.	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)
Secondary	Number of Participants With Worsening Lens Opacity From Baseline During the Treatment-emergent Period: Combined Stage 1 and Stage 2	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.	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

External Links

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