A Global Study to Assess the Drug Dynamics, Efficacy, and Safety of Venglustat (GZ/SAR402671) in Parkinson's Disease Patients Carrying a Glucocerebrosidase (GBA) Gene Mutation

Study Overview
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Brief Summary
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Primary Objectives: Part 1: To determine the safety and tolerability of 4, 8, and 15 milligrams of GZ/SAR402671 (venglustat) administered orally for 4 weeks, as compared to placebo in participants with early-stage Parkinson's disease (PD) carrying a glucocerebrosidase gene (GBA) mutation or other pre-specified variants. Part 2: To determine the efficacy of GZ/SAR402671 administered orally daily, as compared to placebo in participants with early-stage PD carrying a GBA mutation or other pre-specified variants. Secondary Objectives: Part 1: To assess the pharmacokinetic (PK) profile of oral dosing of GZ/SAR402671 in plasma when administered in early-stage PD participants carrying a GBA mutation. To assess the exposure of GZ/SAR402671 in cerebrospinal fluid (CSF) when administered in early-stage PD participants carrying a GBA mutation. Part 2: To demonstrate overall safety and tolerability of GZ/SAR402671 administered orally for 52 weeks in early-stage PD participants carrying a GBA mutation as compared to placebo. To assess the pharmacodynamic response to daily oral dosing of GZ/SAR402671 in plasma and CSF as measured by glucosylceramide (GL-1) when administered in early-stage PD participants carrying a GBA mutation over a 52-week period.

Detailed Description
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Part 1: the total duration was as following: i) Rest of the world (ROW): up to approximately 50 weeks (8.5 weeks of screening, maximum of 36 weeks of treatment and 6 weeks follow-up). ii) Japan only: up to approximately 66 weeks (8.5 weeks of screening, maximum of 52 weeks of treatment and 6 weeks follow-up). Part 2: the total duration was up to approximately 224 weeks that consisted of 8.5 weeks of screening period, 52 weeks of treatment period, 156 weeks of long-term follow-up (LTFU) period and 8 weeks of post-treatment period. At the end of a 52-week main placebo-controlled treatment period, all participants were evaluated for possibility to transition to receive active treatment for 156 weeks plus 8-week post-treatment observation.

Official Title
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Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of GZ/SAR402671 in Patients With Early-stage Parkinson's Disease Carrying a GBA Mutation or Other Pre-specified Variant

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Drug: venglustat GZ/SAR402671
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male and female adults with a diagnosis of PD and who were heterozygous carriers of a GBA mutation associated with PD. Participants carrying known sequence variants associated with GBA-PD must had rapid eye movement (REM) sleep behavior disorder (RBD) confirmed by historically documented polysomnography or by questionnaire. Age greater than or equal to (>=) 18 years to 80 years inclusive at the time of informed consent signing (FOR JAPANESE PARTICIPANTS ONLY: Age >=20 years to 80 years, inclusive, at the time of signing the informed consent. Note: Japanese participants refers only to Japanese participants enrolled and living in Japan). Had symptoms of PD >=2 years. Hoehn and Yahr (H and Y) stage of 2 or lower at baseline. Stable medication regimen of PD drugs for at least 30 days (at least 60 days for rasagiline) prior to randomization. The participant was willing to abstain from grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for the duration of the entire treatment period (Part 1 and Part 2, Periods 2 and 3). Signed written consent. Exclusion criteria: Parkinsonism due to drug(s) or toxin(s). Participants carrying the LRRK2 G2019S mutation. Participants with Gaucher disease (GD) as defined by clinical signs and symptoms (i.e., hepatosplenomegaly, cytopenia, skeletal disease) and/or marked deficiency of GCase activity compatible with GD. Montreal Cognitive Assessment score less than 20. Participants with prior surgical history of deep brain stimulation (DBS). Participants with baseline brain MRI without contrast showing a structural abnormality that is a possible cause of their PD signs or symptoms. Hepatic insufficiency with liver function tests (LFT) greater than (>) 2 times upper limit of normal at Screening Visit. The participant had a documented diagnosis, as per local regulations, of any of the following infections: hepatitis B, hepatitis C, human immunodeficiency virus 1 or 2. Renal insufficiency as defined by creatine >1.5 times normal at Screening Visit. The participant had received strong or moderate inducers or inhibitors of CYP3A4 within 30 days or 5 half-lives prior to randomization, whichever is longer. The participant had, according to World Health Organization (WHO) Grading, a cortical cataract > one-quarter the lens circumference (grade cortical catact-2 [COR-2]) or a posterior subcapsular cataract >2 millimeters (grade posterior subscapsular cataract [PSC-2]). Participant with nuclear cataracts would not be excluded. The participant was currently receiving potentially cataractogenic medications, including chronic regimen (more frequently than every 2 weeks) of any dose or route of corticosteroids or any medication that could cause cataract or worsen the vision of participants with cataract (eg, glaucoma medications) according to the Prescribing Information. If female, pregnant (defined as positive beta-human chorionic gonadotrophin [Beta-HCG] blood test) or lactating or breast-feeding. Any medical disorders and/or clinically relevant findings that, in the opinion of the Investigator, could interfere with study-related procedures. This included condition(s) that precluded the safe performance of routine lumbar punctures, such as prohibitive spinal diseases, bleeding diasthesis, or clinically significant coagulopathy or thrombocytopenia. Current participation in another investigational interventional study. Any medications specifically used for treating memory dysfunction, such as, but not limited to cholinesterase inhibitors or memantine, within 30 days or 5 half-lives of these medications prior to randomization, whichever was longer. The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GZ/SAR402671<br>Part 1: Increasing doses of GZ/SAR402671 were administered once per day. Part 2: A dose of GZ/SAR402671 (determined in Part 1) was administered once per day. | Drug: venglustat GZ/SAR402671<br>* Pharmaceutical form: capsule Route of administration: oral<br>|
| Placebo Comparator: Placebo<br>A matching placebo for Parts 1 and 2 was administered once per day. | Drug: Placebo<br>* Pharmaceutical form: capsule Route of administration: oral<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug and does not necessarily had to have a causal relationship with the treatment. Serious AEs (SAEs) were any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. TEAEs were the AEs that developed or worsened or became serious during the TEAE period (defined as the period from the time of first investigational medicinal product [IMP] administration up of 6 weeks after the last administration of the IMP). | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Abnormal Physical Examination Findings | Physical examination included following observations/measurements: general appearance; heart, skin, respiratory auscultation; head, eyes, ears, nose, and throat, extremities/joints, and abdomen. New onset of abnormal physical examination was defined as a normal physical examination at Baseline and an abnormal physical examination during the treatment-emergent (TE) period (defined as the period from the time of first IMP administration up of 6 weeks after the last administration of the IMP). Abnormalities in physical examination were based on investigator's evaluation. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Abnormal Neurological Examination Findings | Neurological examination included at least assessments of the participant's cranial nerves, motor system (including muscle atrophy, tone, and power), mental status, deep tendon reflex, sensation, and cerebellar function. Abnormalities in neurological examination were based on investigator's evaluation. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology | Criteria for potentially clinically significant abnormalities (PCSA): Hemoglobin: less than or equal to (<=) 115 grams per liter (g/L) (Male[M]) or <=95 g/L (Female[F]), greater than or equal to (>=) 185 g/L (M) or >=165 g/L (F), Decrease from baseline (DFB) >=20 g/L; Hematocrit: <=0.37 volume/volume (v/v) (M) or <=0.32 v/v (F), >=0.55 v/v (M) or >=0.5 v/v (F); Red blood cells (RBC): >=6 Tera/L; Platelets: less than (<) 100 Giga/L, >=700 Giga/L; White blood cells (WBC): <3.0 Giga/L (Non-Black [NB]) or <2.0 Giga/L (Black [B]), >=16.0 Giga/L; Neutrophils: <1.5 Giga/L (NB) or <1.0 Giga/L (B); Lymphocytes: <lower limit of normal (LLN), greater than (>) 4.0 Giga/L; Monocytes: <LLN, >0.7 Giga/L; Basophils: >0.1 Giga/L; Eosinophils: >0.5 Giga/L or >upper limit of normal (ULN) (if ULN >=0.5 Giga/L). | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters | Criteria for PCSA: Alanine Aminotransferase (ALT): >3 ULN, >5 ULN; Aspartate aminotransferase (AST): >3 ULN; Alkaline phosphatase: >1.5 ULN; Total Bilirubin: >1.5 ULN; ALT and Bilirubin: >3 ULN and >2 ULN; Direct Bilirubin and Bilirubin: >35% and >1.5 ULN. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Parameters | Criteria for PCSA: Creatinine: >=150 micromoles per liter (mcmol/L) (adults), >=30% change from baseline, >=100% change from baseline; Blood urea nitrogen: >=17 millimoles (mmol)/L. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters | Criteria for PCSA: Glucose: <=3.9 mmol/L and <LLN; >=11.1 mmol/L (unfasted [unfas]) or >=7 mmol/L (fasted [fas]); Albumin: <=25 g/L. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Electrolytes Parameters | Criteria for PCSA: Sodium: <=129 mmol/L, >=160 mmol/L; Potassium: <3 mmol/L, >=5.5 mmol/L and Chloride: <80 mmol/L, >115 mmol/L. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities | Criteria for PCSA: Systolic blood pressure (SBP) supine: <=95 millimeters of mercury (mmHg) and DFB >=20 mmHg; >=160 mmHg and increase from baseline (IFB) >=20 mmHg; Diastolic blood pressure (DBP) supine: <=45 mmHg and DFB >=10 mmHg; >=110 mmHg and IFB >=10 mmHg; SBP (Orthostatic): <=-20 mmHg; DBP (Orthostatic): <=-10 mmHg; Heart rate (HR) supine: <=50 beats per minute (bpm) and DFB >=20 bpm; >=120 bpm and IFB >=20 bpm; Weight: >=5% DFB; >=5% IFB. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Ophthalmological Abnormalities | Clinically significant observations in left eye, right eye and any eye (any eye among left and right) were assessed by the investigator based on methods like visual acuity, slit lamp examination, examination of the cornea, lens, and retina. Any abnormal clinically significant ophthalmological examination finding (which was present at screening or not) on any eye during the treatment-emergent period corresponded to cornea verticillata, cataract and abnormal overall evaluation | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 1: Number of Participants With Potentially Clinically Significant Electrocardiogram Abnormalities | Criteria for PCSA: HR: <50 bpm; <50 bpm and DFB >=20 bpm, <40 bpm; >90 bpm, <90 bpm and IFB >=20 bpm, >100 bpm; PR Interval: >200 milliseconds (msec), >200 msec and IFB >=25%, >220 msec; QRS Interval: >110 msec, >110 msec and IFB >=25%, >120 msec; QT Interval: >500 msec; QTc Bazett (QTcB) interval: >450 msec, >480 msec, IFB >30 and <=60 msec, IFB >60 msec; QTc Fridericia (QTc F): >450 msec, >480 msec, IFB >30 and <=60 msec, IFB >60 msec. | From the first IMP administration up to 6 weeks after the last administration of the IMP (i.e., up to 42 weeks for ROW and up to 58 weeks for Japanese participants) | 
| Part 2: Change From Baseline to Week 52 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II+III Total Score | MDS-UPDRS is a multimodal scale consisting of 4 parts. Part II assessed motor experiences of daily living (total score range: 0 to 52). It contained 13 questions completed by the participant. Part III assessed the motor signs of PD and was administered by the rater (total score range: 0 to 132). Part III contained 33 scores based on 18 items. In both parts, higher score indicated more severe symptoms. For each question in both parts, numeric score was assigned between 0 to 4, where 0=Normal, 1=Slight, 2=Mild, 3=Moderate, 4=Severe. MDS-UPDRS Total Part II and III score = sum of Part II and III scores with score ranged from 0 (no symptom) to 184 (severe symptoms), where higher scores reflected more severe symptoms of PD. Data for this OM was not planned to be collected and analyzed for Part 1, Part 2: DB period re-randomized participants and Part 2 LTFU period, as pre-specified in protocol. | Baseline to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Change From Baseline to Week 52 in Parkinson's Disease Cognitive Rating Scale (PD-CRS) Total Score | The PD-CRS detects early cognitive impairment in Parkinson's disease. It is composed of 2 scales, the fronto-subcortical scale (items: sustained attention, working memory, alternating and action verbal fluency, clock drawing, immediate, and delayed free recall verbal memory) and the posterior-cortical scale (items: confrontation naming and clock copying). The total score of the fronto-subcortical scale (sum of all items) ranged from 0 (worst) to 104 (maximum score indicates better) and the total score of the posterior-cortical scale (sum of all items) ranged from 0 (worst) to 30 (maximum score indicates better). The PD-CRS Total score = the sum of PD-CRS fronto-subcortical score and the PD-CRS posterior-cortical score, which ranged from 0 to 134, where higher score = less impairment. | Baseline to Week 52 | 
| Part 2: Change From Baseline to Week 52 in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I+ II+III Score | MDS-UPDRS is a multimodal scale consisting of 4 parts. Part I assessed non-motor experiences of daily living and has 2 components (total score range: 0 to 52): Part IA contained 6 questions and was assessed by the examiner (total score range: 0 to 24). Part IB contained 7 questions on non-motor experiences of daily living which was completed by the participant (total score range: 0 to 28). Part II (13 questions completed by the participant) assessed motor experiences of daily living (total score range: 0 to 52). Part III assessed motor signs of PD and was administered by the rater (total score range: 0 to 132). Part III contained 33 scores based on 18 items. In all parts, higher score indicated more symptoms. For each question, numeric score was assigned between 0 to 4, where 0=Normal, 1=Slight, 2=Mild, 3=Moderate, 4=Severe. MDS-UPDRS total score = sum of Parts I, II, and III (Range: 0 to 236). Higher score = more severe symptoms of PD. | Baseline to Week 52 | 
| Part 2: Change From Baseline to Week 52 in Hoehn and Yahr (H and Y) Score | H and Y scale measured how Parkinson's symptoms progress and the level of disability. Scale allocated stage scores were from 0 to 5 to indicate relative level of disability as: Stage 0: no symptoms; Stage 1: symptoms on one side of the body only; Stage 2: symptoms on both sides of the body, without impairment of balance; Stage 3: Mild to moderate bilateral disease; some postural instability; physically independent; Stage 4: Severe disability; still able to walk or stand unassisted and Stage 5: Wheelchair bound or bedridden unless aided, where higher stage score described an increased severity of disease. | Baseline to Week 52 |