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

Conditions: Parkinson's Disease

Summary: 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.

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.

Eligibility criteria:
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.