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
Condition: Parkinson's Disease
MeSH terms: Parkinson Disease
Intervention: venglustat GZ/SAR402671; Placebo
Intervention description: Pharmaceutical form: capsule Route of administration: oral; Pharmaceutical form: capsule Route of administration: oral
Intervention MeSH terms: Venglustat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 273.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

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.
    

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.