E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Parkinson's disease (PD) carrying a GBA mutation |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061536 |
E.1.2 | Term | Parkinson's disease |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-Part 1: To determine the safety and tolerability of GZ/SAR402671 administered orally for 4 weeks, as compared to placebo in patients with early-stage Parkinson's disease (PD) carrying a GBA mutation or other pre-specified variants. -Part 2: To determine the efficacy of GZ/SAR402671 administered orally daily, as compared to placebo in patients with early-stage Parkinson's disease carrying a GBA mutation or other prespecified variants. |
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E.2.2 | Secondary objectives of the trial |
Part 1: -To assess the pharmacokinetic (PK) profile of oral dosing of GZ/SAR4027671 in plasma when administered in early-stage Parkinson's disease patients carrying a GBA mutation. -To assess the exposure of GZ/SAR402671 in cerebrospinal fluid (CSF) when administered in early-stage Parkinson's disease patients carrying a GBA mutation. Part 2: -To demonstrate overall safety and tolerability of GZ/SAR4027671 administered orally for 52 weeks in early-stage Parkinson's disease patients 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 Parkinson's disease patients carrying a GBA mutation over a 52-week period. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Male and female adults with a diagnosis of PD and who are heterozygous carriers of a GBA mutation associated with PD. -Patients carrying known sequence variants associated with GBA-PD must have rapid eye movement (REM) sleep behavior disorder (RBD) confirmed by historically documented polysomnography or by questionnaire. -Age ≥18 years to 80 years inclusive at the time of informed consent signing. -Has 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 patient is willing to abstain from grapefruit containing products for 72 hours prior to administration of the first dose of GZ/SAR402671 and for duration of the entire treatment period (Part 1 and Part 2, Periods 2 and 3). -Signed written consent. |
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E.4 | Principal exclusion criteria |
-Parkinsonism due to drug(s) or toxin(s). -Patients carrying the LRRK2 G2019S mutation. -Patients with Gaucher disease (GD) as defined by clinical signs and symptoms (ie, hepatosplenomegaly, cytopenia, skeletal disease) and/or marked deficiency of GCase activity compatible with GD. -Montreal Cognitive Assessment score <20. -Patients with prior surgical history of deep brain stimulation (DBS). -Patients 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) >2 times upper limit of normal at Screening Visit. -The patient has 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 patient has received strong or moderate inducers or inhibitors of CYP3A4 within 30 days or 5 half-lives prior to randomization, whichever is longer. -The patient has, according to World Health Organization (WHO) Grading, a cortical cataract > onequarter the lens circumference (grade cortical catact-2 [COR-2]) or a posterior subcapsular cataract >2 mm (grade posterior subscapsular cataract [PSC-2]). Patient with nuclear cataracts will not be excluded. -The patient is 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 can cause cataract or worsen the vision of patients with cataract (eg, glaucoma medications) according to the Prescribing Information. -If female, pregnancy (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 includes condition(s) that preclude the safety 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 is longer. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1 - Part 1: Number of patients with AE 2 - Part 2 : Change in Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part II and III score, performed during the OFF state |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1 - During treatment emergent period (from first IMP to 6 weeks after last IMP) 2 - From baseline to Week 52 |
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E.5.2 | Secondary end point(s) |
- Part 2 : Change from baseline in Parkinson's Disease Cognitive Rating Scale (total score) - Part 2 : Change in Movement Disorder Society Unified Parkinson’s Disease Rating Scale Part I, II, and III score, performed during the OFF state - Part 2 : Change from baseline in Hoehn and Yahr score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Austria |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
Norway |
Portugal |
Singapore |
Spain |
Sweden |
Taiwan |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |