Clinical trial NCT02906020: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Parkinson's Disease
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2016-09-19
Enrollment: 273
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Primary outcomes:
measure: Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs)
timeFrame: 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)
measure: Part 1: Number of Participants With Abnormal Physical Examination Findings
timeFrame: 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)
measure: Part 1: Number of Participants With Abnormal Neurological Examination Findings
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Parameters
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Electrolytes Parameters
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Ophthalmological Abnormalities
timeFrame: 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)
measure: Part 1: Number of Participants With Potentially Clinically Significant Electrocardiogram Abnormalities
timeFrame: 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)
measure: 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
timeFrame: Baseline to Week 52
Secondary outcomes:
measure: Part 2: Change From Baseline to Week 52 in Parkinson's Disease Cognitive Rating Scale (PD-CRS) Total Score
timeFrame: Baseline to Week 52
measure: 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
timeFrame: Baseline to Week 52
measure: Part 2: Change From Baseline to Week 52 in Hoehn and Yahr (H and Y) Score
timeFrame: Baseline to Week 52
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Investigational Site Number :8400017
state: Arizona
city: Scottsdale
country: United States
facility: Investigational Site Number :8400011
state: Arizona
city: La Jolla
country: United States
facility: Investigational Site Number :8400004
state: California
city: Palo Alto
country: United States
facility: Investigational Site Number :8400019
state: California
city: Sunnyvale
country: United States
facility: Investigational Site Number :8400013
state: California
city: New Haven
country: United States
facility: Investigational Site Number :8400015
state: Connecticut
city: Boca Raton
country: United States
facility: Investigational Site Number :8400008
state: Florida
city: Chicago
country: United States
facility: Investigational Site Number :8400016
state: Illinois
city: Chicago
country: United States
facility: Investigational Site Number :8400005
state: Illinois
city: Boston
country: United States
facility: Investigational Site Number :8400014
state: Massachusetts
city: New York
country: United States
facility: Investigational Site Number :8400018
state: New York
city: New York
country: United States
facility: Investigational Site Number :8400010
state: New York
city: New York
country: United States
facility: Investigational Site Number :8400001
state: New York
city: Portland
country: United States
facility: Investigational Site Number :8400021
state: Oregon
city: Portland
country: United States
facility: Investigational Site Number :8400020
state: Oregon
city: Portland
country: United States
facility: Investigational Site Number :8400009
state: Oregon
city: Philadelphia
country: United States
facility: Investigational Site Number :8400002
state: Pennsylvania
city: Fairfax
country: United States
facility: Investigational Site Number :8400006
state: Virginia
city: Kirkland
country: United States
facility: Investigational Site Number :8400012
state: Washington
city: Innsbruck
country: Austria
facility: Investigational Site Number :0400001
city: Vancouver
country: Canada
facility: Investigational Site Number :1240003
state: British Columbia
city: Ottawa
country: Canada
facility: Investigational Site Number :1240002
state: Ontario
city: Montreal
country: Canada
facility: Investigational Site Number :1240001
state: Quebec
city: Paris
country: France
facility: Investigational Site Number :2500001
city: Kiel
country: Germany
facility: Investigational Site Number :2760002
city: Tübingen
country: Germany
facility: Investigational Site Number :2760001
city: Larissa
country: Greece
facility: Investigational Site Number :3000002
city: Haifa
country: Israel
facility: Investigational Site Number :3760002
city: Petah-Tikva
country: Israel
facility: Investigational Site Number :3760003
city: Tel Aviv
country: Israel
facility: Investigational Site Number :3760001
city: Tel HaShomer
country: Israel
facility: Investigational Site Number :3760004
city: Rozzano
country: Italy
facility: Investigational Site Number :3800006
state: Milano
city: Catanzaro
country: Italy
facility: Investigational Site Number :3800001
city: Milano
country: Italy
facility: Investigational Site Number :3800004
city: Pavia
country: Italy
facility: Investigational Site Number :3800003
city: Salerno
country: Italy
facility: Investigational Site Number :3800002
city: Nagoya-shi
country: Japan
facility: Investigational Site Number :3920005
state: Aichi
city: Kyoto-shi
country: Japan
facility: Investigational Site Number :3920002
state: Kyoto
city: Osaka-shi
country: Japan
facility: Investigational Site Number :3920004
state: Osaka
city: Bunkyo-ku
country: Japan
facility: Investigational Site Number :3920001
state: Tokyo
city: Kodaira-shi
country: Japan
facility: Investigational Site Number :3920003
state: Tokyo
city: Trondheim
country: Norway
facility: Investigational Site Number :5780001
city: Coimbra
country: Portugal
facility: Investigational Site Number :6200002
city: Torres Vedras
country: Portugal
facility: Investigational Site Number :6200003
city: Singapore
country: Singapore
facility: Investigational Site Number :7020001
city: Singapore
country: Singapore
facility: Investigational Site Number :7020002
city: Barcelona
country: Spain
facility: Investigational Site Number :7240002
state: Barcelona [Barcelona]
city: Sevilla
country: Spain
facility: Investigational Site Number :7240001
city: Stockholm
country: Sweden
facility: Investigational Site Number :7520001
city: Taoyuan County
country: Taiwan
facility: Investigational Site Number :1580001
city: London
country: United Kingdom
facility: Investigational Site Number :8260001
state: London, City Of
city: Oxford
country: United Kingdom
facility: Investigational Site Number :8260002
state: Oxfordshire
Study officials:
affiliation: Sanofi
name: Clinical Sciences & Operations
role: STUDY_DIRECTOR
References:
citation: Peterschmitt MJ, Saiki H, Hatano T, Gasser T, Isaacson SH, Gaemers SJM, Minini P, Saubadu S, Sharma J, Walbillic S, Alcalay RN, Cutter G, Hattori N, Hoglinger GU, Marek K, Schapira AHV, Scherzer CR, Simuni T, Giladi N, Sardi SP, Fischer TZ; MOVES-PD Investigators. Safety, Pharmacokinetics, and Pharmacodynamics of Oral Venglustat in Patients with Parkinson's Disease and a GBA Mutation: Results from Part 1 of the Randomized, Double-Blinded, Placebo-Controlled MOVES-PD Trial. J Parkinsons Dis. 2022;12(2):557-570. doi: 10.3233/JPD-212714.