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

Parkinson's Disease Clinical Trial

— MOVES-PD  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02906020
• Other study ID #: ACT14820
• Secondary ID: 2016-000657-12U1
• Status: Terminated
• Phase: Phase 2
• Start date: December 15, 2016
• Est. completion date: May 27, 2021

Study information

• Verified date: May 2022
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 273
• Est. completion date: May 27, 2021
• Est. primary completion date: December 18, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Parkinson Disease
• Parkinson's Disease

Intervention

Drug:
• venglustat GZ/SAR402671
Pharmaceutical form: capsule Route of administration: oral
• Placebo
Pharmaceutical form: capsule Route of administration: oral

Locations

Country	Name	City	State
Austria	Investigational Site Number :0400001	Innsbruck
Canada	Investigational Site Number :1240001	Montreal	Quebec
Canada	Investigational Site Number :1240002	Ottawa	Ontario
Canada	Investigational Site Number :1240003	Vancouver	British Columbia
France	Investigational Site Number :2500001	Paris
Germany	Investigational Site Number :2760002	Kiel
Germany	Investigational Site Number :2760001	Tübingen
Greece	Investigational Site Number :3000002	Larissa
Israel	Investigational Site Number :3760002	Haifa
Israel	Investigational Site Number :3760003	Petah-Tikva
Israel	Investigational Site Number :3760001	Tel Aviv
Israel	Investigational Site Number :3760004	Tel HaShomer
Italy	Investigational Site Number :3800001	Catanzaro
Italy	Investigational Site Number :3800004	Milano
Italy	Investigational Site Number :3800003	Pavia
Italy	Investigational Site Number :3800006	Rozzano	Milano
Italy	Investigational Site Number :3800002	Salerno
Japan	Investigational Site Number :3920001	Bunkyo-ku	Tokyo
Japan	Investigational Site Number :3920003	Kodaira-shi	Tokyo
Japan	Investigational Site Number :3920002	Kyoto-shi	Kyoto
Japan	Investigational Site Number :3920005	Nagoya-shi	Aichi
Japan	Investigational Site Number :3920004	Osaka-shi	Osaka
Norway	Investigational Site Number :5780001	Trondheim
Portugal	Investigational Site Number :6200002	Coimbra
Portugal	Investigational Site Number :6200003	Torres Vedras
Singapore	Investigational Site Number :7020001	Singapore
Singapore	Investigational Site Number :7020002	Singapore
Spain	Investigational Site Number :7240002	Barcelona	Barcelona [Barcelona]
Spain	Investigational Site Number :7240001	Sevilla
Sweden	Investigational Site Number :7520001	Stockholm
Taiwan	Investigational Site Number :1580001	Taoyuan County
United Kingdom	Investigational Site Number :8260001	London	London, City Of
United Kingdom	Investigational Site Number :8260002	Oxford	Oxfordshire
United States	Investigational Site Number :8400008	Boca Raton	Florida
United States	Investigational Site Number :8400014	Boston	Massachusetts
United States	Investigational Site Number :8400005	Chicago	Illinois
United States	Investigational Site Number :8400016	Chicago	Illinois
United States	Investigational Site Number :8400006	Fairfax	Virginia
United States	Investigational Site Number :8400012	Kirkland	Washington
United States	Investigational Site Number :8400004	La Jolla	California
United States	Investigational Site Number :8400015	New Haven	Connecticut
United States	Investigational Site Number :8400001	New York	New York
United States	Investigational Site Number :8400010	New York	New York
United States	Investigational Site Number :8400018	New York	New York
United States	Investigational Site Number :8400019	Palo Alto	California
United States	Investigational Site Number :8400002	Philadelphia	Pennsylvania
United States	Investigational Site Number :8400009	Portland	Oregon
United States	Investigational Site Number :8400020	Portland	Oregon
United States	Investigational Site Number :8400021	Portland	Oregon
United States	Investigational Site Number :8400011	Scottsdale	Arizona
United States	Investigational Site Number :8400017	Scottsdale	Arizona
United States	Investigational Site Number :8400013	Sunnyvale	California

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Austria,  Canada,  France,  Germany,  Greece,  Israel,  Italy,  Japan,  Norway,  Portugal,  Singapore,  Spain,  Sweden,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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)
Primary	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:	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)
Primary	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)
Primary	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)
Primary	Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters	Criteria for PCSA: Glucose: <=3.9 mmol/L and	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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)
Primary	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	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
Secondary	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
Secondary	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