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
- Interventions
- Drug: Placebo
- Registration Number
- NCT02906020
- Lead Sponsor
- Genzyme, a Sanofi Company
- 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 273
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description GZ/SAR402671 venglustat GZ/SAR402671 Part 1: Increasing doses of GZ/SAR402671 were administered once per day. Part 2: A dose of GZ/SAR402671 (determined in Part 1) was administered once per day. Placebo Placebo A matching placebo for Parts 1 and 2 was administered once per day.
- Primary Outcome Measures
Name Time Method Part 1: Number of Participants With Abnormal Neurological Examination Findings 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) 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.
Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Renal Parameters 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) 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.
Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Electrolytes Parameters 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) 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.
Part 1: Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities 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) 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.
Part 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Treatment-Emergent Serious Adverse Events (TESAEs) 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) 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).
Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Liver Function Parameters 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) 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.
Part 1: Number of Participants With Potentially Clinically Significant Electrocardiogram Abnormalities 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) 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.
Part 1: Number of Participants With Abnormal Physical Examination Findings 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) 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.
Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematology 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) 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: \<lower limit of normal (LLN), greater than (\>) 4.0 Giga/L; Monocytes: \<LLN, \>0.7 Giga/L; Basophils: \>0.1 Giga/L; Eosinophils: \>0.5 Giga/L or \>upper limit of normal (ULN) (if ULN \>=0.5 Giga/L).
Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters 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) Criteria for PCSA: Glucose: \<=3.9 mmol/L and \<LLN; \>=11.1 mmol/L (unfasted \[unfas\]) or \>=7 mmol/L (fasted \[fas\]); Albumin: \<=25 g/L.
Part 1: Number of Participants With Potentially Clinically Significant Ophthalmological Abnormalities 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) 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
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 Baseline to Week 52 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.
- Secondary Outcome Measures
Name Time Method Part 2: Change From Baseline to Week 52 in Parkinson's Disease Cognitive Rating Scale (PD-CRS) Total Score Baseline to Week 52 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.
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 Baseline to Week 52 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.
Part 2: Change From Baseline to Week 52 in Hoehn and Yahr (H and Y) Score Baseline to Week 52 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.
Trial Locations
- Locations (52)
Investigational Site Number :0400001
🇦🇹Innsbruck, Austria
Investigational Site Number :3760003
🇮🇱Petah-Tikva, Israel
Investigational Site Number :3920001
🇯🇵Bunkyo-ku, Tokyo, Japan
Investigational Site Number :7020001
🇸🇬Singapore, Singapore
Investigational Site Number :8400011
🇺🇸Scottsdale, Arizona, United States
Investigational Site Number :3000002
🇬🇷Larissa, Greece
Investigational Site Number :5780001
🇳🇴Trondheim, Norway
Investigational Site Number :8400017
🇺🇸Scottsdale, Arizona, United States
Investigational Site Number :7020002
🇸🇬Singapore, Singapore
Investigational Site Number :8400014
🇺🇸Boston, Massachusetts, United States
Investigational Site Number :8400019
🇺🇸Palo Alto, California, United States
Investigational Site Number :8400018
🇺🇸New York, New York, United States
Investigational Site Number :8400010
🇺🇸New York, New York, United States
Investigational Site Number :8400004
🇺🇸La Jolla, California, United States
Investigational Site Number :2500001
🇫🇷Paris, France
Investigational Site Number :3760002
🇮🇱Haifa, Israel
Investigational Site Number :8400012
🇺🇸Kirkland, Washington, United States
Investigational Site Number :1240002
🇨🇦Ottawa, Ontario, Canada
Investigational Site Number :2760001
🇩🇪Tübingen, Germany
Investigational Site Number :6200003
🇵🇹Torres Vedras, Portugal
Investigational Site Number :3800003
🇮🇹Pavia, Italy
Investigational Site Number :3760001
🇮🇱Tel Aviv, Israel
Investigational Site Number :3920005
🇯🇵Nagoya-shi, Aichi, Japan
Investigational Site Number :6200002
🇵🇹Coimbra, Portugal
Investigational Site Number :3800006
🇮🇹Rozzano, Milano, Italy
Investigational Site Number :3800004
🇮🇹Milano, Italy
Investigational Site Number :7520001
🇸🇪Stockholm, Sweden
Investigational Site Number :3920003
🇯🇵Kodaira-shi, Tokyo, Japan
Investigational Site Number :1580001
🇨🇳Taoyuan County, Taiwan
Investigational Site Number :3920002
🇯🇵Kyoto-shi, Kyoto, Japan
Investigational Site Number :3920004
🇯🇵Osaka-shi, Osaka, Japan
Investigational Site Number :3800002
🇮🇹Salerno, Italy
Investigational Site Number :8260001
🇬🇧London, London, City Of, United Kingdom
Investigational Site Number :8260002
🇬🇧Oxford, Oxfordshire, United Kingdom
Investigational Site Number :7240002
🇪🇸Barcelona, Barcelona [Barcelona], Spain
Investigational Site Number :7240001
🇪🇸Sevilla, Spain
Investigational Site Number :8400001
🇺🇸New York, New York, United States
Investigational Site Number :8400015
🇺🇸New Haven, Connecticut, United States
Investigational Site Number :8400016
🇺🇸Chicago, Illinois, United States
Investigational Site Number :8400005
🇺🇸Chicago, Illinois, United States
Investigational Site Number :8400021
🇺🇸Portland, Oregon, United States
Investigational Site Number :8400020
🇺🇸Portland, Oregon, United States
Investigational Site Number :8400009
🇺🇸Portland, Oregon, United States
Investigational Site Number :8400002
🇺🇸Philadelphia, Pennsylvania, United States
Investigational Site Number :8400006
🇺🇸Fairfax, Virginia, United States
Investigational Site Number :8400013
🇺🇸Sunnyvale, California, United States
Investigational Site Number :8400008
🇺🇸Boca Raton, Florida, United States
Investigational Site Number :3760004
🇮🇱Tel HaShomer, Israel
Investigational Site Number :1240001
🇨🇦Montreal, Quebec, Canada
Investigational Site Number :2760002
🇩🇪Kiel, Germany
Investigational Site Number :3800001
🇮🇹Catanzaro, Italy
Investigational Site Number :1240003
🇨🇦Vancouver, British Columbia, Canada