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

NCT02906020 | Terminated Phase 2 Results DMC FDA Drug

• 3 other identifiers: ACT148202016-000657-12U1111-1180-6918
• Study Type: interventional
• Target: 273
• Locations: 16 countries
• Sites: 52

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.

Conditions

Parkinson's Disease

Outcome Measures

Primary Outcomes (12)

• 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)

• 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)

• 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)

• 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: \<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).

  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)

• 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)

• 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)

• Part 1: Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Metabolic Parameters

  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.

  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)

• 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)

• 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)

• 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)

• 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)

• 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 Outcomes (3)

• Part 2: Change From Baseline to Week 52 in Parkinson's Disease Cognitive Rating Scale (PD-CRS) Total Score

  Baseline to Week 52

• 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

• Part 2: Change From Baseline to Week 52 in Hoehn and Yahr (H and Y) Score

  Baseline to Week 52

Study Arms (2)

GZ/SAR402671

EXPERIMENTAL

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.

Drug: venglustat GZ/SAR402671

Placebo

PLACEBO COMPARATOR

A matching placebo for Parts 1 and 2 was administered once per day.

Drug: Placebo

Interventions

venglustat GZ/SAR402671 DRUG

Pharmaceutical form: capsule Route of administration: oral

GZ/SAR402671

Placebo DRUG

Pharmaceutical form: capsule Route of administration: oral

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (52)

Investigational Site Number :8400017

Scottsdale, Arizona, 85258, United States

Location

Investigational Site Number :8400011

Scottsdale, Arizona, 85259, United States

Location

Investigational Site Number :8400004

La Jolla, California, 92093, United States

Location

Investigational Site Number :8400019

Palo Alto, California, 94304, United States

Location

Investigational Site Number :8400013

Sunnyvale, California, 94085, United States

Location

Investigational Site Number :8400015

New Haven, Connecticut, 06510, United States

Location

Investigational Site Number :8400008

Boca Raton, Florida, 33486, United States

Location

Investigational Site Number :8400016

Chicago, Illinois, 60611, United States

Location

Investigational Site Number :8400005

Chicago, Illinois, 60612-3854, United States

Location

Investigational Site Number :8400014

Boston, Massachusetts, 02114, United States

Location

Investigational Site Number :8400018

New York, New York, 10003, United States

Location

Investigational Site Number :8400010

New York, New York, 10016, United States

Location

Investigational Site Number :8400001

New York, New York, 10032, United States

Location

Investigational Site Number :8400021

Portland, Oregon, 97210, United States

Location

Investigational Site Number :8400020

Portland, Oregon, 97225, United States

Location

Investigational Site Number :8400009

Portland, Oregon, 97239, United States

Location

Investigational Site Number :8400002

Philadelphia, Pennsylvania, 19107, United States

Location

Investigational Site Number :8400006

Fairfax, Virginia, 22030, United States

Location

Investigational Site Number :8400012

Kirkland, Washington, 98034, United States

Location

Investigational Site Number :0400001

Innsbruck, 6020, Austria

Location

Investigational Site Number :1240003

Vancouver, British Columbia, V6T 2B5, Canada

Location

Investigational Site Number :1240002

Ottawa, Ontario, K1Y 4E9, Canada

Location

Investigational Site Number :1240001

Montreal, Quebec, H3A 2B4, Canada

Location

Investigational Site Number :2500001

Paris, 75013, France

Location

Investigational Site Number :2760002

Kiel, 24105, Germany

Location

Investigational Site Number :2760001

Tübingen, 72076, Germany

Location

Investigational Site Number :3000002

Larissa, 41110, Greece

Location

Investigational Site Number :3760002

Haifa, 3109601, Israel

Location

Investigational Site Number :3760003

Petah Tikva, 49100, Israel

Location

Investigational Site Number :3760001

Tel Aviv, 64239, Israel

Location

Investigational Site Number :3760004

Tel Litwinsky, 52621, Israel

Location

Investigational Site Number :3800006

Rozzano, Milano, 20089, Italy

Location

Investigational Site Number :3800001

Catanzaro, 88100, Italy

Location

Investigational Site Number :3800004

Milan, 20126, Italy

Location

Investigational Site Number :3800003

Pavia, 27100, Italy

Location

Investigational Site Number :3800002

Salerno, 84131, Italy

Location

Investigational Site Number :3920005

Nagoya, Aichi-ken, 466-8560, Japan

Location

Investigational Site Number :3920002

Kyoto, Kyoto, 606-8507, Japan

Location

Investigational Site Number :3920004

Osaka, Osaka, 530-8480, Japan

Location

Investigational Site Number :3920001

Bunkyo-ku, Tokyo, 113-8431, Japan

Location

Investigational Site Number :3920003

Kodaira-shi, Tokyo, 187-8551, Japan

Location

Investigational Site Number :5780001

Trondheim, 7006, Norway

Location

Investigational Site Number :6200002

Coimbra, 3000-075, Portugal

Location

Investigational Site Number :6200003

Torres Vedras, 2560-280, Portugal

Location

Investigational Site Number :7020001

Singapore, 169608, Singapore

Location

Investigational Site Number :7020002

Singapore, 308433, Singapore

Location

Investigational Site Number :7240002

Barcelona, Barcelona [Barcelona], 08025, Spain

Location

Investigational Site Number :7240001

Seville, 41013, Spain

Location

Investigational Site Number :7520001

Stockholm, 14186, Sweden

Location

Investigational Site Number :1580001

Taoyuan, 33305, Taiwan

Location

Investigational Site Number :8260001

London, London, City of, NW1 2PG, United Kingdom

Location

Investigational Site Number :8260002

Oxford, Oxfordshire, OX3 9DZ, United Kingdom

Location

Related Publications (3)

• Giladi N, Alcalay RN, Cutter G, Gasser T, Gurevich T, Hoglinger GU, Marek K, Pacchetti C, Schapira AHV, Scherzer CR, Simuni T, Minini P, Sardi SP, Peterschmitt MJ. Safety and efficacy of venglustat in GBA1-associated Parkinson's disease: an international, multicentre, double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2023 Aug;22(8):661-671. doi: 10.1016/S1474-4422(23)00205-3.

  PMID: 37479372 DERIVED

• Schidlitzki A, Stanojlovic M, Fournier C, Kaufer C, Feja M, Gericke B, Garzotti M, Welford RWD, Steiner MA, Angot E, Richter F. Double-Edged Effects of Venglustat on Behavior and Pathology in Mice Overexpressing alpha-Synuclein. Mov Disord. 2023 Jun;38(6):1044-1055. doi: 10.1002/mds.29398. Epub 2023 Apr 12.

  PMID: 37050861 DERIVED

• 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.

  PMID: 34897099 DERIVED

MeSH Terms

Conditions

Parkinson Disease

Interventions

venglustat

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Limitations and Caveats

This study did not achieve its primary or secondary endpoints at the time of the analysis of the double-blind 52-week treatment period of Part 2 and was terminated early.

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi aventis recherche & développement

Contact-US@sanofi.com

800-633-1610

Study Officials

• Clinical Sciences & Operations

  Sanofi

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 14, 2016
• First Posted: September 19, 2016
• Study Start: December 15, 2016
• Primary Completion: December 18, 2020
• Study Completion: May 27, 2021
• Last Updated: May 24, 2022
• Results First Posted: February 28, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share

Locations

US (19); IT (5); AU (1); SG (2); TW (1); IL (4); FR (1); NO (1); SE (1); JP (5); CA (3); PT (2); GR (1); DE (2); GB (2); ES (2)