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

NCT ID: NCT02906020

Last Updated: 2022-05-24

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 273 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-12-15
• Study Completion Date: 2021-05-27

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.

Conditions

Parkinson's Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

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.

Group Type: EXPERIMENTAL

venglustat GZ/SAR402671

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Pharmaceutical form: capsule Route of administration: oral

Interventions

venglustat GZ/SAR402671

Pharmaceutical form: capsule Route of administration: oral

Intervention Type: DRUG

Placebo

Pharmaceutical form: capsule Route of administration: oral

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Genzyme, a Sanofi Company

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Sciences & Operations

Role: STUDY_DIRECTOR

Sanofi

Locations

Investigational Site Number :8400017

Scottsdale, Arizona, United States

Investigational Site Number :8400011

Scottsdale, Arizona, United States

Investigational Site Number :8400004

La Jolla, California, United States

Investigational Site Number :8400019

Palo Alto, California, United States

Investigational Site Number :8400013

Sunnyvale, California, United States

Investigational Site Number :8400015

New Haven, Connecticut, United States

Investigational Site Number :8400008

Boca Raton, Florida, United States

Investigational Site Number :8400016

Chicago, Illinois, United States

Investigational Site Number :8400005

Chicago, Illinois, United States

Investigational Site Number :8400014

Boston, Massachusetts, 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 :8400001

New York, New York, 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 :8400012

Kirkland, Washington, United States

Investigational Site Number :0400001

Innsbruck, , Austria

Investigational Site Number :1240003

Vancouver, British Columbia, Canada

Investigational Site Number :1240002

Ottawa, Ontario, Canada

Investigational Site Number :1240001

Montreal, Quebec, Canada

Investigational Site Number :2500001

Paris, , France

Investigational Site Number :2760002

Kiel, , Germany

Investigational Site Number :2760001

Tübingen, , Germany

Investigational Site Number :3000002

Larissa, , Greece

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 Litwinsky, , Israel

Investigational Site Number :3800006

Rozzano, Milano, Italy

Investigational Site Number :3800001

Catanzaro, , Italy

Investigational Site Number :3800004

Milan, , Italy

Investigational Site Number :3800003

Pavia, , Italy

Investigational Site Number :3800002

Salerno, , Italy

Investigational Site Number :3920005

Nagoya, Aichi-ken, Japan

Investigational Site Number :3920002

Kyoto, Kyoto, Japan

Investigational Site Number :3920004

Osaka, Osaka, Japan

Investigational Site Number :3920001

Bunkyo-ku, Tokyo, Japan

Investigational Site Number :3920003

Kodaira-shi, Tokyo, Japan

Investigational Site Number :5780001

Trondheim, , Norway

Investigational Site Number :6200002

Coimbra, , Portugal

Investigational Site Number :6200003

Torres Vedras, , Portugal

Investigational Site Number :7020001

Singapore, , Singapore

Investigational Site Number :7020002

Singapore, , Singapore

Investigational Site Number :7240002

Barcelona, Barcelona [Barcelona], Spain

Investigational Site Number :7240001

Seville, , Spain

Investigational Site Number :7520001

Stockholm, , Sweden

Investigational Site Number :1580001

Taoyuan, , Taiwan

Investigational Site Number :8260001

London, London, City of, United Kingdom

Investigational Site Number :8260002

Oxford, Oxfordshire, United Kingdom

Countries

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

References

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.

Reference Type: DERIVED

PMID: 37479372 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37050861 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34897099 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-000657-12

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

U1111-1180-6918

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACT14820

Identifier Type: -

Identifier Source: org_study_id