Clinical trial NCT05819359: Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD
Official title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in Subjects With Parkinson's Disease With a Pathogenic Variant in the Glucocerebrosidase (GBA1) Gene
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Parkinson's Disease
Keywords: Parkinson Disease
Neurodegenerative Diseases
Central Nervous System Diseases
Glucocerebrosidase (GCase) activity
Parkinsonian Disorders
Basal Ganglia Diseases
Movement Disorders
GBA1 gene
BIA 28-6156
Phase 2
Lead sponsor: Bial R&D Investments, S.A.
Sponsor class: INDUSTRY
First posted: 2023-04-19
Enrollment: 237
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this randomized, double-blind, placebo-controlled study is to assess the efficacy of BIA 28-6156 over placebo in delaying clinical meaningful motor progression over 78 weeks in subjects with Parkinson's disease who have a pathogenic variant in the glucocerebrosidase 1 (GBA1) gene (GBA-PD).

Detailed description: This is a 2-part (Part A \[Genetic Screening\] and Part B \[Double-Blind Treatment\]), Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy, safety, tolerability, pharmacodynamics, and pharmacokinetics of 2 fixed dose levels of BIA 28-6156 (10 and 60 mg/day) in approximately 237 subjects with genetically confirmed GBA-PD.

Part A (Genetic Screening) will identify individuals with a PD risk-associated variant in the GBA1 gene for potential enrolment into Part B (Double-Blind Treatment) of the study. Part B will consist of a screening period to ensure that all protocol inclusion/exclusion criteria for Part B of the study are met (up to 5 weeks). After screening period, eligible subjects will be randomized into 1 of 3 treatment arms (BIA 28-6156 10 mg/day, BIA 28-6156 60 mg/day, or placebo) in a 1:1:1 ratio, and enter a double-blind treatment period up to 78 weeks, followed by a 30-day (4 weeks) of safety follow-up period.

Subjects must be receiving a stable dose of PD medication for at least 30 days before screening (for Part B \[Double-Blind Treatment\]) and will continue to receive their usual PD medications throughout the study.

Eligibility criteria: Inclusion Criteria:

Subjects who satisfy all of the following criteria will be eligible for Part A (Genetic Screening) of the study:

* The subject is ≥35 and ≤80 years of age at the time of informed consent.
* The subject has a clinical diagnosis of PD for at least 1 year and for no longer than 7 years before initiation of screening (for Part A), as confirmed by a neurologist using the MDS Criteria for Parkinson's Disease.
* The subject has a modified Hoehn and Yahr score ≤2.5.
* The subject is receiving symptomatic treatment for PD.
* The subject is capable of giving signed informed consent.

Subjects who satisfy all the following criteria will be eligible for Part B (Double-Blind Treatment) of the study:

* Informed Consent - The subject is capable of giving signed informed consent.
* The subject has a known GBA-PD risk-associated variant (as determined in Part A \[Genetic Screening\] of this study).
* The subject has a score ≥22 on the Montreal Cognitive Assessment (MoCA) scale.
* The subject does not have severe motor fluctuations or disabling dyskinesias in the clinical judgment of the investigator.
* The subject has been on stable doses of PD medications for at least 30 days (at least 60 days for rasagiline) before initiation of screening in Part B (Double-Blind Treatment).
* The subject is able to comply with the study restrictions.
* The subject has a body mass index (BMI) of 18 to 40 kg/m2.
* If a sexually active man or a women of childbearing potential, the subject agrees to use highly effective birth control or to remain abstinent during the trial and for 30 days after the last dose of IMP. Complete abstinence from sexual intercourse if this is the subject's usual and preferred lifestyle; or sexual partner with surgical sterilization (e.g., tubal ligation, hysterectomy and/or bilateral oophorectomy, vasectomy).

Exclusion Criteria:

• Individuals who do not satisfy the inclusion criteria for Part A (Genetic Screening) will be excluded.

Subjects who meet any of the following criteria for Part B (Double-Blind Treatment) are not eligible for the study.

* The subject has Gaucher's disease (GD), as defined by clinical signs and symptoms (i.e., hepatosplenomegaly, cytopenia, skeletal disease), and/or a medical history of marked deficiency of GCase activity compatible with GD.
* The subject is homozygous for a GBA1 pathogenic variant that is known to be associated with GD or compound heterozygous for 2 alleles that are known to be associated with GD.
* The subject carries a known PD-associated LRRK2 pathogenic variant.
* The subject has atypical or secondary parkinsonism by medical history or in the opinion of the investigator. Atypical parkinsonism includes, but is not limited to, diagnoses of progressive supranuclear palsy, cortico-basal syndrome, and multiple system atrophy. Secondary parkinsonism includes drug-induced, toxin-induced, postinfectious, posttraumatic, or vascular parkinsonism.
* The subject has a history of (within 60 days before initiation of screening) or has planned upcoming major surgery that could interfere with, or for which the treatment might interfere with, the conduct of the study or that would pose an unacceptable risk to the subject in the opinion of the investigator.
* The subject has any active or chronic disease or condition other than PD that could interfere with, or for which the treatment might interfere with, the conduct of the study or pose an unacceptable risk to the subject in the opinion of the investigator based on medical history, physical examination, vital signs, 12-lead ECG, or clinical laboratory tests. Minor deviations of laboratory values from the normal range may be acceptable if judged by the investigator to have no/minor clinical relevance.
* The subject has a recent history (last 6 months) of abuse of addictive substances (alcohol, illegal substances), currently uses \>21 units of alcohol per week, or is a regular recreational user of sedatives, hypnotics, tranquillizers, or any other addictive agent in the opinion of the investigator.
* The subject has a positive test for drugs of abuse at screening or before administration of the first dose of investigational medicinal product (IMP) that the investigator judges as clinically relevant. A positive test for tetrahydrocannabinol (THC) is exclusionary. A positive test for cannabinoids (not containing THC) is not exclusionary if the subject is a recreational user (not an abuser) of cannabinoids, in the opinion of the investigator, and agrees to abstain from using cannabinoids within 12 hours before study visits. A positive drug screen that is attributed to an allowed prescription drug is not exclusionary but should be agreed with the medical monitor.
* The subject is currently pregnant, is planning pregnancy within the timeframe of the study, or is breastfeeding.
* The subject is using a strong inhibitors and inducers CYP3A4 at the time of screening for Part B (Double-Blind Treatment).
* The subject is using a breast cancer resistance protein (BCRP) substrate (e.g., pravastatin, rosuvastatin, glyburide) at the time of screening for Part B (Double-Blind Treatment).
* The subject has used any of the following medications within 60 days before Baseline: typical or atypical antipsychotics (including, but not limited to, clozapine, pimavanserin, olanzapine, risperidone, and aripiprazole), metoclopramide, prochlorperazine, methyldopa, tetrabenazine, deutetrabenazine, valbenazine, or reserpine.
* The subject has received a vaccination within 14 days before administration of the first dose of IMP.
* The subject has a prior history of or there is a plan to conduct deep brain stimulation (DBS), lesional procedures, (i.e., thalamotomy), or focused ultrasound; to initiate gene therapy treatment for PD; or to initiate use of any formulation of intestinal infusion or continuous subcutaneous infusion of PD medications.
* The subject is currently participating in or has participated in an investigational drug study within 3 months or 5 half-lives, whichever is longer; in a therapeutic device study within 3 months before the first dose of IMP; or has previously participated in a gene therapy trial. Concurrent participation in an observational study is acceptable.
* The subject has a positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), or human immunodeficiency virus 1 (HIV-1) or 2 (HIV-2) at screening. If reflex testing for hepatitis B or HCV DNA is negative, the subject may be eligible for the study.
* The subject has renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) of \<60 mL/min at screening.
* The subject has cirrhosis (Child-Pugh A, B, or C) or any of the following laboratory values at screening: serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>2 times the upper limit of normal (ULN) or bilirubin \>2 × ULN except if the subject has known or suspected Gilbert's disease.
* The subject has a QT interval corrected for heart rate by Fridericia's method (QTcF) value \>450 msec if male or \>470 msec if female at screening.
* The subject provides a positive response on Question 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) based on the last 6 months or, in the opinion of the investigator, presents a serious risk of suicide at screening.
* The subject had a positive severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) test (any type) result within the 30 days before signing informed consent for Part B (Double-Blind Treatment) or has 2 or more current symptoms (e.g., sore throat, cough, fever) at the same time that are consistent with the Coronavirus disease 2019 (COVID-19) infection (not tested) in the opinion of the investigator.
* The subject has a clinical history that is consistent with a previous COVID-19 infection and has not recovered fully, maintaining nonspecific symptoms like, for example, fatigue, shortness of breath, difficulty concentrating, sleep disorders, fever, anxiety, and depression.
* The subject has previously received BIA 28-6156 or has a known allergy or hypersensitivity to BIA 28-6156 or any components of the formulation.
* The subject is an unsuitable candidate to receive BIA 28-6156 or is unable or unlikely to comply with the dosing schedule or study evaluations in the judgment of the investigator.

Primary outcomes:
measure: Time from baseline to clinically meaningful progression on motor aspects of experiences of daily living (assessed by MDS-UPDRS Part II score and MDS-UPDRS Part III score)
timeFrame: From Baseline up to Week 78
Secondary outcomes:
measure: Time from baseline to clinically meaningful progression on motor signs of the disease (assessed by MDS-UPDRS Part III score)
timeFrame: From Baseline up to Week 78
measure: Time from baseline to any worsening on the Clinical Global Impression - Change (CGI-C) scale
timeFrame: From Baseline up to Week 78
measure: Time from baseline to any worsening on the Patient Global Impression - Change (PGI-C) scale
timeFrame: From Baseline up to Week 78
measure: Change from Baseline to Week 78 in the MDS-UPDRS Total (Part I-IV) score
timeFrame: From Baseline up to Week 78
measure: Change from Baseline to Week 78 in the Modified Hoehn and Yahr score
timeFrame: From Baseline up to Week 78
measure: Change from Baseline to Week 78 in the 39-Item Parkinson's Disease Questionnaire (PDQ-39) score
timeFrame: From Baseline up to Week 78
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Boca Raton
country: United States
facility: Parkinson's Center and Movement Disorders of Boca Raton
state: Florida
city: Miami
country: United States
facility: University of Miami, Dept. of Neurology
state: Florida
city: Ocala
country: United States
facility: Renstar Medical Research
state: Florida
city: Atlanta
country: United States
facility: Morehouse School of Medicine
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Baylor University Medical Center
state: Maryland
city: Baltimore
country: United States
facility: The Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Farmington Hills
country: United States
facility: Quest Research Institute, LLC
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Saint Paul
country: United States
facility: Struthers Parkinson's Center- East
state: Minnesota
city: Saint Paul
country: United States
facility: Park Nicollet Struther's Parkinson's Center (Struthers Parkinsons Center at HealthPartners)
state: Minnesota
city: New Brunswick
country: United States
facility: Robert Wood Johnson Medical School
state: New Jersey
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai Beth Israel
state: New York
city: New York
country: United States
facility: Weil Cornell Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Northwell Health Physician Partners
state: New York
city: New York
country: United States
facility: Northwell Health
state: New York
city: Rochester
country: United States
facility: University of Rochester Neurology
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: South Euclid
country: United States
facility: University Hospitals Cleveland Medical Center
state: Ohio
city: Toledo
country: United States
facility: Univerity of Toledo
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Parkinson's Disease and Movement Disorders Cente at University of Pennyslvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Charleston
country: United States
facility: MUSC
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt Medical Center
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center - San Antonio
state: Texas
city: Salt Lake City
country: United States
facility: Intermountain Healthcare
state: Utah
city: Kirkland
country: United States
facility: Evergreen Neuroscience Institute
state: Washington
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Spokane
country: United States
facility: Inland Northwest Research
state: Washington
city: Gatineau
country: Canada
facility: Clinique Neuro-Outaouais (Neuro-Outaouais Clinic)
state: Quebec
city: Montréal
country: Canada
facility: Montreal Neurological Institute & Hospital
state: Quebec
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
city: Nantes
country: France
facility: CHU de Nantes - Hopital Nord Laennec
city: Nice
country: France
facility: CHU de Nice Hopital Pasteur
city: Nîmes
country: France
facility: CHU de Nimes
city: Paris
country: France
facility: Assistance Publique-Hopitaux de Paris (AP-HP) - Hopital Pitie-Salpetriere - Centres d'Investigation Clinique (CIC) Paris-Est
city: Rennes
country: France
facility: CHU de Rennes Hopital Pontchaillou
city: Toulouse
country: France
facility: CIC Toulouse
city: Toulouse
country: France
facility: Hopital Paule de Viguier
city: Beelitz-Heilstätten
country: Germany
facility: Neurologisches Fachkrankenhaus für, Bewegungsstörungen und Parkinson
city: Biskirchen
country: Germany
facility: Gertrudis Clinic Biskirchen, Parkinson-Center
city: Kassel
country: Germany
facility: Paracelsus-Elena-Klinik
city: Marburg
country: Germany
facility: Universitats klinikum Marburg
city: Munich
country: Germany
facility: Klinikum der Universität München, Campus Grosshadern, Neurologische Klinik und Poliklinik
city: Munich
country: Germany
facility: Ludwig-Maximilians University Munich
city: Wolfach
country: Germany
facility: Parkinson-Klinik Ortenau GmbH&Co KG
city: Bologna
country: Italy
facility: IRCCS Istituto Delle Scienze Neurologiche DI
city: Brescia
country: Italy
facility: Spedali Civilia di Brescia
city: Brindisi
country: Italy
facility: Ospedale Antonio Perrino
city: Milano
country: Italy
facility: Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
city: Milano
country: Italy
facility: IRCCS Carlo Besta Neurological Institute
city: Napoli
country: Italy
facility: Universita degli Studi della Campania Luigi Vanvitelli - Clinica Neurologia I
city: Padova
country: Italy
facility: Universita degli Studi di Padova - Azienda Ospedaliera di Padova - Clinica Neurologica
city: Roma
country: Italy
facility: IRCSS San Raffaele Pisana
city: Rozzano
country: Italy
facility: Istituto Clinico Humanitas
city: Salerno
country: Italy
facility: A.O.U. San Giovanni di Dio Ruggi d'Aragona Centro Parkinson- Piano Rialzato Corpo QT
city: Amsterdam
country: Netherlands
facility: Amsterdam Medical Center UMC
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: St. Antonius Ziekenhuis (St. Antonius Hospital) - Utrecht
city: Bydgoszcz
country: Poland
facility: Centrum Medyczne NEUROMED Sp. z o.o. ul.
city: Kraków
country: Poland
facility: Krakowkska Akademia Neurologii Sp. z o.o
city: Łódź
country: Poland
facility: NeuroKlinika Gabinet Lekarski
city: Coimbra
country: Portugal
facility: Centro Hospitalar Universitario de Coimbra
city: Guimarães
country: Portugal
facility: Hospital Senhora da Oliveira de Guimaraes
city: Porto
country: Portugal
facility: Centro Hospitalar Universitario de Santo Antonio
city: Porto
country: Portugal
facility: Hospital S.JOÃO
city: Torres Vedras
country: Portugal
facility: CNS - Campus Neurologico
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
city: Barakaldo
country: Spain
facility: Hospital Universitario Cruces
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Vall D´Hebron
city: Madrid
country: Spain
facility: Hospital Universitaio de La Princesa
city: Madrid
country: Spain
facility: Hospital Ruber Internacional
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Lund
country: Sweden
facility: Skane University Hospital, Lund University
city: Uppsala
country: Sweden
facility: Neurologmottagningen, QD 62
city: Dundee
country: United Kingdom
facility: NHS Tayside-Ninewells Hospital and Medical School
city: Glasgow
country: United Kingdom
facility: Glasgow Memory Clinic
city: London
country: United Kingdom
facility: King's College London - David Goldberg Centre
city: Newcastle Upon Tyne
country: United Kingdom
facility: The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital
city: Plymouth
country: United Kingdom
facility: University Hospitals Plymouth NHS Trust
Study officials:
affiliation: Bial R&D Investments, S.A.
name: Raquel Costa
role: STUDY_DIRECTOR
References: