Overview
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).
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
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.