ACTIVATE: Efficacy, Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of BIA 28-6156 in GBA-PD

Sponsor

Bial R&D Investments, S.A. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT05819359

Collaborator

(none)

237

Enrollment

Locations

Arms

Anticipated Duration (Months)

3.2

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Parkinson's Disease	Drug: BIA 28-6156 10 mg Drug: BIA 28-6156 60 mg Drug: Placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

237 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Mar 31, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Mar 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: BIA 28-6156 10 mg Participants will be randomized to receive BIA 28-6156 10 mg during the Treatment Period.	Drug: BIA 28-6156 10 mg BIA 28-6156 10 mg, once daily, oral administration.
Experimental: BIA 28-6156 60 mg Participants will be randomized to receive BIA 28-6156 60 mg during the Treatment Period.	Drug: BIA 28-6156 60 mg BIA 28-6156 60 mg, once daily, oral administration.
Placebo Comparator: Placebo Placebo	Drug: Placebo Placebo, once daily, oral administration.

Arm

Intervention/Treatment

Experimental: BIA 28-6156 10 mg

Participants will be randomized to receive BIA 28-6156 10 mg during the Treatment Period.

Drug: BIA 28-6156 10 mg

BIA 28-6156 10 mg, once daily, oral administration.

Experimental: BIA 28-6156 60 mg

Participants will be randomized to receive BIA 28-6156 60 mg during the Treatment Period.

Drug: BIA 28-6156 60 mg

BIA 28-6156 60 mg, once daily, oral administration.

Placebo Comparator: Placebo

Placebo

Drug: Placebo

Placebo, once daily, oral administration.

Outcome Measures

Primary Outcome Measures

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) [From Baseline up to Week 78]
Time from baseline to clinically meaningful progression on motor aspects of experiences of daily living, as assessed by ≥2-point increase from baseline in Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II score and no improvement in the Motor Examination, as assessed by ≥0-point increase from baseline in MDS-UPDRS Part III score. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. Part II assesses motor experiences of daily living (Range 0-52). It contains 13 questions which are to be rated by the patient and/or caregiver. Part III assesses the motor signs of PD and is rated by the investigator (Range 0-132). Part III contains 33 scores based on 18 items. For each question a numeric score is assigned between 0-4, where 0 = Normal, 1 = Slight, 2 = Mild, 3 = Moderate, 4 = Severe. A higher score indicates more severe symptoms of PD.

Secondary Outcome Measures

Time from baseline to clinically meaningful progression on motor signs of the disease (assessed by MDS-UPDRS Part III score) [From Baseline up to Week 78]
Time from baseline to clinically meaningful progression on motor signs of the disease, as assessed by a ≥5-point increase from baseline in the MDS-UPDRS Part III score. MDS-UPDRS is a multimodal scale assessing impairment and disability consisting of 4 parts. Part III assesses the motor signs of PD and is rated by the investigator (Range 0-132). Part III contains 33 scores based on 18 items. A higher score indicates more severe symptoms of PD.
Time from baseline to any worsening on the Clinical Global Impression - Change (CGI-C) scale [From Baseline up to Week 78]
The Clinical Global Impression of Change (CGI-C) is a scale used to assess the overall clinical improvement or worsening of a patient's condition over time. The CGI-C scale ranges from 1 to 7, with lower scores indicating greater improvement (1 - Very much improved, 2 - Much improved, 3 - Minimally improved, 4 - No change, 5 - Minimally worse, 6 - Much worse, 7 - Very much worse).
Time from baseline to any worsening on the Patient Global Impression - Change (PGI-C) scale [From Baseline up to Week 78]
The Patient Global Impression of Change (PGI-C) is a self-report tool used to assess a patient's perception of their overall improvement or worsening in a particular health-related domain over time. The PGI-C scale asks patients to rate their overall improvement or worsening since the start of treatment on a seven-point scale, with lower scores indicating greater improvement (1 - Very much improved, 2 - Much improved, 3 - Minimally improved, 4 - No change, 5 - Minimally worse, 6 - Much worse, 7 - Very much worse)
Change from Baseline to Week 78 in the MDS-UPDRS Total (Part I-IV) score [From Baseline up to Week 78]
The MDS-UPDRS assesses nonmotor and motor experiences of daily living, motor examination, and motor complication categories. The MDS-UPDRS Part I-IV total score was calculated as the sum of the individual item scores from these categories. Each item is rated on a scale from 0 to 4 on which 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. A higher score indicates more severe symptoms of PD.
Change from Baseline to Week 78 in the Modified Hoehn and Yahr score [From Baseline up to Week 78]
The Modified Hoehn and Yahr scale measures the severity of Parkinson's disease by assessing the patient's motor symptoms and functional impairment. The scale has seven stages, ranging from 1 to 5, with higher scores indicating more severe disease. (1 - Unilateral involvement only; 1.5 - Unilateral and axial involvement; 2 - Bilateral involvement without impairment of balance; 2.5 - Mild bilateral disease with recovery on pull test; 3 - Mild to moderate bilateral disease; some postural instability; physically independent; 4 - Severe disability; still able to walk or stand unassisted; 5 - Wheelchair bound or bedridden unless added).
Change from Baseline to Week 78 in the 39-Item Parkinson's Disease Questionnaire (PDQ-39) score [From Baseline up to Week 78]
The PDQ-39 is the most thoroughly validated and extensively used self-report measure for the assessment of health-related quality of life in patients with PD. The questionnaire measures 39 items, which assess 8 domains of health: mobility (10 items), activities of daily living (6 items), emotional well being (6 items), stigma (4 items), social support (3 items), cognitions (4 items), communication (3 items), and bodily discomfort (3 items). Each item is scored on the following scale: 0 = never, 1 = occasionally, 2 = sometimes, 3 = often, and 4 = always. Items in each subscale and the total scale can be summarized into an index and transformed linearly to a scale from 0 (perfect health as assessed by the measure) to 100 (worst health as assessed by the measure).

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cedars-Sinai	Los Angeles	California	United States	90048
2	University of Colorado	Aurora	Colorado	United States	80045
3	Parkinson's Disease and Movement Disorders Center of Boca Raton	Boca Raton	Florida	United States	33486
4	Renstar Medical Research	Ocala	Florida	United States	34470
5	Northwestern University	Chicago	Illinois	United States	60611
6	University of Kansas Medical Center	Kansas City	Kansas	United States	66103
7	Baylor University Medical Center	Baltimore	Maryland	United States	21287
8	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02115
10	Quest Research Institute, LLC	Farmington Hills	Michigan	United States	48334
11	Mayo Clinic	Rochester	Minnesota	United States	55905
12	Park Nicollet Struther's Parkinson's Center (Struthers Parkinsons Center at HealthPartners)	Saint Paul	Minnesota	United States	55130
13	Park Nicollet Struther's Parkinson's Center (Struthers Parkinsons Center at HealthPartners)	Saint Paul	Minnesota	United States	55427
14	Rutgers Robert Wood Johnson Medical School	New Brunswick	New Jersey	United States	08901
15	Mount Sinai Beth Israel	New York	New York	United States	10003
16	Weill Cornell Medicine	New York	New York	United States	10021
17	Columbia University Medical Center	New York	New York	United States	10032
18	Northwell Health	New York	New York	United States	10075
19	University of Rochester Neurology	Rochester	New York	United States	14642
20	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
21	University Hospitals Cleveland Medical Center	South Euclid	Ohio	United States	44121
22	Parkinson's Disease and Movement Disorders Cente at University of Pennyslvania	Philadelphia	Pennsylvania	United States	19107
23	Thomas Jefferson University	Philadelphia	Pennsylvania	United States	19107
24	Vanderbilt Medical Center	Nashville	Tennessee	United States	37232
25	Baylor College of Medicine	Houston	Texas	United States	77030
26	University of Texas Health Science Center - San Antonio	San Antonio	Texas	United States	78229
27	Inland Northwest Research	Spokane	Washington	United States	99202
28	Clinique Neuro-Outaouais (Neuro-Outaouais Clinic)	Gatineau	Quebec	Canada
29	Montreal Neurological Institute-Hospital	Montréal	Quebec	Canada
30	CHU Nantes	Nantes		France
31	CHU Nice	Nice		France	6002
32	Centre Hospitalier Universitaire de Nimes (CHU) - Hopital Universitaire Caremeau	Nîmes		France
33	Assistance Publique-Hopitaux de Paris (AP-HP) - Hopital Pitie-Salpetriere - Centres d'Investigation Clinique (CIC) Paris-Est	Paris		France
34	Centre Hospitalier Universitaire (CHU) de Rennes - Hopital de Pontchaillou - Centre d'Investigation Clinique (CIC) - Inserm 1414	Rennes		France
35	CIC Toulouse	Toulouse		France
36	Neurologisches Fachkrankenhaus für, Bewegungsstörungen / Parkinson	Beelitz-Heilstätten		Germany	14547
37	Gertrudis Clinic Biskirchen, Parkinson-Center	Biskirchen		Germany	35638
38	Paracelsus-Kliniken Deutschland GmbH & Co. KGaA - Paracelsus-Elena-Klinik - Zentrum fuer Parkinson-Syndrome und Bewegungsstoerungen (Centre of Parkinsonism and Movement Disorders)	Kassel		Germany	34128
39	Philipps-Universitaet Marburg; Philipps-Universitaet Marburg - Klinik fuer Neurologie	Marburg		Germany	35039
40	Klinikum der Universität München, Campus Grosshadern, Neurologische Klinik und Poliklinik	Munich		Germany	81377
41	Parkinson-Klinik Ortenau GmbH&Co KG	Wolfach		Germany	77709
42	ASST Spedali Civili di Brescia	Brescia		Italy	25123
43	Ospedale "Antonio Perrino"	Brindisi		Italy	72100
44	Fondazione IRCCS Ca' Granda Ospedale Maggiore	Milano		Italy	20122
45	Fondazione IRCCS Istituto Neurologico "Carlo Besta"	Milano		Italy	20133
46	Azienda Ospedaliera Universitaria, "Luigi Vanvitelli"	Napoli		Italy	80138
47	Universita degli Studi di Padova - Azienda Ospedaliera di Padova - Clinica Neurologica	Padova		Italy	35128
48	IRCCS San Raffaele Pisana di Roma	Roma		Italy	163
49	Istituto Clinico Humanitas	Rozzano		Italy	20086
50	Azienda Ospedaliera Universitaria OO.RR. San Giovanni di Dio e Ruggi d'Aragona	Salerno		Italy	84125
51	Amsterdam UMC - Locatie AMC (Academisch Medisch Centrum)	Amsterdam		Netherlands
52	University Medical Center Groningen	Groningen		Netherlands
53	St. Antonius Ziekenhuis (St. Antonius Hospital) - Utrecht	Utrecht		Netherlands
54	Centrum Medyczne Neuromed	Bydgoszcz		Poland	85-163
55	Krakowska Akademia Neurologii Sp. z o.o.	Kraków		Poland	31-505
56	NeuroKlinika Gabinet Lekarski prof. Andrzej Bogucki	Łódź		Poland	90-640
57	Hospital Sra da Oliveira	Guimarães		Portugal	4835-044
58	Instituto de Medicina Molecular (IMM)	Lisboa		Portugal	1649-028
59	Centro Hospitalar do Porto (CHP) - Hospital Geral de Santo Antonio (HGSA)	Porto		Portugal	4099-001
60	Centro Hospitalar S. João, E.P.E Serviço de Neurologia	Porto		Portugal	4200-319
61	Hospital Universitario Germans Trias i Pujol	Badalona		Spain	08916
62	Hospital Universitario Cruces	Barakaldo		Spain	48903
63	Hospital de la Santa Creu i de Sant Pau	Barcelona		Spain	08025
64	Hospital Universitari Vall d'Hebron	Barcelona		Spain	08035
65	Hospital Universitario de La Princesa	Madrid		Spain	28006
66	Hospital Ruber Internacional	Madrid		Spain	28034
67	Hospital Universitario Virgen del Rocio	Sevilla		Spain	41013
68	Skanes Universitetssjukhus - Lund (Universitetssjukhuset i Lund)	Lund		Sweden	221 85
69	Karolinska Universitetssjukhuset - Solna - Neurologiska kliniken (Neurology Clinic)	Solna		Sweden	171 76
70	University of Dundee - Ninewells Hospital and Medical School	Dundee		United Kingdom
71	Glasgow Memory Clinic	Glasgow		United Kingdom
72	King's College London - David Goldberg Centre	London		United Kingdom
73	The Newcastle Upon Tyne Hospitals NHS Foundation Trust	Newcastle Upon Tyne		United Kingdom
74	Plymouth Hospitals NHS Trust - Derriford Hospital	Plymouth		United Kingdom