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
- Trial ID
- 2022-501783-18-00
- Protocol
- BIA 28-6156-201
- Sponsor
- Bial R&D Investments S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of BIA 28-6156 in delaying meaningful clinical motor progression in subjects with Parkinson's Disease (PD) who possess a pathogenic variant in the GBA1 gene (GBA-PD). This is assessed using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III. The clinical relevance of this objective lies in its potential to provide a therapeutic option that could slow the progression of motor symptoms in this specific subset of PD patients, thereby improving their quality of life and functional capabilities.
Secondary objectives include:
- Assessing the efficacy of BIA 28-6156 in delaying meaningful clinical motor progression in subjects with GBA-PD as assessed by MDS-UPDRS Part III.
- Evaluating the efficacy of BIA 28-6156 in slowing disease progression and functional impairment in subjects with GBA-PD, using various scales such as the MDS-UPDRS, bradykinesia subscore of the MDS-UPDRS Part III, the modified Hoehn and Yahr scale, the Parkinson’s Disease Cognitive Rating Scale (PD-CRS), the 39-Item Parkinson’s Disease Questionnaire (PQD-39), the EQ-5D-5L scale, the Clinical Global Impression - Change (CGI-C) scale, the Patient Global Impression - Change (PGI-C) scale, the Clinical Global Impression – Severity (CGI-S) scale, and the Patient Global Impression – Severity (PGI-S) scale.
- Further exploratory, safety, pharmacodynamic, pharmacokinetics, and pharmacogenomic objectives are detailed in the study protocol.
Participants
The clinical trial involves a total of **156 participants** diagnosed with **Parkinson's Disease** who possess a pathogenic variant in the GBA1 gene, known as GBA-PD. The study population includes both male and female subjects, aged between **35 and 80 years**. Participants were selected based on their ability to provide informed consent and their compliance with study requirements, including the use of a Smartphone application and Smartwatch for monitoring. The trial population is characterized by individuals who have been clinically diagnosed with Parkinson's Disease for at least one year but not more than seven years, and who are receiving stable doses of Parkinson's Disease medications. Participants are required to have a body mass index (BMI) between 18 and 40 kg/m² and must not exhibit moderate motor complications or clinically significant psychosis. The study also considers lifestyle factors, requiring participants to use highly effective birth control methods if they are sexually active and of childbearing potential. The trial includes a vulnerable population, ensuring careful consideration of ethical standards and participant safety.
Plans and Procedures
The clinical trial is designed as a **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** who have a pathogenic variant in the glucocerebrosidase (GBA1) gene. The trial aims to assess the efficacy of BIA 28-6156 in delaying meaningful clinical motor progression, as measured by the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III. The study is expected to run from September 2023 to June 2026, with participant involvement lasting up to 78 weeks.
Participants will undergo a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, clinical diagnosis of Parkinson's Disease, and genetic screening for GBA1 variants. Following successful screening, participants will enter the double-blind treatment phase, where they will be randomly assigned to receive either BIA 28-6156 or a placebo. The trial includes regular follow-up visits to monitor safety, efficacy, and adherence to the study protocol. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.
Participants are expected to comply with study restrictions, including the use of a smartphone application and smartwatch to measure Parkinson's Disease-related motor signs. Conditions that may lead to early termination from the study include the development of moderate motor complications, clinically significant psychosis, or non-compliance with study requirements. The primary endpoint is the time from baseline to clinically meaningful progression on motor aspects of daily living, while secondary endpoints include progression on motor signs of the disease and other exploratory measures.
Treatment
The clinical trial involves the administration of **BIA 28-6156**, an investigational medication formulated as a film-coated tablet. The active substance in BIA 28-6156 is **5,7-dimethyl-N-((1R,4R)-4-(pentyloxy)cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide**, a chemical compound that functions as an allosteric activator of the enzyme beta-glucocerebrosidase (GCase). The medication is administered orally, with a maximum daily dose of 10 mg for one group and 60 mg for another, over a treatment period of up to 78 days. The total maximum dose for the 10 mg group is 780 mg, while for the 60 mg group, it is 4680 mg. Participant compliance with the dosing schedule is monitored throughout the study.
The trial also includes a **placebo** group, which receives a non-active substance designed to mimic the appearance of the BIA 28-6156 film-coated tablet. The placebo is administered orally with the same frequency and duration as the experimental medication to maintain the double-blind nature of the study. The use of a placebo allows for the assessment of the efficacy and safety of BIA 28-6156 by providing a comparator against which the effects of the investigational drug can be measured.
Efficacy
The efficacy of BIA 28-6156 in subjects with Parkinson's disease with a pathogenic variant in the glucocerebrosidase (GBA1) gene will be assessed using the Movement Disorder Society - Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and Part III. The primary endpoint is defined as the time from baseline to clinically meaningful progression on motor aspects of experiences of daily living, indicated by a ≥2-point increase in the MDS-UPDRS Part II score and no improvement in the Part III score. Secondary endpoints include the time from baseline to clinically meaningful progression on motor signs of the disease, assessed by a ≥5-point increase in the MDS-UPDRS Part III score.
These efficacy parameters will be measured at specified intervals throughout the study duration, which is estimated to conclude by June 16, 2026. The study employs a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results. The assessments will be conducted using validated scales, ensuring that the data collected is robust and scientifically sound. Further secondary, exploratory, safety, pharmacodynamic, pharmacokinetics, and pharmacogenomic endpoints are detailed in the study protocol, providing a comprehensive evaluation of the investigational product's efficacy and safety profile.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Part A (Genetic Screening): The subject is ≥35 and ≤80 years of age at the time of informed consent.
- Part B (Double-Blind Treatment): The subject has been on stable doses of PD medications (as listed in Table 6) for at least 30 days (at least 60 days for rasagiline) before initiation of screening in Part B (Double-Blind Treatment).
- Part B (Double-Blind Treatment): The subject is able to comply with the study restrictions and is willing and able to use a Smartphone application and to wear a Smartwatch to measure PD-related motor signs for the duration of the study.
- Part B (Double-Blind Treatment): The subject has a body mass index (BMI) of 18 to 40 kg/m2 .
- Part B (Double-Blind Treatment): If a sexually active man or a woman of childbearing potential, the subject agrees to use highly effective birth control (Appendix 3 of the study protocol) or to remain abstinent during the trial and for 30 days after the last dose of IMP. Acceptable (highly effective) methods of contraception for this study include hormonal contraceptives (combined oral contraceptive, patch, vaginal ring, injectable, or implant); intrauterine device or system; 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).
- Part A (Genetic Screening): 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 (Postuma, 2015).
- Part A (Genetic Screening): The subject has a modified Hoehn and Yahr score ≤2.5.
- Part A (Genetic Screening): The subject is receiving symptomatic treatment for PD.
- Part A (Genetic Screening): The subject is capable of giving signed informed consent, which includes understanding the purpose and risks of the study, compliance with the requirements and restrictions that are listed in the ICF and this protocol, and authorization to use confidential health information in accordance with national and local subject privacy regulations.
- Part B (Double-Blind Treatment): The subject is capable of giving signed informed consent, which includes understanding the purpose and risks of the study, compliance with the requirements and restrictions that are listed in the ICF and in this protocol, and authorization to use confidential health information in accordance with national and local subject privacy regulations.
- Part B (Double-Blind Treatment): The subject has a known GBA-PD risk-associated variant (as determined in Part A [Genetic Screening] in this study). A list of permissible GBA1 mutations is presented in Appendix 4 of the study protocol.
- Part B (Double-Blind Treatment): The subject has a score ≥22 on the MoCA scale.
- Part B (Double-Blind Treatment): The subject does not have moderate motor complications as assessed by a score ≥3 in any of the subitems of the MDS-UPDRS Part IV.
- Part B (Double-blind treatment): The subject does not have clinically significant psychosis in the clinical judgment of the investigator.
Exclusion Criteria
- Part A (Genetic Screening): Individuals who do not satisfy the inclusion criteria for Part A (Genetic Screening; Section 5.2.1 of study protocol) will be excluded.
- Part B (Double-Blind Treatment): The subject is currently pregnant, is planning pregnancy within the timeframe of the study, or is breastfeeding.
- Part B (Double-Blind Treatment): The subject is using a strong CYP3A4 modulator at the time of screening for Part B (Double-Blind Treatment). CYP3A4 strong inhibitors and inducers include, but are not limited to, the medications that are listed in Appendix 4 of the study protocol.
- 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 BCRP substrate medications that are considered exclusionary (based on concomitant use with BCRP inhibitors, as provided in the Summary of Product Characteristics [SmPC], for the medication) are included, but are not limited to, the medications that are listed in Appendix 4 of the study protocol.
- 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, quetiapine, risperidone, and aripiprazole); metoclopramide; prochlorperazine; methyldopa; tetrabenazine; deutetrabenazine; valbenazine; or reserpine or a prior history or continuation or initiation during the study of ambroxol at doses >120 mg/day.
- Part B (Double-Blind Treatment): The subject has received a vaccination within 14 days before administration of the first dose of IMP.
- Part B (Double-Blind Treatment): The subject has a prior history of or there is a plan to conduct 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): The subject has renal insufficiency as defined by an estimated glomerular filtration rate (eGFR) of <60 mL/min at screening.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): The subject has 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.
- Part B (Double-Blind Treatment): The subject has a QTcF (QT interval corrected for heart rate by Fridericia’s method) value >450 msec if male or >470 msec if female at screening.
- Part B (Double-Blind Treatment): The subject provides a positive response on Question 4 or 5 of the C-SSRS based on the last 6 months or, in the opinion of the investigator, presents a serious risk of suicide at screening.
- Part B (Double-Blind Treatment): The subject had a positive 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 COVID-19 infection (not tested) in the opinion of the investigator.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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 (N370S, D409H, H255Q, D140H, G202R, L324P, I260T, L444P, A190T, R120W).
- Part B (Double-Blind Treatment): The subject carries a known PD-associated LRRK2 pathogenic variant. A list of exclusionary LRRK2 pathogenic variants is provided in Appendix 4 of the study protocol.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-Blind Treatment): 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.
- Part B (Double-blind treatment): The subject has a positive test for drugs of abuse at screening or before administration of the first dose of IMP that the investigator judges as clinically relevant. Use of cannabinoids is not exclusionary if the subject agrees to abstain from using cannabinoids within 12 hours before study visits. A positive drug screen that is attributed to an allowed prescription, including medicines containing THC, or over-the-counter (OTC) drug is not exclusionary but should be agreed with the medical monitor
- Part B (Double-blind treatment): The subject is a member of a protected/vulnerable population, defined as persons who are pregnant, parturient, or breastfeeding; minors; persons who are deprived of liberty; persons who are under psychiatric hospital care; persons who are admitted to a health or social institution for purposes other than research; adults who are under legal protection or who are unable to express their consent; persons who are in an emergency situation and are unable to express their prior consent; and persons are who are non-affiliated or a non-beneficiary of a social security system [This does not apply to persons in the United States without health insurance].
- Part B (Double-blind treatment): The subject is a relative of the investigator or sponsor or the relative of an employee of the sponsor
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 01 Sept 2023 | 12 |
 Germany | Not Recruiting | 01 Sept 2023 | 8 |
 Italy | Not Recruiting | 01 Sept 2023 | 18 |
 The Netherlands | Not Recruiting | 01 Sept 2023 | — |
 Poland | Not Recruiting | 01 Sept 2023 | 10 |
 Portugal | Not Recruiting | 01 Sept 2023 | 8 |
 Spain | Not Recruiting | 01 Sept 2023 | 31 |
 Sweden | Not Recruiting | 01 Sept 2023 | 3 |
| Netherlands | — | — | 6 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
BIA 28-6156 | Test | FILM COATED TABLET | ORAL USE | 10 | 78 | PRD10145114 |
Placebo | Placebo | N/A | — | — | — | N/A |
BIA 28-6156 | Test | FILM COATED TABLET | ORAL USE | 60 | 78 | PRD10145115 |