A 18-month Study to Evaluate the Efficacy, Safety, Tolerability and Pharmacokinetics of Oral UCB0599 in Study Participants With Early-stage Parkinson's Disease

UCB Biopharma SRL496 enrolled

Overview

The purpose of the study is to assess the safety and tolerability of UCB0599 and to demonstrate the superiority of UCB0599 over placebo with regard to clinical symptoms of disease progression over 12 and 18 months in participants diagnosed with early-stage Parkinson's Disease.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

496

Conditions

Early-stage Parkinson's Disease

Interventions

UCB0599DRUG

Drug: UCB0599 Pharmaceutical form: Granules in capsules Route of administration: Oral use Participants will receive UCB0599 in a pre-specified sequence during the Treatment Period.

PlaceboDRUG

Drug: Placebo Pharmaceutical form: Capsules Route of administration: Oral use Participants will receive Placebo in a pre-specified sequence during the Treatment Period.

Eligibility

Sex: ALLMin age: 40 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Study participant must be 40 to 75 years of age inclusive, at the time of signing the informed consent * Study participant has Parkinson's Disease (PD), with a diagnosis made by a neurologist according to the 2015 Movement Disorder Society criteria within 2 years of Baseline Visit (including diagnosis during Screening) * The following diagnostic criteria must be met: bradykinesia AND at least ONE of the following: muscular rigidity, or resting tremor * A Screening Dopamine Transporter Imaging with Single Photon Emission Computed Tomography (DaT-SPECT), or a historical DaT-SPECT within 3 months of the Screening Visit that has been qualified by the central reader, shows evidence of dopamine transporter deficit per study requirements and as determined by a central reader * Study participant is in the ≤2.5 modified Hoehn and Yahr stage at Screening * Study participant has never taken medications for the treatment of motor symptoms of PD and is not expected to require starting symptomatic treatment (ST) with a high likelihood in the next 6 months as far as clinical judgement allows * Study participant has never taken part in disease-modifying treatment studies directed at neurodegenerative disease (NDD) * Study participant does not take N-acetyl cysteine or other cysteine donors or glutathione precursors on a regular basis as a food supplement * Study participant is willing, competent, and able to comply with all aspects of the protocol, including follow-up schedule and biospecimen collection * Study participant has a body mass index (BMI) of 16 to 34kg/m² (inclusive) * Contraception i) A male participant must agree to use contraception during the Treatment Period and for at least 90 days after the last dose ofstudy medication and refrain from donating sperm during this period ii) A female participant is eligible to participate if she is not pregnant, not breastfeeding, andat least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance during the Treatment Period and for at least 1 month after the last dose of study medication. The study participant must have a negative serum pregnancy test at Screening, which is to be confirmed negative by urine testing prior to the first dose of study medication at Baseline (Visit 3). If oral contraception is used, an additional barrier method will be required during the study as a study medication related-gastrointestinal upset or a drug interaction by CYP3A4 induction could interfere with efficacy Exclusion Criteria: * Study participant has a known hypersensitivity to any components (and/or its excipients) of the study medication or comparative drugs as stated in the protocol * Study participant has a brain magnetic resonance imaging (MRI) scan performed during Screening indicative of a clinically significant abnormality or a historical MRI scan during the 6 months before Screening Visit 1 of sufficient quality to show such abnormalities. In case of doubt, the significance is determined on a case-by-case basis in close collaboration with the Medical Monitor and should not include abnormalities like age-appropriate brain atrophy, minor white matter signals, or mild vasculopathy * Study participant has any contraindication for the brain MRI or Dopamine Transporter Imaging with Single Photon Emission Computed Tomography (DaT-SPECT) imaging * Study participant has a Montreal Cognitive Assessment (MoCA) score less than 23, indicating mild cognitive impairment or other significant cognitive impairment or clinical dementia at Screening that, in the opinion of the Investigator, would interfere with study evaluation * Study participant has abnormalities in lumbar spine previously known or determined by a Screening lumbar x-ray (if conducted) that could preclude lumbar puncture, in the opinion of the Investigator. The participant must be excluded from lumbar puncture but not from study participation * Study participant has clinically significant electrocardiogram (ECG) abnormality at Screening, in the opinion of the Investigator * Study participant has past history of use of medications for the treatment of motor symptoms of PD. Short (up to 4 weeks) past use of medications for the treatment of motor symptoms is permitted following a sufficient washout period. Medications included are: levodopa (maximum 400mg per day), dopamine agonists, monoamine oxidase B (MAO-B) inhibitors, anticholinergics, or amantadine. A sufficient washout period is at least 3 months prior to the Baseline Visit

Locations (115)

Outcomes

Primary Outcomes

Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III Sum Score at Day 0

MDS-UPDRS is a multimodal scale. Part I assessed non-motor experiences of daily living and has 2 components (0-52 possible points). Part IA contains 6 questions and is assessed by the examiner (0-24 possible points). Part IB contains 7 questions on non-motor experiences of daily living completed by participant (0-28 possible points). Part II assessed motor experiences of daily living (0-52 possible points) and includes 13 questions completed by participant. Part III assessed motor signs of PD and was administered by rater (0-52 possible points). Part III contained 33 questions based on 18 items. For all questions of each part, numeric score response options linked to accepted clinical terms: 0 to 4, 0=Normal, 1=Slight, 2=Mild, 3=Moderate, 4=Severe. Total Score equals sum of Parts I, II, and III (Score: 0-236). Higher score = more severe PD symptoms.

Time frame: Day 0

Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III Sum Score at Month 2

Time frame: Month 2

Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-III Sum Score at Month 4

Data from ClinicalTrials.gov

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Secondary Outcomes

MDS-UPDRS Part III Subscale

MDS-UPDRS part III includes motor items assessing speech, facial expression, rigidity, finger tapping, hand movements, pronation supination movements of hands, toe tapping, leg agility, arising from chair, gait, freezing of gait, postural stability, posture, global spontaneity of movement (body bradykinesia), postural tremor of the hands, kinetic tremor of the hands, rest tremor amplitude, and constancy of rest tremor. It included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms.

Time frame: Day 0, Months 2, 4, 6, 8, 10, 12, 14, 16, 18

MDS-UPDRS Part III Early-stage Parkinson's Disease (ePD) Subscore on Selected Items

The early-stage Parkinson's disease (ePD) subscore is derived from a 15-item subset of the MDS-UPDRS Part III (Motor Examination). It includes all rigidity assessments (neck, upper limbs \[right/left\], and lower limbs \[right/left\]) and bradykinesia-related tasks: finger tapping (right/left), hand movements (right/left), pronation-supination of hands (right/left), toe tapping (right/left), and leg agility (right/left). Each item is scored on a 5-point likert scale (0 = no problem to 4 = severe), resulting in a total ePD subscore range of 0 to 60. Higher scores indicate greater motor impairment, while lower scores reflect better motor function.

Time frame: Day 0, Months 2, 4, 6, 8, 10, 12, 14, 16, 18

MDS-UPDRS Part II Subscale

MDS-UPDRS part II includes motor items assessing speech, saliva and drooling, chewing and swallowing, eating tasks (cutting food and handling utensils), dressing, hygiene, handwriting, doing hobbies and other activities, turning in bed, tremor, getting out of bed, a car or a deep chair, walking and balance, and freezing. Each of the items in the UPDRS is measured on a scale. It included 13-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range for Part II was 0-52, with higher scores reflecting greater severity.

Time frame: Day 0, Months 2, 4, 6, 8, 10, 12, 14, 16, 18

MDS-UPDRS Part I Subscale

MDS-UPDRS part I include several non-motor aspects of experiences of daily living including cognitive impairment, hallucinations and psychosis, depressed mood, anxious mood, apathy, features of dopamine dysregulation syndrome during part 1A and sleep problems, daytime sleepiness, pain and other sensation, urinary problems, constipation problems, lightheadedness on standing, and fatigue during Part 1B. Part I assessed non-motor experiences of daily living and has 2 components (Range 0-52). Part IA contained 6 questions and were assessed by examiner (Range 0-24). Part IB contained 7 questions on non-motor experiences of daily living which were completed by participant (Range 0-28). Each of items in UPDRS is measured on a scale of 0 to 4, where 0 is normal and 4 (higher score) represents severe abnormalities/worse outcome. Total Score Range 0 to 52. Total score is sum of Part IA (0-24) and Part IB (0-28) subscale scores. Higher scores indicated greater severity of non-motor symptoms.

Time frame: Day 0, Months 2, 4, 6, 8, 10, 12, 14, 16, 18

Emerging Symptoms in Participants as Measured by MDS-UPDRS Part II

The participant was considered to have an emerging symptom for the item, if the change from Baseline for the item is greater than 0 for 2 consecutive visits. The magnitude of change from Baseline was not considered to determine the emerging symptom. Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II includes motor items assessing speech, saliva and drooling, chewing and swallowing, eating tasks (cutting food and handling utensils), dressing, hygiene, handwriting, doing hobbies and other activities, turning in bed, tremor, getting out of bed, a car or a deep chair, walking and balance, and freezing. This included 13-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range for Part II was 0-52, with higher scores reflecting greater severity.

Time frame: Baseline to Month 18

Time to Worsening of the Disease as Measured by MDS-UPDRS Part III

Time to worsening of the disease on the MDS-UPDRS III scale as defined by a 5-point increase in MDS-UPDRS III, within the 18-month period. MDS-UPDRS part III includes motor items assessing speech, facial expression, rigidity, finger tapping, hand movements, pronation supination movements of hands, toe tapping, leg agility, arising from chair, gait, freezing of gait, postural stability, posture, global spontaneity of movement (body bradykinesia), postural tremor of the hands, kinetic tremor of the hands, rest tremor amplitude, and constancy of rest tremor. It included 33 scores based on 18-items, each anchored with 5 responses: 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. The scale range was from 0 to 132, with a lower score indicating better motor function and a higher score indicating more severe motor symptoms.

Time frame: Baseline to Month 18

Montreal Cognitive Assessment (MoCA)

The Montreal Cognitive Assessment (MoCA) is a standardized screening tool used to evaluate mild cognitive impairment across multiple cognitive functions i.e. visuospatial/executive function, naming, memory, attention, language, abstraction, delayed recall, and orientation. The total possible score is calculated by summing the scores across all functions ranges from: 0 to 30. A score of 26 or above is considered normal, a lower score indicates cognitive impairment.

Time frame: Screening, Month 18

Change From Screening in Dopamine Transporter Imaging With Single Photon Emission Computed Tomography (DaT-SPECT) Mean Striatum Specific Binding Ratios (SBR)

The change from screening in mean striatum specific binding ratios (SBR) was assessed by DaT-SPECT using 123I-Ioflupane as radiopharmaceutical. The whole striatum was calculated as the average of the SBR data values for the four following "small" regions: left caudate small, left putamen small, right caudate small and right putamen small. The SBR was calculated for each region with the occipital cortex as a reference region, where a lower SBR indicates worse disease. The following formula was used to calculate this: (Average \[Small region\] - Average \[Occipital region\])/ (Average \[Occipital region\]).

Time frame: Screening, Months 12 and 18

Time to Start of Symptomatic Treatment (ST)

Time to start of symptomatic treatment (ST) within the 18-month period.

Time frame: Baseline to Month 18

Symptomatic Treatment (ST) Intake

Cumulative number of participants on symptomatic treatment (ST) at 18 months are reported.

Time frame: Month 18

Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)

An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study medication, whether or not considered related to the study medication. A TEAE is defined as any AE with a start date on or after the first dose of treatment or any unresolved event already present before administration of treatment that worsens in intensity following exposure to the treatment.

Time frame: From Baseline up to 30 days of safety follow-up after the last dose of the study drug (up to 19 months)

Percentage of Participants With Serious TEAEs

Serious adverse event: Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

Time frame: From Baseline up to 30 days of safety follow-up after the last dose of the study drug (up to 19 months)

Percentage of Participants With TEAEs Leading to Participant Withdrawal

Time frame: From Baseline up to 30 days of safety follow-up after the last dose of the study drug (up to 19 months)