Study To Evaluate the Efficacy, Safety and Tolerability of E2027 (Hereinafter Referred to as Irsenontrine) in Participants With Dementia With Lewy Bodies

Study Overview
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Brief Summary
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This study will be conducted to compare Irsenontrine to placebo on the cognitive endpoint of Montreal Cognitive Assessment (MoCA) and the global clinical endpoint of Clinician's Interview Based Impression of Change Plus (CIBIC-Plus) Caregiver Input in participants with dementia with Lewy bodies after 12 weeks of treatment.

Official Title
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A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Study To Evaluate the Efficacy, Safety and Tolerability of E2027 in Subjects With Dementia With Lewy Bodies

Conditions
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Dementia With Lewy Bodies

Intervention / Treatment
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* Drug: Irsenontrine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 50 to 85 years, inclusive at time of consent. Meet criteria for probable dementia with Lewy bodies (DLB) (as defined by the 4th report of the DLB Consortium). Mini-Mental State Examination greater than or equal to (≥)14 and less than or equal to (≤) 26 at Screening Visit. Has experienced visual hallucinations during the past 4 weeks before Screening Visit. If receiving acetylcholinesterase inhibitors (AChEI), must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment-naive participants can be entered into the study but there should be no plans to initiate treatment with AChEIs from Screening to the end of the study. If receiving memantine, must have been on a stable dose for at least 12 weeks before Screening Visit, with no plans for dose adjustment during the study. Treatment naive participants can be entered into the study but there should be no plans to initiate treatment with memantine from Screening to the end of the study. Must have an identified caregiver or informant who is willing and able to provide follow-up information on the participant throughout the course of the study. Provide written informed consent. If a participant lacks capacity to consent in the investigator's opinion, the participant's assent should be obtained, as required in accordance with local laws, regulations and customs, plus the written informed consent of a legal representative should be obtained (capacity to consent and definition of legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit participants who lack capacity to consent to participate in this study, they will not be enrolled. Exclusion Criteria: Any neurological condition that may be contributing to cognitive impairment above and beyond those caused by the participant's DLB, including any comorbidities detected by clinical assessment or magnetic resonance imaging (MRI). History of transient ischemic attacks or stroke within 12 months of Screening. Modified Hachinski Ischemic Scale greater than (>) 4. Parkinsonian (extrapyramidal) features with Hoehn and Yahr stage 4 intravenous or higher. Any major psychiatric diagnosis, including schizophrenia, bipolar disorder and current major depressive disorder as per Diagnostic and Statistical Manual of Mental Disorders Fifth Edition. Geriatric Depression Scale score > 8.

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irsenontrine<br>Participants will be randomized to receive a 50 milligram (mg) once daily oral dose of Irsenontrine for 12 weeks. | Drug: Irsenontrine<br>* Oral hypromellose capsules.<br>* Other names: E2027;|
| Placebo Comparator: Placebo<br>Participants will be randomized to receive a 50 mg once daily oral dose of Irsenontrine-matched placebo for 12 weeks. | Drug: Placebo<br>* Oral hypromellose capsules.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Montreal Cognitive Assessment (MoCA) Total Score at Week 12 of Treatment | The MoCA scale is used for detecting cognitive impairment. The scores range between 0 to 30 points; a score of 26 or above was considered normal. Higher values represent a better outcome. | Baseline and Week 12 | 
| Number of Participants Based on Clinician's Interview Based Impression of Change Plus Caregiver Input (CIBIC-Plus) Scale at Week 12 of Treatment | Number of participants are reported categorized in grades based on the CIBIC-Plus scale. The CIBIC-Plus scale is designed to measure various domains that describe participant function: general, mental/cognitive state, behavior, and activities of daily living. It is a semi-structured global rating derived from a comprehensive interview with the participant and caregiver or informant by an independent rater who has no access to the source data or other psychometric test scores conducted post-randomization as part of the protocol. The CIBIC-Plus was a 7-point scale and scores were: 1 (marked improvement), 2 (moderate improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 6 (moderate worsening), and 7 (marked worsening). Higher values represent a worse outcome. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinician's Global Impression of Change - In Dementia With Lewy Bodies (CGIC-DLB) Scale at Week 12 of Treatment | Number of participants are reported categorized in grades based on the CGIC-DLB scale. The CGIC-DLB scale provided an overall clinician-determined summary measure of change from the participant's clinical status that takes into account all available information from the efficacy endpoints (which include cognitive function, non-cognitive symptoms, behavior, and the impact of the symptoms on the participant's ability to function) and safety data. The (CGIC-DLB) was a 7-point scale and scores were: 1 (marked improvement), 2 (moderate improvement), 3 (minimal improvement), 4 (no change), 5 (minimal worsening), 6 (moderate worsening), and 7 (marked worsening). Higher values represent a worse outcome. | Week 12 | 
| Mean Change From Baseline in the Cognitive Fluctuation Inventory (CFI) Score at Week 12 of Treatment | The CFI scale assessed cognitive fluctuation. It evaluates fluctuation in various domains including attention, ability to perform daily functions, orientation, verbal communication and behavior. The score was based on frequency and severity with a score range of 0 to 12. The scale also assessed the degree of caregiver or informant distress engendered by the symptoms. Higher scores indicating greater impairment. | Baseline and Week 12 | 
| Mean Change From Baseline in the Mini-Mental State Examination (MMSE) Total Score Week 12 of Treatment | The MMSE is a 30-point scale that measured orientation to time and place, registration, immediate and delayed recall, attention, language, and drawing. The total score ranges from 0 (most impaired) to 30 (no impairment). The lower score means severe cognitive deficit and higher score indicates better function. | Baseline and Week 12 | 
| Mean Change From Baseline in the Neuropsychiatric Inventory (NPI-12) Total Score at Week 12 of Treatment | The NPI-12 scale assessed the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia participants: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating changes. The scale also assessed the degree of caregiver or informant distress engendered by each of the symptoms. The sum of the composite scores for the 12 domains yielded the NPI-12 total score. NPI-12 total score ranged from 0 (minimum severity) to 144 (maximum severity); higher score indicates greater neuropsychiatric disturbance. | Baseline and Week 12 | 
| Change From Baseline in NPI-4 Subscore at Week 12 | The NPI scale assesses the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia participants: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating changes. NPI-4 is the subscore covering the domains of delusions, hallucinations, apathy and depression. NPI-4 total subscore ranged from 0 to 48, with higher scores indicating a greater neuropsychiatric disturbance. | Baseline and Week 12 | 
| Change From Baseline in NPI-10 Subscore at Week 12 | The NPI-10 assessed range of behaviors seen in dementia for both frequency and severity. It is a 10 item questionnaire with the following domains: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/liability and aberrant motor behavior. The total score was a sum of the 10 domains, where the score of each domain was calculated as frequency (scale: 1=occasionally to 4=very frequently)*Severity (scale: 1=Mild to 3=Severe). Each domain has a maximum score of 12 and all domains were equally weighted for total score, the range for total score is 0 to 120. Higher scores indicating a greater neuropsychiatric disturbance. | Baseline and Week 12 | 
| Change From Baseline in NPI-D (Caregiver Distress) Total Score at Week 12 | The NPI-D scale assesses the frequency and severity of 12 neuropsychiatric symptoms commonly described in dementia participants: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, motor disturbance, nighttime behaviors, and appetite/eating changes. The scale assesses the degree of caregiver distress engendered by each of the symptoms. The caregiver distress (NPI-D) is rated by caregiver based on his or her own stress on a five point scale from 0 to 5, where: 0(no distress), 1(minimal), 2(mild), 3(moderate), 4(moderately severe), 5(very severe or extreme). NPI-D total score is calculated by summing the scores of the 12 sub-scale distress scores. The NPI-D total scores ranges from 0 to 60 with higher scores indicating greater distress. | Baseline and Week 12 | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Severe TEAEs, Serious TEAEs, Adverse Events (AEs) Resulting in Study Discontinuation | A TEAE was defined as an AE that emerged or worsened in severity relative to baseline during treatment or within 28 days after the last dose of study drug. Severe TEAE was defined as inability to work or to perform normal daily activity. A Serious TEAE is any untoward medical occurrence that at any dose: results in death; is life threatening (that is, the participant was at immediate risk of death from the adverse event as it occurred; this does not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death) requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect or is medically important due to other reasons than the above mentioned criteria. An adverse event (AE) was defined as any untoward medical occurrence in a participant administered an investigational product. | From first dose of study drug up to Week 16 | 
| Number of Participants With Orthostatic Hypotension | Orthostatic hypotension was defined as drop in standing systolic blood pressure greater than or equal to (>=) 20 Millimeter of mercury (mmHg) compared to supine, or drop in standing diastolic blood pressure >=10 mmHg compared to supine. | Week 2, Week 4, Week 6, Week 9 and Week 12 | 
| Number of Participants With Orthostatic Tachycardia | Orthostatic tachycardia by numerical criteria was defined by the following numerical criteria: Standing heart rate (HR) increased by >30 beats/min compared to supine and absolute standing HR was >100 beats/min. | From first dose of study drug up to Week 16 | 
| Number of Participants With Markedly Abnormal Laboratory Values | A laboratory value was determined to be a markedly abnormal value if the postbaseline common toxicity criteria grade increased from baseline and the post-baseline grade was greater than or equal to 2. | From first dose of study drug up to Week 16 | 
| Number of Participants With Abnormal Electrocardiogram (ECG) Findings |  | From first dose of study drug up to Week 16 | 
| Number of Participants With Suicidal Ideation or Suicidal Behavior as Measured Using Columbia Suicide Severity Rating Scale (C-SSRS) | The C-SSRS (mapped to Columbia Classification Algorithm of Suicide Assessment (C-CASA) categories); is an interview-based instrument to systematically assess suicidal ideation and suicidal behavior. C-SSRS assess whether participant experience any of the following: completed suicide; suicide attempt (response of yes on actual attempt); preparatory acts toward imminent suicidal behavior (yes on preparatory acts or behavior, aborted attempt or interrupted attempt), suicidal ideation (yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent, any self-injurious behavior with no suicidal intent (yes on has participant engaged in non-suicidal self-injurious behavior). Here, number of participants with positive response (yes) to suicidal behavior or/and Ideation, any non-suicidal self-injurious behavior was reported. | From first dose of study drug up to Week 16 | 
| Change From Baseline in Total Score of Unified Parkinson's Disease Rating Scale Part III: Motor Examination (UPDRS-III) | The UPDRS scale evaluates extrapyramidal features in motor function in Parkinson's disease. It contains 33 items in 18 categories: (1) speech, (2) facial expression, (3) rigidity, (4) finger tapping, (5) hand movements, (6) supinational and pronation movements of hands, (7) toe tapping, (8) leg agility, (9) arising from chair, (10) gait, (11) freezing of gait, (12) postural stability, (13) posture, (14) body bradykinesia, (15) postural tremor of hands, (16) kinetic tremor of hands, (17) rest tremor amplitude and (18) constancy of rest tremor. Each item is scored 0 to 4, giving a total score range 0 to 132. Higher scores indicating more severe symptoms. | Baseline up to Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irsenontrine, Montreal Cognitive Assessment, Neuropsychiatric Inventory, Mini-Mental State Examination, Cognitive Fluctuation Inventory