Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Participants With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease

Study Overview
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Brief Summary
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This is a Phase 2 study to evaluate safety and efficacy in participants with Mild Cognitive Impairment due to Alzheimer's Disease/Prodromal Alzheimer's Disease (referred to as MCI/Prodromal) and mild to moderate dementia due to Alzheimer's Disease (referred to as mild to moderate AD). This study will have a Core Phase and an Extension Phase.

Official Title
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A Placebo-Controlled, Double-Blind, Parallel-Group, Randomized, Proof-of-Concept, Dose-Finding Study To Evaluate Safety, Tolerability, and Efficacy of E2609 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease (Prodromal Alzheimer's Disease) and Mild to Moderate Dementia Due to Alzheimer's Disease

Conditions
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Alzheimer Disease, Dementia, Alzheimer Type

Intervention / Treatment
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* Drug: E2609
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Participants must meet all of the following criteria to be included in this study: Meets the core clinical research criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA) for MCI due to AD (which is consistent with Prodromal AD) or AD dementia and is 'staged' or classified as either MCI or mild to moderate dementia. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET scan reading. Male or female, age 50 to 85 years, inclusive at time of consent. 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. If receiving an Acetylcholinesterase Inhibitor (AChEI) or memantine, must have been on a stable dose for at least 12 weeks before the Baseline cognitive assessments, with no plans for dose adjustment in the foreseeable future. Treatment-naive participants can be entered into the study but there should be no plans to initiate treatment with AChEIs or memantine at the time of entry into the study. Must have been on stable doses of all other permitted chronically used concomitant medications (that is, not related to their cognitive decline) for at least 4 weeks before randomization. Exclusion criteria: Participants who meet any of the following criteria will be excluded from this study: Any neurological condition that may be contributing to cognitive impairment above and beyond that caused by the participant's AD pathology, including any co-morbidities such as cerebrovascular disease, detected by medical history, neurological examination, or magnetic resonance imaging (MRI). History of transient ischemic attacks or stroke within 12 months of Screening. History of epilepsy. Evidence of depression on a rating scale at Screening or any psychiatric diagnosis or symptoms, (example, hallucinations, major depression, etc.) that could confound the diagnosis or could interfere with study assessments or procedures. This includes suicidal ideation or suicidal behavior within 6 months prior to Screening, or hospitalization or treatment for suicidal behavior in the past 5 years. Abnormally low serum vitamin B12. Thyroid stimulating hormone above the normal range. This applies to all participants regardless of whether or not they are taking thyroid supplements. Participants with liver disease (hepatic impairment), at Screening or Baseline. Participant with Gilbert's syndrome need not be excluded. Not able to have a MRI, PET scanning, or cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP). Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately. History of immunodeficiency disorders. Participants with chronic viral hepatitis. History of Tuberculosis (TB). Participants with no history of TB will be tested for previous TB exposure and a positive test will be exclusionary. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection. Any live vaccine in the 3 months or any active infection within the last 4 weeks before study drug administration (that is, randomization). Any chronic inflammatory disease that is not adequately controlled or requires immunosuppressive or immunomodulatory therapy. T helper cell, cytotoxic T cell, or B cell absolute counts below normal. Immunoglobulin (Ig) IgG, IgA, or IgM levels below normal at Screening or Baseline, unless both the Investigator and the Medical Monitor agree that the finding is not clinically significant. Clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory tests at Screening or Baseline. Exclusionary cardiac factors include: prolonged QT interval greater than 450 millisecond from Electrocardiograms (ECGs); history of risk factors for torsade de pointes or the use of concomitant medications that prolong the QT/corrected QT interval (QTc); left bundle branch block; persistent low or high heart rate; persistent low or high blood pressure; history of cardiac arrhythmias; other clinically significant ECG abnormalities. Type 1 or Type 2 diabetes mellitus that is not well controlled. Malignant neoplasms within 5 years before Screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer that did not require systemic therapy; these do not exclude the participant). Medical conditions (example, cardiac, respiratory, gastrointestinal, renal disease) that are not stably controlled, or which, in the opinion of the investigator(s), could affect the participant's safety or interfere with the study assessments. Hypopigmentation conditions (example, albinism and vitiligo). Known or suspected history of drug or alcohol dependency or abuse within 2 years, current use of recreational drugs or a positive urine drug test. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study. Participation in any other interventional clinical study related to cognitive impairment within 6 months before Screening unless it can be documented that the participant was in a placebo treatment arm. Currently enrolled in another clinical study or used any investigational drug or device within 60 days or 5 half-lives of the investigational medication (whichever is longer) proceeding informed consent. Hypersensitivity to the study drug or any of the excipients or to other Beta Secretase Cleaving Enzyme (BACE) inhibitors, or to the PET tracer, or components of its formulation. Females who are lactating or pregnant. Females of childbearing potential who do not agree to adhere to the protocol specified methods for avoiding pregnancy. Males who do not meet the protocol requirements for avoiding their partners becoming pregnant. Sperm donation is not permitted.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MCI/Prodromal Cohort: Low Dose<br>A low dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Experimental: MCI/Prodromal Cohort: Middle Dose<br>A middle dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Experimental: MCI/Prodromal Cohort: High Dose<br>A high dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Placebo Comparator: MCI/Prodromal Cohort: Placebo<br> | Drug: Placebo<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Experimental: Mild to Moderate AD Cohort: Low Dose<br>A low dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Experimental: Mild to Moderate AD Cohort: High Dose<br>A high dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Placebo Comparator: Mild to Moderate AD Cohort: Placebo<br> | Drug: Placebo<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|
| Experimental: Mild to Moderate AD cohort: Middle Dose<br>A middle dose of E2609 will be assessed. | Drug: E2609<br>* Each participant will receive 2 tablets, which when combined will make up the required doses of E2609 or placebo, to be administered orally once per day (QD) with food.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) | A TEAE is defined as an adverse event that emerges during treatment, having been absent at pre-treatment (Baseline) or re-emerges during treatment, having been present at pre-treatment (Baseline) but stopped before treatment, or worsens in severity during treatment relative to the pre-treatment state, when the adverse event is continuous. | Up to 21 months | 
| Core Phase: Number of Participants With Serious Adverse Events (SAEs) | A SAE is any untoward medical occurrence that at any dose: results in death; is life-threatening (that is, the participant is at immediate risk of death from the adverse event as it occurs, this does not include an event that, has it occurred in a more severe form or is allowed to continue, might have cause death); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect (in the child of a participant who is exposed to the study drug). | Up to 21 months | 
| Core Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values |  | Up to 21 months | 
| Core Phase: Number of Participants With Markedly Abnormal Vital Sign Values | Participants having no markedly abnormal vital sign values (no markedly abnormal high or no markedly abnormal low) in all core phase arms were not included in the data reported. | Month 0(Baseline,Week 2,Week 3,Week 4);Month 1(Week 5,Week 7);Month 2(Week 9,Week 11);Month 3(Week 13);Month 4(Week 17);Month 5(Week 21);Month 6(Week 27);Month 9(Week 40);Month 12(Week 53);Month 15(Week 66);Month 18(Week 79) and Follow-up at Month 1 and 3 | 
| Core Phase: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings | QTcF interval means corrected QT interval (QTc) calculated using Fridericia's formula. | Up to 21 months | 
| Extension Phase: Number of Participants With TEAEs and SAEs | TEAE: adverse event that emerges during treatment, having been absent at pre-treatment or reemerges during treatment, having been present at pre-treatment but stopped before treatment, or worsens in severity during treatment relative to pre-treatment state. Number of participants with TEAEs were reported based on safety assessments of laboratory tests, physical examination, regular measurement of vital signs, magnetic resonance imaging and electrocardiogram parameter values. SAE: any untoward medical occurrence that at any dose: results in death; is life-threatening (immediate risk of death from adverse event, this does not include event that, had it occurred in more severe form or is allowed to continue, might have caused death); requires inpatient or prolongation of existing hospitalization; results in persistent/significant disability/incapacity; is congenital anomaly/birth defect (in child of participant exposed to drug). Number of participants with TEAEs and SAEs were reported. | Up to 34 months | 
| Extension Phase: Number of Participants With Markedly Abnormal Vital Sign Values |  | Up to 34 months | 
| Extension Phase: Number of Participants With Markedly Abnormal ECG Findings | QTcF interval means QTc interval calculated using Fridericia's formula. | Up to 34 months | 
| Extension Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values |  | Up to 34 months | 
| Extension Phase: Number of Participants With Abnormal Magnetic Resonance Imaging (MRI) Findings | Brain MRIs are collected to assess for potential drug-related changes that might have constituted a safety concern. Safety brain MRI is assessed using a standardized procedure that included fluid-attenuated inversion recovery (FLAIR), gradient-echo, T1, and diffusion-weighted sequences to determine the presence of focal lesions including, but not limited to, evidence for ischemic and hemorrhagic stroke, subdural hematoma, neoplasm, arteriovenous malformation, micro and macrohemorrhages, superficial siderosis, lacunar infarcts, white matter abnormalities, and vasogenic edema. Participants with abnormal values related to safety brain MRI were reported. | Up to 34 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Phase: Percent Change From Baseline in Cerebrospinal Fluid (CSF) Amyloid (A) Beta(1-x) and Abeta(1-42) After 1 Month and 18 Months of Treatment | The measurement of the amyloid proteins Abeta(1-x) and Abeta(1-42), in CSF have been shown to be important biomarkers for alzheimer's disease. | Month 1 (Week 5) and Month 18 (Week 79) | 
| Core Phase: Mean Concentration of Elenbecestat in CSF |  | Month 1 (Week 5) and Month 18 (Week 79) | 
| Core Phase: Mean Concentration of Elenbecestat in Plasma |  | Month 0 (Week 3), Month 3 (Week 13), Month 6 (Week 27), Month 12 (Week 53): Pre-dose, 1 to 6 hours Post-dose; Month 1 (Week 5), Month 18 (Week 79): Pre-dose, 4 to 8 hours Post-dose | 
| Extension Phase: Change From Extension Phase Baseline in the Mini-Mental State Examination (MMSE) Scores | MMSE is a 30-point scale that measures orientation to time and place, registration, immediate and delayed recall, attention, language, and drawing. Scores ranges from 0 (most impaired) to 30 (no impairment). Lower score indicates more impairment. | Baseline, at Month 3, at Month 6, at Month 9, at Month 12, at Month 15, at Month 18, at Month 21, at Month 24, at Month 28 and at Month 32 | 
| Extension Phase: Change From Extension Phase Baseline in the Functional Assessment Questionnaire (FAQ) Score | The FAQ has 10 items concerned with performing daily tasks necessary for independent living. The caregiver or informant provides performance ratings on 10 complex activities of daily living performed within the preceding 4 weeks. Score ranges from 0 (independent) to 30 (dependent). Lower score indicates that participant can live independently. Higher score indicates that participant cannot live independently. | Baseline, at Month 3, at Month 6, at Month 9, at Month 12, at Month 15, at Month 18, at Month 21, at Month 24, at Month 28 and at Month 32 | 
| Extension Phase: Percent Change From Extension Phase Baseline in Plasma Amyloid (A) Beta(1-x) Measurements at Months 12 and 24 | The measurement of the amyloid protein Abeta(1-x), in plasma has been shown to be an important biomarker for alzheimer's disease. | Month 12 and Month 24 | 
| Extension Phase: Percent Change From Extension Phase Baseline in Total Hippocampal Volume at Month 24 | Total hippocampal volume is measured by volumetric magnetic resonance imaging (vMRI). Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total hippocampal volume is calculated by summing up right and left hippocampal volumes. | Month 24 | 
| Extension Phase: Percent Change From Extension Phase Baseline in Left and Right Hippocampal Volume at Month 24 | Left and right hippocampal volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Left and right hippocampal volumes represent a summary measure in the left and right hippocampal regions. | Month 24 | 
| Extension Phase: Percent Change From Extension Phase Baseline in Whole Brain Volume at Month 24 | Whole brain volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Whole brain volume represents a summary measure of total brain parenchyma which includes the cerebrum, basal ganglia, diencephalon, and cerebellum. | Month 24 | 
| Extension Phase: Percent Change From Extension Phase Baseline in Total Ventricular Volume at Month 24 | Total Ventricular Volume is measured by vMRI. Volumetric imaging is a 3D technique where all the MRI signals are collected from the entire tissue sample and imaged as a whole entity, therefore providing a high signal to noise ratio. Total ventricular volume represents a summary measure of total including right and left lateral ventricles, third ventricle and fourth ventricle of brain. | Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Prodromal Alzheimer's Disease, E2609, Mild Cognitive Impairment, Mild to Moderate Dementia