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

NCT02322021 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: E2609-G000-2022014-002723-94
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 21

Brief Summary

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.

Conditions

Alzheimer Disease; Dementia, Alzheimer Type

Keywords

E2609; Mild Cognitive Impairment; Mild to Moderate Dementia; Alzheimer's Disease; Prodromal Alzheimer's Disease

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (10)

• 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

  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

  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

  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

Study Arms (8)

MCI/Prodromal Cohort: Low Dose

EXPERIMENTAL

A low dose of E2609 will be assessed.

Drug: E2609

MCI/Prodromal Cohort: Middle Dose

EXPERIMENTAL

A middle dose of E2609 will be assessed.

Drug: E2609

MCI/Prodromal Cohort: High Dose

EXPERIMENTAL

A high dose of E2609 will be assessed.

Drug: E2609

MCI/Prodromal Cohort: Placebo

PLACEBO COMPARATOR

Drug: Placebo

Mild to Moderate AD Cohort: Low Dose

EXPERIMENTAL

A low dose of E2609 will be assessed.

Drug: E2609

Mild to Moderate AD Cohort: High Dose

EXPERIMENTAL

A high dose of E2609 will be assessed.

Drug: E2609

Mild to Moderate AD Cohort: Placebo

PLACEBO COMPARATOR

Drug: Placebo

Mild to Moderate AD cohort: Middle Dose

EXPERIMENTAL

A middle dose of E2609 will be assessed.

Drug: E2609

Interventions

E2609 DRUG

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.

MCI/Prodromal Cohort: High Dose; MCI/Prodromal Cohort: Low Dose; MCI/Prodromal Cohort: Middle Dose; Mild to Moderate AD Cohort: High Dose; Mild to Moderate AD Cohort: Low Dose; Mild to Moderate AD cohort: Middle Dose

Placebo DRUG

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.

MCI/Prodromal Cohort: Placebo; Mild to Moderate AD Cohort: Placebo

Eligibility Criteria

• Age: 50 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Eisai Inc.: lead
• Biogen: collaborator

Study Sites (21)

Unknown Facility

Bellflower, California, United States

Location

Unknown Facility

Costa Mesa, California, United States

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Unknown Facility

Glendale, California, United States

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Unknown Facility

Irvine, California, United States

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Unknown Facility

Aventura, Florida, United States

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Unknown Facility

Boca Raton, Florida, United States

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Unknown Facility

Brooksville, Florida, United States

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Unknown Facility

Lake Worth, Florida, United States

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Unknown Facility

Orlando, Florida, United States

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Unknown Facility

Port Charlotte, Florida, United States

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Unknown Facility

Atlanta, Georgia, United States

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Unknown Facility

Savannah, Georgia, United States

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Unknown Facility

Wichita, Kansas, United States

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Unknown Facility

Kalamazoo, Michigan, United States

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Unknown Facility

Mount Arlington, New Jersey, United States

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Unknown Facility

Scotch Plains, New Jersey, United States

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Unknown Facility

Charlotte, North Carolina, United States

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Unknown Facility

Dayton, Ohio, United States

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Unknown Facility

Port Royal, South Carolina, United States

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Unknown Facility

Dallas, Texas, United States

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Unknown Facility

San Antonio, Texas, United States

Location

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Limitations and Caveats

This study was terminated early by the sponsor on the recommendation of an independent data safety monitoring board following review of unblinded data from the Phase 3 studies E2609-G000-301 (NCT02956486) and E2609-G000-302 (NCT03036280).

Results Point of Contact

• Title: Eisai Ltd.
• Organization: Eisai Medical Information

esi_medinfo@eisai.com

+1-888-274-2378

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 17, 2014
• First Posted: December 22, 2014
• Study Start: November 26, 2014
• Primary Completion: December 20, 2019
• Study Completion: December 20, 2019
• Last Updated: March 5, 2021
• Results First Posted: March 5, 2021

Record last verified: 2021-03

Locations

US (21)