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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

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ClinicalTrials.gov Identifier: NCT02322021
Recruitment Status : Terminated (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).)
First Posted : December 22, 2014
Results First Posted : March 5, 2021
Last Update Posted : March 5, 2021
Sponsor:
Collaborator:
Biogen
Information provided by (Responsible Party):
Eisai Inc.

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.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Dementia, Alzheimer Type Drug: E2609 Drug: Placebo Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 70 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 26, 2014
Actual Primary Completion Date : December 20, 2019
Actual Study Completion Date : December 20, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MCI/Prodromal Cohort: Low Dose
A low dose of E2609 will be assessed.
Drug: E2609
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.

Experimental: MCI/Prodromal Cohort: Middle Dose
A middle dose of E2609 will be assessed.
Drug: E2609
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.

Experimental: MCI/Prodromal Cohort: High Dose
A high dose of E2609 will be assessed.
Drug: E2609
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.

Placebo Comparator: MCI/Prodromal Cohort: Placebo Drug: Placebo
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.

Experimental: Mild to Moderate AD Cohort: Low Dose
A low dose of E2609 will be assessed.
Drug: E2609
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.

Experimental: Mild to Moderate AD Cohort: High Dose
A high dose of E2609 will be assessed.
Drug: E2609
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.

Placebo Comparator: Mild to Moderate AD Cohort: Placebo Drug: Placebo
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.

Experimental: Mild to Moderate AD cohort: Middle Dose
A middle dose of E2609 will be assessed.
Drug: E2609
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.




Primary Outcome Measures :
  1. Core Phase: Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 21 months ]
    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.

  2. Core Phase: Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to 21 months ]
    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).

  3. Core Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values [ Time Frame: Up to 21 months ]
  4. Core Phase: Number of Participants With Markedly Abnormal Vital Sign Values [ Time Frame: 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 ]
    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.

  5. Core Phase: Number of Participants With Markedly Abnormal Electrocardiogram (ECG) Findings [ Time Frame: Up to 21 months ]
    QTcF interval means corrected QT interval (QTc) calculated using Fridericia's formula.

  6. Extension Phase: Number of Participants With TEAEs and SAEs [ Time Frame: Up to 34 months ]
    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.

  7. Extension Phase: Number of Participants With Markedly Abnormal Vital Sign Values [ Time Frame: Up to 34 months ]
  8. Extension Phase: Number of Participants With Markedly Abnormal ECG Findings [ Time Frame: Up to 34 months ]
    QTcF interval means QTc interval calculated using Fridericia's formula.

  9. Extension Phase: Number of Participants With Treatment Emergent Markedly Abnormal Laboratory Safety Test Values [ Time Frame: Up to 34 months ]
  10. Extension Phase: Number of Participants With Abnormal Magnetic Resonance Imaging (MRI) Findings [ Time Frame: Up to 34 months ]
    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.


Secondary Outcome Measures :
  1. 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 [ Time Frame: Month 1 (Week 5) and Month 18 (Week 79) ]
    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.

  2. Core Phase: Mean Concentration of Elenbecestat in CSF [ Time Frame: Month 1 (Week 5) and Month 18 (Week 79) ]
  3. Core Phase: Mean Concentration of Elenbecestat in Plasma [ Time Frame: 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 ]
  4. Extension Phase: Change From Extension Phase Baseline in the Mini-Mental State Examination (MMSE) Scores [ Time Frame: 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 ]
    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.

  5. Extension Phase: Change From Extension Phase Baseline in the Functional Assessment Questionnaire (FAQ) Score [ Time Frame: 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 ]
    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.

  6. Extension Phase: Percent Change From Extension Phase Baseline in Plasma Amyloid (A) Beta(1-x) Measurements at Months 12 and 24 [ Time Frame: Month 12 and Month 24 ]
    The measurement of the amyloid protein Abeta(1-x), in plasma has been shown to be an important biomarker for alzheimer's disease.

  7. Extension Phase: Percent Change From Extension Phase Baseline in Total Hippocampal Volume at Month 24 [ Time Frame: 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.

  8. Extension Phase: Percent Change From Extension Phase Baseline in Left and Right Hippocampal Volume at Month 24 [ Time Frame: 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.

  9. Extension Phase: Percent Change From Extension Phase Baseline in Whole Brain Volume at Month 24 [ Time Frame: 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.

  10. Extension Phase: Percent Change From Extension Phase Baseline in Total Ventricular Volume at Month 24 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   50 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Participants must meet all of the following criteria to be included in this study:

  1. 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.
  2. Amyloid positive Positron Emission Tomography (PET) image based on centralized PET scan reading.
  3. Male or female, age 50 to 85 years, inclusive at time of consent.
  4. 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.
  5. 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.
  6. 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:

  1. 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).
  2. History of transient ischemic attacks or stroke within 12 months of Screening.
  3. History of epilepsy.
  4. 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.
  5. Abnormally low serum vitamin B12.
  6. Thyroid stimulating hormone above the normal range. This applies to all participants regardless of whether or not they are taking thyroid supplements.
  7. Participants with liver disease (hepatic impairment), at Screening or Baseline. Participant with Gilbert's syndrome need not be excluded.
  8. Not able to have a MRI, PET scanning, or cerebrospinal fluid (CSF) collection by Lumbar Puncture (LP).
  9. Severe visual or hearing impairment that would prevent the participant from performing psychometric tests accurately.
  10. History of immunodeficiency disorders.
  11. Participants with chronic viral hepatitis.
  12. History of Tuberculosis (TB). Participants with no history of TB will be tested for previous TB exposure and a positive test will be exclusionary.
  13. History of ophthalmic shingles or ocular Herpes Simplex Virus (HSV) infection.
  14. Any live vaccine in the 3 months or any active infection within the last 4 weeks before study drug administration (that is, randomization).
  15. Any chronic inflammatory disease that is not adequately controlled or requires immunosuppressive or immunomodulatory therapy.
  16. T helper cell, cytotoxic T cell, or B cell absolute counts below normal.
  17. 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.
  18. Clinically significant deviation from normal in physical examination, vital signs, or clinical laboratory tests at Screening or Baseline.
  19. 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.
  20. Type 1 or Type 2 diabetes mellitus that is not well controlled.
  21. 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).
  22. 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.
  23. Hypopigmentation conditions (example, albinism and vitiligo).
  24. 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.
  25. Planned surgery that requires general, spinal, or epidural anesthesia that would take place during the study.
  26. 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.
  27. 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.
  28. 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.
  29. Females who are lactating or pregnant. Females of childbearing potential who do not agree to adhere to the protocol specified methods for avoiding pregnancy.
  30. Males who do not meet the protocol requirements for avoiding their partners becoming pregnant. Sperm donation is not permitted.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02322021


Locations
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United States, California
Bellflower, California, United States
Costa Mesa, California, United States
Glendale, California, United States
Irvine, California, United States
United States, Florida
Aventura, Florida, United States
Boca Raton, Florida, United States
Brooksville, Florida, United States
Lake Worth, Florida, United States
Orlando, Florida, United States
Port Charlotte, Florida, United States
United States, Georgia
Atlanta, Georgia, United States
Savannah, Georgia, United States
United States, Kansas
Wichita, Kansas, United States
United States, Michigan
Kalamazoo, Michigan, United States
United States, New Jersey
Mount Arlington, New Jersey, United States
Scotch Plains, New Jersey, United States
United States, North Carolina
Charlotte, North Carolina, United States
United States, Ohio
Dayton, Ohio, United States
United States, South Carolina
Port Royal, South Carolina, United States
United States, Texas
Dallas, Texas, United States
San Antonio, Texas, United States
Sponsors and Collaborators
Eisai Inc.
Biogen
  Study Documents (Full-Text)

Documents provided by Eisai Inc.:
Study Protocol  [PDF] December 10, 2018
Statistical Analysis Plan  [PDF] February 18, 2020

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Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT02322021    
Other Study ID Numbers: E2609-G000-202
2014-002723-94 ( EudraCT Number )
First Posted: December 22, 2014    Key Record Dates
Results First Posted: March 5, 2021
Last Update Posted: March 5, 2021
Last Verified: March 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Eisai Inc.:
E2609
Mild Cognitive Impairment
Mild to Moderate Dementia
Alzheimer's Disease
Prodromal Alzheimer's Disease
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Cognitive Dysfunction
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders