A 24-Month Study to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Participants With Early Alzheimer's Disease (MissionAD1)

• ClinicalTrials.gov Identifier: NCT02956486
• Recruitment Status: Terminated
• First Posted: November 6, 2016
• Results First Posted: February 3, 2021
• Last Update Posted: February 3, 2021
• Sponsor: Eisai Co., Ltd.
• Collaborator: Biogen
• Information provided by (Responsible Party): Eisai Inc. ( Eisai Co., Ltd. )

Tracking Information

• First Submitted Date: November 3, 2016
• First Posted Date: November 6, 2016
• Results First Submitted Date: January 14, 2021
• Results First Posted Date: February 3, 2021
• Last Update Posted Date: February 3, 2021
• Actual Study Start Date: October 20, 2016
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 14, 2021)

• Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  The clinical dementia rating (CDR) scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment.
• Extension Phase: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) [ Time Frame: From first dose of study drug up to approximately 6 months (including 1 month follow up) for the extension phase ]
  A TEAE is defined as an adverse event that emerged during treatment or within 28 days following the last dose of study drug, having been absent at pretreatment (Baseline) or reemerged during treatment, having been present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the adverse event was continuous. Number of participants with TEAEs (serious and non-serious adverse events) were reported based on their safety assessments of laboratory tests, suicidal ideation and suicidal behavior, drug abuse potential, physical examination, neurological examination, regular measurement of vital signs, magnetic resonance imaging and electrocardiogram parameter values.

• Original Primary Outcome Measures (submitted: November 3, 2016): Change from Baseline in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) score at 24 months [ Time Frame: Baseline; 24 months ]

Current Secondary Outcome Measures (submitted: January 14, 2021)

• Core Phase: Change From Baseline up to Month 24 in Alzheimer's Disease Composite Score (ADCOMS) [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), the Mini Mental State Examination (MMSE), and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance.
• Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  Amyloid PET scan assesses cerebral amyloid load using 3 tracers (florbetapir, florbetaben and flutemetamol) which is standardized into centiloids for evaluation of AD. Centiloid values on centiloid scale is based on mean composite SUVR in cingulate, frontal, parietal and temporal cortexes using whole cerebellum as reference region. SUVR is ratio of tracer uptake in each of cingulate, frontal, parietal and temporal cortexes relative to cerebellum. The centiloid scale anchor points are 0 and 100, where 0 represents a high-certainty amyloid negative scan and 100 represents the amount of global amyloid deposition found in a typical AD scans.
• Core Phase: Change From Baseline up to Month 24 in the CDR-SB Score for Participants Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6 [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates the ratio of tracer uptake in the frontal cortex relative to the cerebellum or the ratio of tracer uptake in the whole brain relative to the cerebellum.
• Core Phase: Change From Baseline up to Month 24 in the ADCOMS for Participants Enriched by Baseline Amyloid PET SUVR Between 1.2 and 1.6 [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance. Amyloid PET scans allow in vivo assessment of cerebral amyloid load. SUVR indicates the ratio of tracer uptake in the frontal cortex relative to the cerebellum or the ratio of tracer uptake in the whole brain relative to the cerebellum.
• Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24 [ Time Frame: Up to Month 24 of the core phase ]
  The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment. In this outcome measure, change per year (mean slope) in CDR-SB score was calculated up to month 24, where higher change indicated more impairment and lower change indicated less impairment.
• Core Phase: Time to Worsening of CDR Score up to Month 24 [ Time Frame: Up to Month 24 of the core phase ]
  The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The global CDR score is computed via an algorithm and ranges from 0 to 3. Higher score indicates more impairment. In this outcome measure, time (in months) to worsening of CDR score (that is, an increase from baseline by at least 0.5 points on the global CDR scale on 2 consecutive scheduled visits) up to month 24 was calculated.
• Core Phase: Time to Conversion to Dementia for Participants Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 24 [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  Time (in months) to conversion to dementia for participants who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis).
• Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition14 (ADAS-Cog14) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0-10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD participants. The total score ranges from 0 to 90. Higher score indicates more impairment.
• Core Phase: Change From Baseline up to Month 24 in the MMSE Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is composed of 30 questions grouped into domains (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Naming [0-2], Repetition [0-1], Comprehension [0-3], Reading [0-1], Writing [0-1], Drawing [0-1]). For each of the MMSE domains, six items are computed (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Language: Naming, Repetition, Comprehension, Reading, Writing, and Drawing [0-9]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score was missing then the total score was missing. Higher score indicates better function.
• Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as follows: 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity was missed, then the total score was missed. Activities rated as "Not Applicable" were not used in the computation of the total score. To account for "Not Applicable" activity, the total score was weighted as:Total Score=Total Score*30/(30 minus 3 times the number of activities marked"Not Applicable").
• Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants are asked to recall words and the number of "No" responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Participants used to recall words after a delay and the number of "No" responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment.
• Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition11 (ADAS-Cog11) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase ]
  ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD participants. The Total score ranges from 0 to 70. Higher score indicates more impairment.
• Core Phase: Change From Last Dose in the CDR-SB Score [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow up (up to Month 27) ]
  The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment.
• Core Phase: Change From Last Dose in the ADCOMS [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27) ]
  ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance.
• Core Phase: Change From Last Dose in the ADAS-cog11 Score [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27) ]
  ADAS-cog11 is a psychometric instrument that evaluates 11-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5] test) and is considered more sensitive for less impaired populations such as MCI/Prodromal and mild AD participants. The Total score ranges from 0 to 70. Higher score indicates more impairment.
• Core Phase: Change From Last Dose in the ADAS-cog14 Score [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27) ]
  ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD participants. The Total Score ranges from 0 to 90. Higher score indicates more impairment.
• Core Phase: Change From Last Dose in the MMSE Score [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27) ]
  The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is composed of 30 questions grouped into domains (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Naming [0-2], Repetition [0-1], Comprehension [0-3], Reading [0-1], Writing [0-1], Drawing [0-1]). For each of the MMSE domains, six items are computed (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Language: Naming, Repetition, Comprehension, Reading, Writing, and Drawing [0-9]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score was missing then the total score was missing. Higher score indicates better function.
• Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score [ Time Frame: From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27) ]
  The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants are asked to recall words and the number of "No" responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Participants used to recall words after a delay and the number of "No" responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment.
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  The CDR scale is a clinical global rating scale that requires interviewing both the participant and an informant who knows and has contact with the participant. The CDR scale is a clinician directed assessment of both cognition and function, and is intended to capture the state and therefore the disease stage of the participant. The CDR scale assesses 6 domains of participant function (memory, orientation, judgement and problem solving, community affairs, home and hobbies and personal care) on a 5-point scale in which no impairment=0, questionable impairment=0.5, mild impairment=1, moderate impairment=2 and severe impairment=3. The CDR-SB is a sum of the individual domain scores and ranges from 0 to 18. Higher score indicates more impairment.
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  ADCOMS is a weighted linear combination of 12 items from three existing clinical scales: the ADAS-cog, the MMSE, and the CDR. Four items are from the ADAS-cog (A4 [Delayed Word Recall], A7 [Orientation], A8 [Word Recognition], A11 [Word Finding]); 2 items are from the MMSE (M1 [Orientation Time], M7 [Drawing]); 6 items are from the CDR (C1 [Personal Care], C2 [Community Affairs], C3 [Home and Hobbies], C4 [Judgment and Problem Solving], C5 [Memory], C6 [Orientation]). Composite score is derived from the variables from the 12 items, and ranges from 0 to 1.97, where higher score indicates worse performance.
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  The MMSE is a cognitive instrument commonly used for screening purposes, for staging of disease severity and is often measured longitudinally in AD clinical studies to follow disease progression and treatment effects. MMSE is composed of 30 questions grouped into domains (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Naming [0-2], Repetition [0-1], Comprehension [0-3], Reading [0-1], Writing [0-1], Drawing [0-1]). For each of the MMSE domains, six items are computed (Orientation to Time [0-5], Orientation to Place [0-5], Registration [0-3], Attention and Calculation [0-5], Recall [0-3], Language: Naming, Repetition, Comprehension, Reading, Writing, and Drawing [0-9]). The MMSE Total Score is the sum of the six domains and ranges from 0 to 30. If any domain score is missing then the total score is missing. Higher score indicates better function.
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  FAQ scores 10 items & measures activities of daily living (paying bills/balancing checkbook, assembling tax records, shopping alone for clothes or groceries, playing game of skill such as bridge or chess/working on a hobby, heating water & turning off stove, preparing balanced meal, keeping track of current events, paying attention & understanding television program, remembering appointments, driving or traveling out of neighborhood). Each item is rated as follows: 0=Normal, 1=Has difficulty but does by self, 2=Requires assistance, 3=Dependent, or 8=Not Applicable. The total score is the sum of all 10 items & ranges from 0 to 30. Higher score indicates more impairment. If any activity was missed, then the total score was missed. Activities rated as "Not Applicable" were not used in the computation of the total score. To account for "Not Applicable" activity, the total score was weighted as:Total Score=Total Score*30/(30 minus 3 times the number of activities marked"Not Applicable").
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  ADAS-cog14 is a psychometric instrument that evaluates 14-items (Immediate Word-recall [0 to 10], Commands [0-5], Constructional Praxis [0-5], Delayed Word-recall [0-10], Naming Objects/Fingers [0-5], Ideational Praxis [0-5], Orientation[0-8], Word Recognition [0-12], Remembering Test Instructions [0-5], Comprehension[0-5], Word Finding Difficulty [0-5], Spoken Language Ability [0-5], Executive Function [0-5], and Number Cancellation [0-5] test). It is considered to be more sensitive for less impaired populations such as MCI/Prodromal and mild AD participants. The total score ranges from 0 to 90. Higher score indicates more impairment.
• Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  The ADAS-cog14 Word List is a summation of two items: "Immediate Word-recall" and "Delayed Word-recall". Immediate Word-recall test: Participants are asked to recall words and the number of "No" responses for each trial (total 3 trials) are summed. Subscore: sum of scores from 3 trials, divided by 3. Score ranges from 0 to 10. Delayed Word-recall: Participants used to recall words after a delay and the number of "No" responses are summed. Score ranges from 0 to 10. The Total Score ranges from 0 to 20. Higher score indicates more impairment.
• Extension Phase: Time to Conversion to Dementia for Participants Who Were Not Clinically Staged as Having Dementia at the Core Phase Baseline up to Month 12 of the Extension Phase [ Time Frame: Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase ]
  Time (in months) to conversion to dementia for participants who were not clinically staged as having dementia at the core phase baseline (that is time from randomization to conversion to dementia in clinical diagnosis).

Original Secondary Outcome Measures (submitted: November 3, 2016)

• Time to worsening of Clinical Dementia Rating (CDR) score by 24 months [ Time Frame: up to 24 months ]
  Worsening of the global CDR score is defined as an increase from baseline by at least 0.5 points on the global CDR scale on two consecutive scheduled visits at which global CDR is undertaken.
• Time to conversion to dementia for participants who were not clinically staged as dementia at baseline based on clinical diagnosis [ Time Frame: up to 24 months ]
• The rate of change over time (mean slope) based on the CDR-SB score over 24 months [ Time Frame: 24 months ]
• Change from Baseline in the Alzheimer's Disease Assessment Scale-Cognition14 (ADAS-cog14) score at 24 months [ Time Frame: Baseline; 24 months ]
• Change from Baseline in the Mini Mental State Examination (MMSE) score at 24 months [ Time Frame: Baseline; 24 months ]
• Change from Baseline in the Functional Assessment Questionnaire (FAQ) score at 24 months [ Time Frame: Baseline; 24 months ]

• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: November 3, 2016)

• Change from Baseline in amyloid positron emission tomography standardized uptake value ratio (PET SUVR) composite at 24 months for brain amyloid levels [ Time Frame: Baseline; 24 months ]
• Change from Baseline in cerebrospinal fluid (CSF) biomarkers t-tau and p-tau at 24 months [ Time Frame: Baseline; 24 months ]
• Change from Baseline in CSF amyloid biomarkers Aβ(1-40), Aβ(1-42), and Aβ(1-x) at 24 months [ Time Frame: Baseline; 24 months ]
• Change from Baseline in total hippocampal volume at 12 and 24 months using volumetric magnetic resonance imaging (vMRI) [ Time Frame: Baseline; 12 months; 24 months ]
• Change from Baseline in the preservation of connectivity on functional MRI (fMRI) [ Time Frame: Baseline; 12 months; 24 months ]

Descriptive Information

• Brief Title: A 24-Month Study to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Participants With Early Alzheimer's Disease
• Official Title: A Placebo-Controlled, Double-Blind, Parallel-Group, 24 Month Study With an Open-Label Extension Phase to Evaluate the Efficacy and Safety of Elenbecestat (E2609) in Subjects With Early Alzheimer's Disease
• Brief Summary: The name of this trial is MissionAD1. This phase 3 study consists of a Core and Open Label Extension (OLE) Phase in participants with Early Alzheimer's Disease (EAD), and will be conducted to evaluate the efficacy and safety of E2609. The Core is a 24-month treatment, multicenter, double blind, placebo controlled parallel group study. The OLE is a 24-month treatment, one group study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) will be pooled.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: Elenbecestat
  Oral tablet.
  Other Name: E2609
• Drug: Placebo
  Oral tablet.

Study Arms

• Experimental: Core Study: Elenbecestat 50 mg
  Participants will receive one 50 milligram (mg) elenbecestat tablet, orally, once a day in the morning. The core study will be double blinded.
  Intervention: Drug: Elenbecestat
• Placebo Comparator: Core Study: Placebo
  Participants will receive one matching placebo tablet, orally, once a day in the morning. The core study will be double blinded.
  Intervention: Drug: Placebo
• Experimental: Open-label Extension Phase: Elenbecestat 50 mg
  Participants completing the core study will receive one 50 mg elenbecestat tablet, orally, once a day in the morning.
  Intervention: Drug: Elenbecestat

• Publications *: Bullich S, Mueller A, De Santi S, Koglin N, Krause S, Kaplow J, Kanekiyo M, Roe-Vellve N, Perrotin A, Jovalekic A, Scott D, Gee M, Stephens A, Irizarry M. Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study. Alzheimers Res Ther. 2022 Jul 27;14(1):105. doi: 10.1186/s13195-022-01048-x.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 14, 2021): 2212
• Original Estimated Enrollment (submitted: November 3, 2016): 1330
• Actual Study Completion Date: January 15, 2020
• Actual Primary Completion Date: January 15, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Core Study

• Mild cognitive impairment due to Alzheimer's disease (AD) or mild AD dementia including

  1. Mini Mental State Examination score equal to or greater than 24
  2. Clinical Dementia Rating (CDR) global score of 0.5
  3. CDR Memory Box score of 0.5 or greater
• Impaired episodic memory confirmed by a list learning task
• Positive biomarker for brain amyloid pathology as indicated by either amyloid positron emission tomography or cerebrospinal fluid AD assessment or both

Extension Phase

• Participants who complete the Core Study

Exclusion Criteria:

Core Study

• Females who are breastfeeding or pregnant at Screening or Baseline. Females of child-bearing potential must use a highly effective method of contraception throughout the entire study period and for 28 days after study drug discontinuation
• Any condition that may be contributing to cognitive impairment above and beyond that caused by the participant's AD
• Participants with a history of seizures within 5 years of Screening
• History of transient ischemic attacks or stroke within 12 months of Screening
• Psychiatric diagnosis or symptoms (example, hallucinations, major depression, delusions etc.)
• Suicidal ideation or any suicidal behavior within 6 months before Screening or has been hospitalized or treated for suicidal behavior in the past 5 years

• Have any contraindications to magnetic resonance imaging (MRI) scanning or

  1. Have lesions that could indicate a dementia diagnosis other than AD on brain MRI
  2. Exhibit other significant pathological findings on brain MRI.
• Participants who have a history of moderate to severe hepatic impairment (example, Child-Pugh Class B or C)

• Results of laboratory tests conducted during Screening that are outside the following limits:

  1. Absolute lymphocyte count below the lower limit of normal (LLN)
  2. Thyroid stimulating hormone above normal range
  3. Abnormally low Vitamin B12 levels
• Participants at increased risk of infection
• Have received any live vaccine/live attenuated vaccine in the 3 months before randomization
• Any chronic inflammatory disease that is not adequately controlled or that requires systemic immunosuppressive or immunomodulatory therapy
• Any other clinically significant abnormalities
• Severe visual or hearing impairment
• A prolonged corrected QT (QTc) interval (QT interval with Fridericia's correction [QTcF] greater than 450 milliseconds [ms])
• Malignant neoplasms within 5 years of Screening
• Known or suspected history of drug or alcohol abuse
• Taking prohibited medications, which must be reviewed with the Investigator
• Have participated in a recent clinical study

Note: Other protocol-defined Inclusion/Exclusion Criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Bulgaria, Canada, Czechia, France, Germany, Greece, Japan, Korea, Republic of, Poland, Portugal, Russian Federation, Slovakia, Spain, United Kingdom, United States
• Removed Location Countries: Czech Republic, Romania, Serbia, Sweden

Administrative Information

• NCT Number: NCT02956486
• Other Study ID Numbers: E2609-G000-301; 2016-003928-23 ( EudraCT Number ); 2016-004128-42 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Eisai Inc. ( Eisai Co., Ltd. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Eisai Co., Ltd.
• Original Study Sponsor: Same as current
• Collaborators: Biogen
• Investigators: Not Provided
• PRS Account: Eisai Inc.
• Verification Date: January 2021