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

Sponsor
Eisai Co., Ltd. (Industry)
Overall Status
Terminated
CT.gov ID
NCT02956486
Collaborator
Biogen (Industry)
2,212
Enrollment
258
Locations
3
Arms
38.8
Actual Duration (Months)
8.6
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
2212 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
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
Actual Study Start Date :
Oct 20, 2016
Actual Primary Completion Date :
Jan 15, 2020
Actual Study Completion Date :
Jan 15, 2020

Arms and Interventions

Arm Intervention/Treatment
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.

Drug: Elenbecestat
Oral tablet.
Other Names:
  • E2609

    		•
    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.

    Drug: Placebo
    Oral tablet.
    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.

    Drug: Elenbecestat
    Oral tablet.
    Other Names:
  • E2609

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score [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.

    2. Extension Phase: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) [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.

    Secondary Outcome Measures

    1. Core Phase: Change From Baseline up to Month 24 in Alzheimer's Disease Composite Score (ADCOMS) [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.

    2. Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) [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.

    3. 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 [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.

    4. 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 [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.

    5. Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24 [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.

    6. Core Phase: Time to Worsening of CDR Score up to Month 24 [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.

    7. 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 [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).

    8. Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition14 (ADAS-Cog14) Score [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.

    9. Core Phase: Change From Baseline up to Month 24 in the MMSE Score [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.

    10. Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score [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").

    11. Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score [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.

    12. Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition11 (ADAS-Cog11) Score [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.

    13. Core Phase: Change From Last Dose in the CDR-SB Score [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.

    14. Core Phase: Change From Last Dose in the ADCOMS [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.

    15. Core Phase: Change From Last Dose in the ADAS-cog11 Score [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.

    16. Core Phase: Change From Last Dose in the ADAS-cog14 Score [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.

    17. Core Phase: Change From Last Dose in the MMSE Score [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.

    18. Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score [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.

    19. Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score [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.

    20. Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS [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.

    21. Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score [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.

    22. Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score [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").

    23. Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score [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.

    24. 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 [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.

    25. 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 [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).

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    50 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Facility #1 Chandler Arizona United States 85226
    2 Facility #1 Colton California United States 92324
    3 Facility #1 Costa Mesa California United States 92626
    4 Facility #1 Fullerton California United States 92835
    5 Facility #1 Imperial California United States 92251
    6 Facility #1 Irvine California United States 92618
    7 Facility #1 Lemon Grove California United States 91945
    8 Facility #1 Oceanside California United States 92054
    9 Facility #2 Oceanside California United States 92054
    10 Facility #1 Oxnard California United States 93030
    11 Facility #1 Panorama City California United States 91402
    12 Facility #1 San Diego California United States 92123
    13 Facility #1 Denver Colorado United States 80218
    14 Facility #1 Atlantis Florida United States 33462
    15 Facility #1 Aventura Florida United States 33187
    16 Facility #2 Aventura Florida United States 33187
    17 Facility #1 Boynton Beach Florida United States 33437
    18 Facility #1 Coral Gables Florida United States 33134
    19 Facility #2 Coral Gables Florida United States 33134
    20 Facility #1 Delray Beach Florida United States 33445
    21 Facility #1 Doral Florida United States 33122
    22 Facility #1 Hialeah Florida United States 33016
    23 Facility #2 Miami Florida United States 33122
    24 Facility #11 Miami Florida United States 33125
    25 Facility #9 Miami Florida United States 33125
    26 Facility #10 Miami Florida United States 33126
    27 Facility #4 Miami Florida United States 33133
    28 Facility #1 Miami Florida United States 33137
    29 Facility #6 Miami Florida United States 33144
    30 Facility #3 Miami Florida United States 33155
    31 Facility #7 Miami Florida United States 33174
    32 Facility #8 Miami Florida United States 33176
    33 Facility #2 Orlando Florida United States 32801
    34 Facility #1 Orlando Florida United States 32806
    35 Facility #3 Orlando Florida United States 32807
    36 Facility #1 Palm Beach Gardens Florida United States 33410
    37 Facility #1 Pompano Beach Florida United States 33064
    38 Facility #1 Port Charlotte Florida United States 33952
    39 Facility #1 Port Orange Florida United States 32127
    40 Facility #1 Spring Hill Florida United States 34609
    41 Facility #1 Tampa Florida United States 33613
    42 Facility #2 Tampa Florida United States 33614
    43 Facility #1 The Villages Florida United States 32162
    44 Facility #1 Atlanta Georgia United States 30328
    45 Facility #1 Columbus Georgia United States 31909
    46 Facility #1 Decatur Georgia United States 30033
    47 Facility #1 Suwanee Georgia United States 30024
    48 Facility #1 Meridian Idaho United States 83642
    49 Facility #1 Northbrook Illinois United States 60062
    50 Facility #2 Wichita Kansas United States 67214
    51 Facility #1 Boston Massachusetts United States 2115
    52 Facility #1 Farmington Hills Michigan United States 48334
    53 Facility #1 Chesterfield Missouri United States 63005
    54 Facility #1 O'Fallon Missouri United States 63368
    55 Facility #2 Saint Louis Missouri United States 63104
    56 Facility #1 Saint Peters Missouri United States 63303
    57 Facility #1 Mount Arlington New Jersey United States 7856
    58 Facility #2 Springfield New Jersey United States 7081
    59 Facility #1 West Long Branch New Jersey United States 7764
    60 Facility #1 Amherst New York United States 14226
    61 Facility #1 Brooklyn New York United States 11229
    62 Facility #1 New York New York United States 10032
    63 Facility #1 Canton Ohio United States 44718
    64 Facility #1 Centerville Ohio United States 45459
    65 Facility #1 Cleveland Ohio United States 44195
    66 Facility #1 Dayton Ohio United States 45459
    67 Facility #1 Lakewood Ohio United States 44107
    68 Facility #1 Westerville Ohio United States 43081
    69 Facility #1 Oklahoma City Oklahoma United States 73116
    70 Facility #1 Portland Oregon United States 97210
    71 Facility #1 Jenkintown Pennsylvania United States 19046
    72 Facility #1 Media Pennsylvania United States 19063
    73 Facility #1 Philadelphia Pennsylvania United States 19104
    74 Facility #1 East Providence Rhode Island United States 02914
    75 Facility #1 Providence Rhode Island United States 2906
    76 Facility #1 Port Royal South Carolina United States 29935
    77 Facility #1 Cordova Tennessee United States 38018
    78 Facility #2 Nashville Tennessee United States 37203
    79 Facility #1 Nashville Tennessee United States 37212
    80 Facility #1 Austin Texas United States 78757
    81 Facility #1 Dallas Texas United States 75231
    82 Facility #1 Houston Texas United States 77084
    83 Facility #1 San Antonio Texas United States 78229-3900
    84 Facility #3 San Antonio Texas United States 78240
    85 Facility #1 Salt Lake City Utah United States 84108
    86 Facility #1 Bennington Vermont United States 5201
    87 Facility #1 Hampton Virginia United States 23666
    88 Facility #1 Madison Wisconsin United States 53705
    89 Facility #2 Caba Buenos Aires Argentina -1405
    90 Facility #1 Caba Buenos Aires Argentina C1012AAR
    91 Facility #4 Caba Buenos Aires Argentina C1126AAB
    92 Facility #3 Caba Buenos Aires Argentina C1427
    93 Facility #1 Ciudad Autonoma de Buenos Aires Buenos Aires Argentina 1111
    94 Facility #3 Ciudad Autonoma de Buenos Aires Buenos Aires Argentina 1430
    95 Facility #2 Ciudad Autonoma de Buenos Aires Buenos Aires Argentina C1230AAZ
    96 Facility #1 Cordoba Capital Argentina X5003DCE
    97 Facility #1 Rosario Santa Fe Argentina 2000
    98 Facility #4 Buenos Aires Argentina 1199
    99 Facility #5 Caba Argentina C1428AQK
    100 Facility #2 Cordoba Argentina X5004A0A
    101 Facility #3 Cordoba Argentina X5009BIN
    102 Facility #1 Santa Fe Argentina 3000
    103 Facility #1 Darlinghurst New South Wales Australia 2010
    104 Facility #1 Macquarie Park New South Wales Australia 2113
    105 Facility #1 Tumbi Umbi New South Wales Australia 2261
    106 Facility #1 Brisbane Queensland Australia 4032
    107 Facility #1 Caulfield Victoria Australia 3162
    108 Facility #1 Geelong Victoria Australia 3220
    109 Facility #1 Heidelberg Victoria Australia 3084
    110 Facility #1 Malvern Victoria Australia 3144
    111 Facility #2 Melbourne Victoria Australia
    112 Facility #1 Parkville Victoria Australia 3050
    113 Facility #1 Nedlands Western Australia Australia 6009
    114 Facility #3 Melbourne Australia 3146
    115 Facility #1 Vienna Austria 1130
    116 Facility #1 Pleven Bulgaria 5800
    117 Facility #1 Plovdiv Bulgaria 4002
    118 Facility #1 Ruse Bulgaria 7002
    119 Facility #4 Sofia Bulgaria 1142
    120 Facility #3 Sofia Bulgaria 1309
    121 Facility #1 Sofia Bulgaria 1431
    122 Facility #2 Sofia Bulgaria 1431
    123 Facility #1 Kamloops British Columbia Canada V2C 5T1
    124 Facility #1 Kelowna British Columbia Canada V1Y 1Z9
    125 Facility #1 West Vancouver British Columbia Canada V7T 1C5
    126 Facility #1 Halifax Nova Scotia Canada B3S 1M7
    127 Facility #1 Kentville Nova Scotia Canada B4N 4K9
    128 Facility #1 Ottawa Ontario Canada K1N 5C8
    129 Facility #1 Peterborough Ontario Canada K9H 2P4
    130 Facility #1 Montreal Quebec Canada H1M 1B1
    131 Facility #1 Sherbrooke Quebec Canada J1L 0H8
    132 Facility #1 Hradec Kralove Czechia 500 09
    133 Facility #1 Kladno Czechia 272 01
    134 Facility #1 Olomouc Czechia 779 00
    135 Facility #1 Praha 10 Czechia 109 00
    136 Facility #1 Montpellier Herault France 34295
    137 Facility #1 Bordeaux France 33076
    138 Facility #1 Bron Cedex France 69677
    139 Facility #1 Marseille Cedex 05 France 13385
    140 Facility #1 Nantes France 44800
    141 Facility #1 Paris France 75013
    142 Facility #1 Rouen France 76000
    143 Facility #1 Toulouse France 31059
    144 Facility #1 Neuburg Bayern Germany 86633
    145 Facility #1 Hoppegarten Brandenburg Germany 15366
    146 Facility #1 Oranienburg Brandenburg Germany 16515
    147 Facility #1 Frankfurt Hessen Germany 60528
    148 Facility #1 Leipzig Saxony Germany 4107
    149 Facility #1 Berlin Germany 10245
    150 Facility #2 Berlin Germany 10629
    151 Facility #1 Gera Germany 7551
    152 Facility #1 Homburg/Saar Germany 66241
    153 Facility #1 Schwerin Germany 19053
    154 Facility #5 Athens Greece 11528
    155 Facility #4 Athens Greece 15123
    156 Eisai Trial Site 1 Anjo-shi Aichi Japan 446-8510
    157 Eisai Trial Site 1 Nagoya-shi Aichi Japan 467-8602
    158 Eisai Trial Site 1 Obu-shi Aichi Japan 474-8511
    159 Eisai Trial Site 1 Yoshida-gun Fukui Japan 910-1193
    160 Eisai Trail Site 1 Kitakyushu-shi Fukuoka Japan 808-0024
    161 Eisai Trial Site 1 Omuta-shi Fukuoka Japan 837-0911
    162 Eisai Trial Site 1 Fujioka-shi Gunma Japan 375-0017
    163 Eisai Trial Site 1 Otake-shi Hiroshima Japan 739-0651
    164 Eisai Trial Site 2 Himeji-shi Hyogo Japan 670-0981
    165 Eisai Trial Site 1 Himeji Hyogo Japan 671-1227
    166 Eisai Trial Site 1 Kobe Hyogo Japan 650-0017
    167 Facility #1 Miki Kagawa Japan 761-0793
    168 Eisai Trial Site 3 Takamatsu City Kagawa Japan 760-8557
    169 Eisai Trial Site 1 Fujisawa-shi Kanagawa Japan 251-0038
    170 Eisai Trial Site 4 Kyoto City Kyoto Japan 616-8255
    171 Eisai Trial Site 1 Kyoto-shi Kyoto Japan 602-8566
    172 Eisai Trial Site 2 Kyoto-shi Kyoto Japan 602-8566
    173 Eisai Trial site 5 Kyoto-shi Kyoto Japan 607-8113
    174 Eisai Trial Site 1 Shimogyo-ku Kyoto Japan 600-8558
    175 Eisai Trial Site 1 Higashimorokatagun Miyazaki Japan 880-1111
    176 Eisai Trial Site 2 Okayama-shi Okayama-ken Japan 701-1192
    177 Eisai Trial Site 1 Kurashiki-shi Okayama Japan 710-0813
    178 Eisai Trial Site 2 Kurashiki-shi Okayama Japan 710-8692
    179 Eisai Trial Site 1 Okayama-shi Okayama Japan 700-8557
    180 Eisai Trial Site 1 Hirakata Osaka Japan 573-1121
    181 Eisai Trial Site 1 Naniwa-Ku Osaka Japan 556-0017
    182 Eisai Trial Site 1 Osaka-shi Osaka Japan 534-0021
    183 Eisai Trial Site 3 Osaka-shi Osaka Japan 543-8555
    184 Eisai Trial Site 2 Osaka-shi Osaka Japan 545-8586
    185 Eisai Trial site 2 Sakai-shi Osaka Japan 593-8301
    186 Eisai Trial Site 1 Suita-shi Osaka Japan 565-0871
    187 Eisai Trial Site 2 Suita-shi Osaka Japan 565-0874
    188 Eisai Trial Site 1 Suminoe-ku Osaka Japan 559-0004
    189 Eisai Trial Site 1 Kanzaki-gun Saga Japan 842-0192
    190 Eisai Trial Site 1 Otsu-shi Shiga Japan 520-2192
    191 Eisai Trial Site 2 Otsu Shiga Japan 520-0832
    192 Eisai Trial Site 1 Tokushima-shi Tokushima Japan 770-8503
    193 Eisai Trial Site 1 Bunkyo-ku Tokyo Japan 113-0034
    194 Eisai Trial Site 2 Bunkyo-ku Tokyo Japan 113-8603
    195 Eisai Trial Site 1 Kodaira-shi Tokyo Japan 187-8551
    196 Eisai Trial Site 1 Minato-ku Tokyo Japan 108-0073
    197 Eisai Trial Site 1 Setagaya-ku Tokyo Japan 158-8531
    198 Eisai Trial Site 1 Shinjuku-ku Tokyo Japan 169-0073
    199 Eisai Trial Site 1 Sumida-ku Tokyo Japan 130-0004
    200 Eisai Trial Site 1 Hofu-shi Yamaguchi Japan 747-0802
    201 Eisai Trial Site 1 Kumamoto Japan 860-8556
    202 Eisai Trial Site 3 Kyoto Japan 606-0851
    203 Eisai Trial Site 1 Osaka Japan 553-0003
    204 Facility #1 Bucheon-si Gyeonggi-do Korea, Republic of 14647
    205 Facility #1 Seongnam Gyeonggi Korea, Republic of 13620
    206 Facility #1 Busan Korea, Republic of 49201
    207 Facility #1 Incheon Korea, Republic of 22332
    208 Facility #5 Seoul Korea, Republic of 3722
    209 Facility #3 Seoul Korea, Republic of 4763
    210 Facility #1 Seoul Korea, Republic of 5030
    211 Facility #4 Seoul Korea, Republic of 6351
    212 Facility #6 Seoul Korea, Republic of 6973
    213 Facility #2 Seoul Korea, Republic of 7985
    214 Facility #1 Katowice Poland
    215 Facility #1 Kielce Poland 25-411
    216 Facility #1 Krakow Poland 30-149
    217 Facility #1 Poznari Poland 61-853
    218 Facility #1 Poznań Poland
    219 Facility #1 Siemianowice Śląskie Poland 41-100
    220 Facility #1 Warszawa Poland 01-684
    221 Facility #1 Guimarães Portugal 4835-044
    222 Facility #1 Moscow Russian Federation 119991
    223 Facility #1 Bratislava Slovakia 85107
    224 Facility #1 Elche Alicante Spain 3203
    225 Facility #1 Sant Cugat Del Valles Barcelona Spain 8195
    226 Facility #1 Getxo Bizkaia Spain 48993
    227 Facility #1 Donostia/San Sebastian Gipuzkoa Spain 20009
    228 Facility #1 Palma de Mallorca Illes Balears Spain 7120
    229 Facility #1 El Palmar Murcia Spain 30120
    230 Facility #1 Barcelona Spain 8028
    231 Facility #2 Madrid Spain 28049
    232 Facility #1 Madrid Spain 28223
    233 Facility #1 Valencia Spain 46010
    234 Facility #2 Valencia Spain 46026
    235 Facility #1 Cambridge Cambridgeshire United Kingdom CB21 5EF
    236 Facility #1 Chester Cheshire United Kingdom CH2 1BQ
    237 Facility #1 Winwick, Warrington Cheshire United Kingdom WA2 8WA
    238 Facility #1 Plymouth Devon United Kingdom PL6 8BT
    239 Facility #1 Bournemouth Dorset United Kingdom BH1 4JQ
    240 Facility #1 Crowborough East Sussex United Kingdom TN6 1HB
    241 Facility #1 Manchester Greater Manchester United Kingdom M13 9WL
    242 Facility #1 Southampton Hampshire United Kingdom SO30 3JB
    243 Facility #1 Glasgow Lanarkshire United Kingdom G20 0XA
    244 Facility #1 Blackpool Lancashire United Kingdom FY2 0JH
    245 Facility #1 Preston Lancashire United Kingdom PR2 8DW
    246 Facility #2 London Middlesex United Kingdom TW7 6FY
    247 Facility #1 Bath North East Somerset United Kingdom BA1 3NG
    248 Facility #1 Oxford Oxfordshire United Kingdom OX3 7JX
    249 Facility #1 Aberdeen Scotland United Kingdom AB25 2ZH
    250 Facility #1 Sheffield South Yorkshire United Kingdom S5 7JT
    251 Facility #1 Leatherhead Surrey United Kingdom KT22 7AD
    252 Facility #1 Birmingham West Midlands United Kingdom B168QQ
    253 Facility #1 Swindon Wilts United Kingdom SN3 6BW
    254 Facility #2 Glasgow United Kingdom G51 4TF
    255 Facility #1 Guildford United Kingdom GU2 7YD
    256 Facility #1 London United Kingdom W1G 9RU
    257 Facility #4 London United Kingdom W6 8RF
    258 Facility #3 London United Kingdom WC1X 8QD

    Sponsors and Collaborators

    • Eisai Co., Ltd.
    • Biogen

    Investigators

    None specified.

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Eisai Co., Ltd.
    ClinicalTrials.gov Identifier:
    NCT02956486
    Other Study ID Numbers:
    • E2609-G000-301
    • 2016-003928-23
    • 2016-004128-42
    • NCT03036280
    First Posted:
    Nov 6, 2016
    Last Update Posted:
    Feb 3, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Eisai Co., Ltd.
    Elenbecestat
    E2609
    Alzheimer's Disease
    Early Alzheimer's Disease
    Prodromal Alzheimer's Disease
    Dementia
    Dementia, Alzheimer's type
    Mild Cognitive Impairment
    MissionAD1
    Additional relevant MeSH terms:
    Alzheimer Disease

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 426 investigative sites in China, Bulgaria, Croatia, Czech Republic, Greece, Hungary, Poland, Russia, Slovakia, Japan, Canada, Singapore, South Korea, Taiwan, Argentina, Chile, Mexico, Australia, Austria, Denmark, Finland, France, Germany, Italy, Portugal, South Africa, Spain, United Kingdom and the United States from 20 October 2016 to 15 January 2020.
    Pre-assignment Detail This study included 2 parts: Core Phase and Extension Phase. A total of 9758 participants were screened, of which 7546 participants were screen failures and 2212 participants were randomized in the study. The data for the studies E2609-G000-301 (NCT02956486, MissionAD1) and E2609-G000-302 (NCT03036280, MissionAD2) was pooled.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 milligram (mg) tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase. Eligible participants who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Period Title: Core Phase
    STARTED 1108 1104 0
    Treated 1108 1101 0
    Safety Analysis Set (SAS) 1105 1099 0
    Full Analysis Set (FAS) 1084 1062 0
    COMPLETED 29 32 0
    NOT COMPLETED 1079 1072 0
    Period Title: Core Phase
    STARTED 0 0 19
    Treated 0 0 18
    Safety Analysis Set (SAS) 0 0 18
    COMPLETED 0 0 0
    NOT COMPLETED 0 0 19

    Baseline Characteristics

    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg Total
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase. Total of all reporting groups
    Overall Participants 1105 1099 2204
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    72.1
    (7.09)
    71.9
    (7.18)
    72.0
    (7.13)
    Sex: Female, Male (Count of Participants)
    Female
    592
    53.6%
    534
    48.6%
    1126
    51.1%
    Male
    513
    46.4%
    565
    51.4%
    1078
    48.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    162
    14.7%
    158
    14.4%
    320
    14.5%
    Not Hispanic or Latino
    943
    85.3%
    941
    85.6%
    1884
    85.5%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    1
    0.1%
    0
    0%
    1
    0%
    Asian
    233
    21.1%
    247
    22.5%
    480
    21.8%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    2
    0.2%
    2
    0.1%
    Black or African American
    12
    1.1%
    22
    2%
    34
    1.5%
    White
    851
    77%
    817
    74.3%
    1668
    75.7%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    8
    0.7%
    11
    1%
    19
    0.9%

    Outcome Measures

    1. Primary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in mixed effects model for repeated measures (MMRM) who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1078 1053
    Least Squares Mean (Standard Error) [score on a scale]
    2.17
    (0.142)
    1.99
    (0.146)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (mild cognitive impairment [MCI]/Prodromal, mild alzheimer's disease [AD]), concurrent AD medication use, region, apolipoprotein E (ApoE4) status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.385
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter Least Square (LS) Mean Difference
    Estimated Value -0.17
    Confidence Interval (2-Sided) 95%
    -0.57 to 0.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    2. Primary Outcome
    Title Extension Phase: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs)
    Description 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.
    Time Frame From first dose of study drug up to approximately 6 months (including 1 month follow up) for the extension phase

    Outcome Measure Data

    Analysis Population Description
    All safety participants was the group of participants who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 18
    Count of Participants [Participants]
    6
    0.5%
    3. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in Alzheimer's Disease Composite Score (ADCOMS)
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1018 981
    Least Squares Mean (Standard Error) [score on a scale]
    0.24
    (0.014)
    0.23
    (0.015)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.345
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.02
    Confidence Interval (2-Sided) 95%
    -0.06 to 0.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    4. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR)
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The pharmacodynamic (PD) analysis set was the group of participants in the core phase who had sufficient PD data to derive at least 1 PD parameter. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 268 248
    Least Squares Mean (Standard Error) [score on a scale]
    7.81
    (2.500)
    -5.02
    (2.046)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <.001
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -12.83
    Confidence Interval (2-Sided) 95%
    -18.79 to -6.88
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    5. Secondary Outcome
    Title 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
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 664 617
    Least Squares Mean (Standard Error) [score on a scale]
    1.97
    (0.157)
    1.74
    (0.169)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.316
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.23
    Confidence Interval (2-Sided) 95%
    -0.67 to 0.22
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    6. Secondary Outcome
    Title 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
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 627 571
    Least Squares Mean (Standard Error) [score on a scale]
    0.23
    (0.017)
    0.20
    (0.018)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.254
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.03
    Confidence Interval (2-Sided) 95%
    -0.07 to 0.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    7. Secondary Outcome
    Title Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24
    Description 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.
    Time Frame Up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1084 1062
    Least Squares Mean (95% Confidence Interval) [change in score per year]
    0.934
    0.926
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Based on the linear mixed effects model, which included assessment time and treatment group by assessment time interaction as covariate with random intercept and slope.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9088
    Comments
    Method Linear mixed effects model
    Comments
    Method of Estimation Estimation Parameter Difference of Mean Slope
    Estimated Value -0.008
    Confidence Interval (2-Sided) 95%
    -0.145 to 0.129
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    8. Secondary Outcome
    Title Core Phase: Time to Worsening of CDR Score up to Month 24
    Description 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.
    Time Frame Up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1084 1062
    Median (95% Confidence Interval) [months]
    NA
    NA
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Based on a Cox regression model which included treatment group, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6155
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 0.95
    Confidence Interval (2-Sided) 95%
    0.77 to 1.16
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title 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
    Description 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).
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 902 901
    Median (95% Confidence Interval) [months]
    23.05
    21.40
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Based on a Cox regression model which included treatment group, concurrent AD medication use, region, APOE4 status (positive, negative) as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1281
    Comments
    Method Regression, Cox
    Comments
    Method of Estimation Estimation Parameter Hazard Ratio (HR)
    Estimated Value 1.14
    Confidence Interval (2-Sided) 95%
    0.96 to 1.35
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition14 (ADAS-Cog14) Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1010 972
    Least Squares Mean (Standard Error) [score on a scale]
    5.38
    (0.490)
    4.95
    (0.520)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.525
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.43
    Confidence Interval (2-Sided) 95%
    -1.75 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    11. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the MMSE Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1056 1017
    Least Squares Mean (Standard Error) [score on a scale]
    -2.87
    (0.234)
    -2.87
    (0.241)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.977
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.64 to 0.62
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score
    Description 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").
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1038 1001
    Least Squares Mean (Standard Error) [score on a scale]
    5.20
    (0.448)
    5.32
    (0.459)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.854
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.11
    Confidence Interval (2-Sided) 95%
    -1.09 to 1.32
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1050 1005
    Least Squares Mean (Standard Error) [score on a scale]
    1.63
    (0.195)
    1.36
    (0.207)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.314
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.27
    Confidence Interval (2-Sided) 95%
    -0.79 to 0.26
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition11 (ADAS-Cog11) Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 24 of the core phase

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies all participants included in MMRM who were evaluable for this specific outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 1010 972
    Least Squares Mean (Standard Error) [score on a scale]
    4.11
    (0.370)
    4.18
    (0.391)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value and the baseline value by visit interaction as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.895
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.07
    Confidence Interval (2-Sided) 95%
    -0.93 to 1.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title Core Phase: Change From Last Dose in the CDR-SB Score
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 759 734
    Least Squares Mean (Standard Error) [score on a scale]
    0.40
    (0.045)
    0.44
    (0.046)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.542
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.04
    Confidence Interval (2-Sided) 95%
    -0.09 to 0.17
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    16. Secondary Outcome
    Title Core Phase: Change From Last Dose in the ADCOMS
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 666 646
    Least Squares Mean (Standard Error) [score on a scale]
    0.06
    (0.005)
    0.06
    (0.005)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.380
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.02 to 0.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    17. Secondary Outcome
    Title Core Phase: Change From Last Dose in the ADAS-cog11 Score
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 679 647
    Least Squares Mean (Standard Error) [score on a scale]
    0.95
    (0.150)
    0.56
    (0.153)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.063
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.40
    Confidence Interval (2-Sided) 95%
    -0.82 to 0.02
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Core Phase: Change From Last Dose in the ADAS-cog14 Score
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 679 647
    Least Squares Mean (Standard Error) [score on a scale]
    0.96
    (0.196)
    0.40
    (0.201)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.045
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.56
    Confidence Interval (2-Sided) 95%
    -1.11 to -0.01
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Core Phase: Change From Last Dose in the MMSE Score
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 734 719
    Least Squares Mean (Standard Error) [score on a scale]
    -0.22
    (0.101)
    -0.26
    (0.102)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.799
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.04
    Confidence Interval (2-Sided) 95%
    -0.32 to 0.24
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    20. Secondary Outcome
    Title Core Phase: Change From Last Dose in the ADAS-cog14 Word List (Immediate Recall and Delayed Recall) Score
    Description 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.
    Time Frame From last dose in the core phase (up to Month 24) up to 3 months follow-up (up to Month 27)

    Outcome Measure Data

    Analysis Population Description
    The FAS was the group of randomized participants who received at least 1 dose of study drug in the core phase and had baseline and at least 1 post-dose primary efficacy measurement. Here "overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase.
    Measure Participants 707 685
    Least Squares Mean (Standard Error) [score on a scale]
    0.54
    (0.088)
    0.22
    (0.090)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Core Phase: Placebo, Core Phase: Elenbecestat 50 mg
    Comments Analysis was based on the MMRM and factors for treatment group, visit, treatment group by visit interaction, clinical disease staging (MCI/Prodromal, mild AD), concurrent AD medication use, region, ApoE4 status (positive, negative) as fixed effects, and the baseline value as covariate.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.012
    Comments
    Method MMRM
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.32
    Confidence Interval (2-Sided) 95%
    -0.56 to -0.07
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    21. Secondary Outcome
    Title Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in CDR-SB Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    22. Secondary Outcome
    Title Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADCOMS
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    23. Secondary Outcome
    Title Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in MMSE Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    24. Secondary Outcome
    Title Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in FAQ Score
    Description 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").
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    25. Secondary Outcome
    Title Extension Phase: Change From Core Phase Baseline up to Month 12 of the Extension Phase in ADAS-cog14 Score
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    26. Secondary Outcome
    Title 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
    Description 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.
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0
    27. Secondary Outcome
    Title 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
    Description 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).
    Time Frame Baseline (Day 1: before first dose in the core phase) up to Month 12 of the extension phase

    Outcome Measure Data

    Analysis Population Description
    Data could not be reported as the study was terminated prior to reaching the specified time point for assessment in the extension phase. Statistical analysis plan was modified to indicate that the extension phase analysis was not done.
    Arm/Group Title Extension Phase: Elenbecestat 50 mg
    Arm/Group Description In the extension phase, participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after the last dose of elenbecestat in the extension phase.
    Measure Participants 0

    Adverse Events

    Time Frame From first dose of study drug up to approximately 27 months (including 3 months follow up) for the Core Phase and up to approximately 6 months (including 1 month follow up) for the Extension Phase
    Adverse Event Reporting Description In the Core Phase, adverse events were reported for the SAS (the group of participants who received at least 1 dose of study drug and had at least 1 post-dose safety assessment). In the Extension Phase, adverse events were reported for the All Safety Participants analysis set: the group of participants who enrolled into the extension phase and received at least 1 dose of study drug in the extension phase.
    Arm/Group Title Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Arm/Group Description Participants received one elenbecestat matching-placebo tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat matched placebo in core phase. Participants received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food up to 24 months. Participants were followed up for 3 months after last dose of elenbecestat in core phase. Eligible participants who completed the core phase entered the extension phase and received one elenbecestat 50 mg tablet, orally, once daily in the morning with or without food until commercial availability of elenbecestat, or a lack of positive benefit-risk assessment was determined, whichever occurred first. Participants were followed up for 1 month after last dose of elenbecestat in extension phase.
    All Cause Mortality
    Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 6/1105 (0.5%) 3/1099 (0.3%) 0/18 (0%)
    Serious Adverse Events
    Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 117/1105 (10.6%) 134/1099 (12.2%) 0/18 (0%)
    Blood and lymphatic system disorders
    Anaemia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lymphadenopathy 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lymphopenia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cardiac disorders
    Angina pectoris 3/1105 (0.3%) 3 2/1099 (0.2%) 2 0/18 (0%) 0
    Bradycardia 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Atrial fibrillation 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Tachycardia 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Acute myocardial infarction 3/1105 (0.3%) 3 1/1099 (0.1%) 1 0/18 (0%) 0
    Sinus node dysfunction 2/1105 (0.2%) 2 1/1099 (0.1%) 1 0/18 (0%) 0
    Angina unstable 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Cardiac arrest 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Coronary artery stenosis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pericarditis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Myocardial infarction 3/1105 (0.3%) 3 0/1099 (0%) 0 0/18 (0%) 0
    Cardiac failure congestive 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Cardiomyopathy 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Coronary artery disease 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Mitral valve incompetence 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Paroxysmal atrioventricular block 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Sinus arrest 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Congenital, familial and genetic disorders
    Type V hyperlipidaemia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Endocrine disorders
    Thyroid mass 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Eye disorders
    Cataract 1/1105 (0.1%) 1 3/1099 (0.3%) 4 0/18 (0%) 0
    Idiopathic orbital inflammation 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Retinal artery occlusion 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Diplopia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 3/1105 (0.3%) 3 1/1099 (0.1%) 1 0/18 (0%) 0
    Inguinal hernia 2/1105 (0.2%) 2 1/1099 (0.1%) 1 0/18 (0%) 0
    Diarrhoea 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Diverticular perforation 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Duodenal ulcer haemorrhage 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Gastritis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Nausea 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Oesophageal spasm 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Small intestinal obstruction 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Umbilical hernia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Ascites 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Colitis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Pancreatitis acute 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Vomiting 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    General disorders
    Non-cardiac chest pain 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Pyrexia 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Asthenia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Malaise 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Oedema peripheral 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pain 0/1105 (0%) 0 1/1099 (0.1%) 2 0/18 (0%) 0
    Chills 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Hepatobiliary disorders
    Hepatitis acute 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Autoimmune hepatitis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cholecystitis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cholecystitis acute 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Hepatic mass 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Infections and infestations
    Pneumonia 3/1105 (0.3%) 3 5/1099 (0.5%) 5 0/18 (0%) 0
    Influenza 2/1105 (0.2%) 2 5/1099 (0.5%) 5 0/18 (0%) 0
    Urinary tract infection 2/1105 (0.2%) 2 3/1099 (0.3%) 3 0/18 (0%) 0
    Bronchitis 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Cellulitis 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Diverticulitis 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Subcutaneous abscess 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Sepsis 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Abscess limb 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Alpha haemolytic streptococcal infection 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Appendicitis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Atypical pneumonia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Bronchitis viral 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Colonic abscess 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Gastroenteritis viral 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lower respiratory tract infection viral 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lung infection 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pneumonia bacterial 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Gastroenteritis 2/1105 (0.2%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Appendicitis perforated 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Campylobacter gastroenteritis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Enteritis infectious 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Erysipelas 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Febrile infection 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Infected skin ulcer 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Ophthalmic herpes zoster 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Osteomyelitis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Postoperative wound infection 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Pyelonephritis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Urosepsis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Injury, poisoning and procedural complications
    Fall 4/1105 (0.4%) 4 7/1099 (0.6%) 7 0/18 (0%) 0
    Hip fracture 1/1105 (0.1%) 1 3/1099 (0.3%) 3 0/18 (0%) 0
    Femur fracture 0/1105 (0%) 0 3/1099 (0.3%) 3 0/18 (0%) 0
    Head injury 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Rib fracture 2/1105 (0.2%) 2 1/1099 (0.1%) 1 0/18 (0%) 0
    Femoral neck fracture 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Spinal compression fracture 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Brain contusion 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Facial bones fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Foot fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Humerus fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Jaw fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Post procedural complication 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Sternal fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Subcutaneous haematoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Thoracic vertebral fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Tibia fracture 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Accidental overdose 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Coronary vascular graft stenosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Hand fracture 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Radius fracture 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Road traffic accident 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Subdural haematoma 1/1105 (0.1%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Upper limb fracture 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Wrist fracture 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Investigations
    Alanine aminotransferase increased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Aspartate aminotransferase increased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Blood potassium decreased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    C-reactive protein increased 0/1105 (0%) 0 1/1099 (0.1%) 2 0/18 (0%) 0
    Heart rate irregular 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Hepatic enzyme increased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Liver function test increased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pancreatic enzymes increased 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    White blood cell count increased 0/1105 (0%) 0 1/1099 (0.1%) 2 0/18 (0%) 0
    Gamma-glutamyltransferase increased 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Metabolism and nutrition disorders
    Hyperkalaemia 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Dehydration 2/1105 (0.2%) 2 1/1099 (0.1%) 1 0/18 (0%) 0
    Hyperglycaemia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Hyponatraemia 2/1105 (0.2%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Acidosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Diabetes mellitus 1/1105 (0.1%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Diabetes mellitus inadequate control 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Hypokalaemia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Type 2 diabetes mellitus 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Osteoarthritis 6/1105 (0.5%) 6 1/1099 (0.1%) 1 0/18 (0%) 0
    Back pain 0/1105 (0%) 0 1/1099 (0.1%) 2 0/18 (0%) 0
    Intervertebral disc protrusion 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Muscle twitching 0/1105 (0%) 0 1/1099 (0.1%) 2 0/18 (0%) 0
    Haemarthrosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Intervertebral disc degeneration 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Lumbar spinal stenosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Neck pain 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Spinal stenosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Breast cancer 3/1105 (0.3%) 3 1/1099 (0.1%) 1 0/18 (0%) 0
    Benign gastric neoplasm 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Bladder adenocarcinoma stage unspecified 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Endometrial cancer 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Gastric adenoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lung neoplasm malignant 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Lymphoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Metastatic malignant melanoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Rectal adenocarcinoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Salivary gland cancer 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Prostate cancer 2/1105 (0.2%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Lung neoplasm 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Malignant melanoma 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Mucinous adenocarcinoma of appendix 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Pancreatic carcinoma 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Squamous cell carcinoma of pharynx 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Vulval neoplasm 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Waldenstrom's macroglobulinaemia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Nervous system disorders
    Syncope 1/1105 (0.1%) 1 4/1099 (0.4%) 5 0/18 (0%) 0
    Cerebrovascular accident 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Loss of consciousness 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Seizure 1/1105 (0.1%) 1 2/1099 (0.2%) 2 0/18 (0%) 0
    Encephalopathy 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Normal pressure hydrocephalus 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Presyncope 2/1105 (0.2%) 2 1/1099 (0.1%) 1 0/18 (0%) 0
    Dizziness 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Unresponsive to stimuli 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Altered state of consciousness 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Brain injury 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cerebral ventricle dilatation 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Facial paralysis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Generalised tonic-clonic seizure 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Myoclonus 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Paraesthesia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Parkinsonism 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Petit mal epilepsy 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Subarachnoid haemorrhage 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cerebral infarction 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Cerebral ischaemia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Dementia Alzheimer's type 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Epilepsy 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Haemorrhagic stroke 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Hypoaesthesia 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Ischaemic stroke 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Lacunar stroke 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Lumbar radiculopathy 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Partial seizures 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Transient ischaemic attack 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Psychiatric disorders
    Depression 2/1105 (0.2%) 2 2/1099 (0.2%) 2 0/18 (0%) 0
    Aggression 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Delirium 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Delusion 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Agitation 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Completed suicide 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Confusional state 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Disorientation 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Psychotic behaviour 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Hallucination, visual 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Psychotic disorder 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Suicidal ideation 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Renal and urinary disorders
    Acute kidney injury 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Ureterolithiasis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Chronic kidney disease 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Nephrolithiasis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Urethral meatus stenosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Reproductive system and breast disorders
    Prostatitis 0/1105 (0%) 0 2/1099 (0.2%) 2 0/18 (0%) 0
    Benign prostatic hyperplasia 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Cervical polyp 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Cystocele 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease 2/1105 (0.2%) 2 2/1099 (0.2%) 3 0/18 (0%) 0
    Pneumonia aspiration 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Pulmonary embolism 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Acute respiratory failure 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Dyspnoea exertional 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pneumothorax 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Pulmonary hypertension 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Respiratory disorder 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Asthma 1/1105 (0.1%) 2 0/1099 (0%) 0 0/18 (0%) 0
    Epistaxis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Lung disorder 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Nasal polyps 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Pneumothorax spontaneous 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Drug eruption 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Drug reaction with eosinophilia and systemic symptoms 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Hypersensitivity vasculitis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Rash 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Toxic skin eruption 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Urticaria 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Actinic keratosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Vascular disorders
    Hypotension 1/1105 (0.1%) 1 1/1099 (0.1%) 1 0/18 (0%) 0
    Aortic aneurysm 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Deep vein thrombosis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Haematoma 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Hypertensive urgency 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Orthostatic hypotension 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Peripheral artery stenosis 0/1105 (0%) 0 1/1099 (0.1%) 1 0/18 (0%) 0
    Blood pressure inadequately controlled 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Thrombosis 1/1105 (0.1%) 1 0/1099 (0%) 0 0/18 (0%) 0
    Other (Not Including Serious) Adverse Events
    Core Phase: Placebo Core Phase: Elenbecestat 50 mg Extension Phase: Elenbecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 292/1105 (26.4%) 391/1099 (35.6%) 6/18 (33.3%)
    Blood and lymphatic system disorders
    Lymphopenia 18/1105 (1.6%) 18 70/1099 (6.4%) 89 0/18 (0%) 0
    General disorders
    Gait disturbance 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Infections and infestations
    Nasopharyngitis 67/1105 (6.1%) 80 71/1099 (6.5%) 86 0/18 (0%) 0
    Upper respiratory tract infection 50/1105 (4.5%) 56 58/1099 (5.3%) 63 0/18 (0%) 0
    Viral infection 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Injury, poisoning and procedural complications
    Accidental overdose 55/1105 (5%) 79 66/1099 (6%) 101 0/18 (0%) 0
    Fall 60/1105 (5.4%) 71 61/1099 (5.6%) 79 0/18 (0%) 0
    Investigations
    Blood sodium decreased 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Metabolism and nutrition disorders
    Hyponatraemia 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Osteoarthritis 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Pain in extremity 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Nervous system disorders
    Dizziness 45/1105 (4.1%) 49 57/1099 (5.2%) 61 0/18 (0%) 0
    Cognitive disorder 0/1105 (0%) 0 0/1099 (0%) 0 2/18 (11.1%) 2
    Cerebral microhaemorrhage 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Somnolence 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Psychiatric disorders
    Abnormal dreams 36/1105 (3.3%) 42 57/1099 (5.2%) 66 0/18 (0%) 0
    Nightmare 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Renal and urinary disorders
    Urine flow decreased 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Skin and subcutaneous tissue disorders
    Rash 22/1105 (2%) 26 60/1099 (5.5%) 78 0/18 (0%) 0
    Alopecia 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1
    Vascular disorders
    Varicose vein 0/1105 (0%) 0 0/1099 (0%) 0 1/18 (5.6%) 1

    Limitations/Caveats

    This study was terminated early due to an unfavorable risk-benefit ratio including no evidence of potential efficacy and the adverse event profile in participants with drug treatment was worse than that in participants who received placebo. The small sample size at the 24 month time point of the core phase limits the interpretability of the data.

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Eisai Medical Information
    Organization Eisai Ltd.
    Phone +1-888-274-2378
    Email esi_medinfo@eisai.com
    Responsible Party:
    Eisai Co., Ltd.
    ClinicalTrials.gov Identifier:
    NCT02956486
    Other Study ID Numbers:
    • E2609-G000-301
    • 2016-003928-23
    • 2016-004128-42
    • NCT03036280
    First Posted:
    Nov 6, 2016
    Last Update Posted:
    Feb 3, 2021
    Last Verified:
    Jan 1, 2021