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NCT02956486: MissionAD1

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

Terminated Phase 3 Results posted Last updated 3 February 2021
What this trial tests

Phase 3 trial testing Elenbecestat in Alzheimer's Disease in 2,212 participants. Terminated before completion.

Timeline
20 October 2016
Primary endpoint
15 January 2020
15 January 2020

Quick facts

Lead sponsorEisai Co., Ltd.
PhasePhase 3
StatusTerminated
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment2,212
Start date20 October 2016
Primary completion15 January 2020
Estimated completion15 January 2020
Sites258 locations across France, Japan, Russia, Greece, Slovakia, Austria, United Kingdom, Germany

Drugs / interventions tested

Conditions studied

Sponsor

Eisai Co., Ltd. — full company profile →

Who can join

Adults 50 to 85, any sex, with Alzheimer's Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Core Phase: Change From Baseline up to Month 24 in the Clinical Dementia Rating-sum of Boxes (CDR-SB) Score Primary · 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, mil

GroupValue95% CI
Core Phase: Placebo2.17± 0.142
Core Phase: Elenbecestat 50 mg1.99± 0.146
Extension Phase: Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) Primary · 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

GroupValue95% CI
Extension Phase: Elenbecestat 50 mg6
Core Phase: Change From Baseline up to Month 24 in Alzheimer's Disease Composite Score (ADCOMS) Secondary · 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 sco

GroupValue95% CI
Core Phase: Placebo0.24± 0.014
Core Phase: Elenbecestat 50 mg0.23± 0.015
Core Phase: Change From Baseline up to Month 24 in Amyloid Positron Emission Tomography (PET) Standardized Uptake Value Ratio (SUVR) Secondary · 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 am

GroupValue95% CI
Core Phase: Placebo7.81± 2.500
Core Phase: Elenbecestat 50 mg-5.02± 2.046
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 Secondary · 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 im

GroupValue95% CI
Core Phase: Placebo1.97± 0.157
Core Phase: Elenbecestat 50 mg1.74± 0.169
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 Secondary · 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 highe

GroupValue95% CI
Core Phase: Placebo0.23± 0.017
Core Phase: Elenbecestat 50 mg0.20± 0.018
Core Phase: Change Per Year (Mean Slope) in CDR-SB Score up to Month 24 Secondary · 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 im

GroupValue95% CI
Core Phase: Placebo0.9340.838 – 1.030
Core Phase: Elenbecestat 50 mg0.9260.828 – 1.024
Core Phase: Time to Worsening of CDR Score up to Month 24 Secondary · 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 im

GroupValue95% CI
Core Phase: PlaceboNANA – NA
Core Phase: Elenbecestat 50 mgNA24.07 – NA
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 Secondary · 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).

GroupValue95% CI
Core Phase: Placebo23.0521.14 – 24.66
Core Phase: Elenbecestat 50 mg21.4020.45 – 24.43
Core Phase: Change From Baseline up to Month 24 in the Alzheimer's Disease Assessment Scale-cognition14 (ADAS-Cog14) Score Secondary · 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 tota

GroupValue95% CI
Core Phase: Placebo5.38± 0.490
Core Phase: Elenbecestat 50 mg4.95± 0.520
Core Phase: Change From Baseline up to Month 24 in the MMSE Score Secondary · 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 \[0-5\], O

GroupValue95% CI
Core Phase: Placebo-2.87± 0.234
Core Phase: Elenbecestat 50 mg-2.87± 0.241
Core Phase: Change From Baseline up to Month 24 in the Functional Assessment Questionnaire (FAQ) Score Secondary · 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 su

GroupValue95% CI
Core Phase: Placebo5.20± 0.448
Core Phase: Elenbecestat 50 mg5.32± 0.459

Adverse events — posted to ClinicalTrials.gov

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. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Core Phase: Placebo
Serious: 117/1105 (11%)
Deaths: 6/1105
Core Phase: Elenbecestat 50 mg
Serious: 134/1099 (12%)
Deaths: 3/1099
Extension Phase: Elenbecestat 50 mg
Serious: 0/18 (0%)
Deaths: 0/18

Serious adverse events (236 terms)

ReactionSystemCore Phase: PlaceboCore Phase: Elenbecestat 5…Extension Phase: Elenbeces…
FallInjury, poisoning and procedural complications
OsteoarthritisMusculoskeletal and connective tissue disorders
PneumoniaInfections and infestations
InfluenzaInfections and infestations
SyncopeNervous system disorders
Urinary tract infectionInfections and infestations
Hip fractureInjury, poisoning and procedural complications
Femur fractureInjury, poisoning and procedural complications
Breast cancerNeoplasms benign, malignant and unspecified (incl cysts and polyps)
Angina pectorisCardiac disorders
Acute myocardial infarctionCardiac disorders
Myocardial infarctionCardiac disorders
Abdominal painGastrointestinal disorders
CataractEye disorders
BronchitisInfections and infestations
CellulitisInfections and infestations
DiverticulitisInfections and infestations
Subcutaneous abscessInfections and infestations
GastroenteritisInfections and infestations
Cerebrovascular accidentNervous system disorders
Loss of consciousnessNervous system disorders
SeizureNervous system disorders
EncephalopathyNervous system disorders
Normal pressure hydrocephalusNervous system disorders
PresyncopeNervous system disorders
Other adverse events (22 terms — click to expand)

ReactionSystemCore Phase: PlaceboCore Phase: Elenbecestat 5…Extension Phase: Elenbeces…
NasopharyngitisInfections and infestations
LymphopeniaBlood and lymphatic system disorders
Accidental overdoseInjury, poisoning and procedural complications
FallInjury, poisoning and procedural complications
RashSkin and subcutaneous tissue disorders
Upper respiratory tract infectionInfections and infestations
DizzinessNervous system disorders
Abnormal dreamsPsychiatric disorders
Cognitive disorderNervous system disorders
ArthralgiaMusculoskeletal and connective tissue disorders
OsteoarthritisMusculoskeletal and connective tissue disorders
Pain in extremityMusculoskeletal and connective tissue disorders
Cerebral microhaemorrhageNervous system disorders
SomnolenceNervous system disorders
Gait disturbanceGeneral disorders
Viral infectionInfections and infestations
Blood sodium decreasedInvestigations
HyponatraemiaMetabolism and nutrition disorders
NightmarePsychiatric disorders
Urine flow decreasedRenal and urinary disorders
AlopeciaSkin and subcutaneous tissue disorders
Varicose veinVascular disorders

Most-reported serious reactions: Fall, Osteoarthritis, Pneumonia, Influenza, Syncope, Urinary tract infection, Hip fracture, Femur fracture.

Data from ClinicalTrials.gov NCT02956486 adverse events section.

Sponsor's own description

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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies.
    Zhang J, Zhang Y, Wang J, Xia Y, et al · · 2024 · cited 489× · PMID 39174535 · DOI 10.1038/s41392-024-01911-3
  2. Alzheimer's disease drug development pipeline: 2019.
    Cummings J, Lee G, Ritter A, Sabbagh M, et al · · 2019 · cited 485× · PMID 31334330 · DOI 10.1016/j.trci.2019.05.008
  3. Clinical trials of new drugs for Alzheimer disease.
    Huang LK, Chao SP, Hu CJ. · · 2020 · cited 426× · PMID 31906949 · DOI 10.1186/s12929-019-0609-7
  4. Alzheimer's disease drug development pipeline: 2018.
    Cummings J, Lee G, Ritter A, Zhong K. · · 2018 · cited 402× · PMID 29955663 · DOI 10.1016/j.trci.2018.03.009
  5. Alzheimer's disease drug development pipeline: 2020.
    Cummings J, Lee G, Ritter A, Sabbagh M, et al · · 2020 · cited 350× · PMID 32695874 · DOI 10.1002/trc2.12050
  6. Drug candidates in clinical trials for Alzheimer's disease.
    Hung SY, Fu WM. · · 2017 · cited 281× · PMID 28720101 · DOI 10.1186/s12929-017-0355-7
  7. Pathological mechanisms and therapeutic strategies for Alzheimer's disease.
    Ju Y, Tam KY. · · 2022 · cited 260× · PMID 34380884 · DOI 10.4103/1673-5374.320970
  8. Alzheimer's disease drug development pipeline: 2017.
    Cummings J, Lee G, Mortsdorf T, Ritter A, et al · · 2017 · cited 258× · PMID 29067343 · DOI 10.1016/j.trci.2017.05.002

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