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AMARANTH: An Efficacy and Safety Study of Lanabecestat (LY3314814) in Early Alzheimer's Disease

Sponsor
AstraZeneca (Industry)
Overall Status
Terminated
CT.gov ID
NCT02245737
Collaborator
Eli Lilly and Company (Industry)
2,218
Enrollment
254
Locations
3
Arms
48.1
Actual Duration (Months)
8.7
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the efficacy and safety of lanabecestat compared with placebo administered for 104 weeks in the treatment of early Alzheimer´s disease. The study will test the hypothesis that lanabecestat is a disease-modifying treatment for participants with early Alzheimer´s disease, defined as the continuum of participants with mild cognitive impairment (MCI) due to Alzheimer´s disease and participants diagnosed with mild dementia of the Alzheimer´s type, as measured by change from baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) score at week 104 in each of the 2 lanabecestat treatment groups compared with placebo.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Detailed Description

Participants who meet other study entry requirements will be required to undergo either an amyloid positron emission tomography (PET) scan or a lumbar puncture for cerebrospinal fluid (CSF) sampling at screening to document presence of abnormal levels of brain and CSF amyloid for study inclusion. The study includes 2 sub-studies: the participants that undergo a PET scan at screening will be included in the PET-substudy, and participants who undergo a lumbar puncture at screening will be included in the CSF substudy until each of these substudies are completed.

Study Design

Study Type:
Interventional
Actual Enrollment :
2218 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
A 24-month, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy, Safety, Tolerability, Biomarker, and Pharmacokinetic Study of AZD3293 in Early Alzheimer's Disease (The AMARANTH Study)
Actual Study Start Date :
Sep 30, 2014
Actual Primary Completion Date :
Oct 4, 2018
Actual Study Completion Date :
Oct 4, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Lanabecestat 20 milligrams (mg)

Lanabecestat 20 mg given orally once daily for 104 weeks.

Drug: Lanabecestat
Administered orally
Other Names:
  • LY3314814
  • AZD3293

    		•
    Experimental: Lanabecestat 50 mg

    Lanabecestat 50 mg given orally once daily for 104 weeks.

    Drug: Lanabecestat
    Administered orally
    Other Names:
  • LY3314814
  • AZD3293

    		•
    Placebo Comparator: Placebo

    Placebo given orally once daily for 104 weeks.

    Drug: Placebo
    Administered orally

    Outcome Measures

    Primary Outcome Measures

    1. Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) [Baseline, Week 104]

      ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.

    Secondary Outcome Measures

    1. Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL) [Baseline, Week 104]

      The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction.

    2. Change From Baseline on the Functional Activities Questionnaire (FAQ) Score [Baseline, Week 104]

      FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did [the activity] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). FAQ scale is 0 to 30, with higher scores indicating greater impairment. LS Mean was calculated by MMRM with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline and pooled country.

    3. Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score [Baseline, Week 104]

      The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS- Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by- visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction.

    4. Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score [Baseline, Week 104]

      The CDR-SB is a rater administered scale and impairment is scored in of the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction.

    5. Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage [Baseline through Loss of 1 Global Stage or Week 104]

      The CDR global score is a composite score calculated using the Washington University CDR-assignment algorithm applied to the 6 individual domain box scores (Morris 1993). The memory domain is considered the primary category that drives the CDR global outcome, and all other domains are secondary. The CDR global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia).

    6. Change From Baseline in Neuropsychiatric Inventory (NPI) Score [Baseline, Week 104]

      The NPI is a questionnaire administered to caregivers that quantifies behavioral changes. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144, with higher scores indicating greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline NPI score, age at baseline, and baseline NPI score-by-visit interaction.

    7. Change From Baseline on the Mini-Mental State Examination (MMSE) [Baseline, Week 104]

      The MMSE is an instrument used to assess a participant's global cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with a higher score indicating better cognitive performance. LS mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction.

    8. Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42 [Baseline, Week 97]

      Concentration of the peptide Aβ 1-42 in plasma measured by validated immunoassay. LS Mean was determined by Analysis of covariance (ANCOVA) with last observation carried forward (LOCF), terms for treatment, baseline biomarker and age at baseline.

    9. PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40 [Baseline, Week 97]

      Concentration of the peptide Aβ 1-40 in plasma measured by immunoassay. LS Mean was determined by ANCOVA with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline.

    10. Change From Baseline in CSF Total Tau [Baseline, Week 97]

      Cerebrospinal fluid samples are collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.

    11. Change From Baseline in CSF Phosphorylated Tau [Baseline, Week 97]

      Cerebrospinal fluid samples are collected for analysis of concentrations of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.

    12. Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan [Baseline, Week 104]

      Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease. Florbetapir exhibits high affinity specific binding to amyloid plaques. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by florbetapir amyloid PET imaging in a subset of participants. The Centiloid scale standardizes quantitative brain amyloid PET results to allow cross-tracer and cross-methodology comparisons. 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. Florbetapir SUVr was converted to the Centiloid scale using the following conversion: Florbetapir Centiloids = 183 x SUVr - 177. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.

    13. Change From Baseline in Tau PET ((Flortaucipir F18) [Baseline, Week 104]

      Tau PET tracer (flortaucipir F18) longitudinal study measured whether lanabecestat, in participants with mild AD dementia, affected tau density and distribution over time. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the signal intensity in white matter. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.

    14. Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG) [Baseline, Week 104]

      Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the pons + vermis assessed with composite meta and composite meta automated anatomical labeling atlas (ALL). Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.

    15. Change From Baseline in Whole Brain Volume [Baseline, Week 104]

      Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on whole brain volumes. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, baseline vMRI, intracranial volume, disease status at baseline and age at baseline.

    16. Pharmacokinetics (PK): Plasma Concentration of Lanabecestat [Week 4, post dose prior to departure from the clinic]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    55 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Gradual and progressive change in the participant's memory function over more than 6 months, reported by participant and study partner

    • Mini-Mental State Examination score of 20-30 inclusive at screening

    • Objective impairment in memory as evaluated by memory test performed at screening

    • For a diagnosis of mild Alzheimer's Disease (AD), participant meets the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria for probable AD

    • For a diagnosis of MCI due to AD, participant meets NIA-AA criteria for MCI due to AD

    Exclusion Criteria:

    • Significant neurological disease affecting the central nervous system, other than AD, that may affect cognition or ability to complete the study, including but not limited to, other dementias, serious infection of the brain, Parkinson´s disease, or epilepsy or recurrent seizures

    • History of clinically evident stroke, or multiple strokes based on history or imaging results

    • History of clinically important carotid or vertebrobasilar stenosis or plaque

    • History of multiple concussions with sustained cognitive complaints or objective change in neuropsychological function in the last 5 years

    • Participants with a current Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition diagnosis of Major Depressive Disorder or any current primary psychiatric diagnosis other than AD if, in the judgment of the investigator, the psychiatric disorder or symptom is likely to confound interpretation of drug effect, affect cognitive assessments, or affect the participant´s ability to complete the study

    • History of alcohol or drug abuse or dependence (except nicotine dependence) within 2 years before the screening

    • Within 1 year before the screening or between screening and baseline, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptom of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (eg, significant valvular disease, hypertrophic cardiomyopathy), or hospitalization for arrhythmia

    • Congenital QT prolongation

    • History of cancer within the last 5 years, with the exception of non-metastatic basal and/or squamous cell carcinoma of the skin, in situ cervical cancer, non-progressive prostate cancer or other cancers with low-risk of recurrence or spread

    • Current serious or unstable clinically important systemic illness that, in the judgment of the investigator, is likely to affect cognitive assessment, deteriorate, or affect the participant's safety or ability to complete the study, including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, immunologic, or hematologic disorders

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Banner Alzheimer's Institute Phoenix Arizona United States 85006
    2 St Josephs Hospital and Medical Center Phoenix Arizona United States 85013
    3 Banner Sun Health Research Institute Sun City Arizona United States 85351
    4 Territory Neurology & Research Institute Tucson Arizona United States 85704
    5 Positron Research International Fremont California United States 94538
    6 Alliance Research Centers Laguna Hills California United States 92653
    7 Senior Clinical Trials, Inc. Laguna Hills California United States 92653
    8 Collaborative Neuroscience Network - CNS Long Beach California United States 90806
    9 Pacific Research Network Inc San Diego California United States 92103
    10 San Francisco Clinical Research Center San Francisco California United States 94109
    11 Mile High Research Center Denver Colorado United States 80218
    12 Institute for Neurodegenerative Disorders New Haven Connecticut United States 06510
    13 Georgetown University Medical Center Washington District of Columbia United States 20057
    14 Brain Matters Research Delray Beach Florida United States 33445
    15 Direct Helpers Medical Center Hialeah Florida United States 33012
    16 Berma Research Hialeah Florida United States 33016
    17 Galiz Research Hialeah Florida United States 33016
    18 MaxBlue Institute Hialeah Florida United States 33018
    19 Alzheimer's Research and Treatment Center Lake Worth Florida United States 33449
    20 Miami Jewish Health Systems Miami Florida United States 33137
    21 Medical Research Center Miami Florida United States 33144
    22 Allied Biomedical Research Institute, Inc. Miami Florida United States 33155
    23 Advance Medical Research Institute Miami Florida United States 33174
    24 New Horizon Research Center Miami Florida United States 33175
    25 JDH Medical Group, LLC Miami Florida United States 33186
    26 Compass Research Orlando Florida United States 32806
    27 IMIC, Inc. Palmetto Bay Florida United States 33157
    28 Suncoast Neuroscience Associates Saint Petersburg Florida United States 33713
    29 Roskamp Institute Sarasota Florida United States 34243
    30 Infinity Clinical Research, LLC Sunrise Florida United States 33351
    31 Stedman Clinical Trials Tampa Florida United States 33613
    32 Olympian Clinical Research Tampa Florida United States 33614
    33 Compass Research The Villages Florida United States 32162
    34 Premiere Research Institute at Palm Beach Neurology West Palm Beach Florida United States 33407
    35 The Multiple Sclerosis Center of Atlanta Atlanta Georgia United States 30327
    36 Atlanta Center of Medical Research Atlanta Georgia United States 30331
    37 Carman Research Smyrna Georgia United States 30080
    38 University of Chicago Medical Center Chicago Illinois United States 60637
    39 Alexian Brothers Medical Center Elk Grove Village Illinois United States 60007
    40 Community Clinical Research Center Anderson Indiana United States 46011
    41 Indiana University School of Medicine Indianapolis Indiana United States 46202
    42 ActivMed Practices & Research, Inc Methuen Massachusetts United States 01844
    43 Boston Center for Memory Newton Massachusetts United States 02459
    44 Springfield Neurology Associates Springfield Massachusetts United States 01104
    45 Hattiesburg Clinic Hattiesburg Mississippi United States 39401
    46 Millennium Psychiatric Associates, LLV Saint Louis Missouri United States 63141
    47 St. Louis Clinical Trials, LC Saint Louis Missouri United States 63141
    48 Memory Enhancement Center of America, Inc. Eatontown New Jersey United States 07724
    49 AdvanceMed Research Lawrenceville New Jersey United States 08648
    50 Alzheimer's Research Company Manchester New Jersey United States 08759
    51 The Cognitive and Research Center of NJ Springfield New Jersey United States 07081
    52 Advanced Memory Research Institute of New Jersey Toms River New Jersey United States 08755
    53 Bio Behavioral Health Toms River New Jersey United States 08755
    54 Neurology Specialists of Monmouth County West Long Branch New Jersey United States 07764
    55 Integrative Clinical Trials, LLC Brooklyn New York United States 11229
    56 SPRI Clinical Trials, LLC. Brooklyn New York United States 11235
    57 Alzheimer's Disease and Memory Disorders Center Buffalo New York United States 14203
    58 Empire Neurology, PC Latham New York United States 12110
    59 Clinilabs, Inc (New York) New York New York United States 10019
    60 Columbia University Medical Center New York New York United States 10032
    61 University of Rochester Rochester New York United States 14620
    62 Alzheimer's Memory Center Charlotte North Carolina United States 28270
    63 Valley Medical Primary Care Centerville Ohio United States 45459
    64 Christ Hospital Cincinnati Ohio United States 45219
    65 Ohio State University Medical Center Columbus Ohio United States 43221
    66 The Corvallis Clinic P.C. Corvallis Oregon United States 97330
    67 Lehigh Valley Hospital Allentown Pennsylvania United States 18103
    68 Rhode Island Mood & Memory Research Institute East Providence Rhode Island United States 02914
    69 Roper St. Francis Healthcare Charleston South Carolina United States 29401
    70 Radiant Research Greer South Carolina United States 29651
    71 Quillen College of Medicine, East TN State University Johnson City Tennessee United States 37605
    72 Senior Adults Specialty Research Inc Austin Texas United States 78757
    73 Texas Health Physicians Group Dallas Texas United States 75231
    74 Medical Group of Texas Fort Worth Texas United States 76104
    75 University of Texas Health Services Center - Houston Houston Texas United States 77054
    76 University of Utah School of Medicine Salt Lake City Utah United States 84108
    77 The Memory Clinic Bennington Vermont United States 05201
    78 Southern Neurology Kogarah New South Wales Australia 2217
    79 Griffith University Gold Coast Queensland Australia 4222
    80 Royal Adelaide Hospital Adelaide South Australia Australia 5000
    81 Box Hill Hospital Box Hill Victoria Australia 3128
    82 Delmont Private Hospital Glen Iris Victoria Australia 3146
    83 Heidelberg Repatriation Hospital Heidelberg Victoria Australia 3081
    84 The Florey Institute of Neuroscience and Mental Health Parkville Victoria Australia 3052
    85 Australian Alzheimer's Research Foundation Nedlands Western Australia Australia 6009
    86 Neuro Trials Victoria Pty Ltd Noble Park Australia 3174
    87 Jessa Ziekenhuis Hasselt Limburg Belgium 3500
    88 Hopital Universitaire Brugmann Brussel Brussels Belgium 1020
    89 Cliniques Universitaires Saint-Luc Brussels Belgium 1200
    90 Hospital Universitaire Erasme Brussel Brussel Belgium 1070
    91 Universitair Ziekenhuis Antwerpen Edegem Belgium 2650
    92 Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg Leuven Belgium 3000
    93 Heilig Hartziekenhuis Roeselare Belgium 8800
    94 The Medical Arts Health Research Group Kamloops British Columbia Canada V2C 1K7
    95 Okanagan Clinical Trials Kelowna British Columbia Canada V1Y 1Z9
    96 University of British Columbia Vancouver British Columbia Canada V6T 2B5
    97 Royal Jubilee Hospital Victoria British Columbia Canada V8R 158
    98 True North Clinical Research Halifax, LLC Halifax Nova Scotia Canada B3S1M7
    99 Bruyere Continuing Care Ottawa Ontario Canada K1N 5C8
    100 Kawartha Regional Memory Clinic Peterborough Ontario Canada K9H2P4
    101 Toronto Memory Program Toronto Ontario Canada M3B2S7
    102 Toronto Western Hospital Toronto Ontario Canada M5T2S8
    103 CSSS-Institut Universitaire Gériatric de Sherbrooke Sherbrooke Qubec Canada J1J3H5
    104 Clinique de la Memoire de l'Outaouais Gatineau Quebec Canada J8T 8J1
    105 NeuroSearch Developements Greenfield Park Quebec Canada J4V 2J2
    106 Hopital Maisonneure-Rosemount Montreal Quebec Canada H1T 2M4
    107 Hopital de L'Enfant Jesus Quebec City Quebec Canada G1J 1Z4
    108 Q&T Research Sherbrooke Inc Sherbrooke Quebec Canada J1J 2G2
    109 CHU de Toulouse Hopital Purpan Toulouse Cedex 9 France 31059
    110 Hopital Neuro Pierre Wertheimer Bron Cedex France 69677
    111 CHU Dijonon Dijon Cedex France 21033
    112 CHRU Lille - Hopital Roger Salengro Lille Cedex France 59037
    113 CHU Hopital de la Timone Marseille Cedex 05 France 13385
    114 Chu de Nantes Hopital Laennec Nantes France 44093
    115 Hopital Broca Paris France 75013
    116 Hopital de la Pitie Salpetriere Paris France 75013
    117 Hopital Lariboisière Paris France 75475
    118 CHU de Toulouse Toulouse France 31052
    119 Hopital des Charpennes Villeurbanne France 69100
    120 Universitätsklinikum Tübingen Tübingen Baden-Württemberg Germany 72076
    121 Universitätsklinikum Ulm Ulm Baden-Württemberg Germany 89081
    122 Studien und Gedächtniszentrum München München Bayern Germany 80331
    123 Klinikum Rechts der Isar der TU München München Bayern Germany 81675
    124 Institut fur Psychogerontologie Nürnberg Bayern Germany 90402
    125 Neurozentrum Prien Prien am Chiemsee Bayern Germany 83209
    126 Institut für Neuropsychiatrie INP3 Wenzenbach Bayern Germany 93173
    127 Studienzentrum Nord-West Westerstede Niedersachsen Germany 26655
    128 Praxis Dr. Lauter Bochum Nordrhein-Westfalen Germany 44787
    129 St Josef-Hospital Bochum Bochum Nordrhein-Westfalen Germany 44791
    130 Universitätsklinikum Bonn Bonn Nordrhein-Westfalen Germany 53105
    131 Gemeinschaftspraxis für Neurologie Prof. Gereon Nelles Köln Nordrhein-Westfalen Germany 50935
    132 Universitätsklinikum Köln Köln Nordrhein-Westfalen Germany 50937
    133 Neurologische Praxis Siegen Siegen Nordrhein-Westfalen Germany 57076
    134 Universitätsklinikum des Saarlandes Homburg Saarland Germany 66421
    135 Martin-Luther-Universität Halle-Wittenberg Halle (Saale) Sachsen-Anhalt Germany 06097
    136 Universitätsklinikum Otto-von-Guericke-Universität Magdeburg Sachsen-Anhalt Germany 39120
    137 Pharmakologisches Studienzentrum Chemnitz Mittweida Sachsen Germany 09648
    138 Arztpraxis Dr. Christian Oehlwein Gera Thüringen Germany 07551
    139 Gemeinschaftspraxis Dr. R. Ehret & Dr. W. von Pannwitz Berlin Germany 12163
    140 Charité Universitätsmedizin Berlin Berlin Germany 12203
    141 Charité Universitätsmedizin Berlin Berlin Germany 13353
    142 PTE KK Pszichiatriai es Pszichoterapias Klinika Pecs Baranya Hungary 7623
    143 Semmelweis Medical University Budapest Hungary 1083
    144 Del-pesti Centrumkorház - Orszagos Hematologiai és Infektologiai Intezet Budapest Hungary 1097
    145 Debreceni Egyetem Kenezy Gyula Egyetemi Korhaz Debrecen Hungary 4031
    146 Debreceni Egyetem Klinikai Kozpont Debrecen Hungary 4032
    147 Univerisity of Szeged Szeged Hungary 6725
    148 Ospedale Degli Infermi ASR USSL 12 Ponderano Biella Italy 13875
    149 Azienda Ospedaliera San Gerardo Monza Milano Italy 20900
    150 Fondazione San Raffaele Giglio di Cefalu Cefalu Palermo Italy 90015
    151 Universita Di Pisa Pisa PI Italy 56126
    152 Università Politecnica delle Marche Torrette Ancona Italy 60126
    153 IRCCS San Giovanni di Dio Fatebenefratelli Brescia Italy 25125
    154 Fondazione Universitaria degli Studi G D'Annunzio Chieti Italy 66100
    155 Ente Ospedaliero Ospedali Galliera Genova Italy 16132
    156 Fondazione IRCCS Ca'Granda Ospedale Maggiore Policinico Milano Italy 20122
    157 Nuovo Ospedale Civile Sant'Agostino Estense Modena Italy 41010
    158 Policlinico Univ. Agostino Gemelli Roma Italy 00168
    159 Dip.to Med. Sperimentale -Polic.Umberto I -Univ. La Sapienza Roma Italy 00185
    160 Ospedale San Giovanni Calibita Fatebenefratelli Roma Italy 00186
    161 Policlinico Ospedale S. Andrea Roma Italy 00189
    162 Azienda Ospedaliera Citta della Salute della Scienza Torino Torino Italy 10126
    163 National Institute for Longevity Sciences NCGG Obu Aichi Japan 474-0038
    164 National Chiba-East-Hospital Chuo-ku Chiba Japan 260-8712
    165 National Hospital Organization Asahikawa Medical Center Asahikawa Hokkaido Japan 070-8644
    166 Tsukuba University Hospital Tsukuba Ibaraki Japan 305-8576
    167 Iwate Medical University Hospital Morioka Iwate Japan 020-8505
    168 Shonan Kamakura General Hospital Kamakura Kanagawa Japan 247-8533
    169 Nihon Kokan Hospital Kawasaki Kanagawa Japan 210-0852
    170 Yokohama City University Hospital Yokohama Kanagawa Japan 236-0004
    171 Kyoto Prefectural University of Medicine Kyoto-shi Kyoto Japan 602-8566
    172 Rakuwakai Otowarehabilitation Hospital Kyoto-shi Kyoto Japan 607-8113
    173 Ina Central Hospital Ina Nagano Japan 396-8555
    174 Matsumoto Medical Center Matsumoto Nagano Japan 399-0021
    175 Katayama Medical Clinic Kurashiki Okayama Japan 701-0192
    176 Shiroma Clinic Urasoe Okinawa Japan 901-2102
    177 Koshokai aino hospital Ibaraki Osaka Japan 567-0011
    178 Sakaguchi Clinic Sakai Osaka Japan 593-8301
    179 National Sanatorium Toneyama Hospital Toyonaka Osaka Japan 560-8552
    180 Saitama Medical University Hospital Iruma-Gun Saitama Japan 350-0495
    181 Nippon Medical School Hospital Bunkyo-Ku Tokyo Japan 113-8603
    182 The University of Tokyo Hospital Bunkyo-ku Tokyo Japan 113-8655
    183 Nozomi Memory Clinic Mitaka-shi Tokyo Japan 181-0013
    184 Sangenjaya Nakamura Mental Clinic Setagaya Tokyo Japan 154-0004
    185 Kanauchi Medical Clinic Shinjuku-ku Tokyo Japan 160-0023
    186 Tokyo Women's Medical University Hospital Shinjuku-ku Tokyo Japan 162-8666
    187 Memory Clinic Ochanomizu Tsukuba Tokyo Japan 305 8576
    188 National Sanatorium Hokuriku Hospital Nanto Toyama Japan 939-1893
    189 Fukuoka University Hospital Fukuoka Japan 814-0180
    190 Kyoto University Hospital Kyoto Japan 606-8507
    191 Kyoto Minami Hospital Kyoto Japan 610-0113
    192 Utano Hospital Kyoto Japan 616-8255
    193 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Osaka Japan 545-8586
    194 Dong-A University Medical Center Seogu Busan Korea, Republic of 49201
    195 Seoul National University Bundang Hospital Seongnam-si Geonggi-do Korea, Republic of 13620
    196 The Catholic University of Korea-Bucheon St. Mary's Hospital Bucheon-si Gyeonggi-do Korea, Republic of 14647
    197 Hanyang University Guri Hospital Guri-si Gyeonggido Korea, Republic of 11923
    198 Gachon University Gil Medical Center Namdong Incheon Korea, Republic of 21565
    199 Inha University Hospital Incheon Korea, Republic of 22332
    200 Asan Medical Center Seoul Korea, Republic of 05505
    201 Samsung Medical Center Seoul Korea, Republic of 06351
    202 Seoul St. Mary's Hospital Seoul Korea, Republic of 06591
    203 NZOZ Wroclawskie Centrum Alzheimerowskie Wroclaw Dolnoslaskie Poland 53 139
    204 Medycyna Milorzab Lodz Lódzkie Poland 92216
    205 Podlaskie Centrum Psychogeriatrii Białystok Podlaskie Poland 15-732
    206 NZOZ Dom Sue Ryder - Pallmed Sp. z o.o. Bydgoszcz Poland 85-796
    207 NZOZ Wielospecjalistyczna Poradnia Lekarska Katowice Poland 40-123
    208 Specjalistyczna Praktyka Lekarska prof. Grzegorz Opala Katowice Poland 40-588
    209 Centrum Zdrowia Psychicznego Kielce Poland 25411
    210 Centrum Neurologii Klinicznej Krakow Poland 31-505
    211 NZOZ Neuromed M. I M. Nastaj sp. P. Lublin Poland 20-064
    212 Instytut Medycyny Wsi Lublin Poland 20-090
    213 NEURO-CARE Sp. z o.o. Sp. Komandytowa Siemianowice Śląskie Poland 41-100
    214 Centrum Medyczne Warszawa Poland 01-697
    215 Centralny Szpital Kliniczny MSW Warszawa Poland 02-507
    216 Santa Cruz Behavioral PSC Bayamon Puerto Rico 00961
    217 Ivonne Z. Jimenez-Velazquez, MD Carolina Puerto Rico 00984
    218 Instituto de Neurologia Dra. Ivonne Fraga San Juan Puerto Rico 00918
    219 Michel A. Woodbury-Farina, MD. San Juan Puerto Rico 00918
    220 SC Med Life SA Bucuresti Romania 010719
    221 SC Centrul Medical Sana SRL Bucuresti Romania 011025
    222 Policlinica CCBR S.R.L. Bucuresti Romania 30463
    223 SC Med Life SA Timisoara Romania 300166
    224 Hospital General Universitario de Elche Elche Alicante Spain 03203
    225 Hospital General de Catalunya Sant Cugat del Valles Barcelona Spain 08190
    226 Hospital Virgen Del Puerto Plasencia Caceres Spain 10600
    227 Hospital Universitario De Getafe Madrid Getafe Spain 28905
    228 Hospital Puerta De Hierro Majadahonda Madrid Spain 28222
    229 Centro de Atencion Especializada (CAE) OROITU Getxo Vizcaya Spain 48993
    230 Hospital del Mar Barcelona Spain 08003
    231 Hospital Santa Creu I Sant Pau Barcelona Spain 08025
    232 Fundacion ACE-Institut Catala de Neurociences Aplicades Barcelona Spain 08028
    233 Hospital Clinic de Barcelona Barcelona Spain 08036
    234 Hospital Universitari de Bellvitge Barcelona Spain 08907
    235 Hospital Reina Sofia Cordoba Spain 14004
    236 Hospital De La Princesa Madrid Spain 28006
    237 Hospital Universitario Ramon y Cajal Madrid Spain 28034
    238 Hospital Son Espases Palma de Mallorca Spain 07010
    239 Hospital Univ Sant Joan de Reus, S.A. Reus Spain 43204
    240 Fundacion CITA Alzheimer San Sebastian Spain 20009
    241 Hospital Doctor Peset Valencia Spain 46017
    242 Hospital Universitario La Fe de Valencia Valencia Spain 46026
    243 Plymouth Hospitals NHS Trust Plymouth Devon United Kingdom PL6 8BX
    244 Cognitive Treatment & Research Unit Crowborough East Sussex United Kingdom TN6 1HB
    245 Southern Health NHS Southampton Hampshire United Kingdom SO30 3JB
    246 MAC UK Neuroscience Ltd Blackpool Lancs United Kingdom FY20JH
    247 MAC Clinical Research Stourton Leeds United Kingdom LS10 1DU
    248 MAC Clinical Research Cannock Staffordshire United Kingdom WS11 0BN
    249 West London Mental Health NHS Trust Brentford United Kingdom TW8 8DS
    250 Glasgow Memory Clinic Glasgow United Kingdom G20 0XA
    251 Hammersmith Hospital London United Kingdom W12 0NN
    252 Guildford Nuffield Hospital London United Kingdom W1G 9JF
    253 Re-Cognition Health Ltd London United Kingdom W1G 9RU
    254 MAC Clinical Research Manchester United Kingdom M13 9NQ

    Sponsors and Collaborators

    • AstraZeneca
    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon- Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT02245737
    Other Study ID Numbers:
    • 16023
    • I8D-MC-AZES
    • 2014-002601-38
    • D5010C00009
    First Posted:
    Sep 22, 2014
    Last Update Posted:
    Dec 3, 2019
    Last Verified:
    Oct 1, 2019
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Keywords provided by AstraZeneca
    Alzheimer's disease
    Dementia
    Brain Diseases
    Neurogenerative Diseases
    Central Nervous System Diseases
    Nervous System Diseases
    Mental Disorders
    Delirium, Dementia, Amnestic, Cognitive Disorders
    Tauopathies
    Additional relevant MeSH terms:
    Alzheimer Disease

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Placebo Lanabecestat 20 Milligrams (mg) Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Period Title: Overall Study
    STARTED 740 739 739
    Received at Least 1 Dose of Study Drug 738 736 735
    COMPLETED 187 184 168
    NOT COMPLETED 553 555 571

    Baseline Characteristics

    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg Total
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily. Total of all reporting groups
    Overall Participants 740 739 739 2218
    Age (Years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Years]
    71.4
    (6.9)
    71.2
    (7.5)
    71.2
    (7.0)
    71.3
    (7.1)
    Sex: Female, Male (Count of Participants)
    Female
    398
    53.8%
    395
    53.5%
    384
    52%
    1177
    53.1%
    Male
    342
    46.2%
    344
    46.5%
    355
    48%
    1041
    46.9%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    43
    5.8%
    26
    3.5%
    24
    3.2%
    93
    4.2%
    Not Hispanic or Latino
    626
    84.6%
    650
    88%
    644
    87.1%
    1920
    86.6%
    Unknown or Not Reported
    71
    9.6%
    63
    8.5%
    71
    9.6%
    205
    9.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    85
    11.5%
    85
    11.5%
    102
    13.8%
    272
    12.3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    5
    0.7%
    5
    0.7%
    6
    0.8%
    16
    0.7%
    White
    598
    80.8%
    609
    82.4%
    593
    80.2%
    1800
    81.2%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    52
    7%
    40
    5.4%
    38
    5.1%
    130
    5.9%
    Region of Enrollment (Count of Participants)
    Puerto Rico
    13
    1.8%
    11
    1.5%
    12
    1.6%
    36
    1.6%
    Romania
    1
    0.1%
    2
    0.3%
    2
    0.3%
    5
    0.2%
    Hungary
    7
    0.9%
    12
    1.6%
    6
    0.8%
    25
    1.1%
    United States
    171
    23.1%
    171
    23.1%
    179
    24.2%
    521
    23.5%
    Japan
    48
    6.5%
    57
    7.7%
    78
    10.6%
    183
    8.3%
    United Kingdom
    85
    11.5%
    87
    11.8%
    78
    10.6%
    250
    11.3%
    Spain
    74
    10%
    77
    10.4%
    65
    8.8%
    216
    9.7%
    Canada
    58
    7.8%
    59
    8%
    63
    8.5%
    180
    8.1%
    South Korea
    30
    4.1%
    24
    3.2%
    16
    2.2%
    70
    3.2%
    Belgium
    20
    2.7%
    15
    2%
    15
    2%
    50
    2.3%
    Poland
    58
    7.8%
    51
    6.9%
    50
    6.8%
    159
    7.2%
    Italy
    45
    6.1%
    38
    5.1%
    49
    6.6%
    132
    6%
    Australia
    38
    5.1%
    55
    7.4%
    38
    5.1%
    131
    5.9%
    France
    45
    6.1%
    36
    4.9%
    36
    4.9%
    117
    5.3%
    Germany
    47
    6.4%
    44
    6%
    52
    7%
    143
    6.4%
    ADAS-Cog13 (13-item Alzheimer's Disease Assessment Scale) (Units on a Scale) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [Units on a Scale]
    28.6
    (7.9)
    29.0
    (7.7)
    28.5
    (8.2)
    28.7
    (8.0)

    Outcome Measures

    1. Primary Outcome
    Title Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13)
    Description ADAS-Cog13 (13-item version of ADAS-Cog) is a psychometric instrument that evaluates word recall, ability to follow commands, constructional praxis, naming, ideational praxis, orientation, word recognition, memory, comprehension of spoken language, word-finding, and language ability, with a measure of delayed word recall and concentration/ distractibility. The total score of the 13-item scale ranges from 0 to 85, with an increase in score indicating cognitive worsening. Least Squares (LS) mean was determined by mixed-model repeated measures (MMRM) model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, pooled country, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADAS-Cog13 measure.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 723 722 708
    Least Squares Mean (Standard Error) [Units on a scale]
    10.31
    (0.55)
    9.38
    (0.56)
    10.72
    (0.58)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.232
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.93
    Confidence Interval (2-Sided) 95%
    -2.447 to 0.594
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.77
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.599
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.41
    Confidence Interval (2-Sided) 95%
    -1.124 to 1.947
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.78
    Estimation Comments
    2. Secondary Outcome
    Title Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL)
    Description The ADCS-ADL is a 23-item inventory developed as a rater-administered questionnaire answered by the participant's caregiver. The ADCS-ADL measures both basic and instrumental activities of daily living by participants. The range for the ADCS-iADL is 0-59 with higher scores reflecting better performance. LS Mean was determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for ADCS-iADL measure.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 702 700 674
    Least Squares Mean (Standard Error) [Units on a scale]
    -8.87
    (0.60)
    -8.84
    (0.61)
    -8.79
    (0.63)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.971
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.03
    Confidence Interval (2-Sided) 95%
    -1.609 to 1.669
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.83
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.923
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.08
    Confidence Interval (2-Sided) 95%
    -1.580 to 1.743
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.85
    Estimation Comments
    3. Secondary Outcome
    Title Change From Baseline on the Functional Activities Questionnaire (FAQ) Score
    Description FAQ is a 10-item, caregiver-based questionnaire and was administered to the study partner who was asked to rate the participant's ability to perform a variety of activities ranging from writing checks, assembling tax records, shopping, playing games, food preparation, traveling, keeping appointments, traveling out of neighborhood, keeping track of current events and understanding media. FAQ total score was calculated by adding the scores from each of the 10 items. Each activity is rated on a scale from 0 to 3 (Never did and would have difficulty now = 1; Never did [the activity] but could do now = 0; Normal = 0; Has difficulty but does by self = 1; Requires assistance = 2; Dependent = 3). FAQ scale is 0 to 30, with higher scores indicating greater impairment. LS Mean was calculated by MMRM with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline and pooled country.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for FAQ score.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 699 697 674
    Least Squares Mean (Standard Error) [Units on a scale]
    6.09
    (0.38)
    5.96
    (0.39)
    6.71
    (0.40)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.796
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.14
    Confidence Interval (2-Sided) 95%
    -1.172 to 0.899
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.53
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.252
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.61
    Confidence Interval (2-Sided) 95%
    -0.437 to 1.660
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.53
    Estimation Comments
    4. Secondary Outcome
    Title Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score
    Description The iADRS is a composite that measures both cognition and function. The iADRS comprises scores form the ADAS- Cog and the ADCS-iADL. The iADRS is calculated as a linear combination of the total scores of the ADAS-Cog13 (score range 0 to 85 with higher scores reflecting worse performance) and the ADCS-iADL (score range from 0-59 with higher scores reflecting better performance). The iADRS score ranges from 0 to 144 with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by- visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for iADRS.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 696 689 662
    Least Squares Mean (Standard Error) [Units on a scale]
    -19.56
    (0.99)
    -18.45
    (1.02)
    -19.69
    (1.05)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.428
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 1.11
    Confidence Interval (2-Sided) 95%
    -1.637 to 3.852
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.40
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.926
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.13
    Confidence Interval (2-Sided) 95%
    -2.918 to 2.655
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.42
    Estimation Comments
    5. Secondary Outcome
    Title Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
    Description The CDR-SB is a rater administered scale and impairment is scored in of the following categories: memory, orientation, judgment and problem solving, community affairs, home and hobbies and personal care. Impairment is scored on a scale in which no dementia = 0, questionable dementia = 0.5, mild dementia = 1, moderate dementia = 2 and severe dementia = 3. The 6 individual category ratings, or "box scores", were added together to give the CDR-Sum of Boxes which ranges from 0-18, with higher scores indicating greater impairment. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR-SB.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 704 705 676
    Least Squares Mean (Standard Error) [Units on a scale]
    3.02
    (0.17)
    3.17
    (0.17)
    3.17
    (0.18)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.533
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.15
    Confidence Interval (2-Sided) 95%
    -0.322 to 0.622
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.24
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.537
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.15
    Confidence Interval (2-Sided) 95%
    -0.328 to 0.630
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.24
    Estimation Comments
    6. Secondary Outcome
    Title Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage
    Description The CDR global score is a composite score calculated using the Washington University CDR-assignment algorithm applied to the 6 individual domain box scores (Morris 1993). The memory domain is considered the primary category that drives the CDR global outcome, and all other domains are secondary. The CDR global score ranges from 0 to 3 (0 = no dementia, 0.5 = questionable dementia, 1 = mild dementia, 2 = moderate dementia, 3 = severe dementia).
    Time Frame Baseline through Loss of 1 Global Stage or Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CDR Global Score.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 716 714 696
    Median (95% Confidence Interval) [Days]
    548
    547
    548
    7. Secondary Outcome
    Title Change From Baseline in Neuropsychiatric Inventory (NPI) Score
    Description The NPI is a questionnaire administered to caregivers that quantifies behavioral changes. Each of the 12 behavioral domains the caregiver reports as present are scored for Frequency, scale: 1 (Occasionally) to 4 (Very Frequently), and Severity, scale: 1 (Mild) to 3 (Severe). If the domain is reported by the caregiver as 'Not Affected,' that domain is scored as 0. The individual domain scores are calculated by multiplying the frequency times the severity for each domain. NPI Total Score is calculated by adding the individual domain scores together for all 12 domains, with a scores range from 0 to 144, with higher scores indicating greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline NPI score, age at baseline, and baseline NPI score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for NPI.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 697 695 663
    Least Squares Mean (Standard Error) [Units on a scale]
    3.22
    (0.81)
    4.99
    (0.83)
    4.67
    (0.85)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.116
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 1.77
    Confidence Interval (2-Sided) 95%
    -0.441 to 3.986
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.13
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.208
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 1.45
    Confidence Interval (2-Sided) 95%
    -0.808 to 3.704
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.15
    Estimation Comments
    8. Secondary Outcome
    Title Change From Baseline on the Mini-Mental State Examination (MMSE)
    Description The MMSE is an instrument used to assess a participant's global cognitive function. The MMSE assesses orientation to time and place, immediate and delayed recall of words, attention and calculation, language (naming, comprehension and repetition), and spatial ability (copying a figure). The range for MMSE total Score is 0 to 30, with a higher score indicating better cognitive performance. LS mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, pooled country, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for MMSE.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 723 725 709
    Least Squares Mean (Standard Error) [Units on a scale]
    -5.50
    (0.26)
    -5.18
    (0.26)
    -5.49
    (0.27)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.379
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.32
    Confidence Interval (2-Sided) 95%
    -0.391 to 1.027
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.36
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.992
    Comments
    Method Mixed Models Analysis
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value 0.00
    Confidence Interval (2-Sided) 95%
    -0.714 to 0.721
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.37
    Estimation Comments
    9. Secondary Outcome
    Title Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42
    Description Concentration of the peptide Aβ 1-42 in plasma measured by validated immunoassay. LS Mean was determined by Analysis of covariance (ANCOVA) with last observation carried forward (LOCF), terms for treatment, baseline biomarker and age at baseline.
    Time Frame Baseline, Week 97

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-42.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 63 66 79
    Least Squares Mean (Standard Error) [Percent change in Aβ1-42]
    -2.64
    (2.07)
    -53.91
    (2.04)
    -68.13
    (1.87)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -51.27
    Confidence Interval (2-Sided) 95%
    -56.963 to -45.578
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.89
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -65.48
    Confidence Interval (2-Sided) 95%
    -70.947 to -60.022
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.77
    Estimation Comments
    10. Secondary Outcome
    Title PD: Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40
    Description Concentration of the peptide Aβ 1-40 in plasma measured by immunoassay. LS Mean was determined by ANCOVA with LOCF (last observation carried forward), terms for treatment, baseline biomarker and age at baseline.
    Time Frame Baseline, Week 97

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Aβ1-40.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 64 66 79
    Least Squares Mean (Standard Error) [Percent change in Aβ1-40]
    -1.92
    (1.77)
    -59.90
    (1.74)
    -75.17
    (1.60)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -57.99
    Confidence Interval (2-Sided) 95%
    -62.865 to -53.108
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.47
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -73.25
    Confidence Interval (2-Sided) 95%
    -77.926 to -68.575
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.37
    Estimation Comments
    11. Secondary Outcome
    Title Change From Baseline in CSF Total Tau
    Description Cerebrospinal fluid samples are collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
    Time Frame Baseline, Week 97

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Total Tau.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 64 66 79
    Least Squares Mean (Standard Error) [Picogram per milliliter (pg/mL)]
    12.39
    (8.05)
    -7.48
    (8.01)
    -2.92
    (7.30)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.081
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -19.87
    Confidence Interval (2-Sided) 95%
    -42.210 to 2.464
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 11.33
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.157
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -15.31
    Confidence Interval (2-Sided) 95%
    -36.555 to 5.938
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 10.78
    Estimation Comments
    12. Secondary Outcome
    Title Change From Baseline in CSF Phosphorylated Tau
    Description Cerebrospinal fluid samples are collected for analysis of concentrations of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
    Time Frame Baseline, Week 97

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for CSF Phosphorylated Tau.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 63 66 79
    Least Squares Mean (Standard Error) [Picogram per milliliter (pg/mL)]
    0.47
    (0.95)
    -2.16
    (0.94)
    -1.66
    (0.85)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.050
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -2.62
    Confidence Interval (2-Sided) 95%
    -5.243 to -0.002
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.33
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.095
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -2.12
    Confidence Interval (2-Sided) 95%
    -4.618 to 0.373
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 1.27
    Estimation Comments
    13. Secondary Outcome
    Title Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan
    Description Amyloid deposition in the brain is one of the defining neuropathologic findings of Alzheimer's disease. Florbetapir exhibits high affinity specific binding to amyloid plaques. The change from baseline was measured as average standard uptake value ratio (SUVr) in prespecified regions of interest (ROI) assessed by florbetapir amyloid PET imaging in a subset of participants. The Centiloid scale standardizes quantitative brain amyloid PET results to allow cross-tracer and cross-methodology comparisons. 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. Florbetapir SUVr was converted to the Centiloid scale using the following conversion: Florbetapir Centiloids = 183 x SUVr - 177. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for brain amyloid burden.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 133 127 116
    Least Squares Mean (Standard Error) [Units on a scale]
    -2.08
    (1.86)
    -15.76
    (1.89)
    -19.74
    (1.97)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -13.68
    Confidence Interval (2-Sided) 95%
    -18.785 to -8.574
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.60
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -17.66
    Confidence Interval (2-Sided) 95%
    -22.887 to -12.428
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 2.66
    Estimation Comments
    14. Secondary Outcome
    Title Change From Baseline in Tau PET ((Flortaucipir F18)
    Description Tau PET tracer (flortaucipir F18) longitudinal study measured whether lanabecestat, in participants with mild AD dementia, affected tau density and distribution over time. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the signal intensity in white matter. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Tau PET.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 97 94 93
    Least Squares Mean (Standard Error) [Standard Uptake Value ratio (SUVr)]
    0.04
    (0.01)
    0.03
    (0.01)
    0.03
    (0.01)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.426
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.033 to 0.014
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.01
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.660
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.029 to 0.018
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.01
    Estimation Comments
    15. Secondary Outcome
    Title Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG)
    Description Fluorodeoxyglucose (FDG) PET evaluates the regional brain metabolic rates for glucose as a sensitive, in vivo metabolic index of brain function. The outcome reported is the composite summary of the standard uptake value ratio (SUVR) normalized to the pons + vermis assessed with composite meta and composite meta automated anatomical labeling atlas (ALL). Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, disease status at baseline, baseline biomarker and age at baseline. Baseline defined to be within 28 days of starting study drug.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data of brain metabolism.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 83 95 82
    Least Squares Mean (Standard Error) [Standard Uptake Value ratio (SUVr)]
    -0.04
    (0.00)
    -0.05
    (0.00)
    -0.05
    (0.00)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.210
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.015 to 0.003
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.00
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.568
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -0.00
    Confidence Interval (2-Sided) 95%
    -0.013 to 0.007
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.00
    Estimation Comments
    16. Secondary Outcome
    Title Change From Baseline in Whole Brain Volume
    Description Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on whole brain volumes. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA methodology with factors for treatment, baseline vMRI, intracranial volume, disease status at baseline and age at baseline.
    Time Frame Baseline, Week 104

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have baseline and at least one post-baseline data for Whole Brain Volume.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 565 582 550
    Least Squares Mean (Standard Error) [cm^3 (cubic centimeter)]
    -14.16
    (0.34)
    -16.49
    (0.33)
    -17.34
    (0.34)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 20 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -2.34
    Confidence Interval (2-Sided) 95%
    -3.258 to -1.413
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.47
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Placebo, Lanabecestat 50 mg
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.001
    Comments
    Method ANCOVA
    Comments
    Method of Estimation Estimation Parameter LS Mean Difference (Final Values)
    Estimated Value -3.18
    Confidence Interval (2-Sided) 95%
    -4.118 to -2.247
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.48
    Estimation Comments
    17. Secondary Outcome
    Title Pharmacokinetics (PK): Plasma Concentration of Lanabecestat
    Description
    Time Frame Week 4, post dose prior to departure from the clinic

    Outcome Measure Data

    Analysis Population Description
    All randomized participants who received at least one dose of study drug and have evaluable PK data.
    Arm/Group Title Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    Measure Participants 697 662
    Mean (Standard Deviation) [nanograms per milliliter (ng/mL)]
    67.7
    (49.1)
    213
    (149)

    Adverse Events

    Time Frame Up To 104 weeks
    Adverse Event Reporting Description All randomized participants who received at least one dose of study drug. There are gender specific adverse events, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Arm/Group Title Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Arm/Group Description Participants received placebo film-coated oral tablets once daily. Participants received lanabecestat 20 mg film-coated oral tablets once daily. Participants received lanabecestat 50 mg film-coated oral tablets once daily.
    All Cause Mortality
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/738 (0.3%) 4/736 (0.5%) 4/735 (0.5%)
    Serious Adverse Events
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 108/738 (14.6%) 117/736 (15.9%) 147/735 (20%)
    Blood and lymphatic system disorders
    Anaemia 2/738 (0.3%) 3 1/736 (0.1%) 1 1/735 (0.1%) 1
    Cardiac disorders
    Acute coronary syndrome 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Acute myocardial infarction 2/738 (0.3%) 3 0/736 (0%) 0 2/735 (0.3%) 2
    Angina pectoris 2/738 (0.3%) 2 1/736 (0.1%) 1 1/735 (0.1%) 1
    Angina unstable 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Atrial fibrillation 2/738 (0.3%) 3 2/736 (0.3%) 2 1/735 (0.1%) 1
    Atrial flutter 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Bifascicular block 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Bradycardia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Cardiac failure 0/738 (0%) 0 2/736 (0.3%) 2 2/735 (0.3%) 2
    Cardiac tamponade 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Cardio-respiratory arrest 2/738 (0.3%) 2 1/736 (0.1%) 1 0/735 (0%) 0
    Coronary artery disease 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Coronary artery thrombosis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Myocardial infarction 4/738 (0.5%) 4 2/736 (0.3%) 2 0/735 (0%) 0
    Sinus bradycardia 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Sinus node dysfunction 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Stress cardiomyopathy 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Supraventricular extrasystoles 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Supraventricular tachycardia 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Tachycardia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Tricuspid valve incompetence 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Congenital, familial and genetic disorders
    Gastrointestinal arteriovenous malformation 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Ear and labyrinth disorders
    Vestibular disorder 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Eye disorders
    Cataract 0/738 (0%) 0 2/736 (0.3%) 2 1/735 (0.1%) 2
    Pterygium 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Retinal detachment 2/738 (0.3%) 2 0/736 (0%) 0 0/735 (0%) 0
    Retinal haemorrhage 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Gastrointestinal disorders
    Abdominal discomfort 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Alcoholic pancreatitis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Anal incontinence 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 2
    Coeliac artery stenosis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Colitis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Colitis microscopic 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Constipation 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 1
    Diarrhoea 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Enlarged uvula 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Faecaloma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Femoral hernia incarcerated 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Food poisoning 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Gastric ulcer 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Gastritis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Gastrointestinal haemorrhage 2/738 (0.3%) 2 1/736 (0.1%) 1 1/735 (0.1%) 1
    Gastrooesophageal reflux disease 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Haemorrhoids 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Inguinal hernia 1/738 (0.1%) 1 2/736 (0.3%) 2 3/735 (0.4%) 3
    Intestinal mass 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Intestinal obstruction 0/738 (0%) 0 0/736 (0%) 0 3/735 (0.4%) 3
    Large intestine polyp 0/738 (0%) 0 1/736 (0.1%) 2 2/735 (0.3%) 2
    Lower gastrointestinal haemorrhage 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Pancreatitis acute 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Rectal prolapse 0/738 (0%) 0 2/736 (0.3%) 3 0/735 (0%) 0
    Small intestinal obstruction 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Vomiting 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    General disorders
    Asthenia 1/738 (0.1%) 1 1/736 (0.1%) 1 1/735 (0.1%) 1
    Chest pain 1/738 (0.1%) 1 4/736 (0.5%) 4 4/735 (0.5%) 4
    Non-cardiac chest pain 1/738 (0.1%) 1 2/736 (0.3%) 2 1/735 (0.1%) 1
    Pyrexia 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Sudden death 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Systemic inflammatory response syndrome 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hepatobiliary disorders
    Cholelithiasis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Drug-induced liver injury 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Immune system disorders
    Drug hypersensitivity 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Seasonal allergy 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Infections and infestations
    Appendicitis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Bone abscess 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Bronchitis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Cellulitis 1/738 (0.1%) 1 1/736 (0.1%) 1 2/735 (0.3%) 2
    Clostridium difficile colitis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Diverticulitis 1/738 (0.1%) 1 1/736 (0.1%) 1 3/735 (0.4%) 4
    Endocarditis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hepatic cyst infection 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Human anaplasmosis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Infection 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Influenza 0/738 (0%) 0 2/736 (0.3%) 2 4/735 (0.5%) 4
    Intervertebral discitis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Lower respiratory tract infection 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Lower respiratory tract infection viral 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Ophthalmic herpes zoster 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Peritonsillitis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Pneumonia 6/738 (0.8%) 6 3/736 (0.4%) 3 3/735 (0.4%) 3
    Sepsis 2/738 (0.3%) 2 0/736 (0%) 0 1/735 (0.1%) 1
    Septic arthritis streptococcal 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Septic shock 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 1
    Urinary tract infection 6/738 (0.8%) 8 1/736 (0.1%) 1 3/735 (0.4%) 3
    Urinary tract infection pseudomonal 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Vestibular neuronitis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Accidental poisoning 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Alcohol poisoning 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Ankle fracture 1/738 (0.1%) 1 1/736 (0.1%) 1 1/735 (0.1%) 1
    Cervical vertebral fracture 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Chemical burn of gastrointestinal tract 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Clavicle fracture 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Contusion 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Fall 6/738 (0.8%) 6 8/736 (1.1%) 8 4/735 (0.5%) 4
    Femoral neck fracture 0/738 (0%) 0 1/736 (0.1%) 1 2/735 (0.3%) 2
    Femur fracture 1/738 (0.1%) 1 2/736 (0.3%) 2 1/735 (0.1%) 1
    Fibula fracture 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 1
    Forearm fracture 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Head injury 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 1
    Hip fracture 0/738 (0%) 0 3/736 (0.4%) 3 2/735 (0.3%) 2
    Humerus fracture 1/738 (0.1%) 2 0/736 (0%) 0 2/735 (0.3%) 2
    Jaw fracture 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Lacrimal structure injury 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Ligament rupture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Lumbar vertebral fracture 2/738 (0.3%) 2 0/736 (0%) 0 1/735 (0.1%) 1
    Multiple injuries 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Overdose 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Pelvic fracture 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Periprosthetic fracture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Post procedural haemorrhage 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Pubis fracture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Radius fracture 1/738 (0.1%) 1 1/736 (0.1%) 1 2/735 (0.3%) 2
    Rib fracture 2/738 (0.3%) 2 0/736 (0%) 0 0/735 (0%) 0
    Road traffic accident 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Skin laceration 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Skull fracture 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Spinal compression fracture 3/738 (0.4%) 3 0/736 (0%) 0 1/735 (0.1%) 1
    Spinal fracture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Subdural haematoma 3/738 (0.4%) 3 0/736 (0%) 0 3/735 (0.4%) 4
    Subdural haemorrhage 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Thoracic vertebral fracture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Tibia fracture 2/738 (0.3%) 2 0/736 (0%) 0 1/735 (0.1%) 1
    Ulna fracture 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 1
    Upper limb fracture 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Wrist fracture 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Investigations
    Blood potassium decreased 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Metabolism and nutrition disorders
    Decreased appetite 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Dehydration 1/738 (0.1%) 1 4/736 (0.5%) 4 5/735 (0.7%) 5
    Electrolyte imbalance 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hypercalcaemia 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hyperglycaemia 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Hypoglycaemia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Hypokalaemia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Hyponatraemia 0/738 (0%) 0 2/736 (0.3%) 2 1/735 (0.1%) 1
    Hypophosphataemia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Lactic acidosis 2/738 (0.3%) 2 0/736 (0%) 0 0/735 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthritis 0/738 (0%) 0 1/736 (0.1%) 1 2/735 (0.3%) 2
    Back pain 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Bone lesion 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Foot deformity 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Infrapatellar fat pad inflammation 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Intervertebral disc compression 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Intervertebral disc protrusion 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Lumbar spinal stenosis 1/738 (0.1%) 1 0/736 (0%) 0 1/735 (0.1%) 2
    Mobility decreased 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Musculoskeletal chest pain 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Musculoskeletal pain 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Myofascial pain syndrome 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Osteoarthritis 4/738 (0.5%) 4 2/736 (0.3%) 2 1/735 (0.1%) 1
    Osteolysis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Osteoporotic fracture 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Pain in extremity 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Spinal column stenosis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Vertebral foraminal stenosis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Acute myeloid leukaemia 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Adenocarcinoma of colon 1/738 (0.1%) 1 1/736 (0.1%) 1 1/735 (0.1%) 1
    Basal cell carcinoma 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Bile duct adenocarcinoma 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Bladder neoplasm 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Breast cancer 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Breast cancer male 0/341 (0%) 0 1/344 (0.3%) 1 0/354 (0%) 0
    Breast cancer recurrent 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Colon cancer 0/738 (0%) 0 0/736 (0%) 0 2/735 (0.3%) 2
    Endometrial adenocarcinoma 1/397 (0.3%) 1 0/392 (0%) 0 0/381 (0%) 0
    Haemangioma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Invasive ductal breast carcinoma 0/738 (0%) 0 2/736 (0.3%) 2 2/735 (0.3%) 2
    Laryngeal squamous cell carcinoma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Lentigo maligna 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Lung adenocarcinoma 2/738 (0.3%) 2 0/736 (0%) 0 3/735 (0.4%) 3
    Lung neoplasm 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Lung neoplasm malignant 0/738 (0%) 0 2/736 (0.3%) 2 0/735 (0%) 0
    Lymphoma 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Malignant melanoma 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Malignant melanoma in situ 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Malignant neoplasm of unknown primary site 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Metastases to bone 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Metastases to lymph nodes 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Neuroendocrine tumour 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Ovarian adenoma 0/397 (0%) 0 0/392 (0%) 0 1/381 (0.3%) 1
    Pancreatic carcinoma 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Prostate cancer 2/341 (0.6%) 2 2/344 (0.6%) 2 2/354 (0.6%) 2
    Prostatic adenoma 1/341 (0.3%) 1 0/344 (0%) 0 0/354 (0%) 0
    Rectal adenocarcinoma 1/738 (0.1%) 1 1/736 (0.1%) 1 0/735 (0%) 0
    Rectal adenoma 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Rectal cancer 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Small cell lung cancer 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Squamous cell carcinoma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Transitional cell carcinoma 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Nervous system disorders
    Altered state of consciousness 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Central nervous system lesion 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Cerebral haematoma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Cerebral haemorrhage 3/738 (0.4%) 3 0/736 (0%) 0 2/735 (0.3%) 2
    Cerebral microhaemorrhage 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Cerebrovascular accident 2/738 (0.3%) 2 3/736 (0.4%) 3 1/735 (0.1%) 1
    Cervical radiculopathy 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Cholinergic syndrome 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Cognitive disorder 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Dementia with lewy bodies 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Dizziness 1/738 (0.1%) 1 1/736 (0.1%) 1 1/735 (0.1%) 1
    Dyskinesia 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Epilepsy 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Generalised tonic-clonic seizure 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Headache 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hypertensive encephalopathy 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hypoaesthesia 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Intraventricular haemorrhage 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Partial seizures 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Petit mal epilepsy 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Presyncope 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Sciatica 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Seizure 0/738 (0%) 0 1/736 (0.1%) 1 2/735 (0.3%) 2
    Subarachnoid haemorrhage 2/738 (0.3%) 2 1/736 (0.1%) 1 0/735 (0%) 0
    Syncope 2/738 (0.3%) 2 6/736 (0.8%) 6 7/735 (1%) 7
    Thalamic infarction 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Transient ischaemic attack 2/738 (0.3%) 2 2/736 (0.3%) 2 2/735 (0.3%) 2
    Ulnar nerve palsy 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Vasogenic cerebral oedema 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Vocal cord paresis 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Product Issues
    Device failure 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Psychiatric disorders
    Abnormal behaviour 2/738 (0.3%) 2 1/736 (0.1%) 1 1/735 (0.1%) 1
    Acute psychosis 0/738 (0%) 0 2/736 (0.3%) 2 0/735 (0%) 0
    Aggression 1/738 (0.1%) 1 1/736 (0.1%) 1 2/735 (0.3%) 2
    Agitation 2/738 (0.3%) 2 0/736 (0%) 0 2/735 (0.3%) 2
    Anxiety 0/738 (0%) 0 0/736 (0%) 0 2/735 (0.3%) 2
    Confusional state 2/738 (0.3%) 2 1/736 (0.1%) 1 0/735 (0%) 0
    Delirium 1/738 (0.1%) 1 2/736 (0.3%) 2 5/735 (0.7%) 5
    Depression 0/738 (0%) 0 0/736 (0%) 0 4/735 (0.5%) 4
    Depressive symptom 0/738 (0%) 0 0/736 (0%) 0 3/735 (0.4%) 3
    Hallucination 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Hallucination, auditory 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Hallucination, olfactory 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Paranoia 2/738 (0.3%) 2 0/736 (0%) 0 0/735 (0%) 0
    Psychotic disorder 2/738 (0.3%) 2 0/736 (0%) 0 0/735 (0%) 0
    Schizophrenia 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Suicidal ideation 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Suicide attempt 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Renal and urinary disorders
    Acute kidney injury 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Calculus bladder 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Urge incontinence 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Urinary retention 0/738 (0%) 0 1/736 (0.1%) 1 1/735 (0.1%) 1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia 2/341 (0.6%) 2 1/344 (0.3%) 1 1/354 (0.3%) 1
    Postmenopausal haemorrhage 0/397 (0%) 0 1/392 (0.3%) 1 0/381 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Asthma 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Cystic lung disease 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Dyspnoea 0/738 (0%) 0 2/736 (0.3%) 2 1/735 (0.1%) 1
    Obstructive airways disorder 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Pneumonia aspiration 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Pneumothorax 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Pulmonary embolism 0/738 (0%) 0 1/736 (0.1%) 1 2/735 (0.3%) 2
    Pulmonary oedema 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Respiratory arrest 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Sleep apnoea syndrome 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Stridor 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Skin and subcutaneous tissue disorders
    Angioedema 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Drug eruption 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Psoriasis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Surgical and medical procedures
    Cardiac pacemaker insertion 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Cataract operation 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Hip arthroplasty 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Inguinal hernia repair 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Spinal operation 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Synovial cyst removal 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Tumour excision 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Urethral repair 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Vocal cord operation 0/738 (0%) 0 1/736 (0.1%) 1 0/735 (0%) 0
    Vascular disorders
    Aortic aneurysm 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Deep vein thrombosis 0/738 (0%) 0 2/736 (0.3%) 2 0/735 (0%) 0
    Granulomatosis with polyangiitis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Haematoma 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Hypertension 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Hypertensive crisis 1/738 (0.1%) 1 0/736 (0%) 0 0/735 (0%) 0
    Hypotension 2/738 (0.3%) 2 1/736 (0.1%) 1 1/735 (0.1%) 1
    Orthostatic hypotension 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Peripheral artery stenosis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Temporal arteritis 0/738 (0%) 0 2/736 (0.3%) 2 0/735 (0%) 0
    Thrombophlebitis 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Venous thrombosis limb 0/738 (0%) 0 0/736 (0%) 0 1/735 (0.1%) 1
    Other (Not Including Serious) Adverse Events
    Placebo Lanabecestat 20 mg Lanabecestat 50 mg
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 340/738 (46.1%) 357/736 (48.5%) 361/735 (49.1%)
    Gastrointestinal disorders
    Diarrhoea 39/738 (5.3%) 44 62/736 (8.4%) 81 54/735 (7.3%) 62
    Nausea 32/738 (4.3%) 38 33/736 (4.5%) 39 41/735 (5.6%) 50
    Infections and infestations
    Nasopharyngitis 60/738 (8.1%) 69 78/736 (10.6%) 94 76/735 (10.3%) 89
    Upper respiratory tract infection 46/738 (6.2%) 57 39/736 (5.3%) 43 44/735 (6%) 50
    Urinary tract infection 56/738 (7.6%) 70 36/736 (4.9%) 53 32/735 (4.4%) 36
    Injury, poisoning and procedural complications
    Fall 69/738 (9.3%) 86 71/736 (9.6%) 95 73/735 (9.9%) 111
    Musculoskeletal and connective tissue disorders
    Back pain 40/738 (5.4%) 50 36/736 (4.9%) 38 33/735 (4.5%) 35
    Nervous system disorders
    Dizziness 42/738 (5.7%) 48 43/736 (5.8%) 52 51/735 (6.9%) 61
    Headache 52/738 (7%) 56 40/736 (5.4%) 50 46/735 (6.3%) 72
    Psychiatric disorders
    Anxiety 34/738 (4.6%) 40 57/736 (7.7%) 63 48/735 (6.5%) 50
    Depression 31/738 (4.2%) 32 36/736 (4.9%) 39 46/735 (6.3%) 49
    Respiratory, thoracic and mediastinal disorders
    Cough 25/738 (3.4%) 25 46/736 (6.3%) 49 25/735 (3.4%) 29

    Limitations/Caveats

    An independent assessment concluded the trial was not likely to meet the primary endpoint upon completion and therefore, trial stopped for futility.

    More Information

    Certain Agreements

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

    The sponsor shall review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60days but less than or equal to 180days from the time submitted to the sponsor.Authors agree not to publish results until data is compiled. No publication/presentation with respect to the research activities shall be made unless & until any information determined at sponsors sole discretion to be confidential information has been removed.

    Results Point of Contact

    Name/Title AstraZeneca Information Center
    Organization AstraZeneca
    Phone 1-877-240-9479
    Email information.center@astrazeneca.com
    Responsible Party:
    AstraZeneca
    ClinicalTrials.gov Identifier:
    NCT02245737
    Other Study ID Numbers:
    • 16023
    • I8D-MC-AZES
    • 2014-002601-38
    • D5010C00009
    First Posted:
    Sep 22, 2014
    Last Update Posted:
    Dec 3, 2019
    Last Verified:
    Oct 1, 2019