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Clinical Trial Details — Status: Terminated

Administrative data

NCT number NCT02245737
Other study ID # 16023
Secondary ID I8D-MC-AZES2014-
Status Terminated
Phase Phase 2/Phase 3
First received
Last updated
Start date September 30, 2014
Est. completion date October 4, 2018

Study information

Verified date October 2019
Source AstraZeneca
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Terminated
Enrollment 2218
Est. completion date October 4, 2018
Est. primary completion date October 4, 2018
Accepts healthy volunteers No
Gender All
Age group 55 Years to 85 Years
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Lanabecestat
Administered orally
Placebo
Administered orally

Locations

Country Name City State
Australia Royal Adelaide Hospital Adelaide South Australia
Australia Box Hill Hospital Box Hill Victoria
Australia Delmont Private Hospital Glen Iris Victoria
Australia Griffith University Gold Coast Queensland
Australia Heidelberg Repatriation Hospital Heidelberg Victoria
Australia Southern Neurology Kogarah New South Wales
Australia Australian Alzheimer's Research Foundation Nedlands Western Australia
Australia Neuro Trials Victoria Pty Ltd Noble Park
Australia The Florey Institute of Neuroscience and Mental Health Parkville Victoria
Belgium Hospital Universitaire Erasme Brussel Brussel
Belgium Cliniques Universitaires Saint-Luc Brussels
Belgium Hopital Universitaire Brugmann Brussel Brussels
Belgium Universitair Ziekenhuis Antwerpen Edegem
Belgium Jessa Ziekenhuis Hasselt Limburg
Belgium Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg Leuven
Belgium Heilig Hartziekenhuis Roeselare
Canada Clinique de la Memoire de l'Outaouais Gatineau Quebec
Canada NeuroSearch Developements Greenfield Park Quebec
Canada True North Clinical Research Halifax, LLC Halifax Nova Scotia
Canada The Medical Arts Health Research Group Kamloops British Columbia
Canada Okanagan Clinical Trials Kelowna British Columbia
Canada Hopital Maisonneure-Rosemount Montreal Quebec
Canada Bruyere Continuing Care Ottawa Ontario
Canada Kawartha Regional Memory Clinic Peterborough Ontario
Canada Hopital de L'Enfant Jesus Quebec City Quebec
Canada CSSS-Institut Universitaire Gériatric de Sherbrooke Sherbrooke Qubec
Canada Q&T Research Sherbrooke Inc Sherbrooke Quebec
Canada Toronto Memory Program Toronto Ontario
Canada Toronto Western Hospital Toronto Ontario
Canada University of British Columbia Vancouver British Columbia
Canada Royal Jubilee Hospital Victoria British Columbia
France Hopital Neuro Pierre Wertheimer Bron Cedex
France CHU Dijonon Dijon Cedex
France CHRU Lille - Hopital Roger Salengro Lille Cedex
France CHU Hopital de la Timone Marseille Cedex 05
France Chu de Nantes Hopital Laennec Nantes
France Hopital Broca Paris
France Hopital de la Pitie Salpetriere Paris
France Hopital Lariboisière Paris
France CHU de Toulouse Toulouse
France CHU de Toulouse Hopital Purpan Toulouse Cedex 9
France Hopital des Charpennes Villeurbanne
Germany Charité Universitätsmedizin Berlin Berlin
Germany Charité Universitätsmedizin Berlin Berlin
Germany Gemeinschaftspraxis Dr. R. Ehret & Dr. W. von Pannwitz Berlin
Germany Praxis Dr. Lauter Bochum Nordrhein-Westfalen
Germany St Josef-Hospital Bochum Bochum Nordrhein-Westfalen
Germany Universitätsklinikum Bonn Bonn Nordrhein-Westfalen
Germany Arztpraxis Dr. Christian Oehlwein Gera Thüringen
Germany Martin-Luther-Universität Halle-Wittenberg Halle (Saale) Sachsen-Anhalt
Germany Universitätsklinikum des Saarlandes Homburg Saarland
Germany Gemeinschaftspraxis für Neurologie Prof. Gereon Nelles Köln Nordrhein-Westfalen
Germany Universitätsklinikum Köln Köln Nordrhein-Westfalen
Germany Universitätsklinikum Otto-von-Guericke-Universität Magdeburg Sachsen-Anhalt
Germany Pharmakologisches Studienzentrum Chemnitz Mittweida Sachsen
Germany Klinikum Rechts der Isar der TU München München Bayern
Germany Studien und Gedächtniszentrum München München Bayern
Germany Institut fur Psychogerontologie Nürnberg Bayern
Germany Neurozentrum Prien Prien am Chiemsee Bayern
Germany Neurologische Praxis Siegen Siegen Nordrhein-Westfalen
Germany Universitätsklinikum Tübingen Tübingen Baden-Württemberg
Germany Universitätsklinikum Ulm Ulm Baden-Württemberg
Germany Institut für Neuropsychiatrie INP3 Wenzenbach Bayern
Germany Studienzentrum Nord-West Westerstede Niedersachsen
Hungary Del-pesti Centrumkorház - Orszagos Hematologiai és Infektologiai Intezet Budapest
Hungary Semmelweis Medical University Budapest
Hungary Debreceni Egyetem Kenezy Gyula Egyetemi Korhaz Debrecen
Hungary Debreceni Egyetem Klinikai Kozpont Debrecen
Hungary PTE KK Pszichiatriai es Pszichoterapias Klinika Pecs Baranya
Hungary Univerisity of Szeged Szeged
Italy Università Politecnica delle Marche Torrette Ancona
Italy IRCCS San Giovanni di Dio Fatebenefratelli Brescia
Italy Fondazione San Raffaele Giglio di Cefalu Cefalu Palermo
Italy Fondazione Universitaria degli Studi G D'Annunzio Chieti
Italy Ente Ospedaliero Ospedali Galliera Genova
Italy Fondazione IRCCS Ca'Granda Ospedale Maggiore Policinico Milano
Italy Nuovo Ospedale Civile Sant'Agostino Estense Modena
Italy Azienda Ospedaliera San Gerardo Monza Milano
Italy Universita Di Pisa Pisa PI
Italy Ospedale Degli Infermi ASR USSL 12 Ponderano Biella
Italy Dip.to Med. Sperimentale -Polic.Umberto I -Univ. La Sapienza Roma
Italy Ospedale San Giovanni Calibita Fatebenefratelli Roma
Italy Policlinico Ospedale S. Andrea Roma
Italy Policlinico Univ. Agostino Gemelli Roma
Italy Azienda Ospedaliera Citta della Salute della Scienza Torino Torino
Japan National Hospital Organization Asahikawa Medical Center Asahikawa Hokkaido
Japan Nippon Medical School Hospital Bunkyo-Ku Tokyo
Japan The University of Tokyo Hospital Bunkyo-ku Tokyo
Japan National Chiba-East-Hospital Chuo-ku Chiba
Japan Fukuoka University Hospital Fukuoka
Japan Koshokai aino hospital Ibaraki Osaka
Japan Ina Central Hospital Ina Nagano
Japan Saitama Medical University Hospital Iruma-Gun Saitama
Japan Shonan Kamakura General Hospital Kamakura Kanagawa
Japan Nihon Kokan Hospital Kawasaki Kanagawa
Japan Katayama Medical Clinic Kurashiki Okayama
Japan Kyoto Minami Hospital Kyoto
Japan Kyoto University Hospital Kyoto
Japan Utano Hospital Kyoto
Japan Kyoto Prefectural University of Medicine Kyoto-shi Kyoto
Japan Rakuwakai Otowarehabilitation Hospital Kyoto-shi Kyoto
Japan Matsumoto Medical Center Matsumoto Nagano
Japan Nozomi Memory Clinic Mitaka-shi Tokyo
Japan Iwate Medical University Hospital Morioka Iwate
Japan National Sanatorium Hokuriku Hospital Nanto Toyama
Japan National Institute for Longevity Sciences NCGG Obu Aichi
Japan 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 Sakaguchi Clinic Sakai Osaka
Japan Sangenjaya Nakamura Mental Clinic Setagaya Tokyo
Japan Kanauchi Medical Clinic Shinjuku-ku Tokyo
Japan Tokyo Women's Medical University Hospital Shinjuku-ku Tokyo
Japan National Sanatorium Toneyama Hospital Toyonaka Osaka
Japan Memory Clinic Ochanomizu Tsukuba Tokyo
Japan Tsukuba University Hospital Tsukuba Ibaraki
Japan Shiroma Clinic Urasoe Okinawa
Japan Yokohama City University Hospital Yokohama Kanagawa
Korea, Republic of The Catholic University of Korea-Bucheon St. Mary's Hospital Bucheon-si Gyeonggi-do
Korea, Republic of Hanyang University Guri Hospital Guri-si Gyeonggido
Korea, Republic of Inha University Hospital Incheon
Korea, Republic of Gachon University Gil Medical Center Namdong Incheon
Korea, Republic of Dong-A University Medical Center Seogu Busan
Korea, Republic of Seoul National University Bundang Hospital Seongnam-si Geonggi-do
Korea, Republic of Asan Medical Center Seoul
Korea, Republic of Samsung Medical Center Seoul
Korea, Republic of Seoul St. Mary's Hospital Seoul
Poland Podlaskie Centrum Psychogeriatrii Bialystok Podlaskie
Poland NZOZ Dom Sue Ryder - Pallmed Sp. z o.o. Bydgoszcz
Poland NZOZ Wielospecjalistyczna Poradnia Lekarska Katowice
Poland Specjalistyczna Praktyka Lekarska prof. Grzegorz Opala Katowice
Poland Centrum Zdrowia Psychicznego Kielce
Poland Centrum Neurologii Klinicznej Krakow
Poland Medycyna Milorzab Lodz Lódzkie
Poland Instytut Medycyny Wsi Lublin
Poland NZOZ Neuromed M. I M. Nastaj sp. P. Lublin
Poland NEURO-CARE Sp. z o.o. Sp. Komandytowa Siemianowice Slaskie
Poland Centralny Szpital Kliniczny MSW Warszawa
Poland Centrum Medyczne Warszawa
Poland NZOZ Wroclawskie Centrum Alzheimerowskie Wroclaw Dolnoslaskie
Puerto Rico Santa Cruz Behavioral PSC Bayamon
Puerto Rico Ivonne Z. Jimenez-Velazquez, MD Carolina
Puerto Rico Instituto de Neurologia Dra. Ivonne Fraga San Juan
Puerto Rico Michel A. Woodbury-Farina, MD. San Juan
Romania Policlinica CCBR S.R.L. Bucuresti
Romania SC Centrul Medical Sana SRL Bucuresti
Romania SC Med Life SA Bucuresti
Romania SC Med Life SA Timisoara
Spain Fundacion ACE-Institut Catala de Neurociences Aplicades Barcelona
Spain Hospital Clinic de Barcelona Barcelona
Spain Hospital del Mar Barcelona
Spain Hospital Santa Creu I Sant Pau Barcelona
Spain Hospital Universitari de Bellvitge Barcelona
Spain Hospital Reina Sofia Cordoba
Spain Hospital General Universitario de Elche Elche Alicante
Spain Centro de Atencion Especializada (CAE) OROITU Getxo Vizcaya
Spain Hospital De La Princesa Madrid
Spain Hospital Universitario De Getafe Madrid Getafe
Spain Hospital Universitario Ramon y Cajal Madrid
Spain Hospital Puerta De Hierro Majadahonda Madrid
Spain Hospital Son Espases Palma de Mallorca
Spain Hospital Virgen Del Puerto Plasencia Caceres
Spain Hospital Univ Sant Joan de Reus, S.A. Reus
Spain Fundacion CITA Alzheimer San Sebastian
Spain Hospital General de Catalunya Sant Cugat del Valles Barcelona
Spain Hospital Doctor Peset Valencia
Spain Hospital Universitario La Fe de Valencia Valencia
United Kingdom MAC UK Neuroscience Ltd Blackpool Lancs
United Kingdom West London Mental Health NHS Trust Brentford
United Kingdom MAC Clinical Research Cannock Staffordshire
United Kingdom Cognitive Treatment & Research Unit Crowborough East Sussex
United Kingdom Glasgow Memory Clinic Glasgow
United Kingdom Guildford Nuffield Hospital London
United Kingdom Hammersmith Hospital London
United Kingdom Re-Cognition Health Ltd London
United Kingdom MAC Clinical Research Manchester
United Kingdom Plymouth Hospitals NHS Trust Plymouth Devon
United Kingdom Southern Health NHS Southampton Hampshire
United Kingdom MAC Clinical Research Stourton Leeds
United States Lehigh Valley Hospital Allentown Pennsylvania
United States Community Clinical Research Center Anderson Indiana
United States Atlanta Center of Medical Research Atlanta Georgia
United States The Multiple Sclerosis Center of Atlanta Atlanta Georgia
United States Senior Adults Specialty Research Inc Austin Texas
United States The Memory Clinic Bennington Vermont
United States Integrative Clinical Trials, LLC Brooklyn New York
United States SPRI Clinical Trials, LLC. Brooklyn New York
United States Alzheimer's Disease and Memory Disorders Center Buffalo New York
United States Valley Medical Primary Care Centerville Ohio
United States Roper St. Francis Healthcare Charleston South Carolina
United States Alzheimer's Memory Center Charlotte North Carolina
United States University of Chicago Medical Center Chicago Illinois
United States Christ Hospital Cincinnati Ohio
United States Ohio State University Medical Center Columbus Ohio
United States The Corvallis Clinic P.C. Corvallis Oregon
United States Texas Health Physicians Group Dallas Texas
United States Brain Matters Research Delray Beach Florida
United States Mile High Research Center Denver Colorado
United States Rhode Island Mood & Memory Research Institute East Providence Rhode Island
United States Memory Enhancement Center of America, Inc. Eatontown New Jersey
United States Alexian Brothers Medical Center Elk Grove Village Illinois
United States Medical Group of Texas Fort Worth Texas
United States Positron Research International Fremont California
United States Radiant Research Greer South Carolina
United States Hattiesburg Clinic Hattiesburg Mississippi
United States Berma Research Hialeah Florida
United States Direct Helpers Medical Center Hialeah Florida
United States Galiz Research Hialeah Florida
United States MaxBlue Institute Hialeah Florida
United States University of Texas Health Services Center - Houston Houston Texas
United States Indiana University School of Medicine Indianapolis Indiana
United States Quillen College of Medicine, East TN State University Johnson City Tennessee
United States Alliance Research Centers Laguna Hills California
United States Senior Clinical Trials, Inc. Laguna Hills California
United States Alzheimer's Research and Treatment Center Lake Worth Florida
United States Empire Neurology, PC Latham New York
United States AdvanceMed Research Lawrenceville New Jersey
United States Collaborative Neuroscience Network - CNS Long Beach California
United States Alzheimer's Research Company Manchester New Jersey
United States ActivMed Practices & Research, Inc Methuen Massachusetts
United States Advance Medical Research Institute Miami Florida
United States Allied Biomedical Research Institute, Inc. Miami Florida
United States JDH Medical Group, LLC Miami Florida
United States Medical Research Center Miami Florida
United States Miami Jewish Health Systems Miami Florida
United States New Horizon Research Center Miami Florida
United States Institute for Neurodegenerative Disorders New Haven Connecticut
United States Clinilabs, Inc (New York) New York New York
United States Columbia University Medical Center New York New York
United States Boston Center for Memory Newton Massachusetts
United States Compass Research Orlando Florida
United States IMIC, Inc. Palmetto Bay Florida
United States Banner Alzheimer's Institute Phoenix Arizona
United States St Josephs Hospital and Medical Center Phoenix Arizona
United States University of Rochester Rochester New York
United States Millennium Psychiatric Associates, LLV Saint Louis Missouri
United States St. Louis Clinical Trials, LC Saint Louis Missouri
United States Suncoast Neuroscience Associates Saint Petersburg Florida
United States University of Utah School of Medicine Salt Lake City Utah
United States Pacific Research Network Inc San Diego California
United States San Francisco Clinical Research Center San Francisco California
United States Roskamp Institute Sarasota Florida
United States Carman Research Smyrna Georgia
United States Springfield Neurology Associates Springfield Massachusetts
United States The Cognitive and Research Center of NJ Springfield New Jersey
United States Banner Sun Health Research Institute Sun City Arizona
United States Infinity Clinical Research, LLC Sunrise Florida
United States Olympian Clinical Research Tampa Florida
United States Stedman Clinical Trials Tampa Florida
United States Compass Research The Villages Florida
United States Advanced Memory Research Institute of New Jersey Toms River New Jersey
United States Bio Behavioral Health Toms River New Jersey
United States Territory Neurology & Research Institute Tucson Arizona
United States Georgetown University Medical Center Washington District of Columbia
United States Neurology Specialists of Monmouth County West Long Branch New Jersey
United States Premiere Research Institute at Palm Beach Neurology West Palm Beach Florida

Sponsors (2)

Lead Sponsor Collaborator
AstraZeneca Eli Lilly and Company

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Canada,  France,  Germany,  Hungary,  Italy,  Japan,  Korea, Republic of,  Poland,  Puerto Rico,  Romania,  Spain,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Change From Baseline on the 13-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog13) 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. Baseline, Week 104
Secondary Change From Baseline on the Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items (ADCS-iADL) 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. Baseline, Week 104
Secondary Change From Baseline on the Functional Activities Questionnaire (FAQ) Score 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. Baseline, Week 104
Secondary Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score 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. Baseline, Week 104
Secondary Change From Baseline on the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score 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. Baseline, Week 104
Secondary Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage 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). Baseline through Loss of 1 Global Stage or Week 104
Secondary Change From Baseline in Neuropsychiatric Inventory (NPI) Score 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. Baseline, Week 104
Secondary Change From Baseline on the Mini-Mental State Examination (MMSE) 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. Baseline, Week 104
Secondary Pharmacodynamics (PD): Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aß)1-42 Concentration of the peptide Aß 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. Baseline, Week 97
Secondary PD: Percent Change From Baseline in Concentration of CSF Biomarker Aß1-40 Concentration of the peptide Aß 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. Baseline, Week 97
Secondary Change From Baseline in CSF Total Tau 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. Baseline, Week 97
Secondary Change From Baseline in CSF Phosphorylated Tau 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. Baseline, Week 97
Secondary Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan 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. Baseline, Week 104
Secondary Change From Baseline in Tau PET ((Flortaucipir F18) 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. Baseline, Week 104
Secondary Change From Baseline in Brain Metabolism Using Fluorodeoxyglucose (FDG) 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. Baseline, Week 104
Secondary Change From Baseline in Whole Brain Volume 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. Baseline, Week 104
Secondary Pharmacokinetics (PK): Plasma Concentration of Lanabecestat Week 4, post dose prior to departure from the clinic
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