A Study of Lanabecestat (LY3314814) in Participants With Mild Alzheimer's Disease Dementia (DAYBREAK-ALZ)

• ClinicalTrials.gov Identifier: NCT02783573
• Recruitment Status: Terminated
• First Posted: May 26, 2016
• Results First Posted: August 6, 2019
• Last Update Posted: December 3, 2019
• Sponsor: AstraZeneca
• Collaborator: Eli Lilly and Company
• Information provided by (Responsible Party): AstraZeneca

Tracking Information

• First Submitted Date: May 24, 2016
• First Posted Date: May 26, 2016
• Results First Submitted Date: June 11, 2019
• Results First Posted Date: August 6, 2019
• Last Update Posted Date: December 3, 2019
• Actual Study Start Date: July 1, 2016
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2019)

Change From Baseline in Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog13) Score [ Time Frame: Baseline, Week 78 ]

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, acetylcholinesterase Inhibitor (AChEI) use at baseline, pooled site, and covariates for baseline ADAS-Cog13 total score, age at baseline, and baseline ADAS-Cog13 total score-by-visit interaction.

• Original Primary Outcome Measures (submitted: May 24, 2016): Change from Baseline in Alzheimer´s Disease Assessment Scale- Cognitive Subscale (ADAS-Cog-13) Score [ Time Frame: Baseline, Week 78 ]

Current Secondary Outcome Measures (submitted: July 15, 2019)

• Change From Baseline in Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory Instrumental Items Score (ADCS-iADL) [ Time Frame: Baseline, Week 78 ]
  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, AChEI use at baseline, pooled site, and covariates for baseline iADL score, age at baseline, and baseline iADL score-by-visit interaction.
• Change From Baseline in Functional Activities Questionnaire (FAQ) Score [ Time Frame: Baseline, Week 78 ]
  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 determined by MMRM model with factors for treatment, visit, treatment-by-visit interaction, AChEI use at baseline, pooled site, and covariates for baseline FAQ total score, by-visit interaction and age at baseline.
• Change From Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score [ Time Frame: Baseline, Week 78 ]
  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 with factors for treatment, visit, treatment-by-visit interaction, AChEI use at baseline, pooled site, and covariates for baseline iADRS13 total score, age at baseline, and baseline iADRS13 total score-by-visit interaction.
• Change From Baseline in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score [ Time Frame: Baseline, Week 78 ]
  The CDR-SB is a rater administered scale and impairment is scored in each of 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, AChEI use at baseline, pooled site, and covariates for baseline CDR-SB score, age at baseline, and baseline CDR-SB score-by-visit interaction.
• Time to Progression as Measured by Loss of Clinical Dementia Rating (CDR) Global Score Stage [ Time Frame: From Loss of 1 Global Stage through Week 78 ]
  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).
• Change From Baseline in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Baseline, Week 78 ]
  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 a greater severity of neuropsychiatric disturbance. LS Mean was determined by MMRM methodology with factors for treatment, visit, treatment-by-visit interaction, AChEI use at baseline, pooled site, and covariates for baseline NPI score, age at baseline, and baseline NPI score-by-visit interaction.
• Change From Baseline on the Mini-Mental State Examination (MMSE) [ Time Frame: Baseline, Week 78 ]
  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, AChEI use at baseline, pooled site, and covariates for baseline MMSE total score, age at baseline, and baseline MMSE total score-by-visit interaction.
• Percent Change From Baseline in Concentration of Cerebrospinal Fluid (CSF) Biomarker Amyloid Beta (Aβ)1-42 [ Time Frame: Baseline, Week 71 ]
  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.
• Percent Change From Baseline in Concentration of CSF Biomarker Aβ1-40 [ Time Frame: Baseline, Week 71 ]
  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.
• Change From Baseline in CSF Biomarker Total Tau [ Time Frame: Baseline, Week 71 ]
  Cerebrospinal fluid samples were collected for analysis of concentration total tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, baseline biomarker and age at baseline.
• Change From Baseline in CSF Biomarker Phosphorylated Tau [ Time Frame: Baseline, Week 71 ]
  Cerebrospinal fluid samples are collected for analysis of concentration of phosphorylated tau. LS Mean was determined by ANCOVA with LOCF and with factors for treatment, baseline biomarker and age at baseline.
• Change From Baseline in Brain Amyloid Burden Using Florbetapir Amyloid Positron Emission Tomography (PET) Scan [ Time Frame: Baseline, Week 78 ]
  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 using ANCOVA methodology with terms for treatment, baseline biomarker and age at baseline.
• Change From Baseline in Regional Cerebral Blood Flow (rCBF) Using Florbetapir Perfusion Scan [ Time Frame: Baseline, Week 78 ]
  Florbetapir perfusion evaluated the regional cerebral blood flow (rCBF) as a biomarker of brain function and was performed at the same time as the amyloid florbetapir PET. Cerebral perfusion, especially in temporal and parietal areas, is reduced in AD and this pattern of hypoperfusion closely mirrors the hypometabolism pattern observed using FDG PET. Annualized change is derived as change at LOCF divided by (LOCF date - baseline date) multiplied by 365. LS Mean was determined by ANCOVA with LOCF (last observation carried forward) and with factors for treatment, baseline biomarker and age at baseline.
• Change From Baseline in Whole Brain Volume [ Time Frame: Baseline, Week 78 ]
  Magnetic resonance imaging (MRI) was used to evaluate the effect of lanabecestat on brain atrophy/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 with LOCF and with factors for treatment, baseline volumetric magnetic resonance imaging (vMRI), intracranial volume and age at baseline.
• Population Pharmacokinetics (PK): Apparent Oral Clearance of Lanabecestat [ Time Frame: Predose, Week 4, 7, 19, 39, 45 and Week 71 post dose ]
  The apparent oral clearance of lanabecestat was estimated using a population approach. No covariate effects were assessed as part of this analysis.
• Population PK: Central Volume of Distribution of Lanabecestat [ Time Frame: Predose, Week 4, 7, 19, 39, 45 and week 71 post dose ]
  The central volume of distribution for lanabecestat was estimated using a population approach. No covariate effects were assessed as part of this analysis.

Original Secondary Outcome Measures (submitted: May 24, 2016)

• Change from Baseline in Alzheimer´s Disease Cooperative Study Activities of Daily Living Inventory (ADCS-iADL) Instrumental Items Score [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Functional Activities Questionnaire (FAQ) Score [ Time Frame: Baseline, Week 78 ]
• Change from Baseline on the Integrated Alzheimer's Disease Rating Scale (iADRS) Score [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in the Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score [ Time Frame: Baseline, Week 78 ]
• Change in Clinical Dementia Rating (CDR) Global Score [ Time Frame: From Loss of 1 Global Stage through Week 78 ]
• Change from Baseline in Neuropsychiatric Inventory (NPI) Score [ Time Frame: Baseline, Week 78 ]
• Change from Baseline on the Mini-Mental State Examination (MMSE) [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Concentration of Cerebrospinal fluid (CSF) Biomarker Aβ1-42 [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Concentration of CSF Biomarker Aβ1-40 [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in CSF Biomarker Total Tau [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in CSF Biomarker Phosphorylated Tau [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Brain Amyloid Burden using Florbetapir Amyloid Scan [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Regional Cerebral Blood Flow (rCBF) using Florbetapir Perfusion Scan [ Time Frame: Baseline, Week 78 ]
• Change from Baseline in Whole Brain Volume [ Time Frame: Baseline, Week 78 ]
• Population Pharmacokinetics (PK): Apparent Oral Clearance of LY3314814 [ Time Frame: Predose Week 4 through Week 71 ]
• Population PK: Central Volume of Distribution of LY3314814 [ Time Frame: Predose Week 4 through Week 71 ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Lanabecestat (LY3314814) in Participants With Mild Alzheimer's Disease Dementia
• Official Title: A Randomized, Double-Blind, Placebo-Controlled and Delayed-Start Study of LY3314814 in Mild Alzheimer's Disease Dementia
• Brief Summary: The main purpose of this study is to evaluate the efficacy of the study drug known as lanabecestat in participants with mild Alzheimer's disease (AD) dementia.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Alzheimer's Disease

Intervention

• Drug: Lanabecestat
  Administered orally
  Other Names:

  • LY3314814
  • AZD3293
• Drug: Placebo
  Administered orally

Study Arms

• Experimental: Lanabecestat 20 milligrams (mg)
  Participants received Lanabecestat 20 mg film-coated tablets orally once daily until week 156.
  Intervention: Drug: Lanabecestat
• Experimental: Lanabecestat 50 mg
  Participants received Lanabecestat 50 mg film-coated tablets orally once daily until week 156.
  Intervention: Drug: Lanabecestat
• Experimental: Placebo/ Lanabecestat 20 mg
  Placebo given orally once daily for 78 weeks and then 20 mg of lanabecestat given orally once daily until week 156.
  Interventions:

  • Drug: Lanabecestat
  • Drug: Placebo
• Experimental: Placebo/ Lanabecestat 50 mg
  Placebo given orally once daily for 78 weeks and then 50 mg of lanabecestat given orally once daily until week 156.
  Interventions:

  • Drug: Lanabecestat
  • Drug: Placebo

Publications *

• Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, Landry J, Krull JH, Downing AM, Willis BA, Shcherbinin S, Mullen J, Barker P, Schumi J, Shering C, Matthews BR, Stern RA, Vellas B, Cohen S, MacSweeney E, Boada M, Sims JR. Efficacy and Safety of Lanabecestat for Treatment of Early and Mild Alzheimer Disease: The AMARANTH and DAYBREAK-ALZ Randomized Clinical Trials. JAMA Neurol. 2020 Feb 1;77(2):199-209. doi: 10.1001/jamaneurol.2019.3988. Erratum In: JAMA Neurol. 2020 Sep 1;77(9):1179.
• Cebers G, Alexander RC, Haeberlein SB, Han D, Goldwater R, Ereshefsky L, Olsson T, Ye N, Rosen L, Russell M, Maltby J, Eketjall S, Kugler AR. AZD3293: Pharmacokinetic and Pharmacodynamic Effects in Healthy Subjects and Patients with Alzheimer's Disease. J Alzheimers Dis. 2017;55(3):1039-1053. doi: 10.3233/JAD-160701.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: July 15, 2019): 1722
• Original Estimated Enrollment (submitted: May 24, 2016): 1899
• Actual Study Completion Date: September 28, 2018
• Actual Primary Completion Date: September 28, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Participant must meet the National Institute on Aging (NIA) and the Alzheimer's Association (AA) (NIA-AA) criteria for probable AD dementia.
• MMSE score of 20 to 26 inclusive at screening visit.
• For a diagnosis of mild AD dementia, participant must have a CDR global score of 0.5 or 1, with the memory box score ≥0.5 at screening.
• Evidence of amyloid pathology.
• The participant must have a reliable study partner with whom he/she cohabits or has regular contact.

Exclusion Criteria:

• Significant and/or current 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, repetitive head trauma, serious infection of the brain, Parkinson's disease, epilepsy, or cervicocranial vascular disease.
• Participants with 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 assessment, or affect the participant's ability to complete the study. Participants with history of schizophrenia or other chronic psychosis are excluded.
• Within 1 year before the screening visit or between screening and randomization, any of the following: myocardial infarction; moderate or severe congestive heart failure, New York Heart Association class III or IV; hospitalization for, or symptoms of, unstable angina; syncope due to orthostatic hypotension or unexplained syncope; known significant structural heart disease (such as, significant valvular disease, hypertrophic cardiomyopathy); or hospitalization for arrhythmia.
• Congenital QT prolongation.
• Intermittent second- or third-degree atrioventricular (AV) heart block or AV dissociation or history of ventricular tachycardia.
• A corrected QT (QTcF) interval measurement >470 milliseconds (men and women) at screening (as determined at the investigational site).
• History of malignant cancer within the last 5 years.
• History of vitiligo and/or current evidence of post-inflammatory hypopigmentation.
• Calculated creatinine clearance <30 milliliters per minute (Cockcroft-Gault formula; Cockcroft and Gault 1976) at screening.
• Currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 55 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, China, Czechia, Denmark, France, Germany, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Belgium, Czech Republic

Administrative Information

• NCT Number: NCT02783573
• Other Study ID Numbers: 16024; I8D-MC-AZET ( Other Identifier: Eli Lilly and Company ); 2015-005625-39 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://www.clinicalstudydatarequest.com/

• Current Responsible Party: AstraZeneca
• Original Responsible Party: Eli Lilly and Company
• Current Study Sponsor: AstraZeneca
• Original Study Sponsor: Eli Lilly and Company
• Collaborators: 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

• PRS Account: AstraZeneca
• Verification Date: October 2019