A Study of Lanabecestat (LY3314814) in Early Alzheimer's Disease Dementia

Study Overview
=================
Brief Summary
-----------------
This study is an extension of study I8D-MC-AZES (NCT02245737), the AMARANTH study. The purpose of this study is to evaluate the effectiveness of the study drug lanabecestat in participants with early Alzheimer's disease dementia at the time of entry into study I8D-MC-AZES.

Detailed Description
-----------------
Study AZFD was designed to be integrated with 104-week study AZES to form a Delayed-Start study (Study AZES-FD). Study AZES-FD was to be used to test the hypothesis that participants originally randomized to receive placebo in the double-blind feeder study AZES and switched to LY3314814 at the start of study AZFD did not catch up on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13) at Week 26 of study AZFD to participants originally randomized to receive LY3314814 in the double-blind feeder study.

Official Title
-----------------
A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer's Disease Dementia (Extension of Study AZES, The AMARANTH Study)

Conditions
-----------------
Alzheimer's Disease

Intervention / Treatment
-----------------
* Drug: Lanabecestat


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants previously enrolled in AMARANTH (NCT02245737) who meet eligibility criteria for delayed-start I8D-MC-AZFD. Exclusion Criteria: Participants who participate in AMARANTH (NCT02245737) who develop new conditions precluding them from enrolling into I8D-MC-AZFD.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AZES Lanabecestat 20 milligrams (mg)/AZFD Lanabecestat 20 mg<br>Participants who received Lanabecestat 20 mg in the feeder study (AZES) were randomized to receive Lanabecestat 20 mg. | Drug: Lanabecestat<br>* Administered orally<br>* Other names: AZD3293;|
| Experimental: AZES Lanabecestat 50 mg/AZFD Lanabecestat 50 mg<br>Participants who received Lanabecestat 50 mg in the feeder study (AZES) were randomized to receive Lanabecestat 50 mg. | Drug: Lanabecestat<br>* Administered orally<br>* Other names: AZD3293;|
| Experimental: AZES Placebo/AZFD Lanabecestat 20 mg<br>Participants who received placebo in the feeder study (AZES) were randomized to receive Lanabecestat 20 mg. | Drug: Lanabecestat<br>* Administered orally<br>* Other names: AZD3293;|
| Experimental: AZES Placebo/AZFD Lanabecestat 50 mg<br>Participants who received placebo in the feeder study (AZES) were randomized to receive Lanabecestat 50 mg. | Drug: Lanabecestat<br>* Administered orally<br>* Other names: AZD3293;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Analysis 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*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, apolipoprotein E4 (APOE4) status, acetylcholinesterase inhibitor (AChEI) use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline Analysis 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 with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 26 | 
| Change From Baseline on the Functional Activities Questionnaire (FAQ) Score | FAQ is a 10-item, caregiver-questionnaire and was administered to the study partner and 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 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 determined by MMRM with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 26 | 
| 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 with factors for treatment, visit, treatment*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 26 | 
| Change From Baseline on the Mini-Mental Status Examination (MMSE) | The MMSE is an instrument used to assess a participant's 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*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 26 | 
| Change From Baseline Analysis on the ADAS-Cog13 | ADAS-cog13 (13-item 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*visit, baseline efficacy score, baseline efficacy score-by-visit interaction, disease status at baseline, APOE4 status, AChEI use at baseline, age at baseline, and pooled country. | AZES Baseline through AZFD Week 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tauopathies, Alzheimer's Disease, Dementia, Brain Diseases, Neurodegenerative Diseases, Central Nervous System Diseases, Nervous System Diseases, Mental Disorders, Delirium, Dementia, Amnestic, Cognitive Disorders, Memory, Amyloid