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In Early Alzheimer's Disease De Protocol I8D-MC-AZFD(a) A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer’s Disease Dementia (Extension of Study AZES, The AMARANTH Study) NCT02972658 Approval Date: 06-Feb-2018 I8D-MC-AZFD(a) Clinical Protocol Page 1 Protocol I8D-MC-AZFD(a) A Randomized, Double-Blind, Delayed-Start Study of LY3314814 (AZD3293) in Early Alzheimer’s Disease Dementia (Extension of Study AZES, The AMARANTH Study) Confidential Information The information contained in this document is confidential and is intended for the use of clinical investigators. It is the property of Eli Lilly and Company or its subsidiaries and should not be copied by or distributed to persons not involved in the clinical investigation of LY3314814, unless such persons are bound by a confidentiality agreement with Eli Lilly and Company or its subsidiaries. Note to Regulatory Authorities: This document may contain protected personal data and/or commercially confidential information exempt from public disclosure. Eli Lilly and Company requests consultation regarding release/redaction prior to any public release. In the United States, this document is subject to Freedom of Information Act (FOIA) Exemption 4 and may not be reproduced or otherwise disseminated without the written approval of Eli Lilly and Company or its subsidiaries. LY3314814 (Lanabecestat) Study AZFD is a Phase 3 study designed to test whether LY3314814 will slow disease progression in patients with early Alzheimer’s Disease randomized in Study AZES. Eli Lilly and Company Indianapolis, Indiana USA 46285 Protocol Electronically Signed and Approved by Lilly on date provided below. Approval Date: 06-Feb-2018 GMT LY3314814 I8D-MC-AZFD(a) Clinical Protocol Page 2 Table of Contents Section Page 1. Synopsis .............................................................................................................................8 2. Schedule of Activities .......................................................................................................10 3. Introduction ......................................................................................................................13 3.1. Study Rationale............................................................................................................13 3.2. Background..................................................................................................................13 3.3. Benefit/Risk Assessment ..............................................................................................14 4. Objectives and Endpoints..................................................................................................15 5. Study Design.....................................................................................................................16 5.1. Overall Design .............................................................................................................16 5.2. Number of Participants.................................................................................................17 5.3. End of Study Definition ...............................................................................................17 5.4. Scientific Rationale for Study Design...........................................................................18 5.5. Justification for Dose ...................................................................................................18 6. Study Population...............................................................................................................19 6.1. Inclusion Criteria..........................................................................................................19 6.2. Exclusion Criteria ........................................................................................................20 6.3. Lifestyle Restrictions....................................................................................................20 6.4. Screen Failures.............................................................................................................21 6.5. Study Partner ...............................................................................................................21 7. Treatments........................................................................................................................22 7.1. Treatments Administered .............................................................................................22 7.1.1. Packaging and Labeling .......................................................................................22 7.2. Method of Treatment Assignment ................................................................................23 7.2.1. Selection and Timing of Doses.............................................................................23 7.3. Blinding .......................................................................................................................23 7.4. Dosage Modification....................................................................................................24 7.5. Preparation/Handling/Storage/Accountability...............................................................24 7.6. Treatment Compliance .................................................................................................24 7.7. Concomitant Therapy...................................................................................................25 7.7.1. Initiation of Post-Randomization Symptomatic AD Treatments ...........................................................................................................25 7.7.2. Other Medication Considerations Post-Randomization.........................................25 7.8. Treatment after the End of the Study ............................................................................26 7.8.1. Study Extensions..................................................................................................26 7.8.2. Continued Access.................................................................................................26 LY3314814 I8D-MC-AZFD(a) Clinical Protocol Page 3 8. Discontinuation Criteria ....................................................................................................27 8.1. Discontinuation from Study Treatment .........................................................................27 8.1.1. Discontinuation from Study Treatment.................................................................27 8.1.2. Temporary Discontinuation from Study Treatment...............................................28 8.1.3. Discontinuation of Inadvertently Enrolled Patients...............................................28 8.2. Discontinuation from the Study....................................................................................28 8.3. Lost to Follow-Up........................................................................................................29 9. Study Assessments and Procedures ...................................................................................30 9.1. Efficacy Assessments...................................................................................................30 9.1.1. Primary Outcome Efficacy Assessment ................................................................30 9.1.2. Secondary Efficacy Assessments..........................................................................30 9.1.3. Other/Exploratory Assessments............................................................................32 9.1.4. Appropriateness of Assessments ..........................................................................34 9.1.5. Order of Efficacy Assessments and Rater Qualifications ......................................34 9.1.5.1. Order of Efficacy Assessments .......................................................................34 9.1.5.2. Rater Qualifications and Blinding ...................................................................35 9.2. Adverse Events ............................................................................................................36 9.2.1. Serious Adverse Events........................................................................................37 9.2.1.1. Suspected Unexpected Serious Adverse Reactions..........................................37 9.2.2. Complaint Handling.............................................................................................38 9.3. Treatment of Overdose.................................................................................................38 9.4. Safety...........................................................................................................................38 9.4.1. Vasogenic Edema.................................................................................................38 9.4.2. Rash.....................................................................................................................38 9.4.3. Depression ...........................................................................................................39 9.4.4. Disease Progression .............................................................................................39 9.4.5. Laboratory Safety Assessment .............................................................................39 9.4.6. Hepatic Monitoring ..............................................................................................39 9.4.7. Physical and Neurological Examinations..............................................................40
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