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In Adults with Amnestic Mild Cognitive Impairment (Amci) Or Mild Alzheimer’S Disease (AD)

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In Adults with Amnestic Mild Cognitive Impairment (Amci) Or Mild Alzheimer’S Disease (AD) ADC-046-INI IND #: 119,232 NCT01767909 Therapeutic effects of intranasally-administered insulin (INI) in adults with amnestic mild cognitive impairment (aMCI) or mild Alzheimer’s disease (AD) Protocol #: ADC-046-INI IND #: 119,232 PROJECT DIRECTOR / COORDINATION & DATA IND SPONSOR MANAGEMENT CENTER Suzanne Craft, Ph.D. Paul Aisen, M.D. ATRI Director Wake Forest University Alzheimer’s Therapeutic Research Institute School of Medicine (ATRI) Medical Center Boulevard University of Southern California Winston-Salem, NC 27157-1207 PROTOCOL VERSION VERSION DATE Final Protocol v5.0 05DEC2016 Page 1 of 55 ADC-046-INI IND #: 119,232 TABLE OF CONTENTS 1.0! INTRODUCTION ............................................................................................................... 11! 1.1! Primary Aim ................................................................................................................... 11! 1.2! Secondary Aims ............................................................................................................. 11! 1.2.1! Secondary Aim 1 ..................................................................................................... 11! 1.2.2! Secondary Aim 2 ..................................................................................................... 11! 1.2.3! Secondary Aim 3 ..................................................................................................... 11! 1.2.4! Secondary Aim 4 ..................................................................................................... 11! 1.2.5! Secondary Aim 5 ..................................................................................................... 11! 2.0! BACKGROUND AND SIGNIFICANCE ............................................................................. 12! 2.1! Rationale for Insulin ....................................................................................................... 12! 2.2! Insulin as a Therapeutic Agent ...................................................................................... 12! 2.2.1! Intranasal Pathways to the CNS ............................................................................. 13! 2.2.2! Intranasal Delivery System Device ......................................................................... 13! 3.0! PRELIMINARY STUDY ..................................................................................................... 15! 3.1! Participants .................................................................................................................... 15! 3.2! Procedures ..................................................................................................................... 16! 3.3! Safety and Compliance .................................................................................................. 16! 3.4! Statistical Analyses ........................................................................................................ 16! 3.5! Results: Cognitive and Functional Outcome Measures ................................................. 17! 3.6! Results: AD Biomarkers ................................................................................................. 18! 3.7! Results: FDG-PET CMRglc ........................................................................................... 18! 3.8! Safety and Compliance .................................................................................................. 19! 3.9! Implications .................................................................................................................... 20! 4.0! STUDY DESIGN RATIONALE .......................................................................................... 20! 4.1! Rationale for Population Selection ................................................................................. 20! 4.2! Rationale for Dosage Selection ..................................................................................... 20! 4.3! Rationale for Primary and Secondary Outcome Measures ............................................ 21! 4.4! Rationale for Length and Design of Trial ....................................................................... 21! 4.5! Rationale for Magnetic Resonance Imaging .................................................................. 21! 4.6! Rationale for Biofluids .................................................................................................... 22! 5.0! STUDY OVERVIEW .......................................................................................................... 22! 5.1! Study Population ............................................................................................................ 23! 5.2! Diagnosis Criteria ........................................................................................................... 23! 5.3! Inclusion Criteria ............................................................................................................ 24! 5.4! Exclusion Criteria ........................................................................................................... 24! 5.5! Recruitment and Retention Strategies ........................................................................... 25! 6.0! STUDY TIMELINE ............................................................................................................. 26! 7.0! DESCRIPTION OF STUDY VISITS ................................................................................... 26! 7.1! Pre-Screening ................................................................................................................ 26! 7.2! Screening (Visit 1) .......................................................................................................... 26! 7.3! Baseline (Visit 2) ............................................................................................................ 27! 7.4! Month 3 (Visit 3) ............................................................................................................. 28! 7.5! Month 6 (Visit 4) ............................................................................................................. 28! 7.6! Month 9 (Visit 5) ............................................................................................................. 28! 7.7! Month 12 (Visit 6) ........................................................................................................... 29! Page 2 of 55 ADC-046-INI IND #: 119,232 7.8! Month 15 (Visit 7, Open Label) ...................................................................................... 29! 7.9! Month 18 (Visit 8, Open Label) ...................................................................................... 30! 8.0! EARLY TREATMENT/STUDY DISCONTINUATION ........................................................ 30! 8.1! Reasons for Early Discontinuation ................................................................................. 30! 9.0! STUDY-SPECIFIC PROCEDURES ................................................................................... 31! 9.1! Cognitive Evaluations .................................................................................................... 31! 9.1.1! Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog12) ........................ 31! 9.1.2! Mini-Mental State Examinations (MMSE) ............................................................... 31! 9.1.3! Memory Composite (Story Recall and Free and Cued Selective Reminding Test) 31! 9.1.4! Logical Memory Test (Wechsler Memory Scale-Revised) ...................................... 32! 9.1.5! Trail-making Test (Part A and B) ............................................................................ 32! 9.2! Clinical and Functional Evaluations ............................................................................... 32! 9.2.1! Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) ................................... 32! 9.2.2! ADCS-MCI Activities of Daily Living (ADCS-ADL-MCI) .......................................... 32! 9.2.3! Neuropsychiatric Inventory (NPI) ............................................................................ 33! 9.2.4! Modified Hachinski .................................................................................................. 33! 9.3! Research Satisfaction Survey ........................................................................................ 33! 9.4! Treatment Blinding Questionnaire ................................................................................. 33! 10.0! STUDY METHODS ............................................................................................................ 33! 10.1! Safety Assessments .................................................................................................... 33! 10.2! Physical and Neurological Examination ....................................................................... 34! 10.3! Electrocardiogram (ECG) ............................................................................................. 34! 10.4! Clinical Laboratory Evaluations .................................................................................... 34! 11.0! BIOMARKER STUDIES .................................................................................................... 34! 11.1! CSF .............................................................................................................................. 34! 11.2! Blood Collection ..........................................................................................................
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