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Clinical Research Protocol ATX-001 Protocol CLINICAL RESEARCH PROTOCOL ATX-001: A 6-month, Phase II Randomized, Double-Blind, Placebo- Controlled, Flexible Dosing, Crossover Trial of Atomoxetine in Subjects with Mild Cognitive Impairment. Sponsors: Alzheimer’s Drug Discovery Foundation Anonymous Philanthropic Donor Investigator: Allan I. Levey, MD, PhD Department of Neurology Emory University School of Medicine 12 Executive Park Drive Room 268 Atlanta, GA 30329 Co-Investigators: James J. Lah, MD, PhD Department of Neurology Emory University School of Medicine Whitehead Biomedical Research Building, Suite 505C 615 Michael Street Atlanta, GA 30322 William T. Hu, MD, PhD Department of Neurology Emory University School of Medicine Whitehead Biomedical Research Building, Suite 505F 615 Michael Street Atlanta, GA 30322 Janet S. Cellar, DNP, PMHCNS-BC Department of Neurology Emory University School of Medicine 12 Executive Park Drive Atlanta, GA 30329 Protocol Version #11b 1 Date: 27JUL2015 ATX-001 Protocol Table of Contents 1. BACKGROUND AND SIGNIFICANCE ............................................................................ 5 1.1 Preclinical studies ..................................................................................................... 5 1.2 Neuroinflammation .................................................................................................. 5 1.3 Animal Model Experience. ........................................................................................ 6 1.4 Previous Human Experience .................................................................................... 6 2. SPECIFIC AIMS ............................................................................................................... 7 2.1 Aim #1 ........................................................................................................................ 7 2.2 Aim #2 ........................................................................................................................ 7 2.3 Aim #3 ........................................................................................................................ 8 3. PRELIMINARY DATA ...................................................................................................... 8 3.1 NET Inhibition ............................................................................................................ 8 3.2 Measurement of CSF Analytes and Inflammatory Markers in MCI and AD. ......... 9 4. EXPERIMENTAL DESIGN AND METHODS ................................................................. 10 4.1 Overview: ................................................................................................................. 10 4.2 Sample Size and Power. ......................................................................................... 10 4.3 Atomoxetine Dosing. .............................................................................................. 10 4.4 Future research samples. ....................................................................................... 11 5. RESEARCH STUDY PERSONNEL ............................................................................... 11 5.1 Principal Investigator (PI) ....................................................................................... 11 5.2 Co-Investigators ...................................................................................................... 11 5.3 Research Coordinator. ........................................................................................... 11 5.4 Psychometrician ..................................................................................................... 11 5.5 Blinded clinical rater. .............................................................................................. 11 5.6 Statistician. .............................................................................................................. 11 6. SAFETY MONITORING AND ADVERSE EVENT REPORTING ................................... 11 6.1 Internal Safety Monitoring ...................................................................................... 11 6.2 Independent Data Safety Monitoring Board ......................................................... 12 6.3 Emory University Investigational Review Board (IRB) ........................................ 13 7. PATIENT SELECTION ................................................................................................... 14 7.1 Recruitment Plan. .................................................................................................... 14 7.2 Inclusion Criteria ..................................................................................................... 15 Protocol Version #11b 2 Date: 27JUL2015 ATX-001 Protocol 7.3 Exclusion criteria .................................................................................................... 16 7.4 Patient Numbering .................................................................................................. 17 7.5 Randomization ........................................................................................................ 17 Manual Randomization Plan .................................................................................................17 Mis-Randomization Plan .......................................................................................................17 8. STUDY ASSESSMENTS AND PROCEDURES ............................................................ 18 8.1 Informed Consent. .................................................................................................. 18 8.2 Screening Phase. .................................................................................................... 19 8.3 Baseline Visits. ........................................................................................................ 20 8.4 Visit 3/Week 1 (Telephone/Email Visit) + 2 days ................................................... 21 8.5 Visit 4/Week 2 (Office Visit) + 2 days ..................................................................... 21 8.6 Visit 5/Week 3 (Telephone/Email Visit) + 2 days ................................................... 21 8.7 Visit 6/Week 4 (Office Visit) + 2 days ..................................................................... 21 8.8 Visit 7/Week 5 (Telephone/Email Visit) + 2 days ................................................... 22 8.9 Visit 8/Week 6 (Office Visit) + 2 days ..................................................................... 22 8.10 Visit 9/Week 7 (Telephone/Email Visit) + 2 days ................................................ 22 8.11 Visit 10/Week 11 (Telephone/Email Visit) + 2 days ............................................. 22 8.12 Visit 11/Week 18 (Office Visit) + 2 days ............................................................... 23 8.13 Visit 12/Week 22 (Telephone/Email Visit) + 2 days ............................................. 23 8.14 Visit 13/Week 26 (Telephone/Email Visit) + 2 days ............................................. 23 8.15 Visit 14/Week 29 (Office Visit) Crossover Visit ................................................... 23 8.16 Visit 15/Week 30 (Telephone/Email Visit) + 2 days ............................................. 24 8.17 Visit 16/Week 31 (Office Visit) + 2 days ............................................................... 24 8.18 Visit 17/Week 32 (Telephone/Email Visit) + 2 days ............................................. 25 8.19 Visit 18/Week 33 (Office Visit) + 2 days ............................................................... 25 8.20 Visit 19/Week 34 (Telephone/Email Visit) + 2 days ............................................. 25 8.21 Visit 20/Week 35 (Office Visit) + 2 days ............................................................... 25 8.22 Visit 21/Week 36 (Telephone/Email Visit) + 2 days ............................................. 26 8.23 Visit 22/Week 40 (Telephone/Email Visit) + 2 days ............................................. 26 8.24 Visit 23 /Week 47 (Office Visit) + 2 days .............................................................. 26 8.25 Visit 24/Week 51 (Telephone/Email Visit) + 2 days ............................................ 26 8.26 Visit 25/Week 55 (Telephone/Email Visit) + 2 days ............................................. 27 8.27 Visit 26/Week 58 End of Study Visit ..................................................................... 27 8.28 Visit 271/Week 62 Termination Visit .................................................................... 28 Protocol Version #11b 3 Date: 27JUL2015 ATX-001 Protocol 8.29 Assessments: ........................................................................................................ 28 8.30.1 Safety Measurements: ..................................................................................................28 8.31.2 Other Assessments: ......................................................................................................29 8.32 Patient Retention ................................................................................................... 29 9. DATA RECORDING, RETENTION, AND MONITORING .............................................. 29 9.1 Electronic Case Report Forms ............................................................................... 29 9.2 Retention And Availability Of Records ................................................................. 29 10. STATISTICAL ANALYSIS PLAN................................................................................
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