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Investigational Plan ADvance Study Investigational Plan ADvance: A 12-month double-blind, randomized, controlled feasibility study to evaluate the safety, efficacy and tolerability of deep brain stimulation of the fornix (DBS-f) in patients with mild probable Alzheimer’s disease Abbreviated Title: ADvance Study Protocol Number: FNMI-001 IDE Number: G110220 Functional Neuromodulation. 455 Second Street, SE, Suite 402 Charlottesville, VA 22902 CONFIDENTIAL DO NOT COPY This investigational plan contains confidential information for use only by physicians participating in the ADvance Study. This document should be maintained in a secure location and should not be copied or made available for review by any unauthorized person or firm. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 1 OF 70 Investigational Plan ADvance Study Contact Information Role Clinical Contact Regulatory Contact Co-National Principal Investigators Contact Information Kristen Drake Senior Clinical Manager Functional Neuromodulation 962 Redcedar Way Drive Coppell, TX 75019 USA Tel: (214) 543-8321 Email: [email protected] Neuromodulation. Todd Langevin President and Chief Operating Officer Functional Neuromodulation 5504 Brookview Ave Edina, MN, 55424 USA Tel: (763) 607-1214 Email: [email protected] Andres Lozano MD, PhD, FRCSC, FRS Professor & Chair, Neurosurgery Toronto Western Hospital 399 Bathurst St. WW 4-431 Toronto, Ontario M5T 2S8 Canada Tel: (416) 603-6200 Email: [email protected] Constantine Lyketsos, MD Professor and Chair Department of Psychiatry Johns Hopkins Bayview 5300 Alpha Commons Dr. Baltimore, MD 21224 USA Study Monitor Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 Tel: (410) 550-0062 Email: [email protected] Functional Neuromodulation 455 2nd Street S.E., Suite 402 Charlottesville, VA 22902 Fax: 434-291-1001 CONFIDENTIAL PAGE 2 OF 70 Investigational Plan ADvance Study 1. INVESTIGATIONAL PLAN SYNOPSIS ADvance Study Synopsis Protocol Number FNMI-001 Study Device Model 37601 Activa PC Stimulator, Model 3387 Lead with Model 37085 extension (Medtronic, Inc) Primary Objective The primary objective of this feasibility study is to evaluate the safety of DBSf in patients with mild Alzheimer’s disease by assessing all device and/or therapy related adverse events. The secondary objective is to preliminarily estimate the treatment effect size on the outcomes of interest at 12 months post-randomization. The objectives do not involve formal tests of hypotheses. Study Design This is a prospective, multi-center, double-blind randomized controlled feasibility trial designed to estimate the potential clinical benefit, and associated risks, of deep brain stimulation of the fornix (DBS-f) in patients with mild Alzheimer’s disease. Follow-Up Schedule Following screening, baseline and implantation of the device, scheduled follow-up visits will occur at 2 weeks post-implant and at months 1, 3, 6, 9, 12, 13, 15, 18, 21 and 24 months. All subjects, including subjects randomized to the DBS-f Off arm will have the device programmed ON after the 12-month visit. All subjects will be exited from the study at the conclusion of their 24-month visit. At this point, subjects will have the option to continue to be followed for, at a minimum, safety under a long-term follow-up study. Number of Subjects Up to 60 implanted AD subjects (40 in the U.S. and 20 in Canada) Number of Sites and Geographies Up to 9 research sites will participate in the study. Eight (8) research sites will be in the US and one (1) research site will be in Canada. Inclusion Criteria For quality control, prior to surgical implant an expert enrollment review committee consisting of the co-national principal investigators and designated experts will review the eligibility of each subject to ensure they meet enrollment criteria and are truly candidates for the study. If a subject does not meet the criteria per the enrollment review committee, they will be withdrawn from the study and no further follow-up will be required. Patients who meet all of the following criteria may be given consideration for inclusion in this clinical investigation: 1. Informed consent signed by the subject, caregiver AND a surrogate. 2. 45-85 years of age (inclusive) 3. Probable Alzheimer’s disease according to the National Institute of Aging Alzheimer’s disease Association criteria. 4. Clinical Dementia Rating (CDR) global rating of 0.5 or 1 at screening. 5. ADAS-cog-11 score of 12-24 inclusive at screening AND baseline Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 3 OF 70 Investigational Plan ADvance Study ADvance Study Synopsis (with a score ≥ 4 on ADAS-cog item 1). 6. If female, post-menopausal, surgically sterile or willing to use birth control methods for the duration of the study. 7. The patient has an available caregiver or other appropriate knowledgeable informant who can reliably report on daily activities and function and signs the informed consent for participation as such. 8. Patient is living at home and likely to remain at home for the study duration. 9. General Medical Health Rating (GMHR) ≥ 3 (good or excellent general health). 10. Patient must be a good surgical candidate for placement of a deep brain stimulator as judged by the DBS surgical team. 11. Fluency (oral and written) in the language in which standardized tests will be administered. 12. The patient is taking a stable dose of cholinesterase inhibitor (AChEI) medication (donepezil, galantamine, or rivastigmine) for at least 60 days prior to signing the informed consent form and there is no intention to modify the dose over the course of the study (NOTE: These medications may NOT be initiated, discontinued or modified after study initiation for the length of study participation). Exclusion Criteria The subject must not meet any of the following exclusion criteria: 1. Neuropsychiatric Inventory (NPI) total score ≥ 10 or score ≥ 4 in any NPI domain (clinically significant neuropsychiatric symptoms). Apathy score ≥ 4 acceptable. 2. Modified Hachinski ischemia scale score > 4 at screening 3. Subjects at risk for suicide in the opinion of the investigator or the subject answers “yes” to “Suicidal Ideation” Item 4 or 5 on the CSSRS (at time of evaluation) at the screening visit. 4. The subject has answered “yes” on any of the items in the suicidal behavior section of the C-SSRS with reference to the three-month period prior to screening visit. 5. Cornell Scale for Depression and Dementia (CSDD) score > 10 at the screening visit 6. Young Mania Rating Scale (YMRS) ≥ 11 at the screening visit 7. Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit 8. The subject has attempted suicide in the 2 years prior to signing the consent to participate in the study. 9. In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 4 OF 70 Investigational Plan ADvance Study ADvance Study Synopsis study 10. History of head trauma in the 2 years prior to signing the consent to participate in the study 11. History of brain tumor, subdural hematoma, or other clinically significant (in the judgment of the investigator) space-occupying lesion on CT or MRI 12. Active psychiatric disorder 13. Mental retardation 14. Current alcohol or substance abuse as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 15. Contraindications for PET scanning (e.g., insulin dependent diabetes) 16. Contraindications for MRI scanning, including implanted metallic devices (e.g. non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces. 17. Radiation exposure in the 1 year prior to signing the informed consent form that, in combination with the radiation exposure from this study, would exceed 5 rem. 18. Abnormal lab results that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. 19. Abnormal cardiovascular or neurovascular disorder that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. 20. Unstable dose of any medication prescribed for the treatment of memory loss or Alzheimer’s disease. 21. Currently prescribed any non-AD medications that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. 22. Is unable or unwilling to comply with protocol follow-up requirements. 23. Has a life expectancy of < 1 year. 24. Is actively enrolled in another concurrent clinical trial. Primary Safety Endpoint(s) To evaluate the safety of DBS-f in patients with mild Alzheimer’s disease, a detailed assessment of all device and/or therapy related adverse events will be conducted. Secondary Efficacy Endpoint(s) For the assessment of DBS-f therapy in treating mild Alzheimer’s, three efficacy outcomes are of particular clinical interest. These outcomes are: Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 The change in ADAS-cog-13 at 12 months CONFIDENTIAL PAGE 5 OF 70 Investigational Plan ADvance Study ADvance Study Synopsis The change in CDR at 12 months and The change in cerebral glucose metabolism as measured by FDGPET at 12 months Additional Analyses Additional analyses including change from baseline to 12 months in CVLT, ADCS-ADL23, AD-QOL, various neuropsychiatric tests (Letter Fluency, Trail Making Test, Brief Visuospatial Memory Test), NPI, Zarit Caregiver Burden and hippocampal volume as measured by MRI. Randomization At the post-operative 2 Week Visit, all subjects will be randomized in a 1:1 allocation to the therapy ON and OFF groups. The OFF group will have DBS therapy turned off for the first 12 months of follow-up and the ON group will receive therapy for the first 12 months of follow-up. Subjects will be blinded to their treatment assignment until all subjects have completed the 12-month visit or until their study exit at 24-months post-implant, whichever happens first. Study Duration The expected duration of this study is approximately 3 years from the time of first subject enrollment to the time of last subject follow-up visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 6 OF 70 Investigational Plan ADvance Study 2. PROTOCOL AGREEMENT I, the undersigned investigator, have read and understood the terms of the protocol. I agree to perform and conduct the study as described in the protocol and in accordance with the signed Investigator Agreement, ICH Good Clinical Practice Guidelines and applicable federal and local laws. Protocol Number Version Number Version Date FNMI-001 Version 2.6 December 30, 2013 This document contains proprietary and confidential information of Functional Neuromodulation. Do not copy, distribute, or share with others without prior written authorization from Functional Neuromodulation. Principal Investigator signature Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 Date CONFIDENTIAL PAGE 7 OF 70 Investigational Plan ADvance Study Table of Contents 1. INVESTIGATIONAL PLAN SYNOPSIS ................................................................................................................... 3 2. PROTOCOL AGREEMENT ...................................................................................................................................... 7 3. INTRODUCTION ..................................................................................................................................................... 11 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 4. SYSTEM DESCRIPTION ........................................................................................................................................ 14 4.1 4.2 5. Investigational system description ............................................................................................................... 14 Labeling ........................................................................................................................................................ 16 INCLUSION AND EXCLUSION CRITERIA ............................................................................................................ 16 5.1 5.2 6. Purpose ........................................................................................................................................................ 11 Background and Study justification .............................................................................................................. 11 Primary Objective ......................................................................................................................................... 12 Device Name................................................................................................................................................ 12 Intended Use ................................................................................................................................................ 13 Study Overview ............................................................................................................................................ 13 Blinding ........................................................................................................................................................ 13 Study Duration ............................................................................................................................................. 14 Number of Sites and Subjects ..................................................................................................................... 14 Inclusion Criteria .......................................................................................................................................... 16 Exclusion Criteria ......................................................................................................................................... 17 METHODOLOGY .................................................................................................................................................... 18 6.1 6.2 6.3 Study Design ................................................................................................................................................ 18 Follow-up Schedule ..................................................................................................................................... 18 Data Collection Requirements ..................................................................................................................... 21 6.3.1 Screening Visit .................................................................................................................................. 22 6.3.2 Baseline Visit (≤ 59 days post-consent) ........................................................................................... 24 6.3.3 Implant Visit (w/in <60 days p- Screen ICF and p- baseline) ........................................................... 26 6.3.4 2 Week Follow-up Visit (11 – 17 days post-implant) ........................................................................ 29 6.3.5 Month 1 Follow-up Visit (30 – 45 days post-implant) ....................................................................... 32 6.3.6 Month 3 Follow-up Visit (80 – 100 days post-implant) ..................................................................... 33 6.3.7 Month 6 Follow-up Visit (155 – 205 days post-implant) ................................................................... 34 6.3.8 Month 9 Follow-up Visit (220 – 320 days post-implant) ................................................................... 36 6.3.9 Month 12 Follow-up Visit (300 – 420 days post-implant) ................................................................. 37 6.3.10 Month 13 Follow-up Visit (30-45 days) ............................................................................................. 38 6.3.11 Month 15 Follow-up Visit (± 30 days) ............................................................................................... 39 6.3.12 Month 18 Follow-up Visit (± 30 days) ............................................................................................... 40 6.3.13 Month 21 Follow-up Visit (± 30 days) ............................................................................................... 42 6.3.14 Month 24 Follow-up Visit (± 30 days) ............................................................................................... 42 6.3.15 Unscheduled Assessments during Follow-up .................................................................................. 44 6.3.16 Study Medications ............................................................................................................................ 44 7. SUBJECT ENROLLMENT ...................................................................................................................................... 44 8. ADVERSE EVENTS ................................................................................................................................................ 44 8.1 9. Adverse Event Classification ....................................................................................................................... 45 TERMINATION OF PARTICIPATION .................................................................................................................... 45 9.1 9.2 9.3 Lost to Follow-up .......................................................................................................................................... 45 Subject Withdrawal ...................................................................................................................................... 45 Subject Death............................................................................................................................................... 46 Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 8 OF 70 Investigational Plan ADvance Study 9.4 System Revisions......................................................................................................................................... 46 10. STUDY OVERSIGHT AND INTEGRITY ................................................................................................................. 46 10.1 10.2 10.3 10.4 10.5 10.6 Clinical Events Committee ........................................................................................................................... 47 Protection of Human Subjects ..................................................................................................................... 47 Core Lab ...................................................................................................................................................... 48 Data safety and monitoring board ................................................................................................................ 48 Enrollment Review Committee ..................................................................................................................... 48 Case Report Forms ...................................................................................................................................... 48 11. DATA ANALYSIS AND STATISTICAL METHODS ............................................................................................... 49 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 Study Objectives .......................................................................................................................................... 49 Randomization ............................................................................................................................................. 49 Blinding ........................................................................................................................................................ 49 Emergency Unblinding ................................................................................................................................. 49 Primary Endpoint: Safety ............................................................................................................................. 49 11.5.1 Description ........................................................................................................................................ 49 11.5.2 Sample Size...................................................................................................................................... 49 11.5.3 Data Analysis .................................................................................................................................... 50 Secondary Endpoint: Efficacy ...................................................................................................................... 50 11.6.1 Description ........................................................................................................................................ 50 11.6.2 Sample Size...................................................................................................................................... 50 11.6.3 Data Analysis .................................................................................................................................... 50 Sample Size Summary ................................................................................................................................ 50 Additional Analyses ...................................................................................................................................... 51 11.8.1 Analysis of Baseline Demographics ................................................................................................. 51 11.8.2 Data Pooling Analysis ....................................................................................................................... 51 11.8.3 Other Analyses ................................................................................................................................. 51 11.8.4 Non-Randomized Implanted Subjects .............................................................................................. 51 Statistical Methods ....................................................................................................................................... 51 11.9.1 General Principles ............................................................................................................................ 51 11.9.2 Handling of Missing Data .................................................................................................................. 52 12. RISK AND BENEFIT ANALYSIS ........................................................................................................................... 52 12.1 12.2 12.3 Potential Benefits ......................................................................................................................................... 52 Potential Risks ............................................................................................................................................. 52 12.2.1 Surgical and Procedural Risks ......................................................................................................... 52 12.2.2 Device Related Risks ....................................................................................................................... 53 12.2.3 Therapy Related Risks ..................................................................................................................... 53 12.2.4 Other Device Related Risks ............................................................................................................. 53 12.2.5 Pregnancy......................................................................................................................................... 54 12.2.6 Risks Associated with Study Medications ........................................................................................ 54 12.2.7 Risks Associated with Blood Draw ................................................................................................... 54 12.2.8 Risks Associated with MRI ............................................................................................................... 54 12.2.9 Risks Associated with PET ............................................................................................................... 54 Mitigation of Risks ........................................................................................................................................ 55 12.3.1 Mitigation of Known and Anticipated Surgical Risks ........................................................................ 55 12.3.2 Mitigation of Device-Related and Therapy-Related Risks ................................................................ 55 12.3.3 Specific Mitigations for Known PET Risks........................................................................................ 55 12.3.4 Specific Mitigations for Known MRI Risks ........................................................................................ 55 12.3.5 Mitigation for Unknown or Unanticipated Risks ................................................................................ 56 13. SITE REQUIREMENTS .......................................................................................................................................... 56 13.1 13.2 Site Selection ............................................................................................................................................... 56 Study Initiation.............................................................................................................................................. 57 Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 9 OF 70 Investigational Plan ADvance Study 14. MONITORING PROCEDURES............................................................................................................................... 57 14.1 14.2 14.3 14.4 14.5 14.6 Monitoring procedures ................................................................................................................................. 57 Monitoring Reports ....................................................................................................................................... 57 Final Monitoring Visit .................................................................................................................................... 58 Confidentiality............................................................................................................................................... 58 Informed Consent......................................................................................................................................... 58 Securing Compliance ................................................................................................................................... 59 15. SITE RESPONSIBILITIES, RECORDS AND REPORTS ...................................................................................... 59 15.1 15.2 15.3 Responsibilities and record retention ........................................................................................................... 59 Reports ......................................................................................................................................................... 60 Records Custody.......................................................................................................................................... 61 APPENDIX A: DRAFT CASE REPORT FORMS ELEMENTS ...................................................................................... 61 APPENDIX B: SAMPLE INFORMED CONSENT .......................................................................................................... 64 APPENDIX C: DEFINITIONS.......................................................................................................................................... 65 APPENDIX D: REFERENCES ........................................................................................................................................ 68 APPENDIX E: OVERALL MONITORING FOR SERIOUS PSYCHIATRIC ADVERSE EVENTS FOR THE STUDY ... 69 Tables TABLE 1: VISIT W INDOWS ................................................................................................................................................... 19 TABLE 2: DATA COLLECTION REQUIREMENTS ...................................................................................................................... 21 TABLE 3: DEVICE PROGRAMMING REQUIREMENTS – DBS-F ON GROUP ............................................................................... 31 TABLE 4: DEVICE PROGRAMMING REQUIREMENTS – DBS-F OFF GROUP.............................................................................. 31 TABLE 5: FUNCTIONAL NEUROMODULATION RESEARCH ROLES AND RESPONSIBILITIES.......................................................... 46 TABLE 6: PRINCIPAL INVESTIGATOR REPORTING RESPONSIBILITIES ...................................................................................... 60 TABLE 7: OVERIVEW OF ROLES OF STUDY MONITORING ...................................................................................................... 69 Figures FIGURE 1 : SUBJECT ENROLLMENT AND FOLLOW-UP FLOW CHART ....................................................................................... 20 FIGURE 2: SCHEMATIC OF FORNIX AND SURROUNDING STRUCTURES WITH LEAD IN POSITION ................................................. 27 FIGURE 3: MRI SHOWING LEAD WITH FOUR CONTACTS ......................................................................................................... 27 FIGURE 4: DBS ELECTRODE PROJECTED ONTO BRAIN ATLAS ................................................................................................ 28 Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 10 OF 70 Investigational Plan ADvance Study 3. INTRODUCTION 3.1 PURPOSE The purpose of this study is to preliminarily assess the safety and efficacy of the deep brain stimulation in the fornix (DBS-f) for the treatment of mild probable Alzheimer’s disease (AD) in patients who have been treated with a cholinesterase inhibitor for at least 60 days. 3.2 BACKGROUND AND STUDY JUSTIFICATION Alzheimer's Disease (AD) is the sixth leading cause of all deaths in the United States and the fifth leading cause of death in Americans over 65 years. An estimated, 5.4 million people in the US have AD. Almost two-thirds of all Americans living with AD are women. This is primarily explained by the fact that women live longer than men on average. While most people in the United States living with AD are non-Hispanic whites, older African Americans and Hispanics are proportionately more likely than older whites to have AD. It is a progressive neurodegenerative disorder characterized by the gradual deterioration of affected individuals’ memory, intellect, and autonomy. Once diagnosed with AD, the vast majority progress to more severe stages of the disease. The diagnosis of AD is based on the National Institute of Aging Alzheimer’s Association Guidelines. For a diagnosis of probable AD, the patient must first meet the core criteria for dementia. This includes cognitive or behavioral symptoms that interfere with the ability to function at work or usual activities; and represent a decline from the previous levels of functioning and performing; and are not explained by delirium or major psychiatric disorder. The criteria for probable AD are as follows: 1) An insidious onset; 2) A clear-cut history of worsening cognition and 3) The initial and most prominent cognitive deficit must be evident on one of the following categories: A) Amnestic presentation – impairment of learning and recall of recently learned information or B) Non-amnestic presentation, i.e. language presentation, visuospatial presentation or executive dysfunction. There is no cure for AD, no options are available to slow the course of the disease and limited options exist for symptomatic treatment. The medications currently approved temporarily slow worsening of symptoms for about 6 to 12 months and are effective for only about half of the individuals who take them. Five are currently approved to treat the symptoms. Four (donepezil hydrochloride, galantamine hydrobromide, rivastigmine tartrate, tacrine) are focused on cholintesterase inhibition prescribed to treat symptoms related to memory, thinking, language, judgment and other thought processes. The fifth, memantine, is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate receptor antagonist. Alzheimer’s disease (AD) is a major and rapidly growing public health problem for which few effective therapies are available. Current FDA-approved therapies, cholinesterase inhibitors and NDMA receptor antagonists, have modest and often variable effects on clinical symptoms. Their use in clinical management of AD is frequently due to a lack of better alternatives. Treatment development has focused on the amyloid hypothesis, but disappointing results have emerged from trials of the “anti-amyloid” therapies. Advances in neurosurgical techniques and the introduction of DBS have made it possible to modulate the activity of several brain circuits including pain circuits (Davis KD 1998), motor circuits in patients with Parkinson’s disease (Lang AE 1998), essential tremor (Koller W 1997), dystonia (Vidailhet M 2005), and Huntington’s disease (Moro E 2004), as well as circuits modulating mood in patients with treatment resistant depression (Mayberg HS 2005) (Lozano AM 2008)). Interventions in these dysfunctional circuits can have local, trans-synaptic and remote effects (Davis K 1997) and in some cases can produce striking clinical improvements beyond what is achievable with medications. Given our understanding of brain circuits affected in AD, DBS holds promise as a therapeutic strategy that might effectively, and with acceptable risk, target the fornix to potentially improve AD outcomes. The fornix is a major inflow and outflow tract of the hippocampus (Powell TP 1957). Recent neuroimaging research suggests that loss of fornix integrity is an early event in AD that is followed by hippocampal volume loss Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 11 OF 70 Investigational Plan ADvance Study (Mielke MM 2009). Studies of the earliest phases of AD in humans and animal models indicate that one of the first areas affected is the hippocampus, most likely resulting from cortical pathology that leads to dying back of neurons and the spread of the disease into the hippocampus. Targeting therapies at the fornix may slow its degeneration, as well as affect the hippocampus and cortical circuitry. A novel and potentially important therapeutic approach for AD, it is hypothesized that DBS of the fornix (DBS-f) during early AD leads to improvement in clinical and neurobiological outcomes. This hypothesis is supported by promising preliminary results from the Pilot clinical trial of DBS-f in AD that demonstrated the safety and tolerability of DBS-f, as well as a sustained increase in cortical glucose metabolism over one year, in excess of the effects of chronic cholinesterase inhibitors and in contrast to the decreases observed in the course of AD (Laxton AW 2010). Furthermore, studies in rodents demonstrate that DBS-f led to improved memory and hippocampal neurogenesis, possible contributors to the mechanism of action (Toda 2008). A reasonable next step is a Feasibility trial of DBS-f in AD the aim of which is to gain additional experience with DBS-f in AD. The study is focused on safety, preliminary estimation of efficacy and clinical and neurobiological response predictors. Specifically, the study will evaluate the safety and tolerability of DBS-f for the treatment of mild probable AD in a blinded, randomized clinical trial design. The efficacy of DBS-f for mild AD will also be examined by comparing clinical, cognitive and neuroimaging outcomes in patients started on active DBS-f after surgery to those in patients implanted with DBS-f but not activated until after a delay of 12 months. To summarize, the findings and observations to support the rationale for evaluating DBS-f as a treatment for AD are as follows: 1. Evidence from a pilot trial of fornix/hypothalamic stimulation suggests that circuits involved in memory are accessible in humans and that their activity can be modulated by electrical stimulation. 2. The fornix is reasonable target for stimulation due to its role in memory formation. 3. Pilot data suggest that DBS-f can modulate memory circuits in AD patients and produce clinical benefits with an acceptable safety profile. 4. Mapping of electrical activity of AD patients shows DBS-f activates the hippocampus and cortical regions in the brain’s default network. 5. Preliminary evidence suggests that DBS-f produces sustained increases in glucose metabolism in contrast to expected decreases in AD patients over time. 6. As a result of DBS-f in AD patients, hippocampal volumes and glucose metabolism changes may correlate with clinical outcomes. 7. Data from rodent models suggest that the biological mechanism of the effects of DBS-f may be due to promotion of neurogenesis. 8. DBS-f is a unique circuitry-based approach to treating AD. 3.3 PRIMARY OBJECTIVE The primary objective of this feasibility study is to evaluate the safety of DBS-f in patients with mild Alzheimer’s disease by assessing all device and/or therapy related adverse events. The secondary objective is to preliminarily estimate the treatment effect size in the outcomes of interest at 12 months post-randomization. The objectives are not based on formal tests of hypotheses. 3.4 DEVICE NAME The system used in the study includes the Model 37601 Activa PC stimulator, Model 3387 Lead and Model 37085 Extension, all manufactured and commercially available by Medtronic, Inc. Collectively, these devices will be referred to as “the System”. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 12 OF 70 Investigational Plan ADvance Study 3.5 INTENDED USE In this study, the Medtronic DBS System is intended for patients with mild probable Alzheimer’s disease diagnosed according to the National Institute on Aging and Alzheimer’s disease Association criteria (McKhann, et al. 2011). Subjects must be on a stable dose of cholinesterase inhibitor medication. The stimulation will be applied to the fornix area of the brain to modulate neurophysiological activity in the pathological circuits. The System is commercially available in the United States and is indicated for deep brain stimulation for the treatment of symptoms of Parkinson's disease and essential tremor. 3.6 STUDY OVERVIEW This is a prospective, multi-center, double-blind randomized controlled feasibility trial designed to estimate the potential clinical benefit, and associated risks, of deep brain stimulation of the fornix (DBS-f) in patients with mild Alzheimer’s disease. The study will evaluate the effects of DBS-f when administered with concomitant cholinesterase inhibitor medication. Individuals must be taking cholinesterase inhibitor medication on a stable dose for at least 60 days to be eligible for this study. Up to forty U.S. subjects (40) successfully implanted subjects will be randomized in a 1:1 allocation to one of two treatment groups: 1) DBS-f On, or 2) DBS-f Off. For the approximately 15 subjects randomized to DBS-f On, DBS-f treatment will be initiated at the visit approximately 14 days post-implant. For the approximately 15 subjects randomized to DBS-f Off, DBS-f treatment will be turned OFF for the first 12 months of the study, and turned ON for 12-months thereafter if determined to be appropriate by the AD physician. An independent Data Safety and Monitoring Board (DSMB) will review all safety data at intervals which will be prespecified in the charter finalized by the DSMB. As this is a safety assessment only, and since the trial is designed without formal tests of hypotheses, there will be no alpha adjustment to account for the interim analyses. At the point of each interim analysis, a summary of the results will be sent to the FDA and the study design could potentially be modified as a result of the interim analysis. Potential clinical benefit (efficacy) will be ascertained by estimating the treatment effect of DBS-f therapy through 12 months on measures of Alzheimer’s treatments commonly used in clinical trials, including the Alzheimer’s disease Assessment Score-cognitive subscale (ADAS-cog-13), the Clinical Dementia Rating (CDR), and on brain FDG-PET imaging. Safety and tolerability will be assessed throughout the study by ascertainment of adverse events (AEs) including serious AEs, vital signs, physical examination, MRI and PET scans and clinical laboratory tests conducted at follow-up visits throughout the study. All subjects will be followed for 24 months. All subjects will have their device programmed to deliver therapy at the end of their 12-month visit. After completion of their 24-month visit, they will be exited from the study. After exiting the study, all subjects will be given the option to continue long-term follow-up for, at a minimum, safety under a separate study protocol. 3.7 BLINDING Study subjects, the implanting surgeon, study coordinators, the principal investigator and follow-up clinicians responsible for administering questionnaires and outcome assessments will be blinded to treatment assignment until all subjects have completed the 12-month visit or until each subject’s 24-month visit, whichever comes first. The technician responsible for programming the system at each site will not be blinded to the treatment assignment. This is a double-blind study. Every effort must be made to avoid informing study subjects and those collecting the subject’s objective and subjective study data of the treatment assignment of study subjects until all subjects have completed the 12-month follow-up visit or until they are exited from the study at 24months post-implant, whichever happens first. 1. The programming technician will not be blinded to the treatment assignment. If this person is a member of the site staff, this person will be designated at the site as an unblinded delegate on the delegation of authority log. It is possible that this person will be an employee or designee of the Sponsor and will have no formal role at the investigational site other than programming the study Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 13 OF 70 Investigational Plan ADvance Study 2. 3. 4. 5. 6. 7. 8. 3.8 devices. At no point should the programming technician communicate the treatment assignment with the study investigators, the subject, the subject’s caregiver/family, those involved in administering study-specific questionnaires or those responsible for collecting study-specific data of any form. The randomized treatment assignment will not be filed in the subject’s medical record. At no time will study subjects be informed of their treatment assignment or receive any feedback about opinions they may express regarding their treatment assignment. Study subjects will not be treated together or participate in group counseling or other group activities, to avoid between-subject communications which might result in unblinding. Any MRI/PET results will not be included in documents available to clinical evaluators who have responsibility for administering study-specific questionnaires or assessments. All clinical evaluators will do their best to remain unaware of the subject’s treatment assignment, and if they form an opinion as to the subject’s treatment assignment based on clinical signs and symptoms they should do their best not to allow this to influence their treatment or evaluation of the subject, and to not document or express this opinion to anyone. Instances of unblinding will be disclosed to site monitors and the National PI for review and documentation. These procedures may be altered for subject welfare, as in the case of a significant adverse event related to the study or the investigational device. Whenever possible, such alterations will be reviewed with the National PI and the site principal investigator, and must be documented as a protocol deviation. STUDY DURATION The expected duration of this study is approximately 3 years from the time of first subject enrollment to the time of last subject follow-up visit. 3.9 NUMBER OF SITES AND SUBJECTS Subjects will be enrolled to ensure the study meets the required sample size of 40 implanted subjects at no more than 8 investigational sites in the United States and 20 implanted subjects at no more than 1 investigational site in Canada. The point of enrollment is defined as the time the subject signs the Screening Informed Consent to participate in the study. It is anticipated that one of five subjects enrolled in the study will sign the second (Baseline) consent, meet the inclusion/exclusion criteria and will have the device successfully implanted with the leads placed in the appropriate position and will then count as a subject towards the required sample size of 40 in the U.S.. Therefore, it is anticipated that approximately 100 subjects could be enrolled in the study in order to reach the sample size requirement of 40 subjects in the U.S.. 4. SYSTEM DESCRIPTION 4.1 INVESTIGATIONAL SYSTEM DESCRIPTION The DBS System planned for use in the study is the Medtronic Activa PC (P960009/S052) platform. The system components are shown below. All of the implantable devices, external control devices and accessories included in this application are approved by the FDA for deep brain stimulation in the treatment of Parkinson’s disease and Essential Tremor. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 14 OF 70 Investigational Plan ADvance Study Activa PC Model 37601 Implantable Neurostimulator (INS) The Activa® PC neurostimulator is a dual-channel device capable of delivering bilateral stimulation with a single device. Activa PC contains a nonrechargeable battery and microelectronic circuitry to deliver a controlled electrical pulse to precisely targeted areas of the brain. The device is typically implanted subcutaneously near the clavicle, connected to an extension and leads, which are implanted in the brain. Model 3387 DBS Lead Quadripolar, deep brain stimulation lead made of 4 thin, insulated, coiled wires bundled within polyurethane insulation. It has 4 electrodes at the tip, spaced 1.5 mm apart, and delivers stimulation using either one electrode or a combination of electrodes. Model 37085 DBS Extension Kit The DBS extension is used to connect the Activa PC neurostimulator to the DBS lead. The extension runs subcutaneously along the head, neck, and shoulder to connect the lead to the implanted neurostimulator. Model 8840 N’Vision Programmer with Model 8870 Activa RC/PC/SC application software The N'Vision® clinician programmer is an external component used to noninvasively review and adjust neurostimulator output parameters. The clinician programmer is equipped with a touchscreen display for data entry, telemetry head for device programming, and an infrared port through which communications can be established with compatible printers. A plug-in card (application card model 8870) contains the necessary software to program the neurostimulators. Each neurostimulator has a unique recognition code that allows the programmer to use the appropriate software during programming. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 15 OF 70 Investigational Plan ADvance Study Model 37022 External Neurostimulator (ENS) Used for intraoperative test stimulation. Stimulation parameters are downloaded from the N’Vision Programmer. 4.2 LABELING The system used in the ADvance Study at the investigational sites in the United States, Canada and elsewhere is considered an investigational device and will, therefore, be labeled as such during the study. All devices used in the study in the United States will be labeled with “Caution: Investigational Device. Limited by Federal (or United States) law to investigational use.” Devices used in Canada will be labeled with “Investigational Device/Instrument de recherché To Be Used by Qualified Investigators Only/ Réservé uniquement à l’usage de chercheurs compétents”. Device accountability will be documented throughout the study. The system will be provided free of charge to the sites for use in the study. All sites will receive study-specific instructions for use (IFU) prior to enrolling any subjects into the study. After enrollment for the study is completed, the investigator must return all unused systems as instructed by Functional Neuromodulation. 5. INCLUSION AND EXCLUSION CRITERIA Subjects will be enrolled based on the inclusion/exclusion criteria. The Investigator is responsible for screening all potential subjects to determine the appropriateness of enrollment in the ADvance Study. For quality control, prior to surgical implant an expert enrollment review committee consisting of co-national principal investigators and designated experts will review the eligibility of each to ensure they meet enrollment criteria. 5.1 INCLUSION CRITERIA Subjects who meet all of the following criteria may be given consideration for inclusion in this clinical investigation: 1. Informed consent signed by the subject, caregiver AND a surrogate. 2. 45-85 years of age (inclusive) 3. Probable Alzheimer’s disease according to the National Institute of Aging Alzheimer’s disease Association criteria. 4. Clinical Dementia Rating (CDR) global rating of 0.5 or 1 at screen. 5. ADAS-cog-11 score of 12-24 inclusive at screening AND baseline (with minimum score ≥ 4 on item 1). 6. If female, subjects who are post-menopausal or surgically sterile or willing to use birth control methods for the duration of the study. 7. The subject has an available caregiver or appropriate informant who can reliably report on daily activities and function. 8. Subject is living at home and likely to remain at home for the study duration. 9. General Medical Health Rating (GMHR) ≥ 3 (good or excellent general health). Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 16 OF 70 Investigational Plan ADvance Study 10. Subject must be a good surgical candidate for placement of a deep brain stimulator as judged by the DBS surgical team. 11. Fluency (oral and written) in the language in which standardized tests will be administered. 12. The subject is currently taking a stable dose of cholinesterase inhibitor (AChEI) medication (donepezil, galantamine, or rivastigmine) for at least 60 days prior to signing the informed consent form (NOTE: These medications may NOT be initiated, discontinued or modified after study initiation for the length of study participation). 5.2 EXCLUSION CRITERIA The subject must not meet any of the following exclusion criteria: 1. NPI total score ≥ 10 or score ≥ 4 in any NPI domain (clinically significant neuropsychiatric symptoms). Apathy score ≥ 4 acceptable. 2. Modified Hachinski ischemia scale score > 4 at screening 3. Subjects at risk for suicide in the opinion of the investigator or the subject answers “yes” to “Suicidal Ideation” Item 4 or 5 on the C-SSRS (at the time of evaluation) at the screening visit. 4. The subject has answered “yes” on any of the items in the suicidal behavior section of the CSSRS with reference to the three-month period prior to screening visit. 5. Cornell Scale for Depression and Dementia (CSDD) score > 10 at the screening visit 6. Young Mania Rating Scale (YMRS) ≥ 11 at the screening visit 7. Current major psychiatric disorder such as schizophrenia, bipolar disorder or major depressive disorder based on psychiatric consult at screening visit 8. The subject has attempted suicide in the 2 years prior to signing the consent to participate in the study. 9. In the judgment of the investigator, the subject is at significant risk for suicidal behavior during the course of his/her participation in the study 10. History of head trauma in the 2 years prior to signing the consent to participate in the study 11. History of brain tumor, subdural hematoma, or other clinically significant (in the judgment of the investigator) space-occupying lesion on CT or MRI 12. Active psychiatric disorder 13. Mental retardation 14. Current alcohol or substance abuse as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) 15. Contraindications for PET scanning (e.g., insulin dependent diabetes) 16. Contraindications for MRI scanning, including implanted metallic devices (e.g. non-MRI-safe cardiac pacemaker or neurostimulator; some artificial joints metal pins; surgical clips; or other implanted metal parts), or claustrophobia or discomfort in confined spaces. 17. Radiation exposure in the 1 year prior to signing the informed consent form that, in combination with the radiation exposure from this study, would exceed 5 rem. 18. Abnormal lab results that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. 19. Abnormal cardiovascular or neurovascular disorder that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 17 OF 70 Investigational Plan ADvance Study 20. Unstable doses of any medication prescribed for the treatment of memory loss or Alzheimer’s disease. 21. Currently prescribed any non-AD medications that, in the opinion of the investigator and/or enrollment review committee, would preclude participation in the study. 22. Is unable or unwilling to comply with protocol follow-up requirements. 23. Has a life expectancy of < 1 year. 24. Is actively enrolled in another concurrent clinical trial. 6. METHODOLOGY 6.1 STUDY DESIGN This is a prospective, multi-center, double-blind, randomized controlled feasibility trial designed to estimate the potential clinical benefit, and associated risks, of deep brain stimulation of the fornix (DBS-f) in subjects with mild probable Alzheimer’s disease, according to the National Institute of Aging Alzheimer’s disease Association criteria (McKhann, et al. 2011). The study will evaluate the effects of DBS-f when administered with concomitant cholinesterase inhibitor medication. Individuals must be taking cholinesterase inhibitor medication on a stable dose for at least 60 days to be eligible for this study. Up to forty (40) U.S. subjects successfully implanted will be randomized in a 1:1 allocation to one of two treatment groups: 1) DBS-f On, or 2) DBS-f Off. For the approximately 15 subjects randomized to DBS-f On, DBS-f treatment will be initiated at the visit approximately 14 days post-implant. For the approximately 15 subjects randomized to DBS-f Off, DBS-f treatment will be turned OFF for the first 12 months of the study, and turned ON for 12 months thereafter if determined to be appropriate by the AD physician. An independent Data Safety and Monitoring Board (DSMB) will review all safety data at intervals which will be pre-specified in the charter finalized by the DSMB. As this is a safety assessment only, and since the trial is designed without formal tests of hypotheses, there will be no alpha adjustment to account for the interim analyses. At the point of each interim analysis, a summary of the results will be sent to the FDA and the study design could potentially be modified as a result of the interim analysis. Potential clinical benefit (efficacy) will be ascertained by estimating the treatment effect of therapy through 12 months on measures of Alzheimer’s treatments widely used in clinical trials, including the Alzheimer’s disease Assessment Score-cognitive subscale (ADAS-cog-13), the Clinical Dementia Rating (CDR), and on brain FDG-PET imaging. It is hypothesized that subjects of less severity will tend to perform better. Safety and tolerability will be assessed throughout the study by ascertainment of adverse events (AEs) including serious AEs, vital signs, physical examination, MRI and PET scans and clinical laboratory tests conducted at follow-up visits throughout the study. All subjects will be followed for 24 months. All subjects will have their device programmed to deliver therapy at the end of their 12-month visit. After completion of their 24-month visit, they will be exited from the study. After exiting the study, all subjects will be given the option to continue long-term follow-up for, at a minimum, safety under a separate study protocol. 6.2 FOLLOW-UP SCHEDULE Following screening, baseline and implantation of the device, scheduled follow-up visits will occur at 14days post-implant and at Months 1, 3, 6, 9, 12, 13, 15, 18, 21 and 24 months. After 24 months subjects will be exited from this study. An open-label long-term follow-up protocol will be provided to study sites. This study will, at a minimum, include routine safety monitoring typical for patients with implanted DBS systems. Table 1 describes the visit window requirements for the Advance Study and Figure 1 provides an overview of the visits with key data collection items noted for each visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 18 OF 70 Investigational Plan ADvance Study Table 1: Visit Windows Visit Name Screening (Consent) Baseline Implant Visit 2 Week Visit Month 1 Visit Month 3 Visit Month 6 Visit Month 9 Visit Month 12 Visit Month 13 Visit Month 15 Visit Month 18 Visit Month 21 Visit Month 24 Visit Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 Protocol Required Visit Window -≤ 59 days after consent date w/in <60 days p- Screen ICF and pbaseline 11 – 17 days post-implant 30 – 45 days post-implant 80 – 100 days post-implant 155 – 205 days post-implant 240 – 300 days post-implant 335 – 395 days post-implant 30-45 days post-12 month visit 425 – 485 days post-implant 515 – 575 days post-implant 605 – 665 days post-implant 700 – 760 days post-implant CONFIDENTIAL PAGE 19 OF 70 Investigational Plan ADvance Study Figure 1 : Subject Enrollment and Follow-up Flow Chart Screening Visit (n = 100) Informed Consent Inclusion/Exclusion Assessment Medical History, Demographics ECG Lab Tests Clinical Assessments Informed Consent Inclusion/Exclusion Assessment Lab Tests Clinical Assessments MRI PET Scan Baseline Visit Screen Failure (n = 80) DBS-f Implant Visit (n = 30 U.S. subjects) Device Implant Pre & Post-Implant MRI Unsuccessful Implant (i.e. complete system not implanted) Device explanted Followed 1-month for safety 2 Week Visit (Randomization) Clinical Assessments Obtain Randomization Assignment Program Device per Randomization DBS-f On (n = 15) DBS-f Off (n = 15 ) Month 1, Month 3, Month 6, Month 9, Month 12 Clinical Assessments Device programming Lab Tests (Month 1, 6, 12) MRI (Month 12 only) PET Scan (Month 1, Month 6 and Month 12 only) All subjects programmed to DBS-f On at the end of the visit Month 13, 15, 18, 21 24 Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 Clinical Assessments Device Programming Lab Tests (Month 13, 18, and 24) CONFIDENTIAL PAGE 20 OF 70 Investigational Plan ADvance Study 6.3 DATA COLLECTION REQUIREMENTS Table 2: Data Collection Requirements Implant <60 M 13 Baseline (w/in days p- 2 wk M1 M3 M6 M9 M 12 (30-45d Mo 15, (≤ 59 days Screen Screen post (±30d) ICF and (±3d) (30-45d) (±10d) (±25d) (±30d) (±30d) post M consent) 12) p- M 18 M 21 (±30d) (±30d) M 24 (±30d) baseline) Consent X X Eligibility X X Demographics X Physical Exam X X X X X X X X X X X X X X History X Hachinski X CSDD X X X X X X X X X X X YMRS X X X X X X X X X X X C-SSRS X X X X X X X X X X X Psych Consult X X X X X X X X X X X Implant X Programming X X X X X X X X X X X X EKG X Lab Tests X X X X X X X X X X X X Con Meds X X X X X X X X X X X ADAS-cog-13 X X X X X X X X X 2° Neurospsych1 X X X X X X X CDR X X X X X X X X CVLT X X X X X X X ADCS-ADL23 X X X X X X X AD-QOL X X X X X X X Zarit Caregiver X X X X X NPI X X X X X X X X X MRI scan X X (2) X PET scan X X X X AEs X X X X X X X X X X X X If an unscheduled visit occurs, Adverse Events should be collected and reported. If an MRI or PET is conducted, data should be collected, reported and sent to the core lab.1Secondary neuropsychiatric tests: BVMT-R, , Letter Fluency and Trail Making Test. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 21 OF 70 Investigational Plan ADvance Study 6.3.1 Screening Visit Informed consent must be obtained from each subject prior to enrollment into the study and must include the required elements stipulated in 21 CFR Part 50, Subpart B. If the subject does not meet the study inclusion or exclusion criteria based on review of the screening or baseline assessments the subject will be withdrawn from the study and no further follow-up will be required. A second informed consent form, at the baseline visit, must be signed after it is documented that the subject meets all of the study inclusion and exclusion criteria and prior to undergoing implantation of the system. More details on the informed consent requirements for this study can be found in Section 14.5. If the primary caregiver unexpectedly changes during the study, the AD physician will discuss the study requirements with the new primary caregiver along with the subject to ensure that the new primary caregiver is aware of the commitment of the subject for participation in this research study. Written documentation of this discussion including the date of the discussion and the primary caregiver’s commitment to continue attending study-required visits must be saved in the subject file. If, per the site investigator, the subject still meets eligibility criteria after the end of the screening visit, the subject’s qualifications will be reviewed by the enrollment review committee prior to allowing the subject to undergo further testing and possible implant. The enrollment review committee will review the information and notify the investigator of their decision within 10 business days of receipt of all of the screening data. The subject’s primary caregiver is required to sign the informed consent form and to attend all study visits where questionnaires are administered. The following is a list of all assessments and tests that are required during the screening visit. 6.3.1.1 Medical History It is required that the subject’s clinical history and pre-existing conditions be assessed and documented. 6.3.1.2 Physical Exam It is required that a physical exam be completed to assure that the subject has no condition that would obscure assessment of cognitive function. Blood pressure, heart rate and temperature will be measured. The results of the physical exam are needed to complete the General Medical Health Rating and the results should be documented. 6.3.1.3 Concomitant Medications Use It is required that the subject’s medication use be documented at screening, baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.1.4 Electrocardiogram (ECG, EKG) An electrocardiogram will be performed. ECG is a test used for diagnosing heart conditions by recording the electric waves generated during heart activity. 6.3.1.5 Clinical lab tests Clinical laboratory tests will be conducted and documented. Lab tests do not need to be fasting tests. Blood will be drawn for: Pre-operative screening: CBC, complete metabolic profile, INR, and PT, PTT Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 22 OF 70 Investigational Plan ADvance Study 6.3.1.6 Endocrine profile: o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score > 10, they will be excluded from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be excluded from participation in the study. 6.3.1.7 Neuropsychological Testing An audio recording of neuropsychological testing will be collected at the screening visit. Alzheimer Disease Assessment Scale – cognitive sub-scale (ADAS-cog) (Rosen WG 1984). The ADAS-cog will be administered and documented throughout the study. At screening, subjects must have a total ADAS-cog-11 score between 12 and 24 and item 1 must be at least 4. The cognitive portion includes seven performance items and four clinician-rated items assessing memory, language, praxis, and orientation. In this study, an ADAS-cog-13 will be employed with the addition of delayed recall and number cancellation. Clinical Dementia Rating Scale (Hughs CD 1982). The CDR will be performed by trained staff and results documented. CDR is a semi-structured interview with both the subject and the caregiver. The subject is rated in domains of memory, orientation, judgment, problem solving, community activities, home and hobbies and personal care. The global rating score is used to stage severity of Alzheimer dementia and mild cognitive impairment. Neuropsychiatric Inventory (NPI) (Cummings JL 1994) The Neuropsychiatric Inventory (NPI) assesses behavioral and psychological symptoms in dementia. It is based on a structured interview conducted with the primary caregiver or reliable informant. Patients who reveal severe behavioral disturbance on the NPI at this screening visit (NPI score 4 on any item other than apathy) will be excluded from the study. Hachinski ischemia scale A 12-item rating instrument designed to identify vascular symptoms associated with dementia (Rosen W 1980). Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 23 OF 70 Investigational Plan ADvance Study Columbia Suicide Severity Rating Scale (C-SSRS) The C-SSRS (Posner K 2007) is a tool designed to systematically assess and track suicidal behavior and suicidal ideation. The scale takes approximately 5 minutes to administer. The CSSRS will be administered by a trained rater at the site at the screening visit. If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.2 Baseline Visit (≤ 59 days post-consent) The following is a list of all assessments and tests that are required during the baseline visit. 6.3.2.1 Physical Exam (PE) It is required that a physical exam be completed to assure that the subject has no condition that would obscure assessment of cognitive function. The results are also needed to complete the General Medical Health Rating and they should be documented. 6.3.2.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Blood will be drawn to document preoperative values and include: CBC, complete metabolic profile, INR, and PT, PTT. 6.3.2.3 Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.2.4 Neuropsychological Testing It is required that all questionnaires and neuropsychological testing be completed by a clinician or clinical assessor that is blinded to the subject’s randomization assignment at all visits throughout the study. It is recommended that the same clinician administers the questionnaires at each visit. ADAS-cog CDR The California Verbal Learning Test (CVLT) The CVLT is a highly sensitive neuropsychological test that assesses verbal memory abilities. Letter Fluency (Borkowski et al., 1967). For the letter fluency task, the patient is asked to orally generate as many words as possible that begin with the letters “s” and “p,” excluding proper names and different forms of the same word. The subject is allowed one minute to generate words for each letter. This test is added to supplement the category fluency task of the ADAS-Cog. Because mild AD is associated with deficits in executive functioning, this task, which is associated with aspects of executive ability (Baudic et al., 2006), will be added to assess any changes that may result from treatment. Trail Making Test (Reitan, 1958). This timed test measures visuomotor skills and visual scanning as well as flexibility to shift sets under time pressure. Part A requires a patient to consecutively connect circles numbered 1-25, as quickly as possible. Part B requires a subject to consecutively connect circles while alternating between numbers (1-13) and letters (A-L), as quickly as possible. Performance is based on time required to complete each part. Higher scores, measured in Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 24 OF 70 Investigational Plan ADvance Study seconds, indicate longer durations to complete each of the two tasks, hence worse performance. Because deficits in executive functioning are associated with AD (Baudic et al., 2006), this test, which assesses aspects of this domain, will be conducted during the delay period required by the CVLT-II. Brief Visuospatial Memory Test-Revised (BVMT-R; Benedict, 1997). Because the fornix has been associated with spatial memory (Hescham et al., 2012; Walker et al., 1984), the BVMT-R will be conducted. In this test of visuoconstruction, and visual learning and memory, examinees are presented with an array of six geometric designs. The stimulus is presented for 10 seconds, after which patients are instructed to reproduce as many designs as possible after the stimulus is removed from view. Three learning trials are followed by delayed recall and recognition trials. The learning portion will be administered during the delay period required by the CVLT-II. Alzheimer’s disease Cooperative Study - Activities of Daily Living (ADCS-ADL23) The ADCS-ADL23 is a 23-item inventory of informant based items to assess activities of daily living and instrumental activities of daily living, i.e. functional performance, of AD. QOL-AD The QOL-AD is a brief, 13-item measure designed specifically to obtain a rating of the patient's Quality of Life from both the patient and the caregiver . The Zarit Burden Interview (ZBI) Measures subjective burden among caregivers of adults with dementia.using a 22-item self-report inventory that examines burden associated with functional/behavioural impairments and the home care situation. The items are worded subjectively, focusing on the affective response of the caregiver. 6.3.2.5 NPI Magnetic Resonance Imaging (MRI) An MRI scan will be completed at this visit. MRI uses a magnetic field and pulses of radio wave energy to image organs and structures inside the body. This Baseline MRI will be used as a baseline for volumetric changes of the hippocampus, fornix and other brain structures. The MRI scan should be sent to the core lab within 14 days of the visit. The MR imaging sequences will be included in the Core Lab protocol and will be sent to the sites prior to enrolling any subjects in the study. 6.3.2.6 Positron Emission Tomography (PET Scan) A PET scan will be conducted at this visit. PET scans use radioactive tracers to image cerebral glucose metabolism which is sensitive to the diagnosis of Alzheimer’s disease, as well as detecting treatment effects. The PET scan should be sent to the core lab within 14 days of the visit. The PET imaging sequences will be included in the Core Lab protocol and will be sent to the sites prior to enrolling any subjects in the study. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 25 OF 70 Investigational Plan ADvance Study 6.3.3 Implant Visit (within <60 days post-screening consent and following completion of baseline activities) All subjects that meet the inclusion and exclusion criteria, have signed the second study informed consent to continue participation in the study and are approved to continue by the enrollment review committee will undergo the system implant. Prior to the implant procedure the following will be assessed: 6.3.3.1 Physical Exam (PE) It is required that the subject undergo a physical exam to make sure there have been no negative changes in the subject’s health status that would make the subject ineligible for the implant procedure, and the results documented. 6.3.3.2 Concomitant Medications Use It is required that the subject’s medication use be documented prior to and during the procedure. 6.3.3.3 Implant Procedure All subjects that still meet all of the inclusion criteria and none of the exclusion criteria will proceed to study implant. The implant will be conducted under local anesthesia and general anesthesia. Fornix Surgical Approach The target site for the DBS-f Therapy for Alzheimer’s disease is the post commissural fornix. It is recognized that a variety of approaches may be used to target the fornix. The following outline is presented as one possible approach for the physician’s consideration. After placement of the stereotactic frame an MRI image of the brain is obtained. The fornix is identified from the MRI images. The electrode target lies 2mm anterior and parallel to the vertical portion of the fornix within the hypothalamus. The most ventral contact of the Medtronic Model 3387 lead should lie 2mm above the dorsal surface of the optic tract. Refer to Model 3387 Lead Manual for specific instructions for lead placement. The trajectory to the target for the most ventral lead contact should enter from a burr hole placed approximately 2.5 cm lateral to the midline and at, or just anterior to the coronal suture. The lead should be directed toward the target located 2mm anterior to the fornix, 2mm above the optic tract and at the laterality corresponding to the midpoint of the medial/lateral extent of the fornix in the coronal plane. Intraoperative stimulation may be performed at the discretion of the surgeon to evaluate contact position. Figure 2, Figure 3, and Figure 4 show position of the electrode contacts relative to target. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 26 OF 70 Investigational Plan ADvance Study Fornix Figure 2: Schematic of fornix and surrounding structures with lead in position DBS electrode Fornix Figure 3: MRI showing lead with four contacts DBS electrode Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 27 OF 70 Investigational Plan ADvance Study Figure 4: DBS electrode projected onto brain atlas 6.3.3.4 Post-operative Clinical Laboratory Testing It is required that post-operative blood work drawn and the results recorded. The tests include: Complete Metabolic Profile Endocrine profile: o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 28 OF 70 Investigational Plan ADvance Study o 6.3.3.5 ACTH, Cortisol (morning) Post-Implant MRI An MRI scan is required after the implant surgery and prior to discharge to confirm the position of the leads. The MRI should be conducted per the product MRI labeling instructions. If upon reviewing the MRI scan, the investigator determines that the leads are not in an optimal location, the physician with appropriate input from the subject may elect to do one of the following: Attempt to reposition the leads (note: If this is attempted and lead positioning is successful, a second MRI must be collected and submitted to the core lab). The subject may continue into the randomized portion of the study. If lead repositioning is not done or is unsuccessful, this must be documented on the case report form and the subject may continue into the randomized portion of the study. Keep the system implanted without attempted lead repositioning. The subject may continue into the randomized portion of the study. Explant all or part of the system, at the physician’s discretion (note: if any part of the system is explanted, components should be returned to Medtronic for analysis). These subjects will not be eligible to be randomized in the study. Determination of successful lead positioning will be made by the implanting investigator for the purposes of assessing the subject’s eligibility to continue in the randomized portion of the study. For all subjects, the post-implant MRI scan should be sent to the core lab within 14 days of the visit. For subjects with lead repositioning, only the final MRI scan should be sent to the core lab. The core lab’s determination of accurate lead position will be used in any statistical analyses. Subjects who opt for device explant will have a safety visit within the protocol-defined 1-month visit window. All adverse events will be collected and reported through this safety visit. These subjects will not be randomized, however, they will count towards the minimum sample size requirement of 20 subjects. All signed informed consent forms must be maintained at the site. The reason(s) why the subject did not move into the randomization portion of the study must be documented. 6.3.3.6 Device Programming The device stimulation should remain OFF in all subjects. Interrogate the device and save it to disk at the end of the visit. All adverse events will be documented. If the subject has anesthesia administered but ultimately does not receive the full system, they will be withdrawn from the study and followed for 1 month for safety. There will be no further follow-up requirements for these subjects and they will not count towards the minimum sample size requirement of 20 subjects. 6.3.4 2 Week Follow-up Visit (11 – 17 days post-implant) All subjects are required to have a follow-up visit 2 weeks post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 29 OF 70 Investigational Plan ADvance Study 6.3.4.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.4.2 Concomitant Medications Use It is required that the subject’s medication use related to the study be documented at all studyrequired follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.4.3 Randomization Upon completion of the physical exam and medication data collection, the randomization will occur. One half of the subjects will have the stimulation turned on, the other half will have the stimulation left off. If the leads were not placed in the appropriate position per the post-implant MRI, the subject should not be randomized. Site-specific randomization schedules will be created by the study statistician. Random blocks of size 2 and 4 will be used to generate each schedule. The randomization assignment will be obtained by the blinded technician responsible for programming the device. The procedures outlined in Section 3.7 will be implemented to ensure that the blind is maintained. 6.3.4.4 Device programming Do not program the implanted DBS neurostimulator to output parameter settings that would exceed the safe charge density limits. If the following charge density warning is displayed on the clinician programmer after selecting the planned stimulation parameters, reduce voltage to remain within the safe charge density limits. WARNING: CHARGE DENSITY MAY BE HIGH ENOUGH TO CAUSE TISSUE DAMAGE. It is required that the device be programmed per the protocol at this visit. The stimulator will be tested in all subjects. For those subjects that are randomized to the DBS-f On arm, the stimulator will be left on for chronic stimulation. For the subjects randomized to the DBS-f Off arm, the stimulator will be turned on, but set at an amplitude of 0V until the end of the 12-month follow-up visit. All subjects are required to receive the Patient’s Therapy Guide and review content with the investigator or designee. Interrogate the device and save it to disk at the end of the visit. Therapy ON Group: 1. Allow sufficient time for the subject to recover from surgery. 2. Program the neurostimulation system to a unipolar electrode configuration where the neurostimulator case is the positive electrode and electrode 0 is the negative electrode. 3. Set frequency to 130Hz with a 90 microsecond pulse width. 4. Select a lead and start with the most ventral contact. Set the initial amplitude to 1V. Increase amplitude incrementally by 1V every 30-60 seconds until the subject reports experiential phenomena, other memory-related phenomena or autonomic related symptoms including increased heart rate, blood pressure, sweating or flushing. If the subject does not experience any of these effects, stop the testing at 10V. The upper limit will be 10V or the safe charge density level as determined by the programmer, whichever is lower. Record the voltage that produces a side effect. Return the voltage for that electrode to 0V prior to continuing to Step 5. 5. Repeat step 4 for each remaining contact on the first side. 6. Test the contacts on the other lead in the manner described in steps 4 and 5. 7. Identify the contact on each side that produces an experiential or autonomic-related event at the lowest voltage. These contacts will be used as the therapeutic contact. If Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 30 OF 70 Investigational Plan ADvance Study 8. 9. 10. 11. no effect was experienced, the physician must determine which contact to use as the therapeutic contact for the study. For the selected contact, set voltage at 50% of that eliciting a stimulation related event during test stimulation or 3.5V, whichever is lower. Turn the stimulator on to stimulate both leads at the determined voltage. In the event a stimulation-related event is reported by the subject with bilateral stimulation, turn the voltage down in 0.2V increments on each lead until the event is no longer experienced by the subject. Turn on the device set at the documented parameters with Mode set to “Continuous” Document final parameter settings in the eCRF Table 3: Device Programming Requirements – DBS-f On Group Parameters Mode Amplitude (V) Pulse Width (µs) Rate (Hz) Electrode Polarity Settings Continuous Per testing above (Maximum = 3.5V) 90 130 Unipolar Therapy OFF Group: 1. Follow steps 1-9 above for the Therapy ON Group 2. Turn on the device set at the documented parameters with Mode set to “Continuous” and set the amplitude to 0V. 3. Document final test settings and the final parameter settings in the eCRF Table 4: Device Programming Requirements – DBS-f Off Group Parameters Mode Amplitude (V) Pulse Width (µs) Rate (Hz) Electrode Polarity 6.3.4.5 Settings Continuous 0V 90 130 Unipolar Blinding Study subjects, the implanting surgeon, study coordinators, the principal investigator and follow-up clinicians responsible for administering questionnaires and outcome assessments will be blinded to treatment assignment. The technician responsible for programming the system at each site will not be blinded to the treatment assignment. Subjects will be allowed to learn of their randomization assignment after all study subjects have completed their 12-month visit or the subject completes their 24-month visit and is exited from the study, whichever happens first. Procedures for emergency unblinding are outlined in section 11.4. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 31 OF 70 Investigational Plan ADvance Study 6.3.5 Month 1 Follow-up Visit (30 – 45 days post-implant) All subjects are required to have a follow-up visit at 1 month post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.5.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.5.2 Clinical Lab Tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: 6.3.5.3 o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Concomitant Medications Use It is required that the subject’s medication use be documented at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.5.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.5.5 Neuropsychological Testing ADAS-cog Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 32 OF 70 Investigational Plan ADvance Study 6.3.5.6 Pet Scan A PET scan will be acquired at this visit. The PET scan should be sent to the core lab within 14 days of the visit. 6.3.5.7 Device programming It is required that the device be tested in all subjects to confirm electrode function and to record the impedance values. For those subjects that are randomized to the DBS-f On arm, the stimulator will be left on for chronic stimulation per the parameters determined at the 2 week visit. If adverse events are reported that are determined to be stimulation related, the voltage may be adjusted downward in 0.2V increments until the adverse event subsides. For the subjects randomized to the DBS-f Off arm, the stimulator will remain on, but at a amplitude of 0V. Document stimulation parameters and interrogate the device and save it to disk at the end of the visit. For subjects who had a failed implant attempt, a phone visit will be adequate in lieu of an in-office visit, however either will be acceptable. The following information will be collected for these subjects: Adverse Events Vital Status No further visits are required for these subjects. 6.3.6 Month 3 Follow-up Visit (80 – 100 days post-implant) All subjects are required to have a follow-up visit at 3 Month post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.6.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.6.2 Concomitant Medications Use It is required that the subject’s medication use be documented at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.6.3 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 33 OF 70 Investigational Plan ADvance Study 6.3.6.4 Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD NPI 6.3.6.5 Device programming It is required that the device be tested in all subjects to confirm electrode function and to record the impedance values. For those subjects that are randomized to the DBS-f On arm, the stimulator will be left on for chronic stimulation per the parameters determined at the 2 week visit. If adverse events are reported that are determined to be stimulation related, the voltage may be adjusted downward in 0.2V increments until the adverse event subsides. For the subjects randomized to the DBS-f Off arm, the stimulator will remain on, but at an amplitude of 0V. Document stimulation parameters and interrogate the device and save it to disk at the end of the visit. 6.3.7 Month 6 Follow-up Visit (155 – 205 days post-implant) All subjects are required to have a follow-up visit at 6 Month post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.7.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.7.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 34 OF 70 Investigational Plan ADvance Study 6.3.7.3 Concomitant Medications Use It is required that the subject’s medication use be documented at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.7.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.7.5 Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD ZBI NPI 6.3.7.6 PET scan It is required that a PET scan be acquired at this visit. The PET scan should be sent to the core lab within 14 days of the visit. 6.3.7.7 Device programming It is required that the device be tested in all subjects to confirm electrode function and to record the impedance values. For those subjects that are randomized to the DBS-f On arm, the stimulator will be left on for chronic stimulation per the parameters determined at the 2 week visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 35 OF 70 Investigational Plan ADvance Study If adverse events are reported that are determined to be stimulation related, the voltage may be adjusted downward in 0.2V increments until the adverse event subsides. For the subjects randomized to the DBS-f Off arm, the stimulator will remain on, but at an amplitude of 0V. Document stimulation parameters and interrogate the device and save it to disk at the end of the visit. 6.3.8 Month 9 Follow-up Visit (220 – 320 days post-implant) All subjects are required to have a follow-up visit at 9 Month post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.8.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.8.2 Concomitant Medications Use It is required that the subject’s medication use related to the study be documented at all studyrequired follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.8.3 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.8.4 Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD NPI Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 36 OF 70 Investigational Plan ADvance Study 6.3.8.5 Device programming It is required that the device be tested in all subjects to confirm electrode function and to record the impedance values. For those subjects that are randomized to the DBS-f On arm, the stimulator will be left on for chronic stimulation per the parameters determined at the 2 week visit. If adverse events are reported that are determined to be stimulation related, the voltage may be adjusted downward in 0.2V increments until the adverse event subsides. For the subjects randomized to the DBS-f Off arm, the stimulator will remain on, but set to an amplitude of 0V. Document stimulation parameters and interrogate the device and save it to disk at the end of the visit. 6.3.9 Month 12 Follow-up Visit (300 – 420 days post-implant) All subjects are required to have a follow-up visit at 12 Month post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.9.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.9.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: 6.3.9.3 o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Concomitant Medications Use It is required that the subject’s medication use be documented at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.9.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 37 OF 70 Investigational Plan ADvance Study 6.3.9.5 Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD ZBI NPI 6.3.9.6 MRI scan It is required that an MRI scan be conducted to evaluate volume changes of the hippocampus. The MRI scan should be sent to the core lab within 14 days of the visit. 6.3.9.7 PET scan It is required that a PET scan be acquired at this visit. The PET scan should be sent to the core lab within 14 days of the visit. 6.3.9.8 Device programming It is required that the device be tested in all subjects to confirm electrodes function. For all subjects, the device should be programmed to deliver therapy at the end of this visit. It is recommended that device testing described in section 6.3.4.4 is repeated prior to final programming at this visit for all subjects. If adverse events are reported that are determined to be stimulation related, the voltage may be adjusted downward in 0.2V increments until the adverse event subsides. Interrogate the device and save it to disk. 6.3.10 Month 13 Follow-up Visit (30-45 days) All subjects are required to continue to have a follow-up visit at 13 months post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.10.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 38 OF 70 Investigational Plan ADvance Study 6.3.10.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: 6.3.10.3 o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.10.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.10.5 Device programming It is required that the device be tested in all subjects. The device should be programmed to deliver therapy at the end of this visit. If, however, the AD physician feels that it is in the subject’s best interest to have therapy off, the decision should be documented and a protocol deviation will not be collected. Interrogate the device and save it to disk at the end of the visit. 6.3.11 Month 15 Follow-up Visit (± 30 days) All subjects are required to continue to have a follow-up visit at 15 post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.11.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 39 OF 70 Investigational Plan ADvance Study 6.3.11.2 Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.11.3 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.11.4 Device programming It is required that the device be tested in all subjects. The device should be programmed to deliver therapy at the end of this visit. If, however, the AD physician feels that it is in the subject’s best interest to have therapy off, the decision should be documented and a protocol deviation will not be collected. Interrogate the device and save it to disk at the end of the visit. 6.3.12 Month 18 Follow-up Visit (± 30 days) All subjects are required to continue to have a follow-up visit 18-months post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.12.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.12.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone o ACTH, Cortisol (morning) Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 40 OF 70 Investigational Plan ADvance Study 6.3.12.3 Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.12.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.12.5 Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD ZBI NPI 6.3.12.6 Device programming It is required that the device be tested in all subjects. The device should be programmed to deliver therapy at the end of this visit. If, however, the AD physician feels that it is in the subject’s best interest to have therapy off, the decision should be documented and a protocol deviation will not be collected. Interrogate the device and save it to disk at the end of the visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 41 OF 70 Investigational Plan ADvance Study 6.3.13 Month 21 Follow-up Visit (± 30 days) All subjects are required to continue to have a follow-up visit at 21 post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.13.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.13.2 Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.13.3 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. NPI 6.3.14 Month 24 Follow-up Visit (± 30 days) All subjects are required to continue to have a follow-up visit 24 months post-implant. In addition to an adverse event assessment, the following tests/data will be collected at this visit. 6.3.14.1 Physical Exam It is required that the subject undergo a physical examination and the results be documented. 6.3.14.2 Clinical laboratory tests Clinical laboratory tests will be conducted and documented. Lab tests can be non-fasting. Blood will be drawn for: Complete Metabolic Profile Endocrine profile: o TSH, free T3, free T4 o Prolactin o LH, FSH, free testosterone Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 42 OF 70 Investigational Plan ADvance Study o 6.3.14.3 ACTH, Cortisol (morning) Concomitant Medications Use It is required that the subject’s medication use be documented at baseline, during the procedure and at all study-required follow-up visits. Concomitant medication use includes medications used to treat AD, any other health indication, and over-the-counter medications. 6.3.14.4 Psychiatric Consult A staff psychiatrist will evaluate the subject. The psychiatrist will look for the following conditions and will conduct the necessary assessments: Major psychiatric disorder such as schizophrenia, bipolar disease or other major depressive disorder. The subject will be withdrawn from the study if any of these are present. Suicidal ideation or suicide attempts. The subject will be withdrawn from the study if they have suicidal ideation or suicide attempts. Cornell Scale for Depression and Dementia (CSDD). If the subject has a score >10, they will be withdrawn from participation in the study. Young Mania Rating Scale (YMRS). If the subject has a score ≥ 11, they will be withdrawn from participation in the study. Columbia Suicide Severity Rating Scale (C-SSRS). If the subject answers “yes” to question 4, question 5 or to any of the items in the Suicidal Behavior section, they must be excluded from the study. 6.3.14.5 Neuropsychological Testing ADAS-cog CDR CVLT Letter Fluency Trail Making Test BVMT-R ADCS-ADL23 QOL-AD ZBI NPI 6.3.14.6 Device programming It is required that the device be tested in all subjects. The device should be programmed to deliver therapy at the end of this visit. If, however, the AD physician feels that it is in the subject’s best interest to have therapy off, the decision should be documented and a protocol deviation will not be collected. Interrogate the device and save it to disk at the end of the visit. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 43 OF 70 Investigational Plan ADvance Study 6.3.14.7 Unblinding After all subjects have completed the 12-month visit or at the conclusion of this 24-month visit, whichever happens first, subjects can be told of their randomized treatment assignment. If the randomized treatment assignment is discussed with the subject prior to the point in time when all subjects have completed the 12-month visit or prior to the conclusion of the 24-month visit, whichever happens first, a protocol deviation must be reported. 6.3.14.8 Study Exit Subjects will be exited from the study at the conclusion of their 24-month visit. An open-label long-term follow-up protocol will be provided to study sites. This study will, at a minimum, include routine safety monitoring typical for patients with implanted DBS systems. Subjects will be given an option of consenting and being followed under this open-label, long-term follow-up protocol. 6.3.15 Unscheduled Assessments during Follow-up If a subject returns to the study site for an unscheduled (i.e. non-protocol required) follow-up visit, any study assessments that are completed should be documented and submitted to the Sponsor. At a minimum, an adverse event assessment should be completed. If an MRI scan or PET scan is conducted, the data must be collected and submitted to the core lab and entered into the EDC system. 6.3.16 Study Medications It is required that the subject remain on a stable dose of cholinesterase inhibitor medication during the length of study participation. It is physician’s discretion on the medications that the subject is given preprocedure, procedure, and post-procedure. Anxiolytics may not be administered within 8 hours before neuropsychological assessments. 7. SUBJECT ENROLLMENT The point of enrollment is defined as the time the subject signs the Screening Informed Consent to participate in the study. It is anticipated that one of five subjects enrolled in the study will meet the inclusion/exclusion criteria, will sign the baseline (second) Informed Consent and will have the device successfully implanted and will then count as a subject towards the required sample size of 40 in the U.S.. Therefore, it is anticipated that approximately 100 subjects could be enrolled in the study in order to reach the sample size requirement of 40 U.S. subjects. 8. ADVERSE EVENTS An Adverse Event (AE) is defined as any untoward medical occurrence in a study subject whether or not considered related to the study device, study procedures or study requirements that is identified or worsens during the study. Adverse events must be assessed and documented by the investigator at the time of the procedure and at all follow-up visits (scheduled and unscheduled). All suspected AEs must be recorded and reported to the Sponsor. The investigational site may be asked to provide source documentation as required by the Sponsor to facilitate adjudication of adverse events. A Serious Adverse Events (SAE) is defined as any adverse event that: Resulted in death Is life threatening Requires inpatient hospitalization or prolongation of an existing hospitalization Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 44 OF 70 Investigational Plan ADvance Study Results in permanent impairment of a body structure or body function Requires medical or surgical intervention to prevent permanent impairment to body structure or a body function Led to fetal distress, fetal death or congenital abnormality or birth defect. A written report will be provided to the Sponsor within 10 business days after the site research staff becomes aware of the event and must be reported to the IRB/EC per the IRB/EC’s reporting guidelines. An Unanticipated Adverse Device Effect (UADE) is defined as any serious adverse effect on health or safety or any life-threatening problem or death caused by or associated with the study device if that effect, problem or death is not previously identified in nature, severity or degree of incidence in this investigational plan or application, or any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of subjects. In the event of a UADE, the research site staff will notify the Sponsor and the IRB/EC as soon as possible. A written report will be provided to the Sponsor within 10 business days after the research site staff becomes aware of the event and will be provided to the IRB/EC within their reporting guidelines. Please refer to Section 12.2 for a full list of the anticipated risks. 8.1 ADVERSE EVENT CLASSIFICATION An Investigator is required to report all adverse events (anticipated and unanticipated) that may or may not result in invasive intervention, injury or death. All adverse events should be recorded on the Adverse Event eCRF, including an event description, relatedness to the investigational system, the implant procedure and study related testing, corrective actions, seriousness, and clinical outcome for the subject. 9. TERMINATION OF PARTICIPATION All subjects have the right to terminate themselves from participation at any point during the study. In addition, principal investigators also have the ability to terminate subject participation in the study. A description of the reason for the subject’s termination will be documented. Reasons for termination include: completion of study, subject voluntarily withdrawal, physician-directed subject withdrawal, lost-tofollow-up and death. If a subject’s participation in the study is terminated prior to completion of the study for any reason other than death, the device programming is left to the discretion of the physician. 9.1 LOST TO FOLLOW-UP Every attempt must be made to have all subjects complete the follow-up visit schedule. A subject will not be considered lost to follow-up unless efforts to obtain compliance are unsuccessful. At a minimum, the effort to obtain follow-up information must include three attempts to make contact via telephone and if contact via phone is not successful, a certified letter from the Principal Investigator must be sent to the subject’s last known address. Both telephone and letter contact efforts to obtain follow-up must be documented both in the subject’s medical records and on the study electronic case report forms (eCRFs). 9.2 SUBJECT WITHDRAWAL All study subjects have the right to withdraw their consent at any time during the study. Whenever possible, the site staff should obtain written documentation from the subject that wishes to withdraw their consent for future follow-up visits and contact. If the site staff is unable to obtain written documentation, all information regarding the subject’s withdrawal must be recorded in the subject’s medical record. In addition, the appropriate eCRFs must be completed for the subject and clear documentation of the subject’s withdrawal be provided to Functional Neuromodulation Inc. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 45 OF 70 Investigational Plan ADvance Study Withdrawal of a subject from the study can occur at the direction of the Principal Investigator or the sponsor. Reasons for physician-directed subject withdrawal include, but are not limited to: the subject is not adhering to the protocol requirements, the subject has enrolled in another study that conflicts with the ADvance Study primary endpoints, or if the physician deems it in the best interest for the safety or welfare of the subject to withdraw. SUBJECT DEATH 9.3 A subject death during the study should be reported to the Sponsor as soon as possible and, at most within 10 days of the site research staff learning of the death. Initial notification to the sponsor can be done via a telephone call, email or submission of the death and/or adverse event CRF. In addition to completion of the appropriate CRFs, the following should be submitted to the Sponsor if available: A copy of any medical records related to the death Death certificate Autopsy report The site’s IRB/EC should be notified of the death per the IRB/EC reporting requirements. Whenever possible, the model 37601 Activa PC should be interrogated and explanted. Turn off stimulation following interrogation and prior to explant. Study devices and related system components (e.g., leads) should be removed intact and returned promptly to Medtronic for analysis. Any reason for not retrieving the study devices must be clearly stated on the System Change form. 9.4 SYSTEM REVISIONS In the event that a subject must have their system modified, partially removed or completely removed, the subject should return to the surgical center for the system revisions. The revisions should be documented on the appropriate eCRFs. Any explanted components should be sent to Medtronic in a returned product kit. 10. STUDY OVERSIGHT AND INTEGRITY The ADvance Study is sponsored by Functional Neuromodulation. The Sponsor may contract with clinical research organizations, for management of the data and conduct of the study. A summary of the minimum Sponsor and contract research roles and responsibilities is outlined in Table 5. The Sponsor is committed to ensuring that the trial is conducted and data are generated, documented and reported in compliance with the protocol and the applicable regulatory requirements. Table 5: Functional Neuromodulation Research Roles and Responsibilities Functional Neuromodulation. Overall study oversight Selection of investigators and investigational sites Study management Data management and reporting Collection of regulatory documents from study sites Technical support to research sites Monitor the study at all investigational sites Investigator and study coordinator training Manage CEC and DSMB Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 46 OF 70 Investigational Plan ADvance Study The Sponsor and contract personnel can provide technical support to the investigator and other health care personnel (collectively HCP) as needed during implant, during testing required by the investigational plan, and at follow-up visits. Support may include HCP training, addressing HCP questions, or providing clarifications to HCPs concerning the operation of study equipment related to the DBS system or the procedures and forms related to the collection of study data. At the request of the investigator and while under their supervision, the Sponsor and contract personnel may operate equipment during implant or follow-up, assist with the conduct of testing specified in the investigational plan and interact with the subject to accomplish requested activities. Prior to the 12-month visit, only blinded clinicians or technical support staff may operate the device programmer. Typical tasks may include: Interrogating the device or programming device parameters to physician requested settings Performing lead diagnostic testing to obtain sensing thresholds and impedance measurements Clarifying device behavior, operation or diagnostic output as requested by the investigator or other health care personnel Assisting with the collection of study data relating to the device In addition, the Sponsor can perform certain activities to ensure study quality. These activities may include: Observing testing or medical procedures to provide information relevant to protocol compliance. Reviewing collected data and study documentation for completeness and accuracy. The Sponsor and contract personnel will not: 10.1 Practice medicine Provide medical diagnosis or treatment to subjects Discuss a subject’s condition or treatment with a subject without the approval and presence of the HCP. Independently collect study data Enter data on CRFs CLINICAL EVENTS COMMITTEE An independent clinical events committee (CEC) will be established. The CEC will consist of physicians who are not investigators in the study. The committee will likely include, but not be limited to neurosurgeons and neurologists or psychiatrists. The CEC is responsible for conducting a review of all adverse events reported for study subjects. The CEC will adjudicate and classify all events for relatedness to the study system, study procedure and study requirements. The CEC will determine if any serious device-related adverse event is an unanticipated adverse device effect (UADE). The CEC classifications will be used as the official determination of relatedness for reporting purposes. The physician classification will also be reported. 10.2 PROTECTION OF HUMAN SUBJECTS The study investigators have developed a plan to ensure that all institutional, NIH, and federal regulations concerning informed consent will be fulfilled. Before the final protocols are implemented, the appropriate local Institutional Review Board/Ethics Committee will approve protocols and consent forms. The Human Subjects practices that will be used will be guided by the Alzheimer Association Guidelines to IRBs and Investigators. (Association 2004; 18) Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 47 OF 70 Investigational Plan ADvance Study 10.3 CORE LAB An independent blinded core lab will review and analyze the PET scans and MRI scans collected during the study. The results from the core lab will be used for the study endpoint analyses. The physician’s review of the baseline MRI scan will be used to determine study entry criteria. The MRI scan required to map and place the leads at pre and post- implant will be used to verify placement. The core lab protocol and study requirements will be sent to the investigational sites prior to enrollment. The MRI and PET core lab is: Gwenn Smith, PhD Johns Hopkins University 5300 Alpha Commons Drive, 4th Floor Baltimore, MD, 21224 Phone: 410-550-0062 Fax: 410-550-1407 10.4 DATA SAFETY AND MONITORING BOARD An independent Data Safety and Monitoring Board (DSMB) which consists of a practicing neurosurgeon, and two neurologists and/or psychiatrists and one biostatistician will be established. All members will be independent from the sponsor and the participating investigators. DSMB members will complete financial disclosures and be cleared of significant conflicts of interests with the sponsor. In addition members cannot be involved in the conduct of the trial in any other role than that of DSMB. The DSMB will review the progress of the clinical study, including all CEC adjudicated adverse events. The members of CEC and DSMB will not overlap. The DSMB will make recommendations regarding the continuation, suspension or termination of this clinical study. The following key areas will be evaluated by the DSMB to determine if the study is suspended or terminated: Occurrence of unanticipated adverse device effects Occurrence of serious adverse events as defined in the protocol Safety and efficacy trends Benefits versus risks of the study 10.5 ENROLLMENT REVIEW COMMITTEE For quality control, prior to enrollment and surgical implant an expert enrollment review committee consisting of the co-national principal investigators and designated experts will review the eligibility of each subject to ensure they meet enrollment criteria and are truly candidates for the study. If a subject does not meet the criteria per the enrollment review committee, they will be withdrawn from the study and no further follow-up will be required. 10.6 CASE REPORT FORMS Electronic case report forms (eCRFs) will be used to collect study data. The eCRFs will be electronically viewed and signed by the principal investigator. All appropriate sections of the eCRFs must be completed. It is recommended that all eCRFs be completed within two weeks of the visit date. Study monitors designated by the Sponsor will review the information documented in the eCRFs and verify the information recorded is consistent with medical records and other source documents. Errors or incomplete entries will be rectified. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 48 OF 70 Investigational Plan ADvance Study The Sponsor and their designees will use the study data for statistical and tracking purposes and will treat the information as confidential. A representative from FDA or Health Canada may review or copy study records during an audit. The EDC system is secure and access will be controlled via unique user names and passwords. Only people with appropriate delegation of authority at the study sites will be allowed to enter or sign the eCRFs. 11. DATA ANALYSIS AND STATISTICAL METHODS 11.1 STUDY OBJECTIVES The primary objective of this feasibility study is to evaluate the safety of DBS-f in patients with mild Alzheimer’s disease by assessing all device and/or therapy related adverse events. The secondary objective is to preliminarily estimate the treatment effect size in the outcomes of interest at 12 months post-randomization. The objectives are not based on formal tests of hypotheses. 11.2 RANDOMIZATION Subjects will be randomized in a 1:1 fashion to either DBS-f “On” or DBS-f “Off”. 11.3 BLINDING Study subjects, the implanting surgeon, study coordinators the PI and follow-up clinicians who are responsible for administering questionnaires will be blinded to treatment assignment until all subjects have completed the 12-month follow-up visit, or until each subject completed their 24-month visit, whichever happens first. The person responsible for programming the system at each site will not be blinded to the treatment assignment. The person responsible for programming the device will ensure that programming is completed per the requirements procedures described in section 6.3.4.4. These programming parameters must remain consistent through the 24-month follow-up visit unless there are stimulation associated side effects or other safety concerns that require the stimulation parameters to be adjusted. At the end of the 24-month follow-up visit, programming is left to the discretion of the physician. 11.4 EMERGENCY UNBLINDING In the event that a subject and/or physician must know the subject’s randomized assignment to safely manage the subject, the physician or coordinator should call their Sponsor contact and provide rationale for the unblinding. A written justification must be provided to the Sponsor within 5 working days of the unblinding event. 11.5 PRIMARY ENDPOINT: SAFETY 11.5.1 Description The safety endpoint will assess the acute and long-term safety of the system. The primary safety assessment is not based on formal tests of hypotheses. Rather, a detailed assessment of all device and/or therapy related adverse events will be conducted. 11.5.2 Sample Size The primary endpoint for this feasibility study is not based on formal tests of hypotheses. Therefore a formal statistical calculation of sample size for this endpoint has not been calculated. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 49 OF 70 Investigational Plan ADvance Study 11.5.3 Data Analysis Acute safety will be assessed by the rate of serious device or procedure related adverse events from the date of implant through the date of randomization, plus serious procedure related events through 30 days post-implant. The rate and 95% confidence interval will be presented. All subjects undergoing an implant procedure will be included. Long-term safety will be assessed by the rate of serious device or therapy related adverse events from the date of randomization through the date of the Month 12 visit. The rate and 95% confidence interval will be presented by randomization group. All subjects randomized will be included. The rate of serious therapy or Alzheimer’s related adverse events from the date of randomization through the date of the Month 12 visit will also be assessed. The rate and 95% confidence interval will be presented by randomized group. All subjects randomized will be included. Other data summaries will include a detailed summary and rate estimation of all serious adverse events, as well as Kaplan-Meier estimates of the cumulative event rates over time. 11.6 SECONDARY ENDPOINT: EFFICACY 11.6.1 Description For the assessment of DBS-f therapy in treating mild Alzheimer’s, three efficacy outcomes are of particular clinical interest. These outcomes are the improvement in ADAS-cog-13 at 12 months, improvement in CDR and changes in glucose metabolism measured by FDG-PET at 12 months. 11.6.2 Sample Size The secondary (efficacy) endpoint for this feasibility study is not based on formal tests of hypotheses. Therefore a formal statistical calculation of sample size for this endpoint has not been calculated. 11.6.3 Data Analysis The mean change from baseline (pre-implant) to 12 months will be calculated in each treatment group for the outcomes of interest. The differences between randomized groups in mean change will be calculated, along with corresponding 2-sided, 95% confidence intervals. In addition, the within-group improvements will be assessed relative to a null change of zero. Additional analyses will include assessments of change over time in a mixed model regression analysis with repeated measurements. For those subjects randomized to OFF, the mean change from OFF to ON in the off group in all outcomes of interest will be analyzed. Pre-specified sub-group analyses will be conducted, stratified by baseline ADAS-cog-11 scores, to assess differential treatment effects across strata. Further analyses will be conducted to determine the impact of baseline ADAS-cog-13 scores on outcome (i.e. to assess whether the treatment effect diminishes in the more advanced population), including mixed model regression analyses with baseline ADAS-cog-13 as a predictor and fit with an interaction term. Within-group outcomes, by baseline ADAScog-13 score will also be summarized. 11.7 SAMPLE SIZE SUMMARY Sample size for this feasibility study is not based on formal tests of hypothesis. Sixty subjects (40 U.S. & 20 Canada) are sufficient to make an initial assessment of safety, and provide some indication of efficacy. Results from the interim reports of subjects will be used to determine whether further study (via an expansion of this current study) is warranted. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 50 OF 70 Investigational Plan ADvance Study 11.8 ADDITIONAL ANALYSES 11.8.1 Analysis of Baseline Demographics Descriptive statistics will be generated for baseline demographics. Categorical variables will be analyzed using frequency, incidence and event rate. For continuous variables, analyses will include mean, median, standard deviation and range. 11.8.2 Data Pooling Analysis The poolability of the data across centers and geographies will be assessed on the primary efficacy outcomes. In the event that statistical evidence of a difference in either primary efficacy outcome between centers or geography is found (evidenced by a p-value < 0.05), additional analyses of the primary efficacy outcomes will be conducted stratifying by center. In the event some centers have relatively small enrollments, grouping of centers may be employed. 11.8.3 Other Analyses Additional analyses include change from baseline (pre-implant) to 12, 18 and/or 24 months in CVLT, Letter Fluency, Trail Making Test, Brief Visuospatial Memory Test, QOL-AD, Zarit Burden Inventory, ADCS-ADL23, NPI, and hippocampal volume from MRI. Based on the work of (Ihl R 2011) a subset of five ADAS-cog items shown to be most sensitive to memantine effects in mild AD subjects will also be assessed. The five ADAS-cog items of interest for this assessment include: ideational praxis, remembering instructions, language, comprehension, and word finding difficulty. The subsetting methodology described by Ihl et al will also be applied to this dataset to assess the relative strength of treatment effect across other subsets (e.g. ADAS-cog-13) of the ADAS-cog. For the purpose of evidence-based enrichment for a later Pivotal trial, this study will examine clinical and biological predictors of response to DBS-f therapy including the following: clinical dementia severity (CVLT, ADAS-Cog and CDR score); severity of AD brain disease (parietal and temporal cerebral glucose metabolism; hippocampal volume; fornix fractional anisotropy (FA) assessed on diffusion tensor imaging brain MRI). A potential issue of imbalance in the study results is anticipated for subjects based on the baseline ADAS-Cog-11 sub-scores (12-18 and 19-24). The size of this small feasibility study does not allow for stratification at the time of randomization. Therefore, sub-analyses of the study endpoints (both safety and efficacy) will be presented based on these two ADAS-Cog-11 sub-score categories (12-18 and 1924). In addition, the correlation between changes in FDG-PET changes and clinical measures will be assessed at 6 and 12 months. 11.8.4 Non-Randomized Implanted Subjects Subjects in whom the system is explanted prior to randomization will not be included in any of the efficacy analyses or the by-group safety analyses. Their data will be summarized separately. 11.9 STATISTICAL METHODS 11.9.1 General Principles All statistical analyses will be performed using Statistical Analysis Systems (SAS) for Windows (version 9.1.3 or higher, SAS Institute Inc., Cary, NC) or other widely accepted statistical or graphical software. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 51 OF 70 Investigational Plan ADvance Study 11.9.2 Handling of Missing Data The primary efficacy analyses will be conducted on all implanted subjects evaluated at 12 months postimplant. In addition, a series of sensitivity analyses will be conducted using various imputation strategies (last observation carried forward, imputing baseline, imputing population mean). The secondary endpoint analyses will be conducted on the cohort of subjects with complete follow-up. 12. RISK AND BENEFIT ANALYSIS 12.1 POTENTIAL BENEFITS Observations from the pilot studies suggest there may be the potential for diminished rate of decline in cognitive function including specific aspects of memory and possible improvements in quality of life measures related to AD. At this time, it is impossible to say that subjects will benefit from participation in this study. DBS will not cure AD. Information learned from this study may benefit other patients in the future with AD and may inform the design of future clinical trials. 12.2 POTENTIAL RISKS Sources of information about the known and anticipated risks for DBS-f for Alzheimer Disease include early pilot studies conducted for AD or for treatment in the target area (fornix/hypothalamus). The surgical procedure was the same in earlier investigations as that proposed in this investigation. The system proposed for this investigation is similar. In this investigation the neurostimulator Model 37601 Activa PC will be used vs Model 7428 Kinetra used in previous studies. Model 3387 lead is common to both. It is anticipated that the nature and frequency of adverse events associated with the surgical procedure observed in this proposed trial of AD would be similar. While the target site is different, the DBS treatment for movement disorders also provides information as to the surgical and procedural risks of this study. The risks associated with this study are outlined below. As with any medical procedure, there is the possibility of unforeseen risks to the study subject. 12.2.1 Surgical and Procedural Risks Implanting the neurostimulator system carries the same risks associated with other brain surgery procedures: Death may occur as a result of the surgical procedure. Based on similar studies for other indications the risk is estimated at about 0.5%. Causes listed were myocardial infarction, intracranial hemorrhage and pulmonary embolism. Hemorrhage may occur at a low rate (approximately 4-5%). About half of the bleeds that occur are not noticeable and about half are noticeable. Noticeable symptoms may be mild or serious. They could be temporary and resolve over time or permanent. The result of a noticeable hemorrhage could be serious and can result in the following: death, coma, paralysis, stroke, muscle weakness and loss of speech/difficulty speaking Seizures may occur at a very low rate. Historically about 1% of the patients experience a seizure associated with a DBS procedure. Infections may occur. It has been reported to be about 10%. Almost all infections are at the pocket site where they battery (stimulator) was implanted. About half the time the battery has to be removed. In about half of the cases, patients were treated with antibiotics and recovered. Serious brain infection can occur but it is rare – lower than 1 in 1000. Lead breakage or movement may occur (about 3%) and the subject may need to undergo another surgical procedure to fix. Depression, memory impairment, confusion, anxiety, skin tingling, dizziness and headache may occur at a moderately low rate. They range from 7-15%. Depression, suicidal thoughts and suicide have been reported in patients receiving Medtronic DBS Therapy for Movement Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 52 OF 70 Investigational Plan ADvance Study Disorders, although no direct cause and effect relationship has been established. We have put in place a close monitoring program in this study to detect and manage these symptoms if they occur. General complications that may occur with any surgical procedure include: Deep vein thrombosis Phlebitis Pneumonia Urinary infections Pulmonary embolism Reaction to anesthetic agent Nausea and/or vomiting 12.2.2 Device Related Risks Adverse events that can be clearly attributed to the device include: Broken lead or extension Infection Erosion of a system component through the skin Lead or extension connector migration Persistent pain at the neurostimulator site Seroma or hematoma at the neurostimulator site Loss of therapeutic effect Shocking or jolting stimulation Allergic or immune system response to the implanted materials 12.2.3 Therapy Related Risks In addition to those noted above, the following adverse events are possible. Experiential phenomena Flushing Sweating Increased heart rate Increase blood pressure Suicide ideation Adverse cognitive or psychiatric effects Perceptions described as déjà vu Unpleasant generalized warming Transient flashes of light Visual disturbances Sensory changes Cerebral spinal fluid leak These events may result in hospitalization, prolongation of existing hospitalization, unanticipated surgery, and/or modifications to the implanted system or death. 12.2.4 Other Device Related Risks The batteries used for DBS are non-rechargeable and their lifespan is directly related to the parameters of stimulation used. In Parkinson’s disease, batteries last approximately 4-5 years. Replacement is done under local anesthesia on a day surgery basis. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 53 OF 70 Investigational Plan ADvance Study Patients should not undergo diathermy. 12.2.5 Pregnancy It is unknown what effect electrical brain stimulation will have on a developing fetus or sperm. Therefore, women are required to be sterile, post-menopausal or use adequate birth control of the patient’s choice while participating in this study. 12.2.6 Risks Associated with Study Medications Subjects are required to be on a stable does of cholinesterase inhibitor (AChEI) medication to be included in the study and remain on a stable dose during the study. There are no additional protocol required medications; therefore there are no increased risks. 12.2.7 Risks Associated with Blood Draw There are anticipated risks associated with the study-required blood draw. The needle stick may hurt. There is a small risk of bleeding, bruising, and infection at the involved site. 12.2.8 Risks Associated with MRI Individuals with pacemakers, aneurysm clips, shrapnel or other un-allowed implanted metallic devices will be excluded from study. It is important for the subjects to advise the MRI staff if they have had brain surgery for a cerebral aneurysm, implanted medical or metallic devices, shrapnel, or other metal, such as metal in the eyes. All subjects complete the standard MRI screening questionnaire prior to each study and follow standard MRI screening procedures. Thus, inclusion/exclusion criteria have been developed to exclude subjects who have any metallic materials within the body. Study subjects will be required to undergo post-operative MRI to verify the placement of the DBS leads and to check for hemorrhage. There is the potential risk of interaction between the MRI and the DBS system resulting in heating and damage to the implanted system or causing the neurostimulator to move. This could cause serious and permanent injury including coma, paralysis, or death. Additional risks include skin burns, pain, discomfort, shocking sensation/uncomfortable stimulation, or opening of a recent incision. Since it is important to check the possibility for intracranial hematoma and accurately verify electrode position postoperatively, it is believed that the benefit of an MRI exceeds the risks associated with the procedure. MRI-based evaluation of certain brain structures is an endpoint within the study. Published guidelines will be followed during the trial when MRIs are performed (Medtronic, Inc 2010). During the MRI scan, the subject lies in a closed area inside the magnetic tube. The participant may be bothered by feelings of confinement (claustrophobia), and by the noise made by the magnet during the procedure. A mild sedative can be given prior to the MRI scan to help alleviate claustrophobia and anxiety. He/she will be asked to wear earplugs or earphones while in the magnet. MRI staff will be nearby during MRI scan and will have a means of communication with the subject (such as a buzzer held by the subject) which can be used for contact if the subject cannot tolerate the scan. There may be side effects and discomforts that are not known. Also, the study physicians may discover an abnormality on the MRI exam that we are not expecting. Some findings may require additional tests to find out what they are. Any unexpected results will be shared with the subject. They will also be told any new facts that could affect whether they want to stay in the study. If at any time the subject feels uncomfortable, they are advised to ask their study physician to discontinue the study and the subject may be withdrawn. 12.2.9 Risks Associated with PET The PET procedure involves a radiation dose through the administration of the radioligands. The halflife of 18F-FDG is 110 minutes so that the radioactivity will decay over 8-10 hours to almost Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 54 OF 70 Investigational Plan ADvance Study undetectable levels. No PET studies will be performed on pregnant women, as confirmed by pregnancy testing, or women who are nursing. The PET studies also involve insertion of flexible venous catheters. Placement of needles in a vein may cause bleeding, inflammation, infection or fainting. There is a risk of bruising and discoloration at the sites of placement of intravenous catheters, which may persist for several days after the study. To minimize these risks, experienced medical personnel will handle all the blood drawing procedures and sterile conditions will be maintained. The subjects may find that lying still in the scanner for 30 minutes for the PET scans is uncomfortable. To minimize this potential risk, if the subject is uncomfortable, we will reposition the subject and cushion the back with padding. 12.3 MITIGATION OF RISKS Additional risks may exist. Risks can be minimized through the use of strict aseptic technique, compliance with this protocol and technical implant procedures, adherence to the guidelines for subject selection, close monitoring of the subject's physiologic status during implant and follow-up procedures, and by promptly supplying FNMI with all pertinent information required by this protocol to allow the Sponsor optimal trial safety oversight. 12.3.1 Mitigation of Known and Anticipated Surgical Risks Site selection criteria require that participating neurosurgeons have extensive experience with stereotactic surgery and DBS implants. 12.3.2 Mitigation of Device-Related and Therapy-Related Risks Site selection criteria require that participating physician specialists, (e.g., neurologists) have extensive experience in managing Alzheimer’s disease patients. The study will provide the opportunity for training investigational site staff on study procedures. Functional Neuromodulation staff will work closely with study investigators to ensure protocol-specific requirements are followed. Risks are also minimized by the subject selection criteria. Risks are further minimized by obtaining subject informed consent and informing the subject who to contact for more information and emergencies. Subjects will also have regularly scheduled follow-up visits conducted by investigators to ensure subject safety and to ensure that the DBS system is working properly. 12.3.3 Specific Mitigations for Known PET Risks The potential risks related to PET will be minimized in the following manner: 1) Anxiety will be minimized by thoroughly explaining the procedures and answering the subjects’ questions fully. 2) The risks of radiation will be minimized by confirmation of each of the tracer doses administered. The scanning center will assure that the total radiation exposure does not exceed the restrictions set by the Food and Drug Administration (FDA) for research subjects. The center also assures that the radiotracer is given in a quantity that has no physiologic effect. 3) Although idiosyncratic reactions are extremely rare from tracer studies in PET, the subjects are continually monitored for any potential problems during the scanning procedures. A physician will be in attendance at all times during the study and any adverse reactions will be treated immediately. A fully equipped emergency medical cart will be located within the PET Center in case of an untoward reaction or other development of a health related problem. 4) Intravenous catheter placement is a routine procedure at the PET Facility. To minimize the risks associated with the placement of venous catheters, sterile equipment will be used and specially trained medical personnel will insert the venous catheter. 12.3.4 Specific Mitigations for Known MRI Risks The potential risks related to MR will be minimized in the following manner: 1) Claustrophobia from magnetic resonance imaging will be reduced by explaining the nature of the magnetic resonance scanner in detail to all participants prior to their enrollment. Subjects who have history of significant claustrophobia will not be entered into the study and if it occurs, the study will be terminated at the Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 55 OF 70 Investigational Plan ADvance Study subject's request. 2) A possible history of any intraoccular, intracranial, or intrathoracic metal determined during the screening procedures will exclude the subject from the study. The MR scans will be read by a neuroradiologist. Incidental findings will be communicated to the study physician who will communicate the result to the subject and an appropriate referral will be made if clinically indicated. Similar to the PET scanning procedure, a physician will be present at all times during the MR scan. Published guidelines will be followed during the trial when MRIs are performed (Medtronic, Inc 2010). The clinical investigational plan requires that prior to conducting an MRI examination on any subject with a DBS system component implanted, the investigator must read and fully understand all information in the “MRI guidelines for Medtronic DBS systems” which will be sent to the sites prior to activation. This information will also be included in study training materials. 12.3.5 Mitigation for Unknown or Unanticipated Risks The effects of DBS during pregnancy are unknown and therefore pregnant subjects are excluded from the study. Eligibility criteria require female participants to be sterile or post-menopausal. Additionally, all adverse events will be collected and reported in the study in order to collect further information to inform a larger, multi-center pivotal clinical study. Subjects will be followed either by telephone or office visit, as required throughout the study. An independent Clinical Events Committee (CEC) will review and adjudicate all adverse events for causality. A Data Safety and Monitoring Board (DSMB) will review subject safety data and will provide recommendations for study continuation. 13. SITE REQUIREMENTS SITE SELECTION 13.1 The Sponsor or a representative of the Sponsor will assess each potential site to ensure the principal investigator and his/her staff has the facilities and expertise required for the study. Principal investigators and sites will be selected based upon the following factors: Previous experience with clinical research related to Alzheimer’s disease Is currently treating subjects who meet the inclusion/exclusion criteria of this study Ability to enroll an adequate number of subjects Ability to perform required clinical testing including: MRI, PET, neuropsychological testing (ADAScog, CDR, CVLT, ADCS-ADL23, AD-QOL, Zarit Caregiver Inventory, NPI, etc), psychiatric evaluations, clinical lab work Ability and willingness to provide the Sponsor’s representatives access to the hospital records, study files and subject files as they pertain to the study Willingness to participate, including compliance with all aspects of the study Adequate staffing to conduct the study. It is acceptable for the principal investigator to delegate certain study related tasks to one or more subinvestigators or research staff (e.g. study coordinator), however the principal investigator remains responsible for proper conduct of the study at his/her research site. The study is not transferable to another investigator at the site without prior approval of the Sponsor and without proper documentation from the reviewing IRB/EC. The participating surgical center and the participating neurosurgeon will have extensive experience with stereotactic surgery and DBS implant. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 56 OF 70 Investigational Plan ADvance Study 13.2 STUDY INITIATION Before participating in the study, each investigator is required per 21 CFR § 812 to submit to the Sponsor a signed Investigator’s agreement that includes: 1. Investigator’s current signed and dated Curriculum Vitae 2. Investigator’s Financial Disclosure 3. Statement of Investigator’s Relevant Experience 4. Whether or not the Investigator has ever been involved in an investigation or other research that has been terminated 5. The investigators commitment to: a. Conduct the study in accordance with the investigational plan, applicable federal regulations and all reviewing IRB/EC requirements b. Supervise all device testing c. Ensure all requirements for obtaining informed consent are met Prior to the investigator’s participation, the investigator must forward written approval from the appropriate reviewing IRB/EC to the Sponsor or a representative of the Sponsor. The Sponsor or a representative of the Sponsor will conduct a training session with each investigator and his/her research staff to review the investigational plan, Physician Implant Manual, CRFs, the informed consent process, IRB/EC involvement and guidelines, responsibilities and obligations and reporting requirements. This training must be documented and kept on file at the site. The documentation of training will also be sent to the Sponsor or a representative of the Sponsor. This training may occur at a study meeting, group training session or at the research site office/hospital. Upon completion of all of the aforementioned documents and training and written notification from the Sponsor or a representative of the Sponsor, the investigator will be allowed to enroll subjects into this study. 14. MONITORING PROCEDURES 14.1 MONITORING PROCEDURES Functional Neuromodulation, as the sponsor of this study, is responsible for ensuring that adequate monitoring at each site is completed to ensure protection of the rights and safety of subject and the quality/integrity of the data collected and submitted. Monitors are appropriately trained and qualified to monitor for the adherence to the investigational plan, the signed investigator agreement, compliance to the IRB/EC conditions and guidelines and compliance to applicable regulations. Any non-compliance with these items that is not adequately addressed by the principal investigator and/or his/her research site staff is cause for the Sponsor to put the investigator site/staff on hold or withdraw the investigator/site staff from participation in the study. During a monitoring visit, the monitor may review source documents and informed consents for a representative number of subjects and/or CRFs. Frequency of monitoring visits will be based upon enrollment, study duration, compliance and any suspected inconsistency in data that requires investigation. 14.2 MONITORING REPORTS After each monitoring visit, the monitor will send to the principal investigator a letter summarizing the monitoring visit. The letter will include the date of the visit, any findings from the visit and action items requiring follow-up by the principal investigator and/or the research staff. The principal investigator will Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 57 OF 70 Investigational Plan ADvance Study be responsible for ensuring that follow-up actions needing attention are resolved at the site and completed in an accurate and timely manner. 14.3 FINAL MONITORING VISIT Final monitoring visits at the sites will be conducted at the close of the study. The purpose of the final visit is to collect all outstanding study data documents and materials, ensure that the principal investigator’s files are accurate and complete, review record retention requirements with the principal investigator, make a final accounting of all study supplies shipped to the site, provide for appropriate disposition of any remaining supplies and ensure that all applicable requirements are met for the study. This visit may be conducted on site or via telephone. 14.4 CONFIDENTIALITY All information and data sent to Functional Neuromodulation concerning subjects or their participation in this investigation will be considered confidential. Only authorized Functional Neuromodulation personnel or a Functional Neuromodulation representative will have access to these confidential files. Authorized regulatory personnel have the right to inspect and copy all records pertinent to this investigation. Study Data collected during this investigation may be used by Functional Neuromodulation for the purposes of this investigation, publication, to support future research and/or other business purposes. All data presentations and summaries will be reported without identifiable reference to specific subject name. To the extent possible, Functional Neuromodulation will keep subjects’ health information confidential in accordance with all applicable laws and regulations. Functional Neuromodulation may use subjects’ health information to conduct this research, as well as for additional purposes, such as overseeing and improving the performance of its devices, new medical research and proposals for developing new medical products or procedures, and other business purposes. Information received during the study will not be used to market to subjects; subject names will not be placed on any mailing lists or sold to anyone for marketing purposes. 14.5 INFORMED CONSENT Voluntary written informed consent will be required for participation in this study and will be obtained from participants with Alzheimer’s by study personnel following the Alzheimer’s Association guidelines to Investigators. The subject must provide consent himself/herself at screening and baseline. The subject will be asked to designate a legal representative to provide surrogate consent for the study. The surrogate will sign the consent form at baseline indicating they agree to be the surrogate. No study procedures will be undertaken until such consent is obtained. Even after a patient has provided initial consent to participate, baseline and subsequent visits and the implementation of study procedures will be used as opportunities to again explain what is being done, why it is being done, to assure continuing informed consent and to assess capacity. The surrogate will be available to provide ongoing consent should capacity of the subject become impaired. Participants and their authorized legal representatives will be included and consented at the study sites involved using local procedures established by the individual sites and their overseeing IRBs and ECs in accordance with local law, for the enrollment of this vulnerable population. The caregiver, who may or may not be the surrogate, will sign an agreement to attend visits and provide information about the subject. In all cases, prospective participants with dementia will first be assessed for their ability to provide informed consent. Capacity to give consent will be assessed in clinical interviews of participants by clinicians experienced in clinical dementia research who will also be trained in this for the study. In the course of these interviews, these clinicians will assess the ability of participants to: Comprehend the study and its consent form, by asking them to repeat the key elements of the research; Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 58 OF 70 Investigational Plan ADvance Study Understand the study and its consent form, by answering questions about the key elements of the research; Appreciate of the personal nature and consequences of what will or could happen to them if they participate. Interviews will take place in the presence of a caregiver. The designation of a surrogate will be governed by local state and IRB rules. In general, for the purpose of the this study person will be, in order of priority: a legal guardian, or someone who holds a research advance directive for the patient, or a healthcare agent by advance directive, or a healthcare surrogate decision maker by local law such as a spouse, adult child, or sibling. If in this process a potential participant is found not capable of fully providing consent for participation, the participant cannot be enrolled into the trial. The process of obtaining consent and assent will be documented in every case. If potential participants are found able to provide informed consent, they will be asked to do so and their surrogates will co-sign the consent form as a witness. This study will require documented, written informed consent by the subject and his/her caregiver at two time points: 1) At the beginning of the screening visit prior to collection of any study-related information and 2) prior to the surgical implant procedure if all requirements have been met. The surrogate must sign at baseline. 14.6 SECURING COMPLIANCE In the event of repeated noncompliance, as determined by Functional Neuromodulation clinical management, a company monitor or company representative will attempt to secure compliance by one or more of the following actions: Visiting the Investigator Telephoning the Investigator Corresponding with the Investigator If an Investigator is found to be repeatedly noncompliant with the signed agreement, the study protocol, applicable regulatory requirements, or any other conditions of the study, Functional Neuromodulation will either secure compliance or, at its sole discretion, terminate the Investigator's participation in the study according to 21 CFR § 812.46(a). 15. SITE RESPONSIBILITIES, RECORDS AND REPORTS 15.1 RESPONSIBILITIES AND RECORD RETENTION The principal investigator/site must maintain adequate records on all aspects of the study including the following: IRB/EC approval Investigational device disposition Informed Consent forms Case Report Forms Adverse Event information Protocol Deviations Correspondence regarding the study with the Sponsor, other investigators, the core lab, the IRB/EC, the FDA and/or Health Canada Subject termination information The principal investigator/site must maintain the study records for at least two years after termination of the study or the date that the records are no longer required for purposes for supporting regulatory submissions. Disposition of study records is not allowed without prior approval from the Sponsor. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 59 OF 70 Investigational Plan ADvance Study REPORTS 15.2 Reports that are the principal investigator’s responsibility are listed in Table 6. If applicable laws, regulations or IRB/EC requirements mandate stricter reporting requirements than those listed, the stricter requirements must be followed. All required reports must be written unless otherwise noted. Table 6: Principal Investigator Reporting Responsibilities Type of Report Submitted to: Time Frame Unanticipated Adverse Device Effect (UADE) CRO/Sponsor and IRB/EC To CRO/Sponsor ASAP but no later than 10 business days after investigator is first aware of the UADE. To IRB/EC per their guidelines. Serious Adverse Events (SAE) CRO/Sponsor and IRB/EC Withdrawal of IRB/EC approval or other action on part of IRB/EC that affects the study Progress Reports CRO/Sponsor To CRO/Sponsor no later than 10 business days after investigator is first aware of the SAE. To IRB/EC per their guidelines. Within 5 working days of IRB/EC decision. Emergency deviations from the investigational plan CRO/Sponsor and IRB/EC Inappropriate Informed Consent CRO/Sponsor and IRB/EC Emergency Unblinding CRO/Sponsor and IRB/EC Final Report CRO/Sponsor and IRB/EC Other As required Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 IRB/EC CONFIDENTIAL At intervals dictated by the IRB/EC but no less than yearly. To CRO/Sponsor ASAP but no later than 5 business days after the deviation occurs. To IRB/EC per their guidelines. To CRO/Sponsor within 5 business days after the deviation occurs. To IRB/EC per their guidelines. To CRO/Sponsor within 5 business days after the emergency unblinding occurs. To IRB/EC per their guidelines. To CRO/Sponsor within 3 months after termination or completion of study or investigational site’s participation. To IRB/EC per their guidelines. Upon request by CRO, the Sponsor, the IRB/EC, FDA or Health Canada provide accurate, complete and current information about any aspect of the study. PAGE 60 OF 70 Investigational Plan ADvance Study 15.3 RECORDS CUSTODY An investigator may withdraw from the study. If the principal investigator withdraws from the study, responsibility for follow-up and maintaining the records must be transferred to a responsible party (such as another investigator). Notice of transfer must be provided in writing by the principal investigator to CRO/Sponsor, FDA and the IRB/EC not later than 10 days after the transfer occurs. APPENDIX A: DRAFT CASE REPORT FORMS ELEMENTS 1. Screening form a. Screening consent date b. Inclusion/exclusion c. Demographics d. Medical history e. Baseline physical exam f. Clinical lab tests g. Hachinski Ischemia Scale: A 12-item rating instrument designed to identify vascular symptoms associated with dementia h. Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal ideation. The scale takes approximately 5 minutes to administer. The C-SSRS will be administered by a trained rater at the site at the screening visit. i. Electrocardiogram 2. Baseline form a. Baseline consent date 3. Implant form a. Implant procedure b. Device programming 4. 2 Week Visit / Randomization form a. Randomization assignment b. Device programming Follow-up visit forms 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. Device programming/testing results Unblinding Columbia Suicide Severity Rating Scale (C-SSRS) Young Mania Rating Scale (YMRS) Cornell Scale for Depression and Dementia (CSDD) Letter Fluency Trail Making Brief Visuospacial Memory Test – Revised (BVMT-R) Quality Of Life –Alzheimer’s Disease (QOL-AD) Zarit Burden Inventory (ZBI) Physical Exam form Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 61 OF 70 Investigational Plan ADvance Study 16. Clinical Lab Test form 17. Concomitant Medications 18. Alzheimer’s Disease Assessment Scale - Cognitive (ADAS-cog): The ADAS-cog will be administered and documented throughout the study. At screening, subjects must have a total ADAS-cog-11 score between 12 and 24 and item 1 must be at least 4. The cognitive portion includes seven performance items and four clinician-rated items assessing memory, language, praxis, and orientation. In this study, an ADAS-cog-13 will be employed with the addition of delayed recall and digit symbol substitution. 19. Clinical Dementia Rating (CDR): CDR will be performed by trained staff and results documented. CDR is a semi-structured interview with both the subject and the caregiver. The subject is rated in domains of memory, orientation, judgment, problem solving, community activities, home and hobbies and personal care. The global rating score is used to stage severity of Alzheimer dementia and mild cognitive impairment 20. California Verbal Learning Test (CVLT): The CVLT is a highly sensitive neuropsychological test that assesses verbal memory abilities.. 21. Letter Fluency (Borkowski et al., 1967). For the letter fluency task, the patient is asked to orally generate as many words as possible that begin with the letters “s” and “p,” excluding proper names and different forms of the same word. 22. Trail Making Test (Reitan, 1958). This timed test measures visuomotor skills and visual scanning as well as flexibility to shift sets under time pressure. 23. Brief Visuospatial Memory Test-Revised (BVMT-R; Benedict, 1997). A test of visuoconstruction, and visual learning and memory. 24. QOL-AD The QOL-AD is a brief, 13-item measure designed specifically to obtain a rating of the patient's Quality of Life from both the patient and the caregiver. 25. The Zarit Burden Interview (ZBI) Measures subjective burden among caregivers of adults with dementia. using a 22-item self-report inventory that examines burden associated with functional/behavioural impairments and the home care situation. The items are worded subjectively, focusing on the affective response of the caregiver. 26. Alzheimer’s disease Cooperative Study - Activities of Daily Living (ADCS-ADL23): The ADCS-ADL23 is a 23-item inventory of informant based items to assess activities of daily living and instrumental activities of daily living, i.e. functional performance, of AD. 27. Neuropsychiatric Inventory Questionnaire (NPI): The NPI assesses behavioral and psychological symptoms in dementia. It is based on a structured interview conducted with the primary caregiver or reliable informant. Patients who reveal severe behavioral disturbance on the NPI at this screening visit (NPI score 4 on any item other than apathy) will be excluded from the study. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 62 OF 70 Investigational Plan ADvance Study 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. Unscheduled visit form Adverse Event form Adverse Event Follow-up form Death form Protocol Deviation form System Change form Patient Status form Study Withdrawal form CEC Adjudication form Device Experience form MRI Core Lab form PET Core Lab form Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 63 OF 70 Investigational Plan ADvance Study APPENDIX B: SAMPLE INFORMED CONSENT Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 64 OF 70 Investigational Plan ADvance Study APPENDIX C: DEFINITIONS Adverse Event: Any untoward medical occurrence in a study subject whether or not considered related to the study device, study procedures or study requirements that is identified or worsens during the study. Anticipated Adverse Device Effect: An adverse event associated with the investigational device in which the nature, severity, or degree of incidence is known and identified in applicable product labeling, published literature or the Clinical Investigational Plan (CIP). Aphasia: One in a group of speech disorders in which there is a defect or loss of the power of expression by speech, writing, or signs, or a defect or loss of the power of comprehension of spoken or written language. Case Report Forms (CRFs): A Case Report Form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site. Chorea: Chorea refers to rapid complex body movements that look well coordinated and purposeful but are, in fact, involuntary. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR): This is the standard classification of mental disorders used by mental health professionals in the United States. It is not only used for patient diagnosis and treatment, but is also important for collecting and communicating accurate public health statistics. The DSM consists of three major components: the diagnostic classification, the diagnostic criteria sets, and the descriptive text. Erosion: An erosion is an eating away of a surface Extension: The extension is a set of thin wires covered with a protective coating that connects the lead to the neurostimulator. The extension is connected to the end of the lead, just behind the ear (or where your doctor decides is the best placement). The connection point between the lead and the extension is placed under the scalp. The remaining length of the extension is placed under the skin down the neck to the upper chest area and connects to the neurostimulator. For each lead, there is one extension. Fracture: Break Hematoma: A collection of blood that is outside the blood vessel. Hemorrhage: A copious discharge or leakage of blood from a blood vessel Informed Consent Form (ICF): The informed consent form or document provides a summary of the clinical trial (including its purpose, the treatment procedures and schedule, potential risks and benefits, alternatives to participation, etc.) and explains the subjects’ rights as a participant. It is designed to begin the informed consent process, which consists of conversations between the subject and the research team. If the subject then decides to enter the trial, official consent is given by signing the document. A copy of the document is given to the subject and can be used as an information resource throughout the course of the trial. Informed Consent Process: The informed consent process provides a subject with ongoing explanations that will help him or her make educated decisions about whether to begin or continue participating in a trial. Researchers and health professionals know that a written document alone may not ensure that the subject fully understands what participation means. Therefore the research team will discuss with the potential subject the trial’s purpose, procedures, risks and potential benefits, and rights as a participant. While the trial is ongoing, the team will continue to update the participants on any new information that may affect the subject’s situation. Before, during, and even after the trial, subjects will have the opportunity to ask Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 65 OF 70 Investigational Plan ADvance Study questions and raise concerns. Thus, informed consent is an ongoing, interactive process, rather than a onetime information session. Intracranial: Within the cranium, the bony dome that houses and protects the brain. Lead: The lead is a set of thin wires covered with a protective coating. It carries the therapy signal to the electrodes that deliver stimulation to the brain. Approximately 10 cm (4 in) of the lead is implanted inside the brain. The rest of the lead (about 38 cm or 15 in) is implanted under the skin of the scalp. There may be one or two leads implanted, depending on the medical condition being treated. Mentation: Thinking pattern. Migration: Movement out of place. Neurostimulator: The neurostimulator contains the power source of the DBS system. The neurostimulator generates and controls the therapy stimulation. The neurostimulator is implanted just under the skin in the upper chest area. Oculomotor: Control of movement of the eye lid and eye ball, Paralysis: the loss or impairment of voluntary muscular power. Paresis: Paresis is a condition typified by partial loss of movement or by impaired movement. When used without qualifiers, it usually refers to the limbs. Neurologists use the term paresis to describe weakness. Paresthesia: An abnormal sensation of the skin, such as numbness, tingling, pricking, burning, or creeping on the skin that has no objective cause. Protocol Deviation: A study deviation is defined as an event where the investigator did not conduct the study according to the investigational plan, the investigator agreement, or applicable laws and regulations, and the event impacted subject safety or study design. Seizures: Seizures are symptoms of a brain problem because of sudden, abnormal electrical activity in the brain. Serious Adverse Events (SAE): Any adverse event that: Results in death, Is life threatening, Requires inpatient hospitalization or prolongation of an existing hospitalization, Results in permanent impairment of a body structure or body function, Requires medical or surgical intervention to prevent permanent impairment to body structure or a body function, Led to fetal distress, fetal death or congenital abnormality or birth defect. Seroma: Accumulation of fluid in a tissue or organ that can occur after surgery or injury. Source Data: All information in original and identified records and certified copies of original records of clinical findings, observations, or other activities in a clinical investigation, necessary for the reconstruction and evaluation of the clinical investigation (ISO 14155). Source Documents: Original documents, data and records (ISO 14155). NOTE: This may be, for example, hospital records, laboratory notes, pharmacy dispensing records, copies or transcriptions certified after verification as being accurate copies, photographic negatives, radiographs, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical investigation. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 66 OF 70 Investigational Plan ADvance Study Standard Operating Procedure (SOP): A written procedure prescribed for repetitive use as a practice in accordance with agreed upon specifications aimed at obtaining a desired outcome consistently. Stroke: A stroke is the rapidly developing loss of brain function(s) due to disturbance in the blood supply to the brain. This can be due to lack of blood flow caused by blockage or by leakage of blood (hemorrhage). Surrogate: someone who, under state or federal law, has the legal authority to make such decisions for the patient. A surrogate may be (1) a legal guardian; (2) proxy (research agent) named in the participant’s research-specific advance directive; (3) proxy (health care agent) named in an advance directive or durable power of attorney for health care; family member or other surrogate identified by the state law on health care decisions such as the spouse, adult children, parents, adult siblings, other relative, or friend. Unanticipated Adverse Device Effect (UADE): A serious adverse effect on the health or safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the product labeling, published literature or Investigational Plan, or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of subjects. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 67 OF 70 Investigational Plan ADvance Study APPENDIX D: REFERENCES Association, Alzheimer's. "Alzheimer's Association. Consensus Recommendation: Research consent for cognitively impaired adults: Guidelines for Institutional Review Boards and Investigators." Alzheimer Dis Assoc Disord, 2004; 18: 171-175. Cummings JL, Mega M, Gray K, et al. "The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia." Neurol 44(12) (1994): 2308-14. Davis K, Taub E, Houle S, Lang AE, et al. "Globus pallidus stimulation activate the cortical motor system during alleviation of parkinsonian symptoms." Nat Med, no. 3 (1997): 671-674. Davis KD, Kiss ZH, Luo L, Tasker RR, Lozano AM, et al. "Phantom sensations generated by thalamic microstimulation." Nature, no. 391 (1998): 385-387. Hughs CD, Berg L, Danziger WL, Coben LA, Martin RL. "A new clinical scale for the staging of dementia." Br J Psychiatry 140 (1982): 566-572. Ihl R. "Detecting treatment effects with combinations of theADAS-cog items in patients with mild and moderate Alzheimer's disease." Intl J Geriatr Pschychiatry (Wiley Online), 2011. Koller W, Pahwa R, Busenbark K, Hubble J, et al. "High frequency unilateral thalamic stimulation in the treatment of essential tremor and parkinsonian tremor." Ann Neurol, no. 42 (1997): 292-299. Lang AE, Lozano AM. "Parkinson's disease. second of two parts." N Engl J Med, no. 339 (1998): 1130-1143. Laxton AW, Tang-Wai DF, McAndrews MP, Zumstag D, et al. "Phase I Trial of Deep Brain Stimulation of Memory Circuits in Alzheimers' Disease." Ann Neurol, no. 68 (2010): 521-534. Lozano AM, Mayberg HS, Glacobbe P, Hamani C, et al. "Subcallosal cingulate gyrus deep brain stimulation for treatment resistant depression." Biol Psychiatry, no. 64 (2008): 461-467. Mayberg HS, Lozano AM, Voon V, McNeely HE, et al. "Deep brain stimulation for treatment-resistant depression." Neuron, no. 45 (2005): 651-660. McKhann, GM, DS Knopman, H Chertkow, BT Hyman, and et al. ""The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’sAssociation workgroups on diagnostic guidelines for Alzheimer’s disease."." Alzheimer's and Dementia no. 7 (2011): 263-269. Medtronic, Inc. "MRI Guidlines for Medtronic deep brain stimulation systems." www.medtronic.com, 2010. Mielke MM, Kozauer NA, Chan KC, George M, et al. "Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease." Neuroimage, no. 46 (2009): 47-55. Moro E, Lang AE, Strafella AP, Poon YY, et al. "Bilateral globus pallidus stimulation for Huntington's disease." Ann Neurol, no. 56 (2004): 290-294. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. "Columbia Classification Algorithm of Suicide Assessment (CCASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants." Am J Psychiatry 164 (7) (Jul 2007): 1035. Powell TP, Guillery RW, Cowan WM. "A quantitative study of the fornixmamillo-thalamic system." J Anat, no. 91 (1957): 419-437. Rosen W, Terry RD, Field PA, et al. "Pathological verification of ischemic score in differentiation of dementias." Ann Neurol. 7 (1980): 468--8. Rosen WG, Mohs RC, Davis KL. "A New Rating Scale for Alzheimer’s Disease." Am J Psychiatry 141 (1984): 11. Toda, H. "The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation." J Neurosurg, no. 108 (2008): 132-138. Tsivills D, Vann SD, Denby C, Roberts N, et al. "A disproportionate role for the fornix and mamillary bodies in recall versus recognition memory." Nat Neurosci, no. 11 (2008): 834-842. Vidailhet M, Vercueil L, Houeto JL, Krystkowiak P, et al. "Bilateral deep brain stimulation of the globus pallidus in primary generalized dystonia." N Engl J Med, no. 352 (2005): 459-467. Wilson CR, Baxter MG, Easton A, Gaffan D. "Addition of fornix transaction to frontal-temporal disconnection increases the impairment in object-in-place memory in macaque monkeys." Eur J Neurosci, no. 27 (2008): 1814-1822. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 68 OF 70 Investigational Plan ADvance Study APPENDIX E: OVERALL MONITORING FOR SERIOUS PSYCHIATRIC ADVERSE EVENTS FOR THE STUDY Table 7 provides an overview of the roles and responsibilities of study administration and monitoring and reporting SAEs. Table 7: Overview of Roles of Study Monitoring Entity or Individual Functional Neuromodulation (Sponsor) Roles and Qualifications Sponsor of the study. Manages the CRO (if any) and the IDE. Responsible for reporting adverse events to FDA in accordance to the regulations. Responsible for study conduct, data collection and management and for training of clinical site personnel, etc. Overall Study Principal Investigators: Andres Lozano, MD - Neurosurgeon Constantine Lyketsos, MD - Psychiatrist The Overall Study Principal Investigators are physicians who provide oversight for the study. They are a resource for the Sponsor, the CRO and the clinical sites. They, along with the DSMB will assist in making any decisions for breaking the blind and stopping the study. It should be noted that Dr. Andres Lozano is a founder of Functional Neuromodulation, Inc. A lead investigator at a clinical site who will be responsible for the conduct of the study at that site, for collecting appropriate data, including adverse events as required in the protocol, and submitting appropriate reports to their IRBs and sponsor/CRO. He/she will be responsible for oversight of other study personnel at the site. A trained physician responsible for reviewing all incoming adverse events and conducts (first cut) medical assessment. Makes decision to involve the psychiatric principal investigator (Dr. Lyketsos) and sponsor on possible psychiatric AEs. A Clinical Events Committee established by Functional Neuromodulation to review and adjudicate all adverse events. The committee will consist of qualified physicians with support from data management personnel. The Data Safety Monitoring Board will be responsible for reviewing safety data periodically and making recommendations to the Sponsor. The Board will consist of independent, qualified physicians with Alzheimer’s disease and neurosurgery experience. Responsible for liaison with DSMB and for conducting and summarizing all interim and final analyses. Clinical Study Site Principal Investigator Medical Monitor Sponsor CEC DSMB Statistician Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 69 OF 70 Investigational Plan ADvance Study As required, all SAEs will be reported to the sponsor & CRO within the reporting window. A medical monitor designated by the Sponsor will review SAEs and if determined to be a psychiatric event will report the event to Dr. Constantine Lyketsos within 24 hours. Psychiatric SAEs will be tracked and reports provided to Dr. Lyketsos, the chair of the DSMB and the Sponsor monthly. Based on analyses of emerging trends, at any time, Dr. Lyketsos or the chair of the DSMB may convene a meeting to make recommendations to the Sponsor concerning study management, safety procedures or interventions. The following figure outlines the Sponsor’s plan to collect, review and assess psychiatric SAEs across all sites to identify emerging trends and patterns. Sites report SAEs to sponsor/CRO* Designated Medical monitor reviews event within 24 hours to determine if psychiatric in nature Is the event psychiatric related? Y Report event to Dr Lyketsos. Dr. Lyketsos engages site PI and DSMB chair if warranted. Data Management issues aggregate reports and blinded analyses of SAEs to Dr Lyketsos, DSMB chair and Sponsor monthly. Emerging trends detected? Y DSMB meeting convened by chair or Lyketsos based on analyses of emerging trends. Makes recommendations to Sponsor for possible actions ranging from continued monitoring, breaking the blind and/or stopping the trial *Note – All SAEs will be reported to FDA in accordance with reporting requirements in the regulations. All SAEs are adjudicated by CEC. Functional Neuromodulation. Version Number: Version 2.6 Version Date: December 30, 2013 CONFIDENTIAL PAGE 70 OF 70