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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
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Investigational Plan
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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
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Tel: (410) 550-0062
Email: [email protected]
Functional Neuromodulation
455 2nd Street S.E., Suite 402
Charlottesville, VA 22902
Fax: 434-291-1001
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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
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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
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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:

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The change in ADAS-cog-13 at 12 months
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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.
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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
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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
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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
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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
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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
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(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”.
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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
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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.
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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.
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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).
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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.
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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.
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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
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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
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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



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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.
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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
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
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).
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
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
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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.
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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.
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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
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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
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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.
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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
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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.
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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
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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.
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
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)
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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.
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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
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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.
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
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.
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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.
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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)
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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.
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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
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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.
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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
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
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.
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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
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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)
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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.
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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.
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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.
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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.
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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
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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.
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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
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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
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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.
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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
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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;
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
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.
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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
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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.
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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
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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.
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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
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APPENDIX B: SAMPLE INFORMED CONSENT
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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
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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.
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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.
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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.
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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
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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.
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