Clinical trial NCT01522404
Conditions: Mild Cognitive Impairment
Keywords: Mild Cognitive Impairment Memory Loss Alzheimer's Disease
Sponsor: Emory University
Start date: 2012-03-01; Completion date: 2018-06-30
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate the safety of atomoxetine and its effect primarily on the biologic markers (substances that may indicate the presence of a disease) in the cerebrospinal fluid (CSF) of participants diagnosed with Mild Cognitive Impairment (MCI). Additionally, information will be gathered to identify the dose of atomoxetine that is most beneficial, and how taking this medication affects thinking and behavior, as well as imaging and blood biomarkers.The study will also explore rates of change in biomarkers of neurodegeneration (Aß, tau, brain atrophy rates). The results of this research will help determine if atomoxetine alters signs of inflammation and other biomarkers associated with Alzheimer's disease.

Detailed description:
The Alzheimer's Disease (AD) epidemic is a looming crisis, with an urgent need for new therapies to delay or prevent symptom onset and progression. Advances in AD biomarker research have demonstrated changes in amyloid, brain metabolism, and other pathophysiologies prior to the onset of memory loss, with some markers possibly changing one or two decades earlier. Since MCI coincides with the onset of brain atrophy, this early stage of AD pathogenesis may offer a critical window of time to initiate novel therapies aimed at the secondary wave of events that lead to progressive neurodegeneration.

From recently emerged basic research in animal models of AD: loss of norepinephrine (NE) incites a pro-inflammatory condition that is neurotoxic and reduces Aß clearance, and remarkably, rescue of norepinephrine reverses these effects and slows neurodegeneration. This study seeks to extend this proof-of-concept to humans for the first time. The study proposes that atomoxetine, a selective norepinephrine transport inhibitor, is an ideal drug to translate these findings to humans because it is already FDA-approved and safe in the elderly

Subjects with mild cognitive impairment (amnestic or multi-domain subtypes) will be randomly assigned to treatment with placebo or flexible doses of the Norepinephrine Transporter (NET) inhibitor atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose. Participants will be treated for upto 29 weeks, and will undergo venous blood draws and lumbar puncture for biomarker analyses at baseline and up to weeks 29. At a maximum of 29 weeks time point, subjects assigned to active treatment will crossover to placebo and those subjects who were initially randomized to placebo will initiate active treatment.

Participants who complete study are eligible to receive open-label Atomoxetine at the maximum-tolerated dose received during the double-blind phase of the trial. Subjects in the open label are seen every at week 29 upto maximum of 2 years.

Arms: arm 1: Participants in this arm received atomoxetine, starting with 10 mg po daily and increasing weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose for up to weeks 29 and are then crossed over to Inactive compound group arm 2: Subjects in this arm received a matching placebo that have inactive compound for up to weeks 29 and then are crossed over to receive active treatment of Atomoxetine
Interventions: intervention 1: Atomoxetine intervention 2: Placebo
Intervention descriptions: intervention 1: Subjects in this intervention will receive Atomoxetine up to 29 weeks, crossover, dose escalating (up to a maximum dose of 100 mg per day) of oral atomoxetine intervention 2: Subjects in this intervention will receive inactive compound up to weeks 29 and will cross over to the other group

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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CLINICAL RESEARCH PROTOCOL 
 
ATX-001:  A 6-month, Phase II Randomized, Double-Blind, Placebo-
Controlled, Flexible Dosing, Crossover Trial of Atomoxetine in Subjects with 
Mild Cognitive Impairment. 
 
Sponsors: 
Alzheimer’s Drug Discovery Foundation  
Anonymous Philanthropic Donor 
 
Investigator: 
 
Allan I. Levey, MD, PhD 
  
Department of Neurology 
Emory University School of Medicine 
12 Executive Park Drive 
Room 268 
Atlanta, GA 30329 
 
 
Co-Investigators:  
 
James J. Lah, MD, PhD 
Department of Neurology 
Emory University School of Medicine 
Whitehead Biomedical Research Building,  
Suite 505C 
615 Michael Street 
Atlanta, GA 30322 
 
William T. Hu, MD, PhD 
Department of Neurology 
Emory University School of Medicine  
Whitehead Biomedical Research Building,  
Suite 505F 
615 Michael Street 
Atlanta, GA 30322 
 
 
Janet S. Cellar, DNP, PMHCNS-BC 
Department of Neurology 
Emory University School of Medicine  
12 Executive Park Drive 
Atlanta, GA 30329 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Table of Contents 
1. BACKGROUND AND SIGNIFICANCE ............................................................................ 5 
1.1 Preclinical studies ..................................................................................................... 5 
1.2  Neuroinflammation .................................................................................................. 5 
1.3 Animal Model Experience. ........................................................................................ 6 
1.4 Previous Human Experience .................................................................................... 6 
2. SPECIFIC AIMS ............................................................................................................... 7 
2.1 Aim #1 ........................................................................................................................ 7 
2.2 Aim #2 ........................................................................................................................ 7 
2.3 Aim #3 ........................................................................................................................ 8 
3. PRELIMINARY DATA ...................................................................................................... 8 
3.1 NET Inhibition ............................................................................................................ 8 
3.2 Measurement of CSF Analytes and Inflammatory Markers in MCI and AD. ......... 9 
4. EXPERIMENTAL DESIGN AND METHODS ................................................................. 10 
4.1 Overview: ................................................................................................................. 10 
4.2 Sample Size and Power. ......................................................................................... 10 
4.3 Atomoxetine Dosing. .............................................................................................. 10 
4.4 Future research samples. ....................................................................................... 11 
5. RESEARCH STUDY PERSONNEL ............................................................................... 11 
5.1 Principal Investigator (PI) ....................................................................................... 11 
5.2 Co-Investigators ...................................................................................................... 11 
5.3 Research Coordinator. ........................................................................................... 11 
5.4 Psychometrician ..................................................................................................... 11 
5.5 Blinded clinical rater. .............................................................................................. 11 
5.6 Statistician. .............................................................................................................. 11 
6. SAFETY MONITORING AND ADVERSE EVENT REPORTING ................................... 11 
6.1 Internal Safety Monitoring ...................................................................................... 11 
6.2 Independent Data Safety Monitoring Board ......................................................... 12 
6.3 Emory University Investigational Review Board (IRB) ........................................ 13 
7. PATIENT SELECTION ................................................................................................... 14 
7.1 Recruitment Plan. .................................................................................................... 14 
7.2 Inclusion Criteria ..................................................................................................... 15 


 
 
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7.3 Exclusion criteria .................................................................................................... 16 
7.4 Patient Numbering .................................................................................................. 17 
7.5 Randomization ........................................................................................................ 17 
Manual Randomization Plan .................................................................................................17 
Mis-Randomization Plan .......................................................................................................17 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................ 18 
8.1 Informed Consent. .................................................................................................. 18 
8.2 Screening Phase. .................................................................................................... 19 
8.3 Baseline Visits. ........................................................................................................ 20 
8.4 Visit 3/Week 1 (Telephone/Email Visit) + 2 days ................................................... 21 
8.5 Visit 4/Week 2 (Office Visit) + 2 days ..................................................................... 21 
8.6 Visit 5/Week 3 (Telephone/Email Visit) + 2 days ................................................... 21 
8.7 Visit 6/Week 4 (Office Visit) + 2 days ..................................................................... 21 
8.8 Visit 7/Week 5 (Telephone/Email Visit) + 2 days ................................................... 22 
8.9 Visit 8/Week 6 (Office Visit) + 2 days ..................................................................... 22 
8.10 Visit 9/Week 7  (Telephone/Email Visit) + 2 days ................................................ 22 
8.11 Visit 10/Week 11 (Telephone/Email Visit) + 2 days ............................................. 22 
8.12 Visit 11/Week 18 (Office Visit) + 2 days ............................................................... 23 
8.13 Visit 12/Week 22 (Telephone/Email Visit) + 2 days ............................................. 23 
8.14 Visit 13/Week 26 (Telephone/Email Visit) + 2 days ............................................. 23 
8.15 Visit 14/Week 29 (Office Visit) Crossover Visit ................................................... 23 
8.16 Visit 15/Week 30 (Telephone/Email Visit) + 2 days ............................................. 24 
8.17 Visit 16/Week 31 (Office Visit) + 2 days ............................................................... 24 
8.18 Visit 17/Week 32 (Telephone/Email Visit) + 2 days ............................................. 25 
8.19 Visit 18/Week 33 (Office Visit) + 2 days ............................................................... 25 
8.20 Visit 19/Week 34 (Telephone/Email Visit) + 2 days ............................................. 25 
8.21 Visit 20/Week 35 (Office Visit) + 2 days ............................................................... 25 
8.22 Visit 21/Week 36 (Telephone/Email Visit) + 2 days ............................................. 26 
8.23 Visit 22/Week 40 (Telephone/Email Visit) + 2 days ............................................. 26 
8.24 Visit 23 /Week 47 (Office Visit) + 2 days .............................................................. 26 
8.25 Visit 24/Week 51  (Telephone/Email Visit) + 2 days ............................................ 26 
8.26 Visit 25/Week 55 (Telephone/Email Visit) + 2 days ............................................. 27 
8.27 Visit 26/Week 58 End of Study Visit ..................................................................... 27 
8.28 Visit 271/Week 62 Termination Visit .................................................................... 28 


 
 
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8.29 Assessments: ........................................................................................................ 28 
8.30.1 Safety Measurements: ..................................................................................................28 
8.31.2 Other Assessments: ......................................................................................................29 
8.32 Patient Retention ................................................................................................... 29 
9. DATA RECORDING, RETENTION, AND MONITORING .............................................. 29 
9.1 Electronic Case Report Forms ............................................................................... 29 
9.2 Retention And Availability Of Records ................................................................. 29 
10. STATISTICAL ANALYSIS PLAN................................................................................. 30 
12. ASSAY MEASURES AND ANALYSES ....................................................................... 30 
12.1 Lab Manual ............................................................................................................ 30 
12.2 Genotyping ............................................................................................................ 30 
12.3 CSF and Serum Biomarkers. ................................................................................ 30 
12.4 Salivary Amylase................................................................................................... 30 
12.5 Norepinephrine and metabolites ......................................................................... 30 
12.6 Drug levels. ............................................................................................................ 31 
12.7 NET Occupancy. .................................................................................................... 31 
12.8 MRI. ........................................................................................................................ 31 
12.8.1 Clinical Read of MRIs ...................................................................................................31 
12.9 FDG PET Scan. ...................................................................................................... 32 
13.  OPEN LABEL EXTENSION ........................................................................................ 32 
14. TABLE 1 Schedule of Assessments ......................................................................... 33 
15.  STUDY GLOSSARY ................................................................................................... 34 
16. REFERENCES ............................................................................................................. 36 
 
 


 
 
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1. BACKGROUND AND SIGNIFICANCE 
 
The Alzheimer’s Disease (AD) epidemic is a looming crisis, with an urgent need for new 
therapies to delay or prevent symptom onset and progression.  There is growing 
awareness that clinical trials must target stage-appropriate pathophysiological mechanisms 
to effectively develop disease-modifying treatments 1.  Advances in AD biomarker research 
have demonstrated changes in amyloid, brain metabolism, and other pathophysiologies 
prior to the onset of memory loss, with some markers possibly changing one or two 
decades earlier 2,3.  These findings suggest that amyloid-based therapies would optimally 
be targeted long before symptoms first become apparent with mild cognitive impairment 
(MCI).  Alternatively, since MCI coincides with the onset of brain atrophy4-6, this early stage 
of AD pathogenesis may offer a critical window of time to initiate novel therapies aimed at 
the secondary wave of events that lead to progressive neurodegeneration. This proposal 
seeks to apply insights that have recently emerged from basic research in animal models of 
AD: loss of norepinephrine (NE) incites a pro-inflammatory condition that is neurotoxic and 
reduces Aß clearance, and remarkably, rescue of norepinephrine reverses these effects 
and slows neurodegeneration. This proposal seeks to extend this proof-of-concept to 
humans for the first time. We propose that atomoxetine, a selective norepinephrine 
transport inhibitor, is an ideal drug to translate these findings to humans because it is 
already FDA-approved and safe in the elderly. Here we provide a brief rationale for our 
proposal to test the proposed mechanism of action of atomoxetine in subjects with MCI 
using biomarkers of inflammation and neurodegeneration. The study will provide the 
essential next step to move this idea into an NIH funded multi-center clinical trial. 
 
1.1 Preclinical studies have identified a surprising but powerful role for locus coeruleus 
(LC) and NE in AD pathogenesis.  Extensive LC degeneration is nearly universal in AD7-11, 
among the earliest pathologies12-14, and it has long been known that decreased NE is 
linked to cognitive, mood and neuropsychiatric symptoms15-20.  However, recent studies 
show that LC dysfunction in AD animal models also plays a direct causal role in 
pathogenesis, with NE loss accelerating amyloid deposition and neuron death via 
pleiotropic effects on chronic inflammation, neurotrophin expression, cerebral metabolism, 
cholinergic neurons, and blood brain barrier permeability, in addition to deleterious effects 
on cognition – recapitulating key aspects of AD 20-27.  These effects of decreased NE levels 
have been confirmed and extended in several independent laboratories and lines of AD 
mice21,23-25,28. Thus, combining LC lesions with expression of familial AD mutations more 
closely recapitulates the neuropathological and cognitive symptoms of AD than mutant APP 
expression alone, and implicates LC loss as a crucial component of AD.  
 
1.2  Neuroinflammation is a key mechanism linking loss of LC neurons and NE 
innervation with AD. Recent studies provide insights into the mechanisms by which LC 
dysfunction and NE loss contribute directly to AD pathogenesis. Major targets of NE include 
microglia, astrocytes, and endothelia, which in healthy conditions acts through ß-adrenergic 
receptors to suppress the expression of multiple pro-inflammatory genes, including major 
histocompatibility complex class II, tumor necrosis factor-, interleukin-1, and the 


 
 
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inducible nitric oxide synthase 29,30.  Furthermore, NE is critical for the expression of anti-
inflammatory molecules such as nuclear factor kappa B (NF-kappaB) inhibitory IkappaB 
proteins, and of heat shock protein (HSP70)31. Heneka et al.27 demonstrated that in APP23 
transgenic mice, but not wildtype mice, LC lesion profoundly increased Aß plaque load, 
brain inflammation, and spatial memory deficits. These effects of diminished NE levels 
were mediated by impaired microglial phagocytosis and clearance of Aß, and a switch in 
microglial cytokine expression from a neuroprotective anti-inflammatory profile to a pro-
inflammatory and neurotoxic profile 24,26,27.    
 
1.3 Animal Model Experience.  Importantly, treatments that increase NE in AD animal 
models ameliorate AD pathology and cognitive decline.  Pharmacological treatments of 5X 
FAD mice (5 months of age) with the NE transporter (NET) inhibitor atomoxetine and the 
NE precursor L-threo-3,4-dihydroxyphenylserine (LDOPS) effectively raised brain NE 
levels, reduced inflammatory changes, increased expression of  Aß clearance enzymes, 
increased BDNF, reduced Aß burden, and improved spatial memory function 25,32.  
Moreover, as shown in the preliminary data, our colleague Dr. David Weinshenker has 
confirmed and extended many of these findings using a genetic strategy to knock out NET. 
These findings, together with the strong links between LC/NE loss in AD and disease 
progression in AD animal models, clearly demonstrate the exciting disease-modifying 
potential of drugs that increase NE levels. The urgent and essential next step is to translate 
these discoveries to humans in a clinical investigation of the NET inhibitor atomoxetine, an 
FDA-approved drug for treatment of ADHD.  
 
This pilot study in humans will focus on biomarkers and safety. Our central hypothesis is 
that atomoxetine will increase central NE levels and reduce CSF pro-inflammatory 
analytes, increase Aß clearance and slow neurodegeneration in subjects with mild 
cognitive impairment (MCI). The primary outcome will be measures of inflammatory 
markers in the CSF, to test the proposed mechanism of action of NE. The neuro-
inflammatory response observed following LC lesions and its exacerbation of AD pathology 
and behavior in animals, converge with extensive evidence linking inflammation to AD in 
humans as summarized in several excellent reviews 28,33-40. While some evidence comes 
from epidemiological and pathological studies, recent biomarker studies in living subjects 
have also directly shown signs of a pro-inflammatory state 38,39,41,42.  Of note, increased 
pro-inflammatory and decreased anti-inflammatory markers account for the majority of 
changes detectable in a large panel of CSF analytes in MCI and AD 41,42 (see preliminary 
data). Because biomarkers in the CSF are responsive to several different types of drug 
treatments 43,44, including atomoxetine 45, multi-analyte panels will provide an excellent tool 
to investigate treatment effects on inflammatory biomarkers.  
 
1.4 Previous Human Experience Atomoxetine appears to be safe in the elderly, and has 
the potential to prevent, slow, or even reverse disease progression. We believe that 
atomoxetine, an FDA-approved NET inhibitor that is a safe and widely prescribed treatment 
for children and adults with ADHD, is the best choice among currently available pro-
noradrenergic drugs to test in MCI.  Atomoxetine has high affinity and selectivity for the 
NET (Ki for reuptake inhibition in vitro = 1.9 nM for NET vs. 750 nM for SERT and 1600 for 
DAT). It has very weak affinity for adrenergic, dopaminergic, histaminergic, serotonergic, 


 
 
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and cholinergic receptors that are typically blocked by first generation tricyclic reuptake 
inhibitors (e.g., desipramine) 46. 
 
A few studies have examined atomoxetine in elderly patients with neurodegenerative 
disease to assess safety, tolerability and symptomatic effects. Marsh et al 47 studied 12 
patients with Parkinson’s Disease (PD) with doses up to 100 mg daily (mean tolerated dose 
89.6 mg), with excellent safety, tolerability, and improved executive function. Weintraub and 
colleagues 48 found that 80 mg once daily was well tolerated by PD subjects as a treatment 
for depression; only 4 of 29 withdrew because of adverse effects. A 6-month phase II trial in 
mild to moderate AD tested up to 80 mg once daily in 47 subjects, and only 5 of them 
withdrew because of adverse effects 49.  
 
The proposed Phase IIa, double-blind, placebo-controlled, 6 month crossover study will 
examine the effect of atomoxetine in 40 subjects with MCI. The primary outcome will be 
CSF biomarkers of inflammation and their relationship to effects on noradrenergic function.  
We will also explore rates of change in biomarkers of neurodegeneration (Aß, tau, brain 
atrophy rates), and collect data on safety and symptom progression. Collectively, these 
results will inform design of a larger phase II multi-center trial application to the NIH within 2 
years time. 
2. SPECIFIC AIMS 
2.1 Aim #1 To evaluate safety and tolerability of atomoxetine in individuals with MCI 
and define the dose-response effect on biomarkers of noradrenergic function. 
Although atomoxetine is used clinically for ADHD, it is unknown whether atomoxetine 
administration will measurably impact indices of NE tone in subjects with MCI and be safe 
and tolerable in these patients. Safety will be assessed by standard adverse event scales, 
suicidal ideation monitoring, electrocardiograms, and vital signs.  We will determine the 
maximum tolerated doses of atomoxetine (10, 18, 40, 60, 80, 100 mg po daily) and the 
dose-response effect on NET inhibition.  NE metabolites, serum atomoxetine levels, and 
NET occupancy will be measured in the blood each week after escalating doses of 
atomoxetine, and in the CSF after stable maximal tolerated doses. 
EXPECTED OUTCOMES: Atomoxetine will be safe, well-tolerated with a treatment-
associated drop out rate < 15%, and will show a dose-response effect on blood and 
CSF markers of noradrenergic tone, including NE and its primary neuronal metabolite 
dihydroxyphenylglycol (DHPG).  
 
2.2 Aim #2 To assess the effect of chronic atomoxetine treatment (6 months) on 
biomarkers of inflammation and neurodegeneration in subjects with amnestic MCI. In 
rodent models of AD, LC lesions accelerate AD related pathophysiology via dysregulation 
of microglial function and inflammation, whereas NET inhibition improves microglial 
function, ameliorates Aβ plaque deposition, and increases spatial and social memory.  The 
effect of NET inhibition on inflammation and AD biomarkers in a clinical population is 
unknown. This study will examine the effect of atomoxetine on: 
Biomarkers of inflammation (including TNF-alpha, IL1, IL-6, IL-17, IL-10, IL-4 and BDNF 
and VEGF) in blood and CSF using the Rules Based Medicine (RBM) InflammationMAP 
analyte panel. We predict that atomoxetine treatment will measurably reduce CSF levels of 
pro-inflammatory biomarkers and increase levels of anti-inflammatory biomarkers. 


 
 
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CSF biomarkers of AD (Aß40, Aß42, tau, phospho-tau) using highly sensitive and standard 
methods adopted in ADNI. Because these markers are most dynamic during preclinical 
stages of AD pathogenesis, we predict that 6 months of atomoxetine treatment will not 
result in any significant change in CSF Aß, tau and phospho-tau levels compared to 
placebo. 
 
Brain imaging biomarkers (vMRI, ASL-MRI, FDG PET). The annual rate of brain atrophy is 
among the best biomarkers of neurodegeneration and predictive of the conversion from 
MCI to AD. The rate of change in medial temporal lobe atrophy in atomoxetine vs. placebo 
treated subjects will be measured in order to guide statistical projections and power 
analyses for subsequent clinical trials. However, the 6-month design limitation will make it 
unlikely to observe significant changes in atrophy rates, given these are slowly evolving 
processes.   We predict that more robust brain imaging markers of function, including FDG 
PET to measure cerebral metabolism, and arterial spin labeling MRI (ASL-MRI) to measure 
cerebral blood flow, both of which are dynamic and reduced in early stages of AD, will show 
significant improvement with atomoxetine treatment compared to placebo. 
EXPECTED OUTCOMES: Pro-inflammatory analytes, including IL1-alpha, will be 
reduced by ≥ 25% in the CSF with atomoxetine treatment. We also predict significant 
increases in FDG-PET and ASL-MRI measures of cerebral metabolism and blood flow, 
respectively, with atomoxetine treatment.  
 
2.3 Aim #3 To explore the effect of chronic atomoxetine treatment (6 months) on 
cognitive and behavioral symptoms in subjects with amnestic MCI. Although our 
primary goal is to measure drug effects on biomarkers of inflammation, preclinical studies 
have demonstrated symptomatic benefits of NE pharmacotherapies. There are no prior 
studies of atomoxetine effects on symptoms in subjects with MCI. Cognition, function, and 
neuropsychiatric symptoms will be measured at baseline and after 6 months of treatment 
using standardized instruments from ADNI and other ADCS trials.   
EXPECTED OUTCOMES: Atomoxetine treatment will result in a favorable trend on 
cognitive assessments without worsening of behavior and neuropsychiatric symptoms. 
3. PRELIMINARY DATA 
 
3.1 NET Inhibition reduces amyloid deposition in AD mouse models. As described in the 
background, LC lesions consistently and dramatically accelerate Aß deposition through the 
effects of NE loss on microglial function, inflammation, and Aß clearance in a variety of 
transgenic mouse lines with familial AD mutations 21-24,26-28, while enhancing NE levels 
pharmacologically with atomoxetine and the NE precursor LDOPS has beneficial effects on 
AD pathology and behavior 32. 
 
Our collaborator, Dr. David Weinshenker at 
Emory, has pursued complementary studies in 
AD mouse models using genetic approaches. 
Shown here is an example of hippocampal Aß 
burden as measured with Thioflavin S staining in 
an AD mouse model expressing APP/PS1 
mutations (left), and the same strain of mouse 


 
 
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also genetically deficient in the norepinephrine transporter (NET, right panel).  Genetic 
inhibition of NET resulted in a dramatic amelioration of Aß deposition and improved 
behavior (not shown). Although genetic strategies have significant differences from the 
proposed pharmacological treatment with atomoxetine, these results are consistent with 
pharmacological rescue of NE in the AD mouse models, and provide proof-of-principle that 
NE-based treatment strategies offer considerable promise for AD treatment.  
 
3.2 Measurement of CSF Analytes and Inflammatory Markers in MCI and AD. 
Dr. William Hu has established a CSF biomarker 
laboratory for the Emory ADRC and will be responsible 
for the proposed CSF studies. He has established a 
rigorous process with standard operating procedures for 
routine lumbar punctures in the memory disorders clinic, 
using collection and analysis procedures outlined in 
national recommendations based on ADNI that appear 
to predict conversion from MCI to AD 50. An example of 
our results for soluble Aß42, total tau, and phospho-
tau181 in Emory control, MCI, and AD cases are shown in the table. 
Preliminary studies of CSF biomarkers have successfully demonstrated altered 
inflammatory analytes in MCI and AD using 
Rules Based Medicine (RBM) panels.  The figure 
on the right from Dr. Hu shows only those RBM 
analytes that are significantly increased or 
decreased in AD compared to controls and non-
AD dementias 41. Note that many of the altered 
analytes reflect inflammation (e.g., C3, eotaxin, 
HCC-4, IgA, IL-1alpha, IL-23, resistin, IL-7). 
Boxplots show median values and quartiles of 
those CSF biomarkers that differed in levels 
between subjects with normal cognition and AD. 
Values shown are normalized to mean values of 
cognitively normal subjects. The analytes 
elevated in AD are shown on the top (a), and 
analytes decreased in AD on the bottom (b). 
White bars are cognitively normal subjects 
(n=33), blue bars autopsy-confirmed cases of AD (n=66), and red 
bars autopsy-confirmed non-AD neurodegenerative cases (n=25).  
 
Among the inflammatory markers changed in AD, IL1-alpha and 
TECK appear to best predict subsequent cognitive decline. The 
figure on the right shows the correlations with the levels of each 
analyte and annual change in MMSE score. Collectively, these 
results demonstrate our ability to collect and analyze CSF in study 
participants, and highlight the early changes in inflammatory 
biomarkers that occur in MCI and AD.  We predict that increasing 
 
Control 
(n=12) 
MCI/AD 
(n=35) 
Age (SD), 
yr 
58.4 (11.3) 
65.6 (7.6) 
Aß42 
223.7 
(121.4) 
110.6 (59.2) 
Total Tau 
52.1 (26.9) 
126.1 (51.7) 
p-Tau181 
32.4 (23.9) 
82.7 
(36.3) 


 
 
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NE levels in MCI patients treated with atomoxetine will correlate with reductions in CSF IL1-
alpha, TECK, and possibly other inflammatory analytes in the RBM assay.  
4. EXPERIMENTAL DESIGN AND METHODS 
4.1 Overview: A double-blind placebo-controlled crossover trial will be conducted by 
recruitment at a single site (Emory).  Initially, forty subjects with mild cognitive impairment 
(amnestic or multi-domain subtypes) will be randomly assigned to treatment with placebo or 
flexible doses of the NET inhibitor atomoxetine, starting with 10 mg po daily and increasing 
weekly by increments to a maximum of 100 mg po daily or the maximum tolerated dose. 
Participants will be treated for 6 months, and will undergo venous blood draws and lumbar 
puncture for biomarker analyses at baseline and at 6 months. At the six month time point, 
subjects assigned to active treatment will crossover to placebo and those subjects who 
were initially randomized to placebo will initiate active treatment.  The primary goals are to 
measure safety and norepinephrine metabolites in order to verify the intended 
pharmacological response to treatment, and biomarkers of inflammation in order to test the 
hypothesized mechanism of action of treatment. Secondary objectives will mirror the design 
of the ADNI to monitor potential effects of treatment on clinical findings and biomarkers of 
AD progression, including CSF amyloid, tau, and phospho-tau, and volumetric MRI, as well 
as FDG-PET and arterial spin labeling MRI.  
 
4.2 Sample Size and Power.  The study design consists of an atomoxetine group and 
placebo controlled group of MCI. Approximately 15% of subjects with MCI go on to develop 
AD annually 51,52, but the ADNI study has demonstrated that biomarkers of AD provide 
much more robust measures of decline and can dramatically reduce the size of clinical 
trials53. Forty MCI patients will be randomized to placebo or atomoxetine with crossover at 
the six month timepoint. Assuming 15% (n=6) drop-out rate over the course of the trial, 
there will be 34 completers. Based on the inflammatory biomarker studies of our colleague 
Dr. William Hu (see preliminary studies) 41,42,54, and assuming that 80% of the patients 
taking the placebo experience an overall worsening of the RBM analytes that were 
significantly altered (increased or decreased) in AD compared to controls, and at least 25% 
of the patients taking atomoxetine show no worsening profile, would yield 87.7% power. 
This is a reasonable expectation as we expect some key biomarkers will be more reactive 
than others. 
 
4.3 Atomoxetine Dosing. Atomoxetine is a selective norepinephrine reuptake inhibitor that 
is approved by the FDA at a dose range of 10-100 mg daily for the treatment of ADHD in 
adults. It has well-established efficacy and safety in the treatment of ADHD. The drug is 
available for purchase (manufacturer Eli Lilly). Our rationale for atomoxetine dosing is 
based on prior studies.  
 
The trial will consist of a double-blind administration of either atomoxetine, with dose 
escalation from 10-100 mg po daily, or placebo. The schedule will be 10 mg po once daily 
(after breakfast to prevent nausea), with weekly increases pending tolerability: 18 mg week 
2, 40 week 3, 60 mg week 4, 80 mg week 5, and then 100 mg week 6 unless side effects 
emerge. If there are any concerns about side effects, the dose will be decreased to the 
previously tolerated level. Clinician judgment will be used to maintain dose or after one 


 
 
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week increase by 10 mg.  Dosage will be increased in the same manner for subjects who 
crossover from placebo to atomoxetine at the six month timepoint. 
 
A compounding pharmacy approved by Emory’s Investigational Drug Service (IDS) will 
form capsules containing atomoxetine or matching placebo. Study medications will be 
stored at the Emory IDS and dispensed by study personnel. Subjects will be dispensed the 
initial 10 mg or placebo capsules after the baseline visit (2b), and will return every 2 weeks 
for safety assessment and additional medication dispensing. Crossover to either placebo or 
active treatment will occur at week 29.  Participants will be provided sufficient medication 
for dosing adjustments. Weekly phone visits during this dose escalation phase will provide 
additional review of safety and tolerability. Dosing instructions will be provided at each 
phone call or visit.  
 
4.4 Future research samples.  Per individual subject consent, blood, cell lines and 
cerebrospinal fluid samples will be stored indefinitely and may be used for future 
investigation regarding atomoxetine pharmacology and/or side effects, potential 
development of new biomarkers, and potential treatments for Alzheimer’s disease. 
Samples may also be used to deal with future safety issues for atomoxetine or related 
drugs for Mild Cognitive Impairment or Alzheimer’s disease that are not known at the 
present time. These stored samples may also be used for genetic (DNA) research.   
5. RESEARCH STUDY PERSONNEL 
5.1 Principal Investigator (PI) for the study is Allan I. Levey, MD, PhD., Professor and 
Chair, Department of Neurology.  The PI will delegate authority for all study procedures 
performed as noted on the Delegation of Authority log. 
5.2 Co-Investigators include Drs. Lah, Hu, and Cellar. 
5.3 Research Coordinator.  Experienced research coordinator(s) will be utilized to 
coordinate the research study. 
5.4 Psychometrician. Psychometric tools will be administered by research staff certified to 
conduct the specific tests utilized.  The psychometrician will be blinded as to subject 
adverse events. 
5.5 Blinded clinical rater.  Clinical rating tools will be administered by a rater who is 
blinded as to subject adverse events. 
5.6 Statistician. A statistician employed by the School of Public Health will be employed 
for the project. 
6. SAFETY MONITORING AND ADVERSE EVENT REPORTING 
6.1 Internal Safety Monitoring will be performed by the Investigators who will review data 
from all subject visits and review all aspects of patient safety.  Serious and unexpected 
adverse events and/or unanticipated problems involving risks to participants or others will 
be reviewed and reported to the Emory IRB, as per the Emory IRB policies and procedures, 
by the research coordinator in collaboration with the investigators. 
 
All laboratory reports must be reviewed, initialed and dated by the Principal Investigator or 
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involved in the study conduct.  Each abnormal test will be evaluated using the CTCAE 
Version 4 and will be assessed as clinically significant (CS) or not clinically significant 
(NCS).  All CS abnormal laboratory values that represent an unexpected change from 
baseline will be assessed as an Adverse Event (AE) and an AE form will be completed. 
 
Blood pressure cut-off for maximum tolerated dose of atomoxetine is systolic blood 
pressure (SBP) > 160; diastolic blood pressure (DBP) > 100.   Blood pressures will be 
obtained after patient has been sitting with both feet on the floor x 5 minutes.  Three blood 
pressures will be taken and the average of the three blood pressures will be recorded.  In 
the event that a subject experiences blood pressure elevations as described, the dose of 
atomoxetine will be decreased to the maximum dosage to maintain SBP <160 and DBP 
<100. 
 
6.2 Independent Data Safety Monitoring Board has been engaged by the Principal 
Investigator.   
Composition of the DSMB:  The committee will consist of permanent members 
from the Clinical Research Oversight Committee and ad-hoc members from the 
Department of Psychiatry and Behavioral Sciences as needed to review reports.   
 
Submission of Reports to the DSMB:  At least four weeks prior to each DSMB 
meeting, the study principal investigator (PI), or his or her designee, will prepare a 
report to be reviewed during that meeting. The report will follow the template 
available.  Data required for the report include the following: 
1. 
The most recent IRB-approved version of the informed consent form, or most 
recent draft if the study does not yet have IRB approval. 
2. 
A summary of the study protocol. 
3. 
The total number of participants who have signed consent for the study. 
4. 
The total number of participants randomized (if applicable) 
5. 
The number of participants terminating early from the study, with a tally of the 
reasons for these early terminations. 
6. 
The number of serious adverse events that have occurred, with a summary 
report of each event and its resolution. 
A serious adverse event is defined as: “Any adverse experience occurring 
that results in any of the following outcomes: death, a life-threatening 
adverse experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect.” 
7. 
A summary of all adverse events occurring over the course of the study.   
8. 
Copies of all Reportable Events submitted to the IRB.  
1. The PI will notify the DSMB of any and all actions taken by 
the IRB in response to reportable events. 
9. 
A summary and explanation of any breaches of participant confidentiality that 
have occurred during the study. 
10. 
A summary of any new research findings by the PI or others that may alter 
the safety/adverse event profile of the intervention being studied (e.g. newly 
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All data will be presented to the DSMB in a manner to maintain patient confidentiality 
whenever possible.   
 
At the time of the initial study submission to the IRB, the PI will submit the protocol to 
the DSMB.  
 
All Serious Adverse Events and Reportable Events will be reported to the DSMB 
within ten days of their occurrence.   
 
Procedures and Responsibilities of the DSMB:  Upon receipt of a report to the 
DSMB, one of the DSMB co-chairs will assess whether the report requires a full 
DSMB review, or whether an expedited review can be performed.  Expedited 
reviews will be reviewed only by one of the co-chairs.  Criteria for a report to receive 
expedited review include ALL of the following: 
Criteria for Expedited Review: 
1. 
Absence of any Serious Adverse Events (SAEs) or Reportable Events 
during the most recent reporting period. 
2. 
Absence of any adverse event that was not expected (i.e. explained in 
the informed consent form or identified in the protocol. 
3. 
Absence of any significant violations of patient confidentiality. 
 
The DSMB will meet monthly. The DSMB will review each research protocol and 
plans for data and safety monitoring once per year (or every 6 months if the protocol 
is considered 'high risk' by the IRB).  Upon completing the review, the DSMB will 
issue a report that summarizes the following:  
 
All serious and unexpected adverse events or other unanticipated problems that 
involve risk to study participants, and whether these appear related to the study-
based interventions or research assessment protocols. Reports will not specifically 
disclose the treatment arm of the study unless this disclosure is required for safety 
reasons. The DSMB will not receive unblinded data routinely from the PI at the time 
of review. However, the DSMB at any time may request from the PI the unblinded 
treatment assignments if the DSMB believes that knowing the treatment assignment 
could be expected to affect risk/benefit decisions for the trial. 
 
There will be ongoing communication between the PI, the Emory IRB, and the 
DSMB as required. The effective functioning of the DSMB depends completely upon 
the full and timely reporting by the PI of safety-related concerns.  
Statistical consultation will be provided on an as needed basis by the Division of 
Biostatistics.  
 
6.3 Emory University Investigational Review Board (IRB) policies and procedures will 
be employed: Unanticipated Problems involving Risks to Participants or Others 
(UPs): The PI must report to the IRB (using any IRB specified forms, as applicable) any UP 
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Reporting. The PI will advise the Emory IRB of: (a) the relationship between the problem 
and the intervention or study protocol; (b) whether or not a protocol change is necessary to 
reduce risk; and (c) whether the information about the problem affects the informed consent 
process.  
Serious Adverse Events: At the time of renewal for the study, the PI will report to the 
Emory IRB a summary of the serious adverse events related to the research that occurred 
in the previous approval period. If adverse events occur at a greater frequency, severity, or 
duration than was previously anticipated, those become unanticipated and are promptly 
reportable.  
Protocol Deviations: The PI will report to the Emory IRB any circumstances of which the 
PI becomes aware per which there has been a substantive deviation from the protocol that 
adversely affected at least one of the following: 1) the rights, welfare, or safety of subjects; 
2) the subjects’ willingness to continue participation; or 3) the integrity of the research data. 
Deviations that are reported as protocol modifications undertaken to eliminate apparent 
immediate hazards to Human Subjects do not need to be reported twice. The IRB will 
evaluate reported protocol deviations to determine any action to be taken or other reporting 
requirements that need to be fulfilled.  
Protocol Modifications: The PI will request approval of any changes (including, but not 
limited to, any changes in research personnel) that the PI plans to make to a Research 
protocol, which has already been approved by the Emory IRB. Except in cases in which the 
change must be made to eliminate apparent immediate hazards to Human Subjects, the 
Emory IRB must approve of the modification before it can be initiated.  
Non-Compliance: The PI shall notify the IRB of any circumstances of which the PI 
becomes aware of failure to follow Emory IRB Policies &Procedures, federal regulations, or 
other applicable laws. This report shall be made to the IRB as soon as possible after the 
non-compliance occurs. The IRB will work closely with the PI to develop a reasonable 
corrective and preventive action plan that can be implemented by the study team. 
7. PATIENT SELECTION 
7.1 Recruitment Plan.  Drawing from well over 5 million individuals, the Emory ADRC has 
a large clinical practice and clinical research registry of subjects interested in participating 
in research studies. As of September 2011, the ADRC registry has an enrollment of 486 
participants, among them 104 with MCI. The MCI participants include 72 subjects with 
amnestic MCI (single or multiple domain). These ADRC participants all have annual 
research evaluations that include detailed cognitive assessments, and all have consented 
to be contacted for opportunities to participate in research studies.  In addition to the 
existing pool of ADRC participants, the Emory memory disorders clinics, staffed by Drs. 
Levey, Lah, Hu, Cellar and other specialty-trained health professionals provide evaluation 
and treatment ~2000 patients annually, of whom ~500 are new visits (and ~100 MCI). 
Potential study subjects will be identified from those subjects being followed by the Emory 
Alzheimer's Disease Research Center and by the patients of the PI and sub-PI's. Other 
potential study subjects may be recruited if they contact the Emory ADRC specifically to 
find out about potential research studies that might be appropriate for either themselves or 
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7.2 Inclusion Criteria 
1. Subjects must have a subjective memory concern as reported by subject, study 
partner or clinician. 
2. Meets ADNI criteria for diagnosis of MCI 52.  Subjects with amnestic (single or multi-
domain) will be eligible, as both subtypes of MCI are at high risk for progression to 
AD. 
3. Abnormal memory function documented by assessment using the Logical Memory 
subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory 
Scale-Revised (the maximum score is 25):   
(a) <11 for 16 or more years of education 
(b) <9 for 8-15 years of education 
(c) <6 for <7 years of education 
4. Mini-Mental State Exam score between 24 and 30 (inclusive).  Exceptions may be 
made for subjects with less than 8 years of education at the discretion of the PI. 
5. Clinical Dementia Rating = 0.5.  Memory Box score must be at least 0.5. 
6. General cognition and functional performance sufficiently preserved such that a 
diagnosis of AD cannot be made by the physician at the time of the screening visit. 
7. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to 
screen. 
8. Stability of Permitted Medications for 4 weeks.  In particular, subjects may washout 
from excluded medication for at least 4 weeks prior to screening. 
9. Geriatric Depression Scale (GDS) ≤ than 6. 
10. Male or female outpatients aged 50-90 (inclusive). 
11. Study partner has regular contact with the subject adequate to provide a reliable 
assessment of the subject’s level of function, and can be available for all clinic visits, 
either in person or by telephone, for the duration of the study. 
12. Visual and auditory acuity adequate for neuropsychological testing. 
13. Good general health with no diseases expected to interfere with the study. 
14. For women of child-bearing potential (i.e., one who is biologically capable of 
becoming pregnant), must be willing to use a medically acceptable form or birth 
control or practice abstinence for the duration of her participation in the trial.  
Acceptable methods of birth control include: oral or patch contraception, or 
medroxyprogesterone (Depo-Provera®) or other intramuscular contraceptive 
injection, or implantation of levonorgestrel (Norplant®) system, an IUD, a reliably-
employed barrier method (e.g. diaphragm, cervical cap or condom), or a male 
partner who is surgically sterilized. 
15. Modified Rosen Hachinski ≤ 4. 
16. Completed six grades of education or has a good work history (sufficient to exclude 
mental retardation). 
17. Able to communicate in English with study personnel. 
18. Able to understand the nature of the study and must provide written informed 
consent prior to conduct of any study procedures. 
19. Willing to undergo repeated MRIs (3Tesla) and at least three PET scans. No medical 
contraindications to MRI. 
20. Agrees to blood collection for APOE and biomarker testing. 
21. Agrees to lumbar puncture over the course of the study for the collection of CSF.  


 
 
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CSF levels of Ab42, total Tau, and Tau phosphorylated at threonine 181 consistent 
with underlying AD pathology according to established threshold values at Emory 
and the ADNI Biomarker Core  
7.3 Exclusion criteria 
1. Any significant neurologic disease other than MCI and suspected incipient AD, such 
as Parkinson’s disease, multi-infarct dementia, Huntington’s disease, normal 
pressure hydrocephalus, brain tumor, progressive supranuclear palsy, poorly 
controlled seizure disorder, subdural hematoma, multiple sclerosis, or history of 
significant head trauma followed by persistent neurologic deficits or known structural 
brain abnormalities. 
2. Screening/baseline MRI scan with evidence of infection, large vessel infarction or 
other focal structural lesions that could account for the memory deficits.  Subjects 
with multiple lacunes or lacunes in a critical memory structure are excluded.   
3. Contraindication to MRI due to presence of pacemakers, aneurysm clips, artificial 
heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or 
body, or excessive weight. 
4. Presence of clinically significant suicide risk, based on the Investigator’s judgment 
informed by a structured clinician interview.  Any suicide attempt within the past 1 
year of the screening visit is exclusionary. 
5. Major depression, bipolar disorder as described in DSM-IV within the past 1 year, or 
history of schizophrenia (DSM-IV). Psychotic features, agitation or behavioral 
problems within the last 3 months which could lead to difficulty complying with the 
protocol. 
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM-
IV criteria). 
7. Allergic to any component of atomoxetine (Strattera). 
8. Any uncontrolled medical condition that is expected to preclude completion of the 
study, or any medical condition which would represent a contraindication to 
atomoxetine pharmacotherapy (e.g. hepatic insufficiency, untreated hypertension, 
untreated cardiovascular or cerebrovascular disease).  
9. Known serious structural cardiac abnormalities, cardiomyopathy, serious heart 
rhythm abnormalities, or other serious cardiac problems. 
10. History of narrow angle glaucoma. 
11. History of pheochromocytoma. 
12. Clinically significant abnormal findings on screening laboratory tests or physical 
exam.  Abnormalities in Vitamin B12 level, TFTs or LFTs that might interfere with the 
study.  A low Vitamin B12 level is exclusionary, unless follow-up labs (homocysteine 
and methymalonic acid indicate that it is not physiologically significant.  
13. Women who are pregnant or lactating, or who plan to become pregnant during the 
study. 
14. Current use of warfarin (exclusionary for lumbar puncture).  
15. Inability to obtain initial CSF sample.   
16. Use within 60 days of a monoamine oxidase inhibitor .  
17. Current use of anti-psychotic medication. 


 
 
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18. Current use of the following anti-depressant medications that act on NET: 
 duloxetine, venlafaxine, desvenlafaxine, imipramine, or amitryptiline. 
19. Current participation in another clinical trial. Participation in clinical studies involving 
neuropsychological measures being collected more than one time per year. 
20. CSF profile is not consistent with underlying Alzheimer’s Disease pathology. 
21. Reasonable likelihood for non-compliance with the protocol or any other reason, in 
the opinion of the investigator, prohibits enrollment of subject into the study. 
22. Exceptions to these guidelines may be considered on a case-by-case basis at the 
discretion of the protocol director.  
7.4 Patient Numbering 
Patients who have signed the informed consent form to begin screening procedures will 
be assigned a Subject Identification Number at that time. The Subject Identification Number 
will consist of the 3-digit study number (001) followed by a 3-digit subject identifying 
number. The patient will keep the same number throughout the study; a separate 
randomization number will not be provided at Baseline. 
7.5 Randomization 
Subjects will be assigned a randomization number as above.  To achieve balanced patient 
groups, subjects will be randomly assigned on a 1:1 basis in a blinded fashion to 
atomoxetine or placebo treatment during the initial phase, stratified based on APOE4 
results (carrier or non-carrier), and CSF biomarkers for high or low.  To accomplish this, the 
biostatistician will use blocks of size 2 and provide a computer generated randomization to 
the Alzheimer’s Disease Cooperative Study group and the Investigational Drug Service. 
 
When ordering study medication, the study coordinator will receive a blinded subject 
assignment number, via the Alzheimer’s Disease Cooperative Study Group. An identical 
subject assignment legend will be held in safe and confidential custody in a sealed 
envelope by the Investigational Drug Service.  
Manual Randomization Plan 
The study biostatistician will keep a copy of randomization scheme and will be on call. The 
Investigational Drug Service will also have a copy of the randomization scheme and will 
serve as back-up for the study biostatistician if the biostatistician is not available. When 
a subject meets the eligibility criteria and informed consent has been signed, the study 
biostatistician will inform the study coordinator and pharmacist the randomization 
assignment code for the subject based on the randomization plan. 
Mis-Randomization Plan 
There are two scenarios in mis-randomization, i.e., the patient is ineligible and randomized, 
or the patient is assigned to wrong treatment. Considerable care should be taken to avoid 
mis-randomization. If the participant is ineligible and randomized, we must subsequently 
withdraw that participant from the study and classify them as a mis-randomization, the 
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is assigned to wrong treatment group, the patient should remain in the group randomized 
and be included in the analysis based on the “intent-to-treat” (ITT) principle. Secondary 
analysis can be performed according to patient’s actual treatment and compared to the ITT 
analysis. 
 
Unblinding 
In the event that it becomes medically imperative to know what the subject is receiving, the 
investigator will contact the Investigational Drug Service to determine.  Date and reason for 
disclosure must be documented.  If possible, the investigator will confer with the safety 
officer before unblinding. 
8. STUDY ASSESSMENTS AND PROCEDURES  
The study design and assessment schedule are presented in Table 1.  
 
8.1 Informed Consent.  The study will be discussed with the study subject and appropriate 
others (family, study partner) and if they are interested in learning more about the study 
they will be provided with a copy of the informed consent form to review in detail. The study 
subject will be contacted at a later date to determine if they would like to be screened for 
possible participation in the study. If they are interested, a screening visit will be made. 
Potential subjects are encouraged to discuss participation in these studies with their family 
or physician prior to screening for the study.  In addition they are encouraged to contact the 
office with any questions or concerns.  
At the time of the screening visit the consent form will again be reviewed with the study 
subject and appropriate others, questions will be answered and if they are still interested in 
study participation the consent will be signed. Ample opportunity will be given to respond to 
any questions and provide requested information regarding the study. After all questions 
are answered to participant and study partner satisfaction, the consent is signed.   
This study includes subjects who must score between a 24 and 30 on the MMSE (Mini 
Mental Status Examination) and will therefore be experiencing mild cognitive impairment as 
a result of their Alzheimer's disease. Individuals with mild impairment will likely be able to 
provide informed consent however it should not be assumed that all subjects have the 
capacity to consent based only on an MMSE score. Capacity for consent will also be 
determined by the study subject’s ability to engage in a discussion regarding the study and 
their ability to understand what will be involved in study participation. The individual 
obtaining consent will review and discuss the research project and the consent document 
with the potential study participant and their family/study partner/legally authorized 
representative and will decide if they are able to understand the nature of the research, 
appreciate the experimental nature of the study, and understand the potential risks as well 
as alternatives to study participation. 
In the event that the subject is not competent to provide consent, assent is obtained.  A 
study subject’s legally authorized representative will be present during the initial consenting 
process. Signed consent will be obtained from all study subjects. The same process 
described previously will be employed in obtaining legally authorized representative’s 
consent, when deemed necessary.  Consent will be obtained prior to conducting any 
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8.2 Screening Phase.  The following tasks will be performed at the first screening visit 
(1a): 
 Subjects will sign a written informed consent prior to the performance of any 
study-related procedures.  
 The eligibility of the subject to participate in the trial will be assessed by a 
comprehensive evaluation. Patients that appear to be eligible will be 
administered the  
 Mini Mental Status Exam (MMSE),  
 Logical Memory (LM) and  
 Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessments.  
 Geriatric Depression Scale (GDS) 
 
Those participants who do not meet criteria for amnestic MCI will be excluded from 
participation.  Patients meeting criteria for amnestic MCI (single or multi-domain) 
without any exclusionary diagnoses will complete: 
 Medical history, including review of medications 
 Physical and neurologic exams 
 Blood pressure, heart rate, respiratory rate, temperature  
 Height and weight 
 ECG 
 Modified Rosen Hachinski 
 Suicidality assessment  
 Urinalysis  
 Blood work: 
 CBC 
 Comprehensive metabolic panel  
 TSH 
 Vitamin B12 level 
 Coagulation panel 
 Blood work for APOE  
 Serum pregnancy test (for women of child-bearing potential). 
 
If safety laboratory tests and ECG are consistent with protocol eligibility at the 
second screening (1b), the tasks below may be performed on the same day, or may 
be performed on separate days.  Screening 1b will occur within one calendar month 
of screening 1a. 
 If pre-enrollment MRI is not available at the time of screening, the baseline 
MRI will be completed and reviewed prior to screening lumbar puncture 
(LP) to determine eligibility.  Pre-enrollment MRI completed no more than 
two years prior to screening may be used for review.  
 Blood work 
 Inflammatory biomarkers 
 Metabolomics 


 
 
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 Primary Panel for Inflammation, Oxidative, and Nitrosative 
Stress 
 Norepinephrine metabolites (catecholamines) 
 Pax Gene 
 Salivary amylase 
 If the subject has had a clinic LP within 6 months prior to the date of visit 
1b and CSF has been banked for research purposes, no screening LP will 
be performed. The banked CSF will be used for analysis. In all other 
cases, an LP will be performed by an MD or NP following an overnight 
fast.  CSF will be assessed for the following: 
 Glucose 
 Protein 
 Cell count with differential 
 Aβ42, tau, phospho tau 
 Inflammatory Biomarkers 
 NE Metabolites (catecholamines) 
 Contact subject on the day after LP to inquire about new adverse events. 
 
8.3 Baseline Visits. The baseline visit will occur within 1 calendar month of Screening visit 
1b.  Patients that continue to meet eligibility requirements will undergo the following test at 
visit 2A:  
 MRI performed at the Emory Center for Systems Imaging if not performed 
as part of the screening visit.  
 FDG PET Scan 
 
Visit 2b will consist of the following tests/procedures: 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Confirm continued eligibility 
 Blood pressure, heart rate, respiratory rate, temperature  
 Weight, physical and neurologic exams 
 American National Adult Reading Test (ANART) 
 Montreal Cognitive Assessment (MoCA) 
 Category Fluency (Animals) 
 Trails A & B 
 Boston Naming Test (30 item) 
 Auditory Verbal Learning Test  
 Clock drawing 
 Neuropsychiatric Inventory IQ 
 ADAS-Cog 13 (with Delayed Word Recall and Number Cancellation) 
 Activities of Daily Living (FAQ) 
 Blood work 


 
 
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o Serum atomoxetine level 
o NET occupancy 
o Blood work for future research (per individual subject consent) 
 Randomization to drug or placebo 
 Study drug dispensed 
 Subjects will be directed to take their daily pill in the AM after breakfast to 
prevent nausea. 
 
8.4 Visit 3/Week 1 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.5 Visit 4/Week 2 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review 
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.6 Visit 5/Week 3 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.7 Visit 6/Week 4 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 


 
 
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 Interim history review 
 Concomitant medication review 
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.8 Visit 7/Week 5 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.9 Visit 8/Week 6 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 ECG 
 Physical and neurologic exams 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.10 Visit 9/Week 7  (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.11 Visit 10/Week 11 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 


 
 
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8.12 Visit 11/Week 18 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Physical and neurologic exams 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.13 Visit 12/Week 22 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.14 Visit 13/Week 26 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.15 Visit 14/Week 29 (Office Visit) Crossover Visit- May be performed over multiple 
days. 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Physical and neurologic exams 
 Cognitive Testing (full battery) 
 MMSE 
 Logical Memory (LM)  
 Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessments 
 Montreal Cognitive Assessment (MoCA) 
 Category Fluency (Animals) 
 Trails A & B 
 Boston Naming Test (30 item) 
 Auditory Verbal Learning Test  
 Clock drawing 
 Neuropsychiatric Inventory IQ 
 ADAS-Cog 13 (with Delayed Word Recall and Number Cancellation) 
 Activities of Daily Living (FAQ) 
 Geriatric Depression Scale (GDS) 


 
 
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 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Metabolomics 
 Inflammatory biomarkers 
 Primary Panel for Inflammation, Oxidative, and Titrosative 
Stress 
 Salivary amylase 
 Brain MRI 
 FDG PET1 
 Lumbar puncture 1(if LP attempt is unsuccessful, may send to radiology 
for LP under fluoroscopy. CSF will be assayed for: 
 Glucose 
 Protein 
 Cell count with differential 
 Aβ42, tau, phospho tau 
 Inflammatory Biomarkers 
 NE Metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed (crossover) 
 Contact subject on the day after PET scan and LP to inquire about new 
adverse events. 
1Subject to remain on drug until LP and imaging are completed. 
8.16 Visit 15/Week 30 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.17 Visit 16/Week 31 (Office Visit) + 2 days   
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 


 
 
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 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.18 Visit 17/Week 32 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.19 Visit 18/Week 33 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
8.20 Visit 19/Week 34 (Telephone/Email Visit) + 2 days 
 Concomitant medication review 
 Interim history review 
 Adverse event review 
 Study medication compliance review 
 
8.21 Visit 20/Week 35 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 ECG 
 Physical and neurologic exams 
 Blood work 
 CBC 


 
 
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 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
 
8.22 Visit 21/Week 36 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
 
8.23 Visit 22/Week 40 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
 
8.24 Visit 23 /Week 47 (Office Visit) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 Physical and neurologic exams 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Study medication dispensed 
 
8.25 Visit 24/Week 51  (Telephone/Email Visit) + 2 days 
 Interim history review 


 
 
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 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
8.26 Visit 25/Week 55 (Telephone/Email Visit) + 2 days 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Study medication compliance review 
 
8.27 Visit 26/Week 58 End of Study Visit (over 2 days) + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 ECG 
 Physical and neurologic exams 
 Cognitive Testing (full battery) 
 MMSE 
 Logical Memory (LM)  
 Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessments 
 Montreal Cognitive Assessment (MoCA) 
 Category Fluency (Animals) 
 Trails A & B 
 Boston Naming Test (30 item) 
 Auditory Verbal Learning Test  
 Clock drawing 
 Neuropsychiatric Inventory IQ 
 ADAS-Cog 13 (with Delayed Word Recall and Number Cancellation) 
 Activities of Daily Living (FAQ) 
 Geriatric Depression Scale (GDS)Blood work 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Metabolomics 
 Inflammatory Biomarkers 
 Primary Panel for Inflammation, Oxidative, and Nitrosative Stress 
 Salivary amylase 
 Brain MRI  
 FDG PET1 
 Lumbar Puncture1  (if LP attempt is unsuccessful, may send to radiology for 
LP under fluoroscopy.  CSF will be assayed for: 
 Glucose 
 Protein 


 
 
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 Cell count with differential 
 Aβ42, tau, phospho tau 
 Inflammatory Biomarkers 
 NE Metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 Study medication accountability 
 Contact subject on the day after LP to inquire about new adverse events. 
 
8.28 Visit 271/Week 62 Termination Visit + 2 days 
 Blood pressure, heart rate, respiratory rate, temperature 
 Weight 
 ECG 
 Physical and neurologic exams 
 Blood work 
 CBC 
 Comprehensive metabolic profile 
 Serum atomoxetine level 
 NET occupancy 
 Norepinephrine metabolites (catecholamines) 
 Interim history review 
 Concomitant medication review  
 Adverse event review 
 Suicidality assessment 
 
8.29 Assessments:  MCI will be assessed using raters blinded to the study design. The 
battery of tests that is employed for the ADNI2 study (see baseline visit) is used. The 
screening battery will consist of: MMSE, Logical Memory, CDR-SB and Geriatric 
Depression Scale as to determine subject eligibility. 
8.30.1 Safety Measurements: 
a. Suicidality Assesmment – Structured Clinician Interview  will be used to assess for 
suicidality at baseline and throughout the trial. 
b. Vital Signs - Systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart 
rate (HR) will be measured while the patient is in sitting position after five minutes 
rest at each office visit. 
c. Physical Exam – A physician will perform a physical exam on all MCI patients at the 
screening visit to evaluate for any significant medical conditions. Subsequent 
physical exams will be performed by an MD or Nurse Practitioner. 
d. Electrocardiogram – A 12-lead ECG will be performed at the screening visit, at 
weeks 6 and 35 (at maximum tolerated dose), week 58 and at the final study visit. 
ECGs demonstrating patterns consistent with acute or recent myocardial disease or 
significant conduction defects, including a QTc >480 msec (Barrett’s formula), will be 
excluded. 


 
 
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e. Safety Labs - Pre-enrollment lab work is done to ensure subjects are not at undue 
risk to participate in the study.  Serial CBC and CMP will be performed throughout 
the course of the study, as well as at the termination visit.  CSF cell count, glucose 
and protein will be assayed at screening, crossover and termination visits.  Clinical 
assessment of laboratory values is described in section 6.1. 
8.31.2 Other Assessments: 
a. Demographic Data - Demographic data (gender, date of birth, marital status, 
ethnicity, race) will be collected for all patients.  
b. Concomitant Medication - All meds taken by subjects during study will be 
documented. 
8.32 Patient Retention 
Subjects who are enrolled in the study will be reimbursed for parking and transportation 
costs at the amount of $25 for each completed in-office study visit, pro-rated for visits 
completed.  Subjects will also be paid $100 for each MRI, $100 for each LP and $100 for 
each of the three FDG PET scans completed. If all study visits are completed, subjects will 
receive a total of $1300 total. 
 
Reimbursement will be made following visits 2b, 11 and 21.  Emory University is required to 
complete form 1099 for any participant payments over $600 in a year.  To comply with this 
federal mandate the researchers are required to obtain subject’s social security number to 
complete the form. 
9. DATA RECORDING, RETENTION, AND MONITORING 
9.1 Electronic Case Report Forms  
Electronic Case Report Forms will be completed for each patient who signs Informed 
Consent. All clinical information requested in this protocol will be recorded on the eCRFs.  If 
an error is made on documents collected (source documents), a single line will be drawn 
through the error and the correct response will be written adjacent to the error; the change 
will be initialed, and dated. 
 
9.2 Retention And Availability Of Records 
The Investigator will make study data accessible to Regulatory Agency inspectors upon 
request. A file for each patient will be maintained that includes the signed ICF and the 
Investigator’s copies of all source documentation related to that patient. The Investigator 
will ensure the reliability and availability of source documents from which the information on 
the eCRF was derived. 
 
Study documentation will be maintained, including documents created or modified in 
electronic format, for at least 15 years following the completion of the study. ICFs, and 
adequate records for the receipt and disposition of all study drugs will be retained for a 
period of 2 years following the Food and Drug Administration (FDA) or other regulatory 


 
 
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approval date of the drug or until 2 years after the drug investigational program is 
discontinued, unless a longer period is required by applicable law or regulation.  
10. STATISTICAL ANALYSIS PLAN 
Statistical analyses will be performed using SAS 9.3. Given our expected sample size of 34 
at the end of study, we will have some analytical limitations.  Therefore, at the 6- and 12-
month time points, we will assess the overall change (improvement/worsening) among the 
preselected RBM analytes found to be significantly different in preliminary studies of CSF 
markers.  We will then statistically compare the percentage of overall change between the 
atomoxetine and placebo groups using Pearson’s chi-square test or a Fisher Exact test (if 
necessary). Because IL1-alpha and TECK appear to best predict subsequent cognitive 
decline, we will compare the levels of these inflammatory markers in each group using a 
Wilcoxon Rank-Sum test.  We will also use Spearman’s correlation to determine an 
association between NE levels and these two biomarkers. 
12. ASSAY MEASURES AND ANALYSES 
12.1 Lab Manual is available for details pertaining to specific collection, processing, 
storage and transporting guidelines. 
 
12.2 Genotyping for apolipoprotein E4 allele status will be performed in the Emory 
Genetics Core facility.  Apolipoprotein E4 allele status will not be disclosed to study 
subjects. 
 
12.3 CSF and Serum Biomarkers. AD biomarkers including Aß42, tau, and phospho-tau 
levels in the CSF will be assayed at baseline, 6 months, and 12 months following 
atomoxetine or placebo treatment. These assays will be performed in Dr. William Hu’s 
biomarker laboratory using standardized measurements of CSF AD biomarkers 
(Innogenetics, Ghent, Belgium) on a Luminex-200 platform. Specialty assays for additional 
markers such as eotaxin-3, TECK and others have also been established and validated. 
RBM is a commercial vendor performing the multi-analyte panel as described previously 41. 
 
12.4 Salivary Amylase. a noradrenergic biomarker, will be assayed in the laboratory of Dr. 
James Ritchie, using a Salivary α-Amylase assay kit (Salimetrics, State College, PA). 
Approximately 1 ml of saliva will be collected at baseline, 6- and 12 months following 
atomoxetine or placebo treatment. Saliva samples will be stored at -20°C until assay. 
 
12.5 Norepinephrine and metabolites will be assayed in the laboratory of Dr. David 
Goldstein, Chief of Neurocardiology at NINDS and one of the leading authorities in the field. 
The assay will use HPLC with electrochemical detection after batch alumina extraction, a 
method that was perfected in the lab and routinely used for many years. Analytes to be 
measured include the catechols norepinephrine (NE), epinephrine, and dopamine, the 
catecholamine precursor DOPA, the main neuronal metabolite of NE 
(dihydroxyphenylglycol, DHPG), and the main neuronal metabolite of dopamine, 
dihydroxyphenylacetic acid (DOPAC).  
 


 
 
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12.6 Drug levels. Serum atomoxetine levels will be assayed using a highly sensitive liquid 
chromatography tandem mass spectrometry method56 established in the Emory clinical 
laboratories to monitor compliance and quantify dose-response effects. 
 
12.7 NET Occupancy. In the absence of data from PET studies allowing definitive 
knowledge of NET occupancy as a function of drug dose, an ex vivo assay established in 
the laboratory of Dr. Mike Owens, will use serum to estimate NET occupancy. Serum 
samples will be used to directly measure inhibition of active [3H]-monoamine transport in 
cells expressing the human serotonin, norepinephrine or dopamine transporters. Uptake 
measured in drug-free baseline serum is compared to that observed in the subject’s 
samples while on drug and expressed as both % baseline uptake and % occupancy. These 
assays are sensitive to free drug concentrations representative of extracellular space within 
the brain where transporter inhibition is hypothesized to be correlated with therapeutic 
efficacy.  
 
12.8 MRI. Brain MRI scan will be obtained or reviewed at screening to verify eligibility, at 
baseline, at 6 months and after 12 months of treatment or placebo, using protocols adapted 
from the ADNI study as described below. 
  
MRI films performed clinically within the past two years will be reviewed by the investigators 
for eligibility in the study.  If a subject does not have clinical MRI films available, the MRI 
will be performed and reviewed prior to performance of the LP for safety reasons and to 
ensure that the subject meets eligibility criteria. 
  
The 3T MR acquisition sequences 1) Structural MRI, 2) FLAIR, 3) T2*GRE; 4) arterial spin 
labeling (ASL), 5) neuromelanin enhancement; and 6) resting state connectivity.  MRI 
measurements of brain structure have been show to demonstrate brain atrophy (which 
correlates with neuron loss) in MCI and AD and increasing rates of brain atrophy as 
subjects become more impaired.  Therefore, structural MRI is used as a measure of the 
rate of disease progression, and possibly as a measure of treatment effect, in AD treatment 
trials.  Structural MRI (MPRAGE//IRSPGR) data will be used both as the rate of change as 
well as a predictor of future change.  Cerebrovascular disease (especially white matter 
lesions (WMLs) will be assessed with FLAIR.  Recently, iron imaging, especially 
microbleeds (T2* GRE) has been used in anti-amyloid clinical trials, because of the 
association of microbleeds with anti-amyloid therapy; this will be measured with T2*GRE. 
Cerebral blood flow, which closely correlates with cerebral hypometabolism as an early 
biomarker of AD pathogenesis, will be measured by ASL imaging. A novel protocol 
developed at Emory by Drs. Xiaoping Hu and Dan Huddleston to visualize neuromelanin 
containing neurons will be used to quantify norepinephrine containing neurons in the locus 
coeruleus.  Finally, resting state fMRI will be used to determine functional connectivity 
changes that have recently been observed in AD.  
12.8.1 Clinical Read of MRIs 
All MRIs will be reviewed by the investigators and the investigator will determine and 
document any clinically significant findings. 
  


 
 
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12.9 FDG PET Scan.  -Cerebral metabolic rate for glucose (as measured by 
fluorodeoxyglucose [FDG] uptake) will be obtained at baseline and at 6 and 12 month 
timepoints in the study.   
 
In preparation of the FDG PET Scan, subjects will be required to fast for at least four (4) 
hours prior to the scanning session.  Subjects’ blood glucose is checked prior to scanning 
and must be < 180 mg.dL.  After the injection of 5 mCi of tracer, subjects are in a quiet, 
dimly lit room with eyes and ears unoccluded for 30 minutes, after which they are placed in 
the scanner.  Data are acquired as 6 x 5 minute frames. 
 
13.  OPEN-LABEL EXTENSION 
 
Participants who complete study Visit 26 will be eligible to receive open-label Atomoxetine 
at the maximum-tolerated dose received during the double-blind phase of the trial. 
Atomoxetine will be dispensed immediately following Visit 26, after obtaining subject 
consent, in the following manner: 
 40 mg p.o. – for 2 weeks, followed by telephone visit to assess AEs 
 80 mg p.o. – for 4 weeks, followed by a telephone visit to assess AEs 
 100 mg p.o. for 6 months at a time(or maximum tolerated dose based on data from 
double-blind phase of the study) 
 
Subjects who elect to participate in the open-label phase of the study will forego study Visit 
27.  Participants and investigators will remain blinded about when the subjects received 
drug versus placebo during the active phase of the study. Atomoxetine administered during 
the open-label phase will be identical in appearance to drug received during the double-
blind phase of the trial. Participants who wish to receive open-label drug will be asked to 
sign a new consent form (after the investigator or study coordinator has explained 
procedures for the open-label phase of the trial and after all participant questions have 
been addressed).  
 
Participants who elect to receive open-label drug will be required come to the clinic to have 
safety labs performed every six months, including CBC with differential and chemistry 
(including liver enzymes).   Once the results of safety laboratory studies are received, 
open-label Atomoxetine in sufficient quantity for 6 months therapy (100 mg/day) will be 
dispensed at no cost to the participant. For the duration of open-label participation, 
participants will undergo an annual MRI and PET scan, in addition to CSF collection via 
lumbar puncture. In addition, a short battery of cognitive tests (MMSE, CDR) will be 
performed annually. Participants will be asked to report any adverse events that develop 
during the open-label phase of the trial.  
 
The open-label phase of the study will be terminated after 2 years (i.e., 104 weeks) 
following successful completion of the active phase of the study.  The P.I. reserves the right 
to stop open-label dispensing at any time. 


 
 
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14. TABLE 1 Schedule of Assessments 
Schedule of Assessments  
Visit Number 
1a 
1b 
2a 
2b 
3 
4 
5 
6 
7 
8 
9 
10 11 12 13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Study Week 
Screening 
Baseline 
1 
2 
3 
4 
5 
6 
7 
11 18 22 26 
291 
30 
31 
32 
33 
34 
35 
36 
40 
47 
51 
55 
58 
62 
 
a 
b1 
a1 
b 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dosing (max tolerated dose) 
 
 
 
10
mg 
18 
mg 
40 
mg 
60 
mg 
80 
mg 
100 
mg 
 
 
 
 
 
 
10
mg 
18 
mg 
40 
mg 
60 
mg 
80 
mg 
100 
mg 
 
 
 
 
 
 
 
 
Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm  eligibility 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and medication 
review 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical and neurological 
examination 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
 
x 
 
 
x 
 
 
x 
x 
Vital signs + height (screening only) 
& weight 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
ECG  
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
x 
x 
Blood and/or urine7 for clinical labs 
x 
 
 
 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Serum  pregnancy if indicated 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
APOE Genotyping 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for biomarkers, drug levels, 
NE and metabolites 
 
x 
 
x 6 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Labs for future research 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Salivary amylase 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
MRI  
 
x3 
x4,5 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x5 
 
FDG PET 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Lumbar puncture  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x5 
 
Study Drug dispensed 
 
 
 
x 
 
x 
 
x 
 
x 
 
 
x2 
 
 
x 
 
x 
 
x 
 
X2 
 
 
x 
 
 
 
 
Modified Rosen Hachinski 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Telephone Call/Email Contact 
 
 
 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
x 
 
x 
 
x 
 
x 
x 
 
x 
x 
 
 
Cognitive Assessment 
x 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
Suicidality Assessment 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
 
x 
 
x 
 
x 
 
 
x 
 
 
x 
x 
Assessment of current medications, 
interim history, & adverse event 
review 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Study Drug Compliance 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Randomization/Study Arm Crossover 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
1Visit may be performed over 2 days,   23 months of study meds dispensed at V11, V23., 3 MRI  to be done if no clinical MRI w/I past 2 years for review.   4If pre-enrollment MRI is not available at the time of 
screening, the baseline MRI will be completed prior to screening LP to determine eligibility. 5MRI will be done prior to LP to avoid meningeal reactions for subjects who have not had MRI in past 2 years 
Early termination will lead to same visit type as termination week 58 visit. 6 No NE and metabolites at this visit.  7 Urine at Visit 1a only. Areas highlighted in yellow represent office visits.  Visit14/Week 29, 
highlighted in blue is the crossover visit. 


 
 
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15.  STUDY GLOSSARY 
 
AD 
 
 
Alzheimer’s Disease 
ADAS-Cog 
 
Alzheimer’s Disease Assessment Scale – Cognitive 
ADCS  
 
Alzheimer’s Disease Cooperative Study 
ADHD  
 
Attention Deficit Hyperactivity Disorder 
ADNI  
 
Alzheimer’s Disease Neuroimaging Initiative 
ADNI2 
 
NIH grant, Funding began 2011 
AE 
 
 
Adverse Event 
ANART 
 
American National Adult Reading Test 
APOE/APOE4 
Apolipoprotein (APOE) epsilon 4 (APOE4) 
ASL 
 
 
Arterial Spin Labeling 
Aß 
 
 
Beta Amyloid 
BDNF  
 
Brain-derived neurotrophic factor 
CBC  
 
Complete Blood Count 
CDR-SB  
 
Clinical Dementia Rating-Sum of Boxes  
CFR   
 
US Code of Federal Regulations  
CS  
 
 
Clinically Significant  
CSF 
 
 
Cerebrospinal Fluid 
CSSRS  
 
Columbia Suicide Severity Rating Scale 
CT 
 
 
Computerized Tomography 
CTCAE  
 
Common Terminology Criteria for Adverse Events Version 4 
DBP   
 
Diastolic Blood Pressure  
DHPG  
 
Dihydroxyphenylglycol 
DNA  
 
Deoxyribonucleic Acid 
DOPAC  
 
Dihydroxyphenylacetic Acid  
DSMB  
 
Data Safety Monitoring Board 
DSM-IV 
 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition 
DTI 
 
 
Diffusion Tensor Imaging 
ECG  
 
Electrocardiogram 
eCRF  
 
Electronic Case Report Form 
EDC  
 
Electronic Data Capture 
FAQ  
 
Functional Activities Questionnaire (Activities of Daily Living) 
FDA   
 
Food and Drug Administration  
FLAIR  
 
Fluid Attenuation Inversion Recovery 
fMRI  
 
Functional Magnetic Resonance Imaging 
GDS  
 
Geriatric Depression Scale 
HIPAA 
 
Health Insurance Portability and Accountability Act 
HPLC   
 
High Performance Liquid Chromatography  
HR 
 
 
Heart Rate 
HSP70  
 
Heat Shock Protein  
IDS 
 
 
Investigational Drug Service 
IL 
 
 
Interleukin 
IRB 
 
 
Investigational Review Board 
IUD 
 
 
Intrauterine Device 


 
 
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LC 
 
 
Locus Coeruleus 
LDOPS 
 
L-threo-3,4-dihydroxyphenylserine 
LFT 
 
 
Liver Function Tests 
LM 
 
 
Logical Memory 
LP 
 
 
Lumbar Puncture 
MCI 
 
 
Mild Cognitive Impairment 
MMSE 
 
Mini Mental State Exam 
MoCA  
 
Montreal Cognitive Assessment 
MPRAGE 
 
Magnetization Prepared Rapid Gradient Echo 
MR/MRI 
 
Magnetic Resonance/Magnetic Resonance Imaging 
NCS   
 
Not Clinically Significant  
NE 
 
 
Norepinephrine 
NET 
 
 
Norepinephrine Transporter 
NIH 
 
 
National Institutes of Health 
NINDS 
 
National Institute of Neurological Disorders and Stroke 
PD 
 
 
Parkinson’s Disease 
PET 
 
 
Positron-Emission Tomography 
PI 
 
 
Principal Investigator 
RBM   
 
Rules Based Medicine  
SAE 
 
 
Serious Adverse Event 
SBP   
 
Systolic Blood Pressure  
SD 
 
 
Standard Deviation 
T 
 
 
Tesla 
T2*GRE 
 
T2 Star-Weighted Gradient-Echo 
TECK  
 
Thymus-Expressed Chemokine 
TFT 
 
 
Thyroid Function Tests 
UP 
 
 
Unanticipated Problems  
VEGF  
 
Vascular endothelial growth factor 
vMRI  
 
Volumetric Magnetic Resonance Imaging 
WML  
 
White Matter Lesions 
WMS-R 
 
Wechsler Memory Scale – Revised 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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16. REFERENCES 
 
1.  Selkoe DJ. Alzheimer's disease. Cold Spring Harb Perspect Biol 2011;3. 
2.  Ringman JM, Younkin SG, Pratico D, Seltzer W, Cole GM, Geschwind DH, Rodriguez-Agudelo 
Y, Schaffer B, Fein J, Sokolow S, Rosario ER, Gylys KH, Varpetian A, Medina LD, Cummings JL. 
Biochemical markers in persons with preclinical familial Alzheimer disease. Neurology 2008;71:85-
92. 
3.  Petrie EC, Cross DJ, Galasko D, Schellenberg GD, Raskind MA, Peskind ER, Minoshima S. 
Preclinical evidence of Alzheimer changes: convergent cerebrospinal fluid biomarker and 
fluorodeoxyglucose positron emission tomography findings. Archives of neurology 2009;66:632-7. 
4.  Jack CR, Jr., Vemuri P, Wiste HJ, Weigand SD, Aisen PS, Trojanowski JQ, Shaw LM, Bernstein 
MA, Petersen RC, Weiner MW, Knopman DS. Evidence for Ordering of Alzheimer Disease 
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