CAndesartan vs LIsinopril Effects on the BRain and Endothelial Function in eXecutive MCI (CALIBREX)
Phase: PHASE2
Conditions: Hypertension, Mild Cognitive Impairment
Sponsor: Emory University

Hajjar- CALIBREX, Version 8.0-10. 15.2014 
 
 
IRB00070087 
 
NCT01984164 
 
PROTOCOL TITLE 
 
CAndesartan vs LIsinopril effects on the BRain 
and 
Endothelial function in eXecutive MCI 
(CALIBREX) 
 
VERSION 2/5/2015 
 
Principal Investigator: 
 
Ihab Hajjar, MD 
Emory University 
 
 
Supported by: 
 
The National Institute on Aging 
 
R01AG042127 

Hajjar- CALIBREX, Version 8.0-10. 15.2014 
 
 
 
 
 
 
 
 
PROTOCOL TITLE 
 
CAndesartan vs LIsinopril effects on the BRain 
and 
Endothelial function in eXecutive MCI 
(CALIBREX) 
 
VERSION 9.0; 2/5/2015 
 
Principal Investigator: 
 
Ihab Hajjar, MD 
Emory University 
 
 
Supported by: 
 
The National Institute on Aging 
 
R01AG042127 
  
  
 

Hajjar- CALIBREX, Version 9.0-2/05/2015 
 
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TABLE OF CONTENTS 
STUDY TEAM ROSTER .................................................................................... 4 
PARTICIPATING STUDY SITES ....................................................................... 6 
PRÉCIS ............................................................................................................. 7 
1. STUDY OBJECTIVES .................................................................................... 8 
2. BACKGROUND AND RATIONALE ................................................................ 8 
2.1 Background………….. ................................................................................................................ 8 
2.2 Study Rationale ...................................................................................................................... 10 
2.3 Prior Studies ........................................................................................................................... 10 
3. STUDY DESIGN ........................................................................................... 10 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ................................. 10 
4.1 Inclusion Criteria  ................................................................................................................... 10 
4.2 Exclusion Criteria ................................................................................................................... 11 
4.3 Study Recruitment and Payment ........................................................................................... 11 
5. STUDY INTERVENTIONS ............................................................................ 12 
5.1 Interventions, Administration, and Duration ....................................................................... 12 
5.2 Handling of Study Interventions ........................................................................................... 12 
5.3 Concomitant Interventions ................................................................................................... 12 
5.4 Allowed Interventions ........................................................................................................... 12 
5.5 Required Interventions .......................................................................................................... 12 
5.6 Prohibited Interventions ....................................................................................................... 12 
5.7 Adherence Assessment .......................................................................................................... 12 
6. EXPERIMENTAL PROCEDURES AND MEASURES ..................................... 13 
6.1 Questionnaires and Lifestyle and Anthropmetric Measures ................................................ 13 
6.2 Blood Pressure Measurement ............................................................................................... 13 
6.3 Neuropsychological Assessment ........................................................................................... 13 
6.4 Brain MRI Imaging Protocol ................................................................................................. 14 
6.5 Vascular Measures ................................................................................................................. 16 
6.6 Blood Chemistries, Blood Count, and APOE ........................................................................ 17 
7. STUDY SCHEDULE ..................................................................................... 17 
7.1 Schedule of Evaluations ......................................................................................................... 17 
7.2 Description of Evaluations. ................................................................................................... 17 
8. SAFETY ASSESSMENTS .............................................................................. 18 

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8.1 Potential Risks ........................................................................................................................ 19 
8.2 Specification of Safety Parameters. ....................................................................................... 19 
8.3 Antihypertensive Replacement Protocol ............................................................................. 20 
8.4 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters ............ 21 
8.5 Adverse Events and Serious Adverse Events ........................................................................ 21 
8.6 Incidental Findings ................................................................................................................ 24 
8.7 Reporting Procedures ............................................................................................................ 24 
8.8 Follow-up for Adverse Events ............................................................................................... 24 
8.9 Safety Monitoring .................................................................................................................. 24 
9. INTERVENTION DISCONTINUATION ......................................................... 24 
10. STATISTICAL CONSIDERATIONS ............................................................. 25 
10.1 General Design ..................................................................................................................... 25 
10.2 Sample Size and Randomization ......................................................................................... 25 
10.3 Interim Analyses .................................................................................................................. 25 
10.4 Outcomes .............................................................................................................................. 26 
10.5 Data Analyses ....................................................................................................................... 26 
10.6 Sample Size Estimates ........................................................................................................ 28 
11. DATA COLLECTION AND QUALITY ASSURANCE ......................................28 
11.1 Data Collection Forms ......................................................................................................... 28 
11.2 Data Management ............................................................................................................... 28 
11.3 Quality Assurance ................................................................................................................ 28 
12. PARTICIPANT RIGHTS AND CONFIDENTIALITY ..................................... 29 
12.1 Institutional Review Board (IRB) Review ........................................................................... 29 
12.2 Informed Consent Forms ..................................................................................................... 29 
12.3 Cognitive Impairment, Capacity Assessment, and Study Informants and Surrogates ..... 29 
12.4 Participant Confidentiality .................................................................................................. 29 
12.5 Study Discontinuation ........................................................................................................ 30 
13. PUBLICATION OF RESEARCH FINDINGS ................................................ 30 
14. COMMITTEES........................................................................................... 30 
15. REFERENCES ............................................................................................ 31 

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STUDY TEAM ROSTER 
  
Ihab Hajjar, MD, MS (Principal Investigator) 
Section of Geriatrics and Gerontology 
Department of Medicine 
Emory University 
ihajjar@emory.com 
 
 
Allan Levey, MD, PhD (Co-investigator, Neurologist) 
Department of Neurology 
Emory University 
ALEVEY@emory.edu 
 
 
Arshed Ali Quyyumi, MD (Co-investigator, Cardiology) 
Division of Cardiology 
Department of Medicine 
Emory University 
aquyyum@emory.edu 
 
 
Kaundiya Gopinath, PhD (Co-investigator, MRI expert) 
Division of Magnetic Resonance Research 
Department of Radiology 
Emory University 
kaundinya.s.gopinath@emory.edu 
 
Felicia Goldstein, PhD (Co-investigator, Neuropsychologist) 
Department of Neurology 
Emory University 
fgoldst@emory.edu 
 
 
John Hanfelt, PhD (Co-investigator; Statistician) 
Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University,  
Atlanta, GA Atlanta, GA 30322-4201 
jhanfel@emory.edu 
 
 
Joel Kramer, PsyD (Consultant, Neuropsychologist) 
Memory and Aging Center 
University of California San Francisco 
Jkramer@memory.ucsf.edu 
 
 
 
 

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PARTICIPATING STUDY SITES 
  
Wesley Woods Health Center 
 
Emory University Hospital Clinical Research Network 
 

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PRÉCIS  
 
Study Title 
Candesartan vs Lisinopril for executive mild cognitive impairment 
 
Acronym 
CALIBREX 
 
Objectives  
Aim 1: Investigate the effect of candesartan compared to lisinopril on the progression of cognitive function 
evaluated by a battery of neuropsychological tests assessing executive function, memory, attention and 
cognitive speed in hypertensive older adults with executive mild cognitive impairment.  
 
Aim 2: Investigate the effect of candesartan compared to lisinopril on cerebral perfusion, cerebrovascular 
reserve (vasoreactivity to carbon dioxide) assessed by arterial spin labeling MRI and microvascular brain injury 
reflected by diffusion tensor imaging measures of connectivity.  
 
Aim 3: Identify underlying mechanisms explaining the effects of candesartan on neuroimaging (AIM 3A) and 
cognitive (AIM 3B) outcomes relative to lisinopril including effects on arterial stiffness, atherosclerosis (carotid 
intima- media thickness, CIMT), and vascular inflammatory and endothelial markers.  
 
Design and Outcomes   
Our overall aim is to conduct a 1-year double blind randomized control trial comparing candesartan to 
lisinopril in individuals with hypertension and executive mild cognitive impairment. Our measures include 
cognitive function, cerebral perfusion and reserve, markers of vascular brain damage, atherosclerosis, arterial 
stiffness, vascular inflammation and endothelial function. 
 
Interventions and Duration  
The intervention includes candesartan or lisinopril with add-on antihypertensive medications to achieve blood 
pressure control to below 140/90 mm Hg. The duration of the study is 1 year. 
 
  
Sample Size and Population  
Our target sample size is 140.  To achieve this sample size, 160 individuals will be enrolled to account for drop-
outs. Individuals will be recruited from the greater Atlanta area to achieve a final sample of 140 (70 in 
candesartan group, 70 in lisinopril group). Our target population is subjects: 60 years or older, blood pressure 
(BP) >140/90 mm Hg or receiving antihypertensive medications, with executive MCI.  

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1. STUDY OBJECTIVES 
 
Our overall aim is to conduct a 1-year double blind randomized control trial comparing candesartan to 
lisinopril in 140 individuals with hypertension and executive mild cognitive impairment. Our specific aims are: 
 
Aim 1: Investigate the effect of candesartan compared to lisinopril on the progression of cognitive function 
evaluated by a battery of neuropsychological tests assessing executive function, memory, attention and 
cognitive speed in hypertensive older adults with executive mild cognitive impairment.  
 
Hypothesis 1: Candesartan is associated with less decline in executive function compared to lisinopril. 
 
Aim 2: Investigate the effect of candesartan compared to lisinopril on cerebral perfusion, cerebrovascular 
reserve (vasoreactivity to carbon dioxide) assessed by arterial spin labeling MRI and microvascular brain injury 
reflected by diffusion tensor imaging measures of connectivity.  
 
Hypothesis 2: Candesartan is associated with less decline in cerebral perfusion, vasoreactivity to carbon 
dioxide, and evidence of microvascular brain injury (white matter integrity) compared to lisinopril. 
 
Aim 3: Identify underlying mechanisms explaining the effects of candesartan on neuroimaging (AIM 3A) and 
cognitive (AIM 3B) outcomes relative to lisinopril including effects on arterial stiffness, atherosclerosis (carotid 
intima- media thickness, CIMT), and vascular inflammatory and endothelial markers.  
 
Hypotheses 3:  Relative to lisinopril, treatment with candesartan is associated with lower CIMT, arterial 
stiffness, and inflammatory and endothelial function markers at 12 months, which in turn are associated with 
improved cerebral perfusion, vasoreactivity, and white matter integrity measures (Hypotheses 3A) as well as 
less decline in executive function (Hypotheses 3B) at 12 months. 
 
2. BACKGROUND AND RATIONALE  
 
2.1 Background  
 
1- Hypertension and executive function: It is estimated that nearly 30% of older adults and 50% of older 
hypertensives have executive dysfunction, which is generally undetected.1-3 Executive function refers to 
cognitive operations that control and coordinate planning and performing complex tasks.4 It can be viewed as 
the composite of subdomains including set shifting, working memory, fluency, and processing speed.4 It 
reflects the functioning of a broad network of neural structures, with particular involvement of the dorsolateral 
prefrontal cortex.5 This brain region and its white matter connections are highly susceptible to vascular injury.6 
Executive dysfunction without dementia belongs to a larger construct of cognitive disorders in the context of 
vascular brain injury.7-12 Multiple terms have been suggested for this pattern including non-amnesic mild 
cognitive impairment (MCI), executive MCI or mild vascular cognitive impairment (VCI).7,9,13-15 To date, few 
clinical trials have focused on this group.  Beyond lowering blood pressure and reducing the risk for stroke, the 
effectiveness of antihypertensives in reducing the progression of executive dysfunction remains unknown. The 
significance of studying the effect of antihypertensive therapy on executive function is based on these 
observations: only hypertensives with executive dysfunction, rather than memory decline, progressed to 
dementia;16 hypertensive individuals with executive dysfunction have similar mortality to those with 
dementia;17 and, as we have demonstrated in a previous report, hypertension with executive dysfunction has 
higher mortality than hypertension alone.18 
 
2- ACEI vs ARB in the brain: There is a brain renin angiotensin system (RAS) that potentially links 
hypertension to cognitive function.19-23 In the brain, Angiotensin II (Ang II) binds 2 main receptors, among 
others, AT1 and AT2 which have opposing effects. AT1 activation leads to vasoconstriction, endothelial 
dysfunction and smooth muscle hypertrophy. In animals, AT2 activation decreases infarct area after an 
ischemic injury by increasing cerebral perfusion in the penumbra,24 decreases superoxide production,24 
activates neuronal repair systems by promoting neuronal cell differentiation and neurite growth, 25 and 
decreases inflammation and axonal degeneration.26-29 AT2 receptors are distributed in the cerebrovascular wall 

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and in the thalamus, hypothalamus and brain stem among other locations and AT2 activation may positively 
affect cognition.22,30 ACEIs decrease Ang II production and hence decrease activation of both receptors whereas 
ARBs block AT1 but not AT2. ARBs also increase Ang II and possibly up-regulate AT2.31 This selective blockade 
of AT1 and possible hyperstimulation of AT2 may provide superior and brain-specific beneficial effects 
compared to ACEI.32-34 Based on this AT2-hypothesis, we are suggesting that ARBs have superior effects 
relative to ACEIs in executive and cerebrovascular function. In the largest observational study to date, use of 
ARBs was associated with lower risk of dementia and Alzheimer’s disease (AD) compared to ACEI and other 
antihypertensives.11 In our pilot study, candesartan was superior to lisinopril in preserving executive function.  
 
3- Cerebral perfusion in hypertension and executive MCI: Adequate cerebral perfusion is important for 
cognitive performance and hypertension is associated with declines in cerebral perfusion and cerebrovascular 
reserve.35-37 Our recent work has shown that hypertensives have significantly decreased perfusion and reserve 
assessed by ASL-MRI.38 Decline in perfusion is associated with executive dysfunction.37,39,40 In our pilot study, 
we found that decreased cerebrovascular reserve, assessed by measuring the change in cerebral blood flow in 
response to carbon dioxide (CO2),38 is associated with decreased executive function (see prelim data). Other 
studies suggest a decrease in CO2 vasoreactivity in patients with dementia.41,42 Recent work by our 
collaborator’s team suggests that executive MCI patients demonstrate hypoperfusion in the middle frontal 
cortex and precuneus.40 RAS is involved in cerebral perfusion regulation.43,44 We recently reported that genetic 
polymorphisms in RAS are associated with cerebrovascular reserve,45 and others found an association of RAS 
genetic polymorphisms with vascular brain injury.46,47 In animal studies, activation of AT2 improved cerebral 
perfusion and ARBs improved cerebral perfusion and ameliorated ischemic changes from atherosclerosis and 
hypoperfusion.32,34,48,49 Since ACEI and ARB have differential effect on AT1 and AT2, we hypothesize that ARBs 
will be superior to ACEI in their effects on cerebral perfusion and reserve. Our preliminary data suggest that 
ARB use may be associated with improved cerebral blood flow velocity compared to ACEI. 
 
4. White matter integrity and executive function: Hypertension and executive impairment are also associated 
with microvascular brain disease in similar overlapping regions and tracts (frontal and subcortical regions) 
notably presenting as white matter hyperintensities (WMH) on MRI or with loss of white matter integrity on  
diffusion tensor imaging (DTI) even in normally appearing white matter.50-57 DTI-based indices of white matter 
integrity are very sensitive early indicators of vascular damage in the aging brain.58 DTI also provides high 
sensitivity to detect white matter change over a period of 12 months.59 New preliminary work by our team 
suggests that hypertension is associated with decreased Fractional Anisotropy in the frontal lobe. More 
recently, Diffusion Tensor Tractography (DTT) has been used to visualize and quantify integrity in specific 
brain networks and tracts.60 Executive dysfunction is associated with loss of integrity in the left anterior 
cingulate tract61 and precuneus.62 The effect of antihypertensive therapy on white matter integrity has not been 
studied. Since AT2 activation is associated with axonal regeneration and improved neuronal repair,63,64 ARBs 
may have superior effects on white matter integrity measures.  
 
5. Mechanistic approach for the effect of ARBs on the brain: To further support our AT2 hypothesis in the 
brain, we will measure processes that are likely to be affected by AT2. AT2 activation is associated with 
decreases in vascular remodeling and inflammation and restores endothelial dysfunction by improving NO 
homeostasis.28,30 Increased vascular stiffness and atherosclerosis reflected by higher carotid intima-media 
thickness (CIMT) contributes to vascular brain injury and cognitive impairment.65-73 AT1 activation leads to 
greater atherosclerosis and vascular stiffness and ARBs, more so than ACEIs,74 lower CIMT and arterial 
stiffness.75-83 In the cerebral arteries, candesartan resulted in the normalization of mean media thickness, 
leading to decreased arterial stiffness.84 ARBs also lower inflammatory markers, more so than ACEI,85 and 
restore proper endothelial function possibly via AT2 hyperstimulation.34,86 Inflammation also impairs 
endothelial function and increases atherosclerosis.87,88 Recent evidence suggests that proper endothelial 
function requires the replacement of dysfunctional cells and that endothelial progenitor cells (EPC) function as 
a reservoir for newer endothelial cells.89 The number of EPC has been linked with arterial stiffness, 
atherosclerosis, vascular brain injury and dementia.90-92 ARBs may improve the proliferation and function of 
EPCs in hypertension via an antioxidant effect.93 Therefore the potential mechanisms by which ARBs may 
prove to be superior to ACEIs in the brain may be related to their effects on atherosclerosis, vascular stiffness, 
inflammation, and optimal endothelial function and turnover. This project will test these hypotheses.  
 
 

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2.2 Study Rationale 
 
 
Selective blockade of AT1 (ARB) vs dual blockade of AT1 and AT2 (ACEI) allows testing the AT2-
hypothesis.94,95 We suggest that the non-inhibition of AT2, AT2 up-regulation and increased Ang II that results 
from ARB treatment would explain this superior effect. AT1 and AT2 have opposing effects on endothelial 
function, inflammation, and vascular stiffness, which in turn are associated with perfusion, cerebrovascular 
reserve (CO2 vasoreactivity), white matter connectivity and executive function. We will be able to test these 
hypotheses by comparing the effect of ACEI and ARB on executive function (AIM1), cerebrovascular function 
and white matter connectivity (AIM2), and investigate underlying vascular, endothelial, and inflammatory 
mediators (AIM3).  
  
 
2.3 Prior Studies  
 
1- Safety and blood pressure trajectory of short-term withdrawal of antihypertensive medications in older 
adults: The short-term safety of, and blood pressure changes after 
withdrawing hypertension treatment in older adults in preparation 
for clinical trials have not been well established. Participants were 
enrolled in a clinical trial and antihypertensive medications were 
tapered over three weeks (week 1: reduction by 25-50%, week 2: 50-
75%, week 3: off). Blood pressure was measured at the initial visit and 
after stopping all antihypertensive therapy (personnel) and twice a 
day during the taper phase (provided monitor). Trend analyses and 
linear models were used to assess changes in blood pressure. All 
participants (n=53, mean age=71 years, total of 1158 readings) 
successfully tapered their medications with no symptoms. Only 2% of 
the readings exceeded 180/100 mm Hg but none were consecutive.  
Blood pressure gradually increased with an overall increase of 12/6 
mm Hg, 95% confidence interval (CI) [4/1,21/11]. The daily increase 
in blood pressure was 0.2 mm Hg (SE=0.1) in both the systolic and 
diastolic blood pressure. Increases in systolic and diastolic blood 
pressure were comparable for all antihypertensive classes (p>0.05 for all). Blood pressure changes are 
displayed in Figure 1. Short-term (<3-4 weeks) withdrawal of antihypertensive therapy in older adults with 
hypertension is safe and is associated with mild increases in blood pressure. 
  
3. STUDY DESIGN   
 
 
This is a double-blind randomized clinical trial in individuals with hypertension and executive MCI 
without dementia. Participants will be treated for 1-year with candesartan or lisinopril. Additional 
antihypertensives will be added to achieve blood pressure control to below 140/90 mm Hg in both groups. Our 
study will recruit 160 participants to achieve a sample size of 140 with 70 participants in each group. Our 
outcome measures include cognitive function, cerebral perfusion and reserve, markers of vascular brain 
damage, atherosclerosis, stiffness, vascular inflammation and endothelial function.  
 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
4.1. Inclusion Criteria 
 
 
(1) Age: 60 years or older;  
 
 
(2) Hypertension: SBP≥140 mm Hg or DBP≥ 90 mm or receiving antihypertensive medications. 
 
Currently treated hypertensive individuals are eligible if they are willing to taper their medications. We 
 
will use a step-wise protocol of lowering antihypertensive medications;  
 
 
 
(3) Executive MCI will be defined using these criteria: 
  
Figure 1: Trajectory of daily blood pressure over 
time in the study participants. Solid lines are the 
mean blood pressure at each day and dotted lines 
are the 95% confidence interval 

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(a) The Montreal Cognitive Assessment (MoCA) score less than  or equal to 26: MoCA is a 30-
point scale administered in 10 minutes, is validated in multiple languages and is highly 
sensitive to identify mild vascular-related cognitive dysfunction96  (sensitivity 90% and 
specificity 87%).97,98 
 
(b) Executive dysfunction40,101,102: A performance at the 10th percentile or below on at least one 
of four screening tests for executive function: Trail Making Test, Part B (TMT-B), modified 
Stroop interference,Digit Span and Digit Sequencing, and Letter fluency102  
 
(c) Minimal Functional limitation as reflected by the Functional Assessment Questionnaire 
(FAQ)≤7 . 
  
 
 
4.2 Exclusion Criteria 
 
(1) Intolerance to candesartan or lisinopril ;  
 
(2) SBP >200 or DBP >110 mm Hg;  
 
(3) Renal disease or hyperkalemia (SCr>1.99 mg/dl or K> 5.5 meq/dl);  
(4) Active medical or psychiatric problems (An active problem is one that requires medical attention 
and is deemed as a safety risk by the study physician, for example current cancer treatment, infections 
such as  pneumonia, current gastrointestinal or other internal bleeding, HIV treatment, hematological 
disease, Parkinson’s disease, multiple sclerosis) 
 
(5) Uncontrolled congestive heart failure [shortness of breath at rest or evidence of pulmonary edema 
 
on exam);  
 
(6) History of stroke in the past 3 years (self-reported clinical stroke within the past 3 years/ incidental 
 
infarcts on MRI scanning is allowed);  
(7) Inability to perform the study procedures (those with contraindications for MRI will be enrolled but 
will not undergo the MRI; those with history of asthma, COPD, or significant pulmonary disease will 
not undergo the CO2-reactivity protocol);  
 
(8) Women of childbearing potential  
(9) Current use of acetylcholine-esterase inhibitors or NMDA receptor antagonist (memantine) or a 
diagnosis of dementia self-report or care-giver report 
(10) In those who lack decision capacity, a study surrogate who can sign on their behalf will be 
required. Since we are enrolling only those with MCI, we anticipate that most participants will have 
decision capacity 
(11) Current use of Lithium, as most antihypertensive classes may lead to increased lithium toxic levels. 
 
4.3 Study Recruitment and Payment 
 
Potential participants will be identified through community activities, health fairs, advertisements and 
mail out announcements. To recruit minorities, we will perform blood pressure screening activities in targeted 
community barbershops and beauticians, where information about the study will be provided. We have 
previously used barbershops and beauticians for recruitment of African Americans into a hypertension study 
with significant success. Below we describe our recruitment venues: 
 
(i) The Emory Alzheimer's Disease Research Center (ADRC) Clinical Core registry of research participants will 
be utilized for recruitment.  The registry includes about 400 individuals who have consented to participate in 
annual detailed research assessments with neuropsychological testing, neurological examination, and other 
components of a national uniform data set for the NIH designated Alzheimer's disease centers.  This group of 
subject includes about healthy elderly individuals without cognitive symptoms or decline (controls, n=~100)), 
as well as subjects with mild symptoms and memory loss (mild cognitive impairment, n=~150), and 
Alzheimer's disease (n=~100).  All subjects are interested and highly motivated to participate in research 
studies and have consented to be contacted. 
 

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(ii) Community-based recruitment: This will include announcement and recruitment information in 
periodicals and local newspapers. Blood pressure education sessions in local communities eg churches or 
barbershops will also be conducted.  
 
(iii) Physician recruitment: Local physicians (primary care or specialty physicians) will be informed of the 
study and its requirements and provided information about referral to the study personnel. In addition, flyers 
for the study will be posted at outpatient areas in the following facilities: Emory University Hospital, Emory 
Clinic, Grady Memorial Hospital, and the VA medical Center if possible. 
 
(iv) Study Visit Compensation: 
- 
Screening visit with consent and cognitive testing only- $10 gift card. 
- 
Screening visit with consent, cognitive testing, physical exam, and blood sample- $25 gift card. 
- 
Baseline visit- $75 gift card, 3 and 6 month follow up visits- $25 gift card, 12 month follow up visit- $75 
gift card. 
- 
No compensation will be given during the blood pressure medication adjustment visits. 
 
- 
Transportation Reimbursement:A parking validation ticket ($6 value) will be given to those subjects 
who drive and park at the Lowergate parking deck for the ACTSI portion of the study. Patients who 
require taxi service to the study visits can be reimbursed up to $50 each way (Total of $100 per visit). 
This payment will also be given in the form of gift cards. 
 
5. STUDY INTERVENTIONS 
 
5.1 Interventions, Administration, and Duration 
 
 Participants will be randomized into either candesartan or lisinopril treatment groups. Treatment will 
be provided in a capsule format to be taken once a day orally. Both candesartan and lisinopril will be 
formulated into identical capsules. Investigators, study personnel and participants will be blinded for drug 
assignment. Participants will be treated for 1 year. 
 
5.2 Handling of Study Interventions 
 
 The drugs will be stored in the medication room in the Investigational Drug Service (IDS) Pharmacy. 
The location of the IDS pharmacy is The Emory Clinic Bldg. A, Suite 1200, 1365 Clifton Road, NE, Atlanta, 
Georgia 30322.  Access to the med room is limited to the IDS Pharmacists via a badge swipe. Accountability 
records are maintained for all investigational products (IP). Study medication bottles will be either delivered by 
courier to study site, get picked up by study personnel from the pharmacy, hand delivered to subjects, or 
mailed to subject’s home.  Subjects will receive 30, 45, or 90 day supply.  
 
5.3 Concomitant Interventions 
 
 The goal of the trial intervention is to achieve a blood pressure <140/90 mm Hg in at least 90% of the 
participants. To achieve blood pressure control, we will use a stepwise protocol as follows: candesartan 8 
mg→16 mg→32 mg or lisinopril 10 mg→20 mg→40 mg. Both groups will also receive, if needed to achieve 
blood pressure control, HCTZ 12.5 mg→25 mg, Amlodipine 2.5 mg →5 mg→10 mg and metoprolol  12.5 
mg25 mg (extended release)50 mg (extended release). Antihypertensive medications will be increased 
every 2 weeks until blood pressure control (less than 140/90 mm Hg) is achieved. Based on our prior study, we 
anticipate being able to achieve blood pressure control within 4-8 weeks in the majority of the participants. 
Only the candesartan and lisinopril treatments are blinded. The remaining treatments (HCTZ, Amlodipine, and 
Metoprolol) are open-label. In the instance where a participant cannot receive an add-on agent, e.g. if there is a 
history of allergy or intolerance to one of the add-on drugs (HCTZ, Amlodipine, and Metoprolol) or a 
contraindication due to drug-drug interaction (e.g. simvastatin dose >20 mg and amlodipine), then that add-
on agent will be skipped and the next add-on drug will be used.  
 
 
5.4 Allowed Interventions 

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Participants will continue to receive their usual care from their regular primary physicians. 
Hypertension management will be addressed by the study physician (the PI).  
 
5.5 Required Interventions 
 
In addition to the 2 study medications (candesartan and lisinopril), HCTZ, amlodipine, and metoprolol 
are allowed as described above to achieve blood pressure control to below 140/90 mm Hg. Medications will be 
adjusted up or down to maintain blood pressure control (<140/90 mm Hg) during the study period.  
 
5.6 Prohibited Interventions 
 
 Once participants are enrolled, addition of antihypertensive medications by non-study providers is not 
allowed. However, non-hypertensive medications are allowed as part of usual care. If a subject receives an 
antihypertensive medication from a non-study source after enrollment, the study physician will attempt to 
contact the prescribing provider, as long as the participant agrees, to explain the study protocol and request 
that all antihypertensive medications be prescribed through he study physician. If the participant or the 
provider does not agree to these recommendations, the participant will be withdrawn form the study for safety 
reasons. 
 
5.7 Adherence Assessment 
 
Participants will be asked to bring their study medication bottles to the study center at each visit. 
Medication compliance will be assessed using pill count during the titration and follow up periods. We will 
define a compliance rate for a time period, t, as the ratio of:  (the used number of pill prescribed for the number 
of days t- number of pills remaining or unused for the time t/ number of pills prescribed for time t) multiplied 
by 100.  
 
6. EXPERIMENTAL PROCEDURES AND MEASURES  
 
6.1 Questionnaires and lifestyle and anthropometric measures 
 
Study interviews will be conducted in English as necessary and include the following: 
 
(1) Demographic, social and medical history data, as well as a medication inventory will be collected. All 
participants are asked to bring all their prescribed medication bottles. The medication inventory will be done 
by inspecting the participant medication and recording the name, dose, frequency and indication if known.105  
 
(2) Instrumental activities of daily living (IADL) scale .106  
 
(3) We will specifically evaluate functional abilities related to the executive cognitive function using the 
Dysexecutive Functioning Questionnaire (DEX). 107,108 DEX is a 20-item questionnaire, which is completed by 
the participant and study partner and is designed to assess everyday signs of executive difficulties.  
 
(4) Weight and height (stadiometer to measure height with the subjects standing and balance beam scale to 
measure weight without shoes). 
 
(5) Short Physical Performance Battery [SPPB: ability to stand with the feet side-by-side, semi-tandem, and 
tandem, time to walk 8 feet (measured twice), and time to rise from a chair and return to the seated position 5 
times) which assesses balance, gait, strength of the lower extremities, and endurance in older persons];111  
 
(6) Physical activity will be assessed using the Physical Activity Scale for the Elderly (PASE), which measures 
occupational, household, and leisure activities during a one-week period and has high reliability in older 
adults.112,113 
 
6.2. Blood pressure measurement 

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(1) Office blood pressure will be measured according to the American Heart Association guidelines: sitting 
position, rested for 5 minutes, appropriate cuff size (covering 60% of upper arm length and 80% of arm 
circumference), correct cuff placement (1-2 inches above brachial pulse on bare arm), and use of the bell of the 
stethoscope.114 Blood pressure will be measured in both arms. The arm with the higher blood pressure will be 
used throughout the study. We will obtain 2 seated followed by standing blood pressure measurements at 1 and 
3 minutes during each visit.  
 
6.3 Neuropsychological assessment:  
 
(i) Executive function will be assessed using the NINDS-initiated EXecutive Abilities: Measures and 
Instruments for Neurobehavioral Evaluation and Research or “EXAMINER” tool box. This test battery reliably 
and validly assesses executive function in clinical trials [http://examiner.ucsf.edu/].115-117 The battery includes 
11 tasks that generate 15 primary variables. Within this set, the EXAMINER investigators identified tasks 
measuring four domains that fit well in a single factor model of executive function: working memory, 
inhibition, set shifting, and fluency. The EXAMINER battery has excellent psychometric properties with test-
retest reliability of over 0.9 and correlates by over 0.60 with an informant-based measure of day-to-day 
executive functioning, the Frontal Systems Behavior Scale. The parts of EXAMINER that we selected include:  
 
1) Flanker task (inhibition) which involves responding to a central stimulus while ignoring flanking 
stimuli that are either compatible or incompatible with the central stimulus.118  
2) Set-shifting, a measure of mental flexibility assessing the subject's ability to attend to the specific 
attributes of compound stimuli, and to shift that attention when required.119  
3) Spatial 1-Back test assesses spatial working memory and  
4) Dot Counting test assesses verbal working memory.120  
5) Verbal Fluency will be tested using a List Generation test which require the participant to generate 
words beginning with a specific letter, and category fluency in which the participant generates words 
from a specified category (e.g., animals, fruits).121   
 
Data will be scored using an open source web-based data management and scoring system available through 
the EXAMINER project Using item response theory, a single composite executive function score will be 
calculated from the available data points.117  
 
(ii) To assess additional cognitive domains/mood, we will use these tests included in the National Alzheimer’s 
Coordinating Center Uniform Data Set.122,123  
 
1) Hopkins Verbal Learning Test will be used to assess memory domains.103  
2) Digit Span Test (DST) is a brief task that assesses attention.124,125  
3) Boston Naming Test assesses language by measuring ability of naming a visual confrontation drawing 
(15 items).126,127  
4) Trail Making Test: will be used as an additional measure of executive function. 
5) Center for Epidemiologic Studies Depression Scale (CESD),128 and consists of 20 items, each scored 
from 0 to 3 points and higher scores indicate greater depressive symptoms.  
 
6.4 Brain MRI imaging protocols 
 
MRI protocols are performed in 50-60 minutes and will be conducted at The Center for Systems 
Imaging (CSI). Table 1 provides the details of the imaging protocol. 
 
 

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 6.5 Vascular measures 
 
(i) Carotid intima-media thickness and arterial stiffness: High-resolution B-mode ultrasonograms of the right 
common carotid artery will be obtained using a 7.5-MHz linear-array transducer attached to a digital 
ultrasound system. Participants are placed in a supine position with the head rotated to the left by using a 45-
degree head block. Longitudinal images of the common carotid will be obtained. Indices of arterial stiffness 
and wave reflections will be estimated in the supine position using the Sphygmocor device (Atcor Medical, 
Australia), which records sequential high‐quality pressure waveforms at peripheral pulse sites using a high‐
fidelity tonometer. Pulse‐wave velocity (PWV) measured between carotid and femoral arteries is a regional 
assessment of aortic stiffness and is the gold standard index of arterial stiffness. Digital pulse amplitude 
tonometry (PAT) will be used to measure pulse volume amplitude (PVA) in the tip of the index finger, with 
participants resting in the supine position in a quiet, temperature‐controlled environment and during reactive 
hyperemia, which will be elicited by the release of an upper arm blood pressure cuff inflated to suprasystolic 
pressure for 5 minutes. The Endo‐PAT (Itamar‐Medical, Israel) will be used to measure PAT. The reactive 
hyperemia index (RHI) will be calculated as the ratio of the post‐ to pre-occlusion pulse volume amplitude 
(PVA) of the tested arm, divided by the post‐ to preocclusion ratio of the control arm (the average PVA over a 1‐
minute interval starting 1‐minute after cuff deflation divided by the average PVA measured for 1 minute before 
cuff inflation [baseline]). 
 
(ii) Inflammation, endothelial function markers, and APOE: We selected inflammatory biomarkers based on 
the evidence that the marker may be associated with cognition and/or is affected by RAS/ARB. Various studies 
have suggested that these inflammatory markers are associated with cognitive function, increased in 
hypertension, and modulated by Ang II: C-reactive protein (CRP)85,172, cytokines (TNF-α, interleukin 
family),85,172 vascular adhesion molecules (ICAM, VCAM, E- and P-selectin)173-176, metalloprotease 9 (MMP9)85 
fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 activity (PAI-1).172,177-179  
Endothelial progenitor cells (EPC) will be measured according to methods previously described.91 Mononuclear 
cells will be first isolated by density gradient from 10 cc of blood. EPC will be identified by the expression of 
surface antigens CD34+KDR+ which provides the best balance between cell count and accuracy (ICC=0.81, 
CV<10%),180 and reported as the number of cells per cytometric event to avoid error inflation due to variation 
in total blood cells. 91,181 We will use EPC and adhesion molecules to further investigate the association between 
cerebrovascular reactivity and endothelial function. EPC measurement will be completed at ECCRI (Dr. 
Waller’s Lab) at Emory and inflammatory markers and urinary proteins (including isoprostanes) will be done 
at the University of Southern California or the Foundation for Health Improvement and Technology (FHIT). 
Blood/urine samples will be stored at ACTSI then mailed to USC or FHIT in batches. We will perform baseline, 
12 months assessments of the inflammatory biomarkers and baseline, 6 and 12 months assessments of the EPC 
Table 1: Neuroimaging sequences and scanner time 
 
  
Orient. 
Voxel Size [mm] 
Scan Time [min] 
 
Localizer 
  
  
29 sec 
 
T1 MPRAGE 
Sagittal 
1.0x1.0x1.0 
8 min 37sec 
 
3D T2 TSE SAG SPACE 
Sagittal 
1.0x1.0x1.0 
6 min 58 sec 
 
BOLD CVR 
Axial  
3x3x3 
6 min 9 sec 
1off-1on-1off-1on-2 
off  C02  
Remove Mask 
 
 
 
 
3D T2 FLAIR SPACE 
Sagittal 
1.0x1.0x1.0 
7 min 59 sec 
 
2dPCASL 
Axial 
3.4x3.4x5 (1mm gap) 
6min 11 sec 
 
 
 
DTI Axials 
Axial 
2x2x2 
4 min 52 sec 
30 directions 
rs-fMRI 
Axial 
3.0x3.0x3.0 
8 min 9 sec 
 
GRE Field Map 
Axial 
3.0x3.0x3.0 
1 min 20 secs 
 
 
 
Neck Coil scans for labeling efficiency 
 
3D TOF MRA Carotids 
Axial obliq 
0.6x0.6x1.5 
1 min 21 sec 
 
2D Phase Contrast 
Axial obliq 
0.7x0.7x5 
 27 sec 
 
Total Scan Time 
  
  
53 
 

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and urine chemistries. Blood samples will be drawn at baseline for APOE genotype as well. APOE will be 
performed USC or FHIT. 
 
6.6 Blood  chemistries and blood count,  
 
Blood chemistries including electrolytes (potassium, sodium, chloride and bicarbonate as well as 
calcium and blood urea nitrogen (BUN), and creatinine) will be measured at baseline and during the follow-up 
as part of the safety monitoring for hyperkalemia and renal insufficiency, as shown in Table 2. A complete 
blood count will also be collected at baseline and 6, and 12 months.  Blood will be drawn after application of a 
tourniquet, by use of a small gauge needle, from an ante-cubital vein, and by an appropriately trained 
professional from subjects. These are part of assessing safety of the study drug and will be performed at the 
local Emory Clinical Laboratory.  
 
7. STUDY SCHEDULE  
 
7.1 Schedule of Evaluations 
The flow of the participants from screening to exit is described diagrammatically in figure 4 and the list 
of study procedures performed at each visit is detailed in Table 2. 
 
Table 2: Study procedures at various stages of the study 
Phase: 
Screening/Enrollment 
Baseline 
Titration 
Follow-up 
Number of visits 
Phone 
1 
1 
3-5 
3 
Months 
0 
2-4w 
1 
2-3 
3 
6 
12 
Informed Consent 
 
X 
  
  
  
  
  
Study forms 
Screen1 
Screen2 
Baseline 
FU-tit 
FU3 
FU6 
FU12 
UBACC 
 
X 
 
 
 
 
 
Phone contact/frequency* 
X  
W 
 
 
M 
M 
M 
Screening Cognition and FAQ 
  
X  
 
 
 
 
 
Letter to PMD 
 
X  
 
 
 
 
X  
Antihypertensive taper 
 
X  
 
 
 
 
 
H&P 
 
X 
X 
 
 
 
 
Medication inventory 
 
X 
X 
X 
X 
X 
X 
Weight 
  
  
X 
X 
X 
X 
X 
Height 
 
 
X 
 
 
 
X 
Blood pressure  
  
X  
X 
X 
X 
X 
X 
BMP 
 
X 
 
X** 
X 
X 
X 
CBC 
 
 
X 
 
 
X 
X 
IADL, SPPB, DEX , CESD 
 
 
X 
 
 
 
X 
Neuropsychological measures 
   
 
X 
  
  
 X 
X 
Brain MRI 
 
 
X  
 
 
 
X 
Vascular imaging 
 
 
X 
 
 
 
X 
APOE 
 
 
X 
 
 
 
 
EPC & Urine Chemistries 
 
 
X 
 
 
X 
X 
Inflammatory markers 
 
 
X 
 
 
X 
X 
Screening for AE/SAE 
 
  
  
X 
X 
X 
X 
Time estimate, in minutes 
15 
40-60 
210-240 
20-30 
20-
30 
60-
90 
210-
240 
*: Frequency is at least once or twice per week (W) during tapering pre-visit antihypertensive medications and 
Monthly (M) during the FU phase. 
**: BMP during titration is either at 2 weeks (if only step one is needed) or 4 weeks if step 2 is needed 
 
 
 

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Study Visit Windows Table:  
Study Visit Windows TABLE 3 
Baseline 
Within 1 week of completed tapering; patient should 
not be off BP meds for longer than 1 week. 
Med adjustment/Titration 
+/- 3 days of 2 week visit after BL 
Med adjustment/Titration 
If blood pressure is not regulated at first titration 
visit, must return +/- 3 days of next 2 week visit- 
return every 2 weeks until BP is regulated. 
3 month F/U 
+/- 2 weeks of scheduled visit 
6 month F/U 
+/- 2 weeks of scheduled visit 
12 month F/U 
+/- 2 weeks of scheduled visit 
 
7.2 Description of Evaluations  
 
7.2.1 Screening: Initial eligibility will be determined via phone interview.. This screening process will determine 
the specific inclusion and exclusion criteria that can be evaluated by self-report, including age, hypertension or 
blood pressure diagnosis, and prior medical issues detailed in the inclusion/exclusion criteria. Data collected 
during this interview will be stored de-identified for future data analysis with no links to the patient or their 
PHI. A study ID number will be used to collect data and will not be linked to the participant. Those who are 
eligible via phone interview will be invited for a clinic screening visit along with their next-of-kin, if possible.  
The screening visit will include: explaining study details and obtaining informed consent, cognitive assessment, 
medical history, current medications, 2 seated blood pressure measurements, and baseline metabolic panel. 
Eligible participants currently receiving antihypertensive medications who agree to stop antihypertensive 
medications will be instructed on a taper protocol and asked to return for baseline evaluation and 
randomization.  
 
7.2.2 Consenting Procedure: A signed consent form will be obtained from each participant or the participant’s 
legally authorized representative. A single informed consent form will describe both the screening and study 
procedures. The consent form will describe the purpose of the study, the procedures to be followed, and the 
risks and benefits of participation. A copy will be given to each participant and this fact will be documented in 
the participant’s study record and the participant’s medical record as per Emory University policy. During the 
consenting process, an assessment for decisional capacity to participate in clinical research will be performed. 
A validated brief instrument for decisional capacity assessment will be administered:182 The University of 
California, San Diego Brief Assessment of Capacity to Consent (UBACC) instrument is a 10 item questionnaire 
that asks the participant about key areas of the informed consent. A score greater than 14.5 correlates with 
a core of greater than 16 on the MacArthur Competency Assessment Tool for Clinical Research (MacCAT-
CR).182 MacCAT-CR is the most validated instrument in assessing decisional capacity in clinical research183 and 
a score greater than 16 has been traditionally considered adequate in prior NIH studies.184 Participants who are 
deemed non-decisional but still qualify for the study will need to have a surrogate consistent with the intent of 
the Common Rule (45 CFR 46, Subpart A).The following are, in order, possible surrogates: 
  
(1) The person's agent designated by an advance health care directive. 
(2) The conservator or guardian of the person having the authority to make health 
care decisions for the person. 
(3) The spouse of the person. 
(4) The domestic partner of the person as defined in Section 297 of the Family Code 
(5) An adult son or daughter of the person. 
(6) A custodial parent of the person. 
(7) Any adult brother or sister of the person. 
(8) Any adult grandchild of the person. 

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(9) An available adult relative with the closest degree of kinship to the person. 
 
When there are two or more available persons who are in different orders of priority pursuant to subdivision 
(c), refusal to consent by a person who is a higher priority surrogate shall not be superseded by the consent of a 
person who is a lower priority surrogate. 
 
7.2.3 Enrollment, Baseline, and Randomization: During this phase, blood pressure measurements, detailed 
neuropsychological assessments, physical exam, brain MRI, and carotid ultrasound will be completed. Blood 
samples will also be collected for APOE, inflammatory and endothelial markers. Randomization and study 
intervention will occur after baseline data collection.  Participants will then be started on the study 
medications. For all study related testing, the test results will not be disclosed to you unless deemed necessary by the 
study Physician. 
.  
 
7.2.4 Follow-up Visits: Following randomization, participants will be seen every two weeks,  where 
antihypertensive study medications will be increased until they achieve blood pressure control (<140/90 
mmHg), according to the designated trial protocol for blood pressure control. Blood pressure, heart rate, 
weight, adverse events (AE) and serious adverse events (SAE), pill count (to assess compliance), and use of 
non-study medications data will be collected. Once hypertension control is achieved, participants will be seen 
at 3, 6 and 12 months visits. Repeat neuropsychological assessment, blood draws (EPC and inflammatory 
markers), and urine collection will be conducted at the 6 and 12 months visit. Repeat neuroimaging and 
vascular ultrasound will be repeated at 12 months. BMP will also be checked at 2 weeks after randomization if 
only step one is needed, 4 weeks post randomization if treatment beyond step 1 is needed, and at 3, 6 and 12 
months as shown in Table 2. Participants will also be contacted by phone as described in Table 2, Monthly 
during the follow-up phase. During these phone calls, participants will be asked about missing any doses in 
their medications and screened for any potential adverse events. 
 
 
8. SAFETY ASSESSMENTS  
 
All data derived from this study is for research purposes only. Subjects will be monitored at all times for 
adverse events.  
 
8.1 Potential Risks 
 
The proposed study will utilize widely used and approved procedures including: commonly used 
neuropsychological questionnaires and interview materials, blood pressure measurements, brain MRI, carotid 
ultrasound, and blood draws.  Neuropsychological assessment may be accompanied by anxiety, frustration and 
overall fatigue. The attachment and removal of a blood pressure cuff, cuffs for venous occlusion, and 
ultrasound probe on the neck may cause mild discomfort. Brain imaging requires the participant to stay still 
and lie down for 50-60 minutes, which may cause boredom and minimal reversible back pain. Because of the 
closed space and noise, undergoing an MRI may be associated with anxiety or panic reactions. Claustrophobic-
prone individuals will not be asked to undergo the MRI portion. We will ask participants to breathe via a mask 
air richer in CO2 than normal atmospheric air (5-8%) during the brain MRI procedure. The CO2 reactivity 
procedures were well tolerated by elderly subjects in our prior studies, and have been performed numerous 
times in our laboratory without complications.  The reported potential side effects may include a feeling of 
dizziness, faintness, or anxiety during CO2 inhalation. 
 
 
The discontinuation of blood pressure medications may be associated with a risk of marked blood 
pressure elevation and development of associated neurological or cardiac symptoms: headaches, dizziness, 
blurred vision, chest pain or ischemic neurological events. In our pilot study, none of the participants 
experienced these symptoms.  To minimize this risk, medications will be slowly tapered over a 2-4 week period 
while study personnel carefully monitor subjects.  
 
 
The proposed study will utilize drugs approved by the Food and Drug Administration for the treatment 
of hypertension. They are well tolerated by young and elderly individuals and have been used extensively in 

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clinical practice. Possible side effects include: dizziness, cough (lisinopril), weakness, fatigue, lower extremity 
edema and constipation (amlodipine), and hypotension.  Renal failure and hyperkalemia are also potential 
complications of candesartan and lisinopril. HCTZ may cause renal failure, volume depletion, and 
hypokalemia. Lisinopril may cause a dry cough and angioedema. Beta blockers may be associated with 
weakness and bradycardia.  Adverse events will be queried at each visit. Alternatives to antihypertensive 
medications include no therapy, which is not safe or ethical in patients with hypertension. Drug-drug 
interaction will be assessed by the study physician. If there is contraindication to use the candesartan or 
lisinopril and one of the other participant’s medications then he/she will not be able to enroll in the study. If 
the contraindication is between an add-on agent (amlodipine, metoprolol, or HCTZ) then the participant will 
be enrolled but we will avoid using that agent as an add-on as described in section 5.3.  Use of lithium is a 
contraindication for both lisinopril and candesartan and hence lithium users are excluded. The following 
combinations of medications are contraindicated for the add-on drugs: Simvastatin >20 mg with amlodipine, 
reserpine with metoprolol, and clonidine with metoprolol.   
 
8.2 Specification of Safety Parameters 
 
The study medications may lead to adverse drug reactions (rash, edema, and in severe cases 
anaphylaxis) and uncomfortable side effects.  If this occurs, the study medication will be discontinued and the 
subject's primary care provider notified. If the subject cannot tolerate the study medication, the study 
medication will be stopped and he/she will be referred to their primary care physician for ongoing 
hypertension treatment. The participant will however be continued in the study and asked to undergo the final 
visit evaluations. Subjects will be monitored carefully for symptoms, blood pressure control, and blood 
chemistry abnormalities during treatment, as described in the methods section above. A physician (PI) and 
trained personnel will be available at all times to respond to subjects’ concerns.  In the event of an emergency, 
resuscitation equipment is readily available in all the research areas where subjects are evaluated. 
Antihypertensive medications will also be adjusted up/down to maintain blood pressure below 140/90 mm Hg 
and above 100/45 mm Hg or at the discretion of the study physician for maintaining safety. For example, if 
blood pressure readings are high at their study visits but normal/low at home or the subject reports orthostatic 
dizziness the clinician will use his judgment to change the dosage of the study meds. 
 
 
The subject’s primary care physician will be informed of study plans. Frequent monitoring will include 
visits, blood pressure checks, laboratory testing and phone contact. Blood testing for kidney function and 
electrolytes (potassium) will be performed at baseline, 1, 3, 6 and 12 months. If needed, additional calls, visits, 
or laboratory testing will be conducted as decided by the PI and /or the primary care physician. If symptoms 
develop during any of the evaluations, procedures will be terminated immediately. The experimental 
procedures will be conducted in a well-supervised facility and subjects will be under constant observation by 
skilled professionals. Those who could not continue on the study medications will be asked to return for 
collection of outcome measure if they agree to return for the final assessment visit.   
 
(i)  CO2 Administration: CO2 will be given via mask connected to a tank at a concentration of 5-8% and will be 
mixed with air and/or oxygen and nitrogen. To minimize respiratory discomfort, CO2 breathing intervals will 
be kept as short as possible to achieve desired increase in ETCO2 and will never exceed 2 minutes in length 
(continuous 2-minutes or two 1-minute blocks interspaced with 1-minute off). Heart rate, blood pressure, 
oxygen levels, and ETCO2 will be continuously and non-invasively monitored in order to limit risk for 
insufficient oxygenation, hypertension, and significant distress. In addition, the MR gantry is equipped with a 
camera/Glass window allowing continuous monitoring of the subjects from the MR control room; subjects are 
given a pneumatic bulb that starts off an alarm in the control room in case of emergency. CO2 administration 
will be promptly terminated if any of the following conditions occur: any complaint of subject discomfort, 
appearance of new neurologic symptom, systolic blood pressure increase of >50-55 mmHg or mean arterial 
blood pressure increase of >35-40 mmHg over normo-capnic levels, or pulse acceleration over baseline of 30-
40 beats per minute. To further minimize risk of complications, subjects with active asthma or chronic 
obstructive pulmonary disease, will not be given CO2.  
 
(ii) Neuroimaging: Should subjects feel discomfort during the MRI procedure the experiment will be 
terminated upon their request. The operators of the MRI scanner will take steps such as using foam pads when 
necessary to minimize the risk of excessive heating or burns from contact with the MRI transmitting and 

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receiving coil or conductive materials. Subjects will be screened for magnetic material before each study, per 
the standard of care at the MRI suite. Patients with pacemakers, aneurysm clips, metallic prostheses or 
shrapnel fragments are at risk at an MR environment and will be excluded from the neuroimaging portion of 
the study. Women of childbearing age will not be included. Earplugs or close fitting silicon padded headphones 
will be provided to protect from damage to the inner ear due to the loud tone produced by the MRI scanner.  
Subjects will be observed and monitored at all times by the operators, and can be moved out of the machine at 
their request. Subjects will be able to communicate through an intercom with the physician/scientist or 
technician at all times. In addition the MR gantry is equipped with a camera allowing continuous monitoring of 
the subjects from the MR control room; subjects are given a pneumatic bulb that starts off an alarm in the 
control room in case of emergency. All people entering the exam room where the magnet is located will be 
screened for magnetic material before entering the room. This will apply to subjects, experimenters, and staff.  
 
(iii) Incident dementia: Although limited information is available, it is estimated that the yearly conversion rate 
is close to 7% in executive MCI.185 We will screen at each visit for any new diagnosis related to cognition 
(dementia, delirium, others), new medication started (cholinesterase inhibitors or memantine), or proxy/self-
report of new diagnosis of dementia. The physician (PI) will review the clinical history with the study 
neurologist (Dr. Levey) and a consensus diagnosis will be made. We will compare the number of people who 
develop incident clinical dementia in both groups as part of our safety analyses.  
 
8.3 Antihypertensive replacement protocol 
 
Those with hypertension who are receiving antihypertensive medications will have their current 
medications tapered gradually using an established protocol that has minimal risk. Their primary care provider 
will also be notified, if the participant agrees, before initiating any changes in the participant’s blood pressure 
medications.  If the subject agrees then a letter will be faxed or mailed to their primary care physician 
providing information about contacting the study personnel regarding any concerns or comments about the 
antihypertensive replacement. Participants will be provided with an automated blood pressure monitor and a 
blood pressure diary (Home Blood Pressure Monitoring Flow Sheet) to monitor their blood pressures at home.  
Contact by the study personnel will be weekly, or more if needed,  for review of blood pressures. Once the 
participant is off all antihypertensive medications, he or she will undergo the baseline evaluation. The following 
protocol will be used for the withdrawal: 
 
1- All participants will receive personalized written instructions on tapering and discontinuation of 
antihypertensive medications, description of symptoms associated with possible adverse events and 
familiarization with the study protocol (Home Blood Pressure Monitoring Flow Sheet). They will be instructed 
to share this information with their spouses or other members of their households. The timeline for medication 
tapering is summarized in the following table: 
 
  
Number of 
antihypertensive meds 
Week 1 
Week 2 
Week 3 
Week 4 
 
Day 0-7 
Day 8-14 
Day 15-21 
Day 22-28 
One antihypertensive med 
Half weekly dose 
No meds 
Baseline Visit 
 
 
2 antihypertensive meds 
Half weekly dose 
med 1 
Full weekly dose 
med 2 
No med 1 
Half weekly 
dose med 2 
No meds 
Baseline visit 
 
3 antihypertensive meds 
Half weekly dose 
med 1 
Full weekly dose 
med 2 and 3 
No med 1 
Half weekly 
dose med 2 
Full weekly 
dose med 3 
No med 1 and 2 
Half weekly 
dose med 3 
 
No Meds 
Baseline visit 
 

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2- Subjects and/or proxy will be provided with a portable automated blood pressure (BP) monitor and a diary 
to take home. They will be asked to measure BP 2x times a day (morning and before sleep) and record into a 
diary.  
 
3-Daily/weekly dose reduction are shown in the Table above. Baseline visit will performed after all 
antihypertensive medications have been stopped. 
 
4- A summary of symptoms will be provided to the subjects and/or their proxy. They will be asked to share this 
information with their spouses or other family members living in the same household or other close caregiver. 
They will be instructed to call the investigators immediately if any of these symptoms occur to arrange the 
transfer to the nearest emergency room. They will be provided with a pager number for the investigators. 
Weekly contact with the subject will be conducted by phone to obtain the blood pressure readings and review of 
any symptom that occurred.   
 
5- The subjects will be asked to repeat the blood pressure measurement within 60 minutes if the reading is 
above 180/110 mm HG and call the investigators ( by phone or pager) anytime that they have two consecutive 
readings exceeding 180 mm Hg systolic or 110 mm Hg diastolic or have any unexpected discomfort, dizziness, 
or headaches. The study physician will then recommend based on the prior blood pressure readings and the 
participant symptoms to either alter the way the blood pressure medication is being reduced, take extra dose of 
the blood pressure medication, or resume all usual doses of all blood pressure medications immediately (the 
doses before the study) and continue measuring blood pressure as instructed. A failed taper is defined as 
persistent (>2 consecutive readings on 2 consecutive days) elevation in blood pressure >180/110 mm Hg. In 
the event that the participant failed the taper, the participant is asked to go back on their usual 
antihypertensive medications and is withdrawn form the study. The study personnel will contact the subject 
daily to obtain the blood pressure readings. This will continue until the blood pressure is back to the level 
before the medication reduction was started and they will be referred to their primary care physician for 
chronic blood pressure management.  For their safety they will not be included in the study. 
 
8.4 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters  
 
At each encounter, standardized adverse event (AE) monitoring forms will be completed. At any point during 
the study period an adverse event is identified, it will be recorded in the participant research record along with 
the time/place of the event. The study physician will be immediately notified and the participant evaluated 
either by phone (if participant is not on site) or face-to-face (if participant is on site). Depending on the 
physician assessment, further evaluation maybe performed such as scheduling additional visits, further lab 
work, exam, or referral to the emergency department. Details about the safety parameters will be recorded and 
entered into a database. Comparisons between the 2 groups will be conducted to assess overall and between 
group differential safety. 
 
8.5 Adverse Events and Serious Adverse Events 
 
During the screening process, if the participant is identified to have a problem requiring medical 
attention such as severely elevated blood pressure, they are referred to their primary care physician or the 
emergency room. The primary care physician will be notified of screening results by mail upon the participant 
request. Adverse events will be reported to the Emory IRB, the data safety monitoring board (DSMB), the NIH 
funding agency, and the primary care provider of the participant. If the participant does not have a primary 
care provider, they will be referred to one. The timing of reporting depends on whether the adverse event is 
expected, is serious or not, and whether it suggests that other participants are at higher risk of harm. As shown 
in the flow diagram, any subject who develops a serious adverse event (SAE) requiring emergency medical care 
during the conduct of the study protocols will be referred for immediate medical care at the local hospital and 
intervention will be stopped. Subjects will be subsequently referred back to their primary care physician for 
ongoing hypertension care. SAEs will be reported to the above-named agencies within 24 hours of their 
discovery. Other adverse events (non-serious) will be reported within 2 weeks of their discovery. The flow of AE 
and SAE is shown in the next figure (Figure 2). Unexpected AE will be rated by the PI and the physician co-
investigators as definitely, probably, or possibly related to research participation. 

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21
 
YES 
YES 
NO
NO 
YES 
NO
YES 
           Figure 2: Serious Adverse Event/Adverse Event Process Flow
Is event 
expected 
re nature, 
severity or 
frequency? 
 
Is adverse event 
Complete AE  form 
definitely related, 
probably related or 
possibly related to 
participation in the
research? 
Adverse Event 
occurs at Study 
Site 
Submit with 
routine 
DSMB/Safety 
officer reports 
PI is notified as soon as
event is known. 
Principal Investigator (or designee) 
notifies NIA, DSMB Chair or Safety 
Officer within 24 hours of being
notified, and also notifies IRB
DSMB Chair, IRB, 
or NIA may ask for 
additional information 
Event is included in 
listing of serious adverse
events in DSMB report 
Is the serious
event 
unexpected, 
related or 
possibly
related? 
Does adverse event 
suggest that the 
research places 
participants or others 
at a greater risk of 
physical or 
psychological harm 
that was previously 
known or recognized? 
Report to IRB, 
DSMB, and NIA 
generally within 2 
weeks of event. 
Report to other 
Is it an 
Investigation
al Product? 
Report to FDA within 7 
Report other serious 
and unexpected 
events within 15 days 
to FDA. 
Must be reported
on Adverse 
Event form 
Is this
adverse 
event 
serious? 
NO
YES 
NO 
STOP
Marketed 
Drug? 
STOP 
STOP 

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8.6 Incidental findings 
 
Incidental blood chemistry abnormalities, such as elevated blood sugar, will be reported to the subject 
and primary care provider. Incidental findings on brain imaging such as brain masses, prior stroke, and 
hemangiomas, will be evaluated by the PI and Dr. Levey (the study neurologist) and relayed to the subject and 
her/his provider. Similarly, incidental carotid ultrasound findings such as carotid stenosis will be evaluated by 
the PI and Dr. Quyymi (the study cardiologist) and also relayed to the subject and his/her provider. In the 
unlikely event that an incidental finding requires immediate attention such as bleeding on MRI, urgent care 
will be provided in a facility of the participant's preference. 
 
8.7 Reporting Procedures 
 
Expected side effects described within the safety parameters will be reported to the IRB, DSMB and 
NIA as part of ongoing progress. SAEs will be reported to the DSMB, NIH and IRB within 24h as shown in 
figure 2. A detailed report will follow within 7 days, and then a final resolution report will be sent. Other causes 
or existing health issues will be investigated and ruled out as the inciting factor prior to the determination of an 
adverse reaction.  Unexpected AE will be reported to the above agencies within 2 weeks. 
 
8.8 Follow-up for Adverse Events 
 
With the permission from the participant, we will contact the participant’s primary care doctor and help 
him/her get medical follow-up. Adverse events that require follow-up such as increased potassium or increased 
creatinine will be monitored until resolved or are further followed by the primary care provider. If emergency 
care or hospitalization was necessary, the study physician will conduct a follow-up phone or face-to-face 
evaluation. If the event requires intervention discontinuation (see section 9 below), the participant will be 
transitioned to his usual antihypertensive medication and referred back to the primary care provider. They will 
be followed for 2 months post-withdrawal. They will also be invited to perform the final visit evaluation 
including all study procedures planned for that visit. 
 
8.9 Safety Monitoring 
 
Safety procedures will be implemented in accordance with NIH safety policies for clinical trials. The 
safety monitoring will be conducted by the PI and a Data and Safety Monitoring Board (DSMB). The DSMB is 
comprised of 4 members (see section 14) in addition to a statistician. Once an SAE has been identified, it will be 
reported to the Emory-IRB. The grant program officer at NIA will also be notified. The DSMB will be asked to 
review the event. Once a year, the DSMB will meet to review progress of the trial (recruitment and follow-up, 
protocol violations), assess the safety of the protocol, and address any issue that limits the study success.   A 
report template will be drafted prior to initiation of recruitment.  The report will include tabulation by 
treatment group of all AE and SAEs to be reviewed by the DSMB. If concerns arise about safety issues, the 
DSMB may request additional data and propose specific analyses.  A report summarizing the discussions and 
recommendations for continuation of the trial will be generated from the DSMB meeting and provided to the 
IRB and NIH funding institute. 
 
9. INTERVENTION DISCONTINUATION  
 
A subject may choose to withdraw from the study for any reason. The investigators may also request that the 
subject withdraw from the study, for safety or other reasons. Withdrawn participants will continue to be 
monitored by the study personnel for 2 months after the event if possible and invited to complete the final visit 
evaluation. The criteria for discontinuing a subject’s participation include: 
 
 
(1) the subject’s request,  

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(2) serious adverse events that requires un-blinding,  
(3) new stroke, transient ischemic attack, or myocardial infarction that limits ability to complete the 
study  
 
(4) Symptomatic dysrhythmia  
 
(4) anaphylaxis or allergic reaction to study medications, 
(5) disturbing and persistent cough ( transient mild cough is not a discontinuation criterion unless 
participant requested it),    
 
(6) inability to participate due to relocation or other personal reasons, 
(7) renal failure (increase in serum Creatinine above 2.5 mg/dl) or hyperkalemia (greater than 5.8 meq) 
 
10. STATISTICAL CONSIDERATIONS  
 
10.1 General Design 
 
The study is a 2-arm double-blinded RCT. The statistical analysis will follow the intention-to-treat 
approach. The analyses will test our hypotheses that subjects on Candesartan will show: (1) less cognitive 
decline in the executive domain, measured by the EXAMINER score, (2) greater cerebral perfusion and lower 
cerebral vasoreactivity, and (3) greater measures of brain connectivity, compared to subjects on lisinopril at 12 
months. Our second set of hypotheses are that relative to lisinopril, treatment with candesartan is associated 
with (1) lower CIMT, and arterial stiffness, and (2) lower inflammatory and higher endothelial function 
markers at 12 months.  We further hypothesize that improvements in these secondary measures are associated 
with improved cerebral perfusion, vasoreactivity, and white matter integrity measures as well as less decline in 
executive function at 12 months. 
 
10.2 Randomization 
 
The study un-blinded biostatistician will provide oversight of randomization fidelity and blinding. To 
ensure equal distribution between the 2 groups on important confounders, we will use block randomization 
with stratification on: 
 
(1) race, (white, non-white). 
(2) number of antihypertensive medications (2 or less vs >2).  
 
Randomization will occur in a 1:1 allocation.  Four separate randomization lists will be prepared 
(race=white, medications=2 or less; race=white, medications>2; race-non-white, medications=2 or less; 
race=non-white, medications>2).  Randomization will use a computerized random number generator (SAS, 
V9.3); the blocking number will not be revealed to investigators or research staff.  Each randomization list will 
include the treatment group allocation, a unique allocation sequence number, and a blank field (to complete 
with subject study ID as randomization occurs).  Randomization lists will be provided to the IDS Pharmacy. 
Only the pharmacy and the un-blinded statistician will have access to the randomization lists.  As the 
pharmacist is notified that an individual subject is eligible for randomization to a given stratum, the 
pharmacist will select the appropriate randomization list, complete the subject ID, and prepare the appropriate 
blinded study product.  The pharmacist will enter the subject ID, date of product randomization, and the 
unique allocation sequence number on a web-based data form.  The statistician will monitor appropriateness of 
randomization (eligibility criteria met, correct stratum used, next allocation sequence used) in real time; 
incorrect randomizations will be immediately recorded as protocol deviations and reported to the principal 
investigator (in a blinded fashion). 
 
10.3 Interim analyses  
 
In addition to the planned regular reporting to the DSMB of trial conduct and safety (see Data and 
Safety Monitoring Plan), formal interim analyses will be conducted for efficacy and futility on the primary trial 
outcome (EXAMINER score).  To avoid un-blinding investigators, the analysis will be conducted by an 
independent data analyst/statistician; this un-blinded statistician will present the interim outcome analysis to 
the DSMB in a closed-session (not involving trial investigators).  We will conduct the interim outcome analyses 
when 25% and 50% of the sample has completed their 12-month assessments. We will use an alpha spending 

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24
function approach with O’Brien-Fleming sequential boundaries to preserve the overall two-sided alpha error 
rate of 0.05.  O’Brien-Fleming alpha levels will be 0.0051 and 0.0415 (2 analyses).   If the boundary is crossed 
at the first interim analysis, the DSMB will convene to decide on termination or continuation of the trial based 
on efficacy.   
 
10.4 Outcomes 
Table 3 provides a list of main outcomes. Other Analyses’ variables: Logical memory, digit span, DSST, 
WMH volume, regional brain measures 
 
10.5 Data Analysis 
 
 The 2 groups will be compared on baseline demographics, education level, physical function (SPPB), 
IADL, DEX, mood (CESD), cognitive and vascular/inflammatory measures and APO-E genotype. Also, baseline 
WMH, perfusion, VR, lacunar infarcts, and hippocampal volumes will be compared between the 2 groups using 
independent t-tests, nonparametric rank-based tests, or chi-square tests as appropriate. We will compare 
number of AE, SAE and incident dementia in the 2 groups as part of our safety analysis using Fisher’s exact 
test; adverse event categories will utilize MedDRA (Medical Dictionary for Regulatory Activities) coding.  To 
assess possible bias due to selective dropout, baseline comparisons between participants who complete vs. do 
not complete 12-month outcome assessments will be performed. To assess if equivalent blood pressure was 
achieved in both groups we will compare mean SBP and DBP in both groups during the follow-up visits. In 
addition, % controlled (defined as SBP<140 mm Hg/90 mm Hg) will be calculated for each visit post-titration. 
We will compare the % control in both groups using chi-square. 
 
Outcome Analysis  
 
 (a) Candesartan and cognitive/neuroimaging outcomes: General linear models will be used to compare the 
candesartan and lisinopril groups. 186,187 Our main explanatory variable is the indicator for treatment group.  
Dependent variables will be the 12-month cognitive and neuroimaging measurements.  For the cognitive 
analyses, our primary outcome is the executive function score derived using item response theory as outlined 
above in the EXAMINER methodology to account for education, age, and race influences on measures of 
executive abilities (developed by our collaborator, Dr. Kramer’s team).188,189 For the cognitive outcome Mixed 
models with repeated measures (3 measurements) will be used. This procedure allows us to model the 
covariance structure to account for the potential variability across subjects in times of follow-up visits.186,187 Our 
main explanatory variable is the indicator for treatment group. The test of treatment effects on trial outcomes 
will be an interaction of treatment by visit (baseline,12 months follow-up). The main covariate adjustments will 
include history of prior stroke and prior exposure to ACEI/ARB. Additional covariate adjustments will be 
selected based on baseline statistically significant differences between the 2 randomized groups. The 
neuroimaging outcomes include measures of global perfusion, reactivity, FA, MD, and tractography metrics 
described above. Table 3 provides a list of main variables. The multivariate models of the neuroimaging 
analysis will include the baseline values of the 12-month outcome variable, randomization stratification 
variables and other covariates that are significantly differ (at p<0.05) between the 2 groups at baseline. We will 
assess if the effects of randomized treatment are independent of blood pressure by comparing models with and 
without blood pressure change from baseline to 12 months.  Summary statistics will include the model-
adjusted mean and 95% confidence interval for each treatment group, and the mean (95% confidence interval) 
group difference on each 12-month outcome, as well as a p-value for group differences.  All tests of significance 
on treatment group comparisons will use a two-sided alpha of 0.05. 
Table 3: Independent, primary and secondary outcomes and other variables to be used in the analyses 
Independent: 
Randomization Group (Candesartan vs Lisinopril) 
Primary outcome: 
Executive function (EXAMINER score) 
Secondary Imaging outcomes: 
Perfusion, CO2 VR, VMR, FA, MD, DTT t-scores, rs-fMRI 
Mediators: 
CIMT, stiffness, inflammatory markers, EPC 
Tertiary outcomes: 
memory, digit span, DSST, WMH volume, regional brain measures 
Stratification variable: 
Race, number of antihypertensive medications 
Covariates: 
Prior stroke and prior use of ACEI/ARB 
Safety: 
AE, SAE, incident dementia 

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(b) Role of vascular/inflammatory measures: Mediation analysis with bootstrapping190 will be used to identify 
the potential role of the vascular, endothelial and inflammatory markers on both our cognitive outcomes and 
neuroimaging outcomes. This method is particularly useful in clinical trials since it has superior statistical 
power for relatively small sample sizes.191,192 It also does not require a large effect size of the intervention on the 
outcome.191 The independent variable is treatment assignment. The dependent measures are executive function 
(EXAMINER score) and neuroimaging variables [perfusion, VR, VMR, FA, MD]. The potential mediators are 
[CIMT, stiffness (DIS, COMP), endothelial and measures (EPC, CRP, cytokines, VCAM, ICAM, MMP and 
PAI1)]. For each mediator, an estimation of the mediation effect will be calculated using the Freedman-
Schatzkin difference in the regression coefficients (β1-β2) for the treatment effect obtained from the 2 
regression 
models 
with 
and 
without 
the 
mediator: 
(outcome= 
α+β1xtreatment 
and outcome= 
α+β2xtreatment+γmediator).193 Bootstrapping method (5000 random samples) will be used to obtain the 
empiric distribution of the mediation effect and a mean, standard error and a confidence interval will be 
calculated.194 The null hypothesis for mediation is that the difference-in-coefficients (β1-β2) is zero.  
 
10.6 Sample Size Estimates 
 
Using ANOVA with repeated correlated measures improves power in clinical trials.195 The 1 year 
correlation with baseline repeated measures ranged from 0.3 to 0.5 in our pilot data.   The effect size for 
candesartan relative to lisinopril was 0.48 [mean difference 12 (pooled SD 25 sec)] for TMT-B, 0.41 [mean 
5.5(13)] for cerebral blood flow and 0.24 [mean 0.30(1.2)] for vasoreactivity to CO2 in our pilot study. Using a 
2-sided α=0.05, we estimate that a sample size of 140 will give us 80% power to detect at least 0.24 effect size. 
To account for dropout rate of 10-15% and a 55% prevalence of eligible subjects, we estimate that we need to 
screen 332 and enroll 160 to achieve a 140 final sample size.  
 
11. DATA COLLECTION AND QUALITY ASSURANCE 
 
11.1 Data Collection Forms 
 
Data collected during interviews and exams will be documented on trial-specific data forms. 
Neuroimaging data will be saved in digital formats on a HIPAA-compliant server. 
 
11.2 Data Management 
 
Once a subject is enrolled into the study, he/she will be assigned a unique identifier number and be 
referred to by initials and the study number only.  Only research team members will have access to the files.   
Data will be entered on a web-based secure trial data system; the data system will include must enter fields, 
range checks, and simple logic checks.   The trial database will include for all variables an electronic data audit 
of data edits (who, when, and why).  A data query report (including missing, out of range, and logic checks) will 
be generated by the trial statistician weekly; timeliness and completeness of responses to data queries will be 
monitored.  Trial databases will be stored on a secure server. A copy of the master participant list will be kept 
by the PI in a locked office. The investigators will keep subjects’ medical records private as far as the law allows. 
The IRB and officials of the sponsor/funding agency will have access to these records as needed within legal 
guidelines.  If study results are published in journals or presented at meetings, we will not use the subjects’ 
name.  All investigators and research team members have successfully completed the online CITI program for 
working with Human Subjects in Research. 
 
11.3 Quality Assurance  
 
11.3.1 Training: Research personnel will be trained by the PI and the ADRC investigators and staff. The process 
of training on data forms completion, neuropsychological assessment and vital sign evaluation will be 
documented in a training log for each study personnel.  
 
11.3.2 Quality Control: To assess quality of data collected the PI along with another investigator will randomly 
and on intervals review data obtained. In addition, quarterly assessment of personnel competencies in 
obtaining data (eg Blood pressure checks, neuropsychological assessments etc) will be performed.  

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26
 
11.3.3 Protocol Deviations: Every attempt will be exercised to maintain compliance with the approved study 
protocol. In the unanticipated event when a deviation is noted, the Emory IRB will be notified. The PI will 
conduct an investigation about the setting, reasons and potential remedies that need to be instituted to rectify 
the deviation and prevent future similar instances. The DSMB will also be notified. 
 
11.3.4 Monitoring: Monitoring will be provided by the DSMB.  
   
12. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
 
12.1 Institutional Review Board (IRB) Review: This protocol and the informed consent document and 
any subsequent modifications will be reviewed by the IRB. 
 
12.2 Informed Consent Forms 
 
Subjects will be recruited via various methods including media announcements, screenings, housing 
facilities visits, and physician offices.  By nurturing close relationships with community leaders and health care 
agencies, and providing free educational programs and health screenings, we expect to be able to recruit the 
population as described above. All potential subjects will provide informed consent, for screening and inclusion 
in the study. Any subject who expresses a desire to discontinue participation in the study after providing 
consent will be removed from the study.  
 
12.3 Cognitive impairment, Capacity Assessment, and Study informants and surrogates 
 
Because of the nature of this research, we may encounter situations where the potential participant, due 
to his or her cognitive impairment, may not be able to understand the procedures of the study and hence not 
capable of providing informed consent. Because we are including only executive MCI, we anticipate that the 
frequency of such a situation is low. During the initial phase, an informal capacity assessment will be 
administered by the study physician (PI), including the UBACC as described in section 7.2.2. The PI will 
determine whether the potential participant is able to: “(1) understand the nature of the research and of his or 
her participation; (2) appreciate the consequences of the participation, including personal consequences; (3) 
show the ability to consider alternatives, including the option not to participate; and (4) show the ability to 
make a reasoned choice.”196 If the potential participant lacks the capacity to consent, then assent will be sought 
from the participant and permission sought from a surrogate.196 The proxy may be patients’ legal guardian (if 
one exists), next of kin, or familial caregiver according to applicable GA law and consistent with the intent of 
US 45 C.F.R. 46 and 21 C.F.R. 50 & 56. That person will also need to consent to the study. If either party 
refuses, we do not enroll the subject. To ensure both the participant and the proxy understand the study 
protocol, we will ask subjects or legal next of kin to explain in their own words the nature of the study and the 
procedures involved. Finally, a study informant will also be interviewed. The study informant can be the proxy 
or a different individual. The criteria for study informant are ability to provide information about the 
participant, willing to provide information about the participant, and have contact with the participant for at 
least once a month (in person or telephone).  
 
 
If there is a clinically significant change in cognitive function that could reasonably change the subject’s 
current status as either capable or not capable, we will reassess the capacity to consent. We will also offer the 
participant the opportunity to appoint a proxy to make ongoing consent decisions regarding the research 
project.196 If capacity is determined to have been lost, we will follow the procedures described in previous 
paragraph to ensure re-consenting and appointing a proxy. 
 
12.4 Participant Confidentiality 
 
Only the investigators  will have access to information about a particular subject. The subject’s primary 
care physician will only be notified if the subject agrees. To maintain confidentiality, subject data will be 
referenced by number and stored in locked computer files and cabinets. Identifying information about a 
subject will not be used during the discussion, presentation, or publication of any research data. Only research 
team members will have access to the files.  Data recorded and stored on the computer will be backed up to a 

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27
disc and stored with the paper files.  A copy of the disc will be kept by the Principal Investigator in a locked file 
drawer.  A copy of the master list will be kept by the PI in a locked office. The investigators will keep subjects’ 
medical records private as far as the law allows. The IRB and officials of the sponsor/funding agency will have 
access to these records as needed within legal guidelines.  If study results are published in journals or 
presented at meetings, we will not use the subjects’ name.  All investigators and research team members have 
successfully completed the online CITI program for working with Human Subjects in Research as well as the 
HIPAA course 
 
12.5 Study Discontinuation 
 
The study may be discontinued at any time by the investigators, the Emory IRB, the NIA, the OHRP, 
the FDA, or other government agencies as part of their duties to ensure that research participants are 
protected.  A list of reasons for discontinuation of the intervention are provided in section 9. Participants who 
discontinue the intervention will continue in the study and undergo the scheduled visits. 
 
13. PUBLICATION OF RESEARCH FINDINGS  
 
Publication of the results of this trial will be governed by the policies and procedures of the NIA and Emory.   
 
14. COMMITTEES 
 
Data Safety Monitoring Board (DSMB): 
 
Peter Novak, MD, PhD,DSMB CHAIR 
Institution University of Massachusetts Medical School 
Department Neurology 
University of Massachusetts Medical School 
55 Lake Avenue North 
Worcester MA 01655 
(508) 856-2527 
Peter.Novak@umassmemorial.org 
 
Ali Ahmed, MD 
Division of Gerontology, Geriatrics and Palliative Care 
Division of Cardiovascular Disease (Secondary) 
Department of Medicine, School of Medicine 
University of Alabama at Birmingham 
1530 3rd Avenue South, CH-19, Suite 219 
Birmingham, Alabama 35294-2041 
(205) 934-9632 
aahmed@uab.edu 
 
Oscar L. Lopez , MD 
University of Pittsburgh 
Professor of Neurology 
(724) 935-1500  
LopezOL@upmc.edu 
 
Inmaculada "Chichi" Aban, PhD 
Associate Professor 
Department of Biostatistics 
School of Public Health 
The University of Alabama at Birmingham 
Office Phone: (205) 934-2732 
Fax: (205) 975-2541 
caban@uab.edu 

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