Conditions: Hypertension Mild Cognitive Impairment
Keywords: Cerebrovascular function
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 176
Healthy volunteers: no

Brief summary:
The aim of this study 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 in their effects on executive function, neuroimaging markers, and vascular indicators.

Detailed description:
* Hypertension is associated with cognitive impairment even in the absence of clinical dementia. To date, no specific treatment is available for this pattern of mild cognitive impairment related to hypertension.
* Objectives or purpose: The aims of this study are to investigate the effects of candesartan on executive function decline and on changes in cerebral perfusion, cerebrovascular reserve and microvascular brain injury. The study also intends to identify potential underlying mechanisms related to vascular structure and function, including atherosclerosis, vascular inflammation, vascular stiffness, and endothelial progenitor cells, by which candesartan may affect the cognitive and cerebrovascular outcomes.
* Study methodology:This is a double blind randomized clinical trial that will be conducted in 140 individuals (70 in the candesartan group, 70 in the lisinopril group). Our target population is subjects: 55 years or older with hypertension and Executive Mild Cognitive Impairment.
* Endpoints to be measured:Our measures include cognitive function, cerebral perfusion and reserve, markers of vascular brain damage, atherosclerosis, stiffness, vascular inflammation and endothelial function.
* Description of intervention, follow-up, and duration of study: Eligible participants will undergo randomization into 2 groups and will be seen frequently until their blood pressure is controlled (\<140/90 mmHg). Participants will be seen at 3, 6 and 12 months afterwards.

Arms:
arm 1: To achieve blood pressure control, we will use a stepwise protocol as follows: candesartan (blinded) 8mg→ 16mg→ 32mg. Both groups will also receive (unblinded) , if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg →10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved. arm 2: To achieve blood pressure control we will use a stepwise protocol as follows: lisinopril (blinded) 10mg→ 20mg→ 40mg. Both groups will also receive (unblinded), if needed to achieve blood pressure control, HCTZ 12.5mg→ 25mg, Amlodipine 2.5mg→ 5mg→ 10mg and metoprolol succinate extended release 12.5mg→ 25mg→ 50mg. Antihypertensive medications will be increased every 2 weeks until control is achieved.

Interventions: intervention 1: Candesartan intervention 2: Lisinopril
Intervention descriptions: intervention 1: blinded intervention 2: Blinded

Protocol document:
Prot_SAP_001.pdf: 
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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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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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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for n-back performance in humans. J Cogn Neurosci. Dec 2009;21(12):2263-2275. 
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Dalley JW, Cardinal RN, Robbins TW. Prefrontal executive and cognitive functions in rodents: neural 
and neurochemical substrates. Neurosci Biobehav Rev. Nov 2004;28(7):771-784. 
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Faw B. Pre-frontal executive committee for perception, working memory, attention, long-term memory, 
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Duncan J, Owen AM. Common regions of the human frontal lobe recruited by diverse cognitive 
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Bassett DS, Meyer-Lindenberg A, Achard S, Duke T, Bullmore E. Adaptive reconfiguration of fractal 
small-world human brain functional networks. Proc Natl Acad Sci U S A. Dec 19 2006;103(51):19518-
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Lee KK, Salamon N. [18F] fluorodeoxyglucose-positron-emission tomography and MR imaging 
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Yuan Y, Gu ZX, Wei WS. Fluorodeoxyglucose-positron-emission tomography, single-photon emission 
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Hodis HN, Mack WJ. Atherosclerosis imaging methods: assessing cardiovascular disease and evaluating 
the role of estrogen in the prevention of atherosclerosis. Am J Cardiol. Jun 20 2002;89(12A):19E-27E; 
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Selzer RH, Mack WJ, Lee PL, Kwong-Fu H, Hodis HN. Improved common carotid elasticity and 
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effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic 
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Markers of Vascular Inflammation. Journal of cardiovascular pharmacology. 2004;44(3):335-339. 
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conversion to dementia in patients with degenerative and vascular forms of MCI. Curr Alzheimer Res. 
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Research consent for cognitively impaired adults: recommendations for institutional review boards and 
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ICF_000.pdf: 
 
CAndesartan vs LIsinopril effects on the BRain and 
Endothelial function in eXecutive MCI (CALIBREX) 
 
Informed Consent Form approved on 10/12/2017 
 
NCT01984164 


Study No.: IRB00070087 
 
Emory University IRB 
IRB use only 
Document Approved On: 10/12/2017 
 
 
Page 1 of 17 
 
Version Date: 6/22/2017 
IRB Form 10012013 
 
  
Emory University 
Consent to be a Research Subject And HIPAA Authorization  
 
 
Title: CAndesartan vs LIsinopril effects on the BRain and Endothelial function in eXecutive 
MCI (CALIBREX) 
 
Principal Investigator: Ihab Hajjar, M.D. 
 
 
 
 
Department of Medicine and Neurology 
 
Section of Geriatrics 
Office: 404.712.7422 
Pager: (404) 686-5500 Pager ID number 71988 
 
Sponsor: National Institute of Health 
 
Investigator-Sponsor: 
 
Study-Supporter: 
 
Introduction 
You are being asked to be in a medical research study. This form is designed to tell you 
everything you need to think about before you decide to consent (agree) to be in the study or not 
to be in the study.  It is entirely your choice.  If you decide to take part, you can change 
your mind later on and withdraw from the research study. The decision to join or not join 
the research study will not cause you to lose any medical benefits.  If you decide not to take part 
in this study, your doctor will continue to treat you. 
 
Before making your decision: 
• Please carefully read this form or have it read to you 
• Please listen to the study doctor or study staff explain the study to you  
• Please ask questions about anything that is not clear 
 
You can take a copy of this consent form, to keep. Feel free to take your time thinking about 
whether you would like to participate. You may wish to discuss your decision with family or 
friends. Do not sign this consent form unless you have had a chance to ask questions and get 
answers that make sense to you.  By signing this form you will not give up any legal rights. 
 


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IRB Form 10012013 
 
A description of this clinical trial is available on http://www.ClinicalTrials.gov, as required by 
U.S. law. This Web site will not include information that can identify you. At most the Web site 
will include a summary of the results. You may search this Web site at any time. 
 
Study Overview 
 
WHY IS THIS STUDY BEING DONE? 
 
High blood pressure can affect a person’s thinking abilities.  The purpose of this study is to 
compare the effect of two high blood pressure drugs, candesartan and lisinopril, on thinking 
abilities and brain activities. Both drugs are approved by the U.S. Food and Drug 
Administration (FDA) for treatment of high blood pressure. However, in this study they are 
considered experimental because they are being used to compare how the drugs affect memory 
and thinking abilities. If you agree you will be randomized, that is selected by a 50% chance, to 
take either candesartan or lisinopril for your blood pressure.  
 
You have been invited to participate because you are 55 years or older and have high blood 
pressure. Participants must also have early/mild limitations in their thinking abilities. We will 
test your thinking ability at our first meeting to confirm that you are eligible to take part in the 
study.  
 
About 160 individuals will take part in this research study at Emory University. 
 
Procedures 
 
If you decide to take part in this study you will sign this informed consent form and your 
participation will last 1 year.  
 
Your participation in the study involves coming to the study center at Emory University for 
interviews, brain scans, an ultrasound, and blood tests. You will receive all blood pressure 
medications during your involvement in this study and may have a physical examination during 
the study. The duration of this study is 1 year. You will be asked to visit the study site at least 5 
times during that year. The following describes what happens at each visit: 
 
Screening visit: (40-60 minutes) 
 
During this visit, we will: 
• Explain the study details  
• Ask you questions about your medical problems and medications 
• Check your blood pressure 


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• Test your thinking abilities. Please note that a large proportion of potential participants 
will not be eligible based on the results of these tests.   
If you qualify and you agree to participate, we will enroll you in this study. You will be asked 
to identify an individual who is willing to act as a study partner and who is familiar with your 
daily activities, if needed. We will also draw a blood sample (half to 1 teaspoon).  
 
If you do not qualify then we will not proceed with your study participation and you will not 
undergo any of the procedures in the remainder of this document. 
 
If you are taking blood pressure medications, you will need to stop these medications before 
you start one of the two study medications used in this study (candesartan or lisinopril). We will 
take special steps to ensure your safety during the process of stopping your blood pressure 
medication:  
 
1. If you agree, we will inform your primary care doctor that you are interested in participating 
in a research study and that your blood pressure medications will be stopped gradually.    
 
2. We will give you an automatic blood pressure machine and a diary to take home with you. 
We will teach you how to use the blood pressure machine and ask you to measure and record 
your blood pressure twice a day (morning and before sleep).  
 
3- You will also be contacted by the study staff at least once or twice a week (more if needed) 
to review your blood pressure recordings and your progress on decreasing your medications. 
 
4. You will receive written instructions on how to lower your current blood pressure 
medications and eventually stop them. The instructions will give the dose of each medication 
that you will be taking each day until you completely stop all blood pressure treatments.  
 
5. If your reading of the upper number is higher than 180 or the lower number is 110or higher, 
we will ask you to repeat the blood pressure check within an hour. If the second reading is still 
above 180/110 or you have any unexpected discomfort, dizziness, or headaches we ask you to 
call us immediately at the number provided on the instruction sheet.  The study physician will 
instruct you on what to do next: which may include altering the way your blood pressure 
medication is being reduced, take an extra dose of your blood pressure medication, or resume 
your usual doses of all your blood pressure medications immediately (the doses you were on 
before you started the study). You will continue measuring your blood pressure as instructed. 
The study personnel will then contact you daily to obtain the blood pressure readings. This will 
continue until your blood pressure is back to the level before you started the medication 
reduction or you have seen/contacted your primary care physician. For your safety, you will not 
be enrolled in the study if you could not stop your blood pressure medication.  


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6. We will see you at the study site after you have stopped your current medications. We will 
provide you with a supply of the study drug (either candesartan or lisinopril) and ask you to 
start the study medication the same day, after you perform the baseline study procedures.  
 
If you are not taking any blood pressure medications before the study, then we will 
schedule the baseline visit without stopping any medication. 
 
Baseline Visit (3 and a half to 4 hours):  
 
You can complete this visit on one day or divide it into 2 parts. During this visit, we will 
measure your blood pressure and heart rate twice while you are seated and 1 and 3 minutes after 
standing. We will measure your weight and height. We will also perform tests to assess your 
thinking abilities, your mood, your balance and how fast you can walk. We may record your 
voice for 5-10 minutes to assess certain patterns in your speech. This will be done during the 
memory tests or during a different time at one or more of your visits.We will also ask you to 
complete a few questionnaires regarding your physical and daily activities. Some of these will 
be mailed to you so you can complete them before your visit. A blood sample (1-and-a-half to 
2-and-a-half Tablespoons) will also be drawn to measure the number of specialized cells in the 
blood that can line up your arteries, the degree of inflammation, and the APOE gene that is 
involved in making a protein called apolipoprotein E. A urine test will also be obtained to check 
for proteins in the urine. The blood and urine tests will be completed either at Emory University 
or an external laboratory. Your samples may be stored temporarily until shipped to the external 
laboratory at Emory University storage sites. 
 
You will have an MRI of your head that will provide us with detailed information about the 
health of your brain. The MRI does not use x-rays or radiation. We would like your permission 
to share your information (after removing your name) with other research investigators and to 
contact you in the future if we need additional information. These choices are optional. You can 
still take part in this study even if you say no to these options. You will initial at the end of this 
form with your choice. 
 
The MRI scans will be obtained at the Emory Center for System Imaging.  These scans will 
take about 50-60 minutes. Before you have the scan, you may be asked to change into a gown 
and remove all metal objects (like earrings or watches) from your body. Throughout the exam, 
there will be loud thumping noises coming from the wall of the scanner. Earplugs will be 
provided to help reduce the noise. You may feel a warming sensation in your body during the 
MRI. You must lie still on a padded table during the scan.  
 
We will be monitoring your blood pressure, heart rate, and comfort level during the scan 
procedure. We will also record the amount of carbon dioxide that you breathe out of your nose.  


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During the scanning procedure, we may place a mask on your face and ask you to breathe a 
mixture of air including small amounts (5-8%) of carbon dioxide for about 2 minutes (either as 
2-minute continuously or as 1- minute intervals).  Then, we may ask you to breathe faster than 
normal for 2 minutes.  The digital pictures of your brain will give us information about your 
brain and the blood circulating into the various brain areas. 
 
You will also have an assessment of the arteries in your neck, also called carotid artery. We will 
ask you not to eat for at least 2 hours before this test. We will use a sound wave machine or an 
ultrasound to see if you have hardening of the arteries. We will first apply gel on your neck and 
then use a small camera that touches your skin to take pictures of your carotid artery. There is 
no radiation during the ultrasound assessment. We will also measure the degree of hardening of 
the arteries in your finger and arm. To do so we will apply a small blood pressure cuff on your 
arm and inflate it for 5 minutes. We will then release the pressure from the cuff. We will 
measure the degree of change in the arteries before and after the cuff inflation. These tests will 
be completed at Emory University Hospital. Parking will be provided if needed.  
 
Once you have completed these tests, we will then randomly assign (like flipping a coin) you to 
receive candesartan or lisinopril. There is about 50% chance of being assigned to either group. 
We will give you a month supply of your assigned drug (candesartan or lisinopril), instruct you 
on how to take it, and ask you to come back in 2 weeks.  The procedures are similar for each of 
the assigned groups. The study will be double-blinded meaning that neither you nor the study 
doctor or personnel will know which study drug you are taking. For all study related testing, the 
test results will not be disclosed to you unless deemed necessary by the study Physician 
 
 
Medication adjustment visits: These visits will last about 20-30minutes. The first one occurs 2 
weeks after the baseline visit. We will measure your blood pressure twice in the seated position 
during each of these visits and at 1 and 3 minutes after standing. If your blood pressure is less 
than 140/90, then you will continue on the same dose, a blood sample will be drawn (half to 1 
teaspoon) to check your potassium level and kidney function, and you will be scheduled for a 
follow-up visit in 3 months. We check potassium and kidney function to monitor for any 
changes as pressure medications may affect both. 
 
If your blood pressure is 140/90 or greater, then we will increase the dose of your medication 
and request that you come back for another visit in 2 weeks.  If your blood pressure is still 
140/90 or greater, then we will increase the dose of your medication further. A blood sample 
will be drawn (half to 1 teaspoon) to check your potassium level and kidney function during this 
visit. Afterwards, we will see you every 2 weeks until your blood pressure is below 140/90. If 
additional medications are needed then hydrochlorothiazide, amlodipine or metoprolol will be 
added in progressive doses.  
 


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Follow-up visits: You will also be seen at 3, 6 and 12 months. We will measure your weight 
and blood pressure at each visit. We will also repeat your tests of the thinking abilities at 6 and 
12 months. Your brain scan, neck ultrasound, walking speed, balance, and ability to perform 
daily activities will be measured again at 12 months.  We will also obtain urine samples and 
draw blood samples at the 6 and 12 months visits: (1-and-a-half to 2-and-a-half Tablespoons). 
During this phase, we will also call you monthly to ask you if you have missed any doses of 
your blood pressure medications or if you have had any problem related to taking your blood 
pressure medication. 
 
Once you complete the study, we will inform you and your primary care doctor of what 
medication you were receiving (un-blinding). You will have the option to continue on the same 
regimen that you were receiving in the study or go back to your previous medication regimen. 
We recommend that you discuss your options with your primary care doctor. You will need to 
make arrangements with your primary care doctor to discuss these options. We will supply you 
with one extra month of the medication regimen so that you have time to make arrangements 
with your primary care doctor.   
 
Risks and Discomforts  
 
Risks from stopping blood pressure medications: During the medication switching phase 
there is a risk of severe elevation of blood pressure, dizziness, loss of balance or coordination, 
severe headache with no known cause, or difficulty speaking. These can be signs of a Stroke. 
Please Call 911 if you have sudden trouble walking, cannot speak, cannot move one arm, or you 
see drooping in your face.  We ask that you share this information with your spouse, other 
members of your household, or someone you are in frequent contact with.   
 
Risks from the study medications: The medications that will be given during the course of the 
study, lisinopril, candesartan, amlodipine, hydrochlorothiazide, and metoprolol are approved by 
the Federal Drug Administration (FDA) and are commonly used by doctors to treat high blood 
pressure.    If you have a side effect or have developed a new medical problem that prevents you 
from taking the study medication you will be asked to resume your previous blood pressure 
medications. You will also be referred back to your primary care doctor for further blood 
pressure treatment. You will continue in the study and will be asked to come back for your 
scheduled visits. 
 
 The possibility of side effects or an allergic reaction related to these medications is no different 
than if your doctor prescribed them.  You will be carefully monitored throughout the study for 
any side effects related to these medications. The potential side effects are listed below. Please 
tell the study doctor or personnel if any of these symptoms are severe or do not go away.  
 


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Lisinopril: Lisinopril may cause: cough, dizziness, headache, excessive tiredness, nausea, 
diarrhea, weakness, skin rash. The following symptoms are uncommon, but if you experience 
any of them, call your doctor and the study personnel immediately: swelling of the face, throat, 
tongue, lips, eyes, hands, feet, ankles, or lower legs, hoarseness, difficulty breathing or 
swallowing, yellowing of the skin or eyes, or fainting. 
 
Candesartan: Candesartan may cause headache, dizziness, back pain, sore throat. The 
following symptoms are uncommon, but if you experience any of them, call your doctor and the 
study personnel immediately: swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, 
or lower legs, hoarseness, difficulty breathing or swallowing, or fainting. 
 
You will be receiving the following additional medications if your blood pressure is not below 
140/90 after taking candesartan or lisinopril. Their potential side effects are listed below: 
 
Amlodipine: Amlodipine may cause swelling of the hands, feet, ankles, or lower legs, 
headache, upset stomach, stomach pain, dizziness or lightheadedness, drowsiness, excessive 
tiredness, flushing (feeling of warmth). The following symptoms are uncommon, but if you 
experience any of them, call your doctor and the study personnel immediately: more frequent or 
more severe chest pain, rapid, pounding, or irregular heartbeat, or fainting.  
 
If you are currently taking a cholesterol lowering drug called SIMVASTATIN (Also called 
ZOCOR) and your dose is greater than 20 mg, then you cannot take Amlodipine due to the risk 
of causing muscle damage when used with more than 20 mg of Simvastatin. You will be able to 
take hydrochlorothiazide or metoprolol if your blood pressure is above 140/90. 
 
Hydrochlorothiazide: Hydrochlorothiazide may cause frequent urination, which might go 
away after you take hydrochlorothiazide for a few weeks. Tell the study doctor if it does not. 
Other potential side effects include: muscle weakness, dizziness, cramps, stomach pain, nausea, 
vomiting, diarrhea, loss of appetite, headache, and hair loss. The following symptoms are 
uncommon, but if you experience any of them, call your doctor and the study personnel 
immediately: sore throat with fever, unusual bleeding or bruising, severe skin rash with peeling 
skin, or difficulty breathing or swallowing. Hydrochlorothiazide may also lower your potassium 
level. We will be monitoring potassium level during your participation in the study. If it 
becomes very low, we may ask you to take a potassium supplement. 
 
Metoprolol: Metoprolol may cause dizziness or lightheadedness, tiredness, depression, nausea, 
dry mouth, stomach pain, vomiting, gas or bloating, heartburn, constipation, rash or itching, 
cold hands and feet, or runny nose. The following symptoms are uncommon, but if you 
experience any of them, call your doctor and the study personnel immediately: shortness of 
breath, wheezing, swelling of the hands, feet, ankles, or lower legs, unusual weight gain, 
fainting, rapid, pounding, or irregular heartbeat, or slow heart rate. 


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Because each person reacts differently to medications, you may experience other side effects 
that are not listed above. Please tell the study doctors if you experience any discomfort or 
unusual symptoms after starting the medications provided by this study. 
 
We will also check if the study medications would interact with your other medications. The 
following list of medications cannot be used with one or more of the medications provided by 
this study. Please let us know if you are currently receiving these medications or if you get 
started on them while you are enrolled in this study: Simvastatin (also called Zocor) at doses 
greater than 20, reserpine (serpalan), clonidine (catapress) or lithium. 
 
 
Risks from study procedures:  
 
There may be minor discomfort from the needle stick when a blood sample is taken during 
screening and follow-up visits and a small chance of a bruise in the area of the needle stick.  In 
rare instances a person may experience dizziness and may faint during a needle stick. 
 
You may experience anxiety, frustration and overall fatigue from the thinking tests. You can 
choose to skip or stop answering any questions that make you uncomfortable. There is possible 
minor discomfort of the ultrasound device placed against your skin. The inflation of the blood 
pressure cuff on your arm may make you feel like your arm went to sleep. This goes away after 
we deflate the cuff  
  
Brain imaging requires you to stay still and lie down for 50-60 minutes which may cause slight 
back pain. You may feel claustrophobic (fear of enclosed spaces) or anxious since you will be 
enclosed in a closed space. If you experience claustrophobia while in the machine the scan will 
be stopped at your request. Some people may be uncomfortable due to the loud noise that 
occurs during the scan. You will be given earplugs to protect your ears. During the scan, a small 
percentage of people may experience muscle twitches, tingling sensations, or headaches, but 
these sensations are not harmful. If you experience such sensations, immediately report them to 
the operator and adjustments will be made to prevent such sensations. 
 
There is a chance that you may feel dizzy or lightheaded when breathing through the mask or 
breathing carbon dioxide.  If you feel dizzy or lightheaded, we will stop the flow of CO2 and the 
mask will be removed.  
 
Women of childbearing potential will not be included in the study. 
 


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When you take the study drug home, keep it out of the reach of children or anyone else who 
may not be able to read or understand the label.  Do not let anyone else take the study drug 
besides you. 
 
 
New Information 
It is possible that the researchers will learn something new during the study about the risks of 
being in it.  If this happens, they will tell you about it. Then you can decide if you want to 
continue to be in this study or not.  You may be asked to sign a new consent form that includes 
the new information if you decide to stay in the study. 
 
Benefits  
This study is not designed to benefit you directly.   However, the potential benefits may include 
improvement in your blood pressure to below the recommended target of 140/90. You may gain 
knowledge about your blood pressure, brain blood flow, and thinking abilities. Your participation 
will also help us understand how blood pressure can affect the brain and ways to prevent its effect. 
The study results may be used to help others in the future. 
Compensation  
Screening Visit Compensation: If you complete the first part of the screening visit (consent and 
thinking test) you will receive a $10 gift card. If you complete both parts of the screening visit 
(consent, thinking test, physical exam, and blood sample) you will receive a $25 gift card.  
 
Study visit compensation: At the Baseline visit you will receive a $75 gift card, at the 3 and 6 
month follow up visits you will receive a $25 gift card, and at the 12 month follow up visit you 
will receive a $75 gift card. No compensation will be given during the blood pressure 
medication adjustment visits. 
 
Transportation Reimbursement: If you need transportation to the study sites, we will reimburse 
you up to $50 each way depending on the miles traveled (Maximum of $100 per visit). This 
payment will also be given in the form of gift cards. A parking validation ticket ($6 value) will 
be given to you if you drive and park at the Lowergate parking deck for the ACTSI portion of 
the study. 
 
Because the payments for this study total to more than $300 for the year, you will be asked to 
fill out a tax form, including your Social Security or Taxpayer Identification Number, in order 
to be reimbursed. 
 
Other Treatment Outside this Study 


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If you decide not to enter this study, there is care available to you outside of this research.  You 
can continue with your current care for your blood pressure.  If you have high blood pressure 
and you are not receiving blood pressure medications, your primary doctor may use similar or 
other blood pressure medications to lower your blood pressure.  The study doctor will discuss 
these with you.  You do not have to be in this study to be treated for your high blood pressure 
 
Confidentiality 
Emory will keep any research records that it creates private to the extent that this is required to 
do so by law.  Whenever possible, a study number, rather than your name, will be used on study 
records.  Your name and other identifying information will not appear when we present or 
publish the study results. 
 
Study records can be opened by court order.  They also may be provided in response to a 
subpoena or a request for the production of documents.  
 
Certain offices and people other than the researchers may look at your medical charts and study 
records. Government agencies and Emory employees overseeing proper study conduct may 
look at your study records.  These include the Food and Drug Administration, the Office for 
Human Research Protections, Emory offices that are part of the Human Research Protection 
Program, and those that are involved in administration and billing. Study sponsors and people 
or companies they use to carry out the study may also look at your study records.   A study 
number rather than your name will be used on study records wherever possible. Your name and 
other facts that might point to you will not appear when we present this study or publish its 
results.  
Medical Record 
 
If you are or have been an Emory Healthcare patient, you have an Emory Healthcare medical 
record.  If you are not and have never been an Emory Healthcare patient, you do not have one.   
An Emory Healthcare medical record will be made for you if an Emory provider or facility 
gives you any services or procedures for this study.  Copies of the consent form/HIPAA 
authorization that you sign will be put in your Emory Healthcare medical record.   
 
Emory Healthcare may create study information about you that can help with your care.  For 
example, the results of study tests or procedures.  These study results will be put in your Emory 
Healthcare medical record. Anyone who has access to your medical records will be able to have 
access to all the study information placed there.  The confidentiality of the study information in 
your medical record will be protected by laws like the HIPAA privacy rule.  State and federal 
laws may not protect the research information from disclosure.  
 
 


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Emory does not control results from tests and procedures done at other places, so these results 
will not be placed in your Emory Healthcare medical record. They will likely not be available to 
Emory Healthcare to help take care of you.  Emory does not have control over any other 
medical records that you may have with other healthcare providers.  Emory will not send any 
test or procedure results from the study to these providers.  If you decide to be in this study, it is 
up to you to let your health providers know.  
 
The researchers will not be looking at the results of these tests and procedures to make 
decisions about your personal health or treatment.   
 
Authorization to Use and Disclose Protected Health Information 
The privacy of your health information is important to us.  We call your health information that 
identifies you, your “protected health information” or “PHI.”  To protect your PHI, we will 
follow federal and state privacy laws, including the Health Insurance Portability and 
Accountability Act and regulations (HIPAA).  We refer to all of these laws as the “Privacy 
Rules.”  Here we let you know how we will use and disclose your PHI for the study. 
 
PHI that will be Used/Disclosed:   
The PHI that we will use and/or disclose (share) for the research study includes 
• Medical information about you including your medical history and present/past 
medications. 
• Results of exams, procedures and tests you have before and during the study. 
• Laboratory test results. 
 
Purposes for which your PHI will be Used/Disclosed: 
We will use and disclose your PHI for the conduct and oversight of the research study.  We will 
use and share your PHI to provide you with study related treatment and for payment for such 
treatment.  We will also use and share your PHI to conduct normal business operations.  We 
may share your PHI with other people and places that help us conduct or carry out the study, 
such as laboratories, data management centers, data monitors, contract research organizations, 
Institutional Review Boards (IRBs) and other study sites. If you leave the study, we may use 
your PHI to determine your health, vital status or contact information. We will use and disclose 
your PHI for the administration and payment of any costs relating to subject injury from the 
study.  
 
Use and Disclosure of Your Information that is Required by Law:   
We will use and disclose your PHI when we are required to do so by law. This includes laws 
that require us to report child abuse or abuse of elder or disabled adults. We will also comply 
with legal requests or orders that require us to disclose your PHI. These include subpoenas or 
court orders.   


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Authorization to Use PHI is Required to Participate: 
By signing this form, you give us permission to use and share your PHI as described in this 
document. You do not have to sign this form to authorize the use and disclosure of your PHI.  If 
you do not authorize the use and disclosure of your PHI for the study, then you may not 
participate in the research study or receive research-related treatment.  You may still receive 
non-research related treatment.   
 
People that will Use and/or Disclose Your PHI: 
The following people and groups will use and disclose your PHI in connection with the research 
study: 
 
• The Principal Investigator and the research staff will use and disclose your PHI to 
conduct the study and give you study related treatment. 
• Emory may use and disclose your PHI to get payment for study related treatment and to 
run normal business operations.  
• The Principal Investigator and research staff will share your PHI with other people and 
groups to help conduct the study or to provide oversight for the study. 
•  The National Institute of Health is the Sponsor of the study.  The Sponsor may use and 
disclose your PHI to make sure the research is done correctly and to collect and analyze 
the results of the research.  The Sponsor may disclose your PHI to other people and 
groups like study monitors to help conduct the study or to provide oversight for the study.   
• The research team and the Sponsor may use and disclose your PHI, including disclosure 
to insurance carriers to administer payment for subject injury.  
  
• The following people and groups will use your PHI to make sure the research is done 
correctly and safely: 
o Emory offices that are part of the Human Research Participant Protection Program 
and those that involved in study administration and billing.  These include the 
Emory IRB, Western IRB, and other IRBs or privacy boards involved in this study; 
the Emory Research and Healthcare Compliance Offices; and the Emory Office for 
Clinical Research.  
o Government agencies that regulate the research including:  [Office for Human 
Research Protections; Food and Drug Administration; Veterans Administration]. 
o Public health agencies. 
o Research monitors and reviewers. 
o Accreditation agencies. 
 
Expiration of Your Authorization 
This authorization will not expire because it is a research study. 


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Revoking Your Authorization 
If you sign this form, at any time later you may revoke (take back) your permission to use your 
information.  If you want to do this, you must write to: Ihab Hajjar, MD. 
 
At that point, the researchers would not collect any more of your PHI.  But they may use or 
disclose the information you already gave them so they can follow the law, protect your safety, 
or make sure that the study was done properly and the data are correct.  If you revoke your 
authorization you will not be able to stay in the study.  
 
Other Items You Should Know 
Not all people and entities are covered by the Privacy Rules.  HIPAA only applies to health care 
providers, health care payers or health care clearinghouses.  If we disclose your information to 
people who are not covered by the Privacy Rules, including HIPAA, then your information 
won’t be protected by the Privacy Rules.  People who do not have to follow the Privacy rules 
can use or disclose your information with others without your permission if they are allowed to 
do so by the laws that cover them.   
 
To maintain the integrity of this research study, you generally will not have access to your PHI 
related to this research until the study is complete.  When the study ends, and at your request, 
you generally will have access to your PHI that we maintain in a designated record set.  A 
designated record set is data that includes medical information or billing records that your 
health care providers use to make decisions about you. If it is necessary for your health care, 
your health information will be provided to your doctor.  
 
We may remove identifying information from your PHI.  Once we do this, the remaining 
information will not be subject to the Privacy Rules.  Information without identifiers may be 
used or disclosed with other people or organizations and/or for other purposes besides this 
study.   
 
In Case of Injury 
 
If you get ill or injured from being in the study, Emory would help you to get medical treatment.   
Emory and the sponsor have not, however, set aside any money to pay you or to pay for this 
medical treatment. The only exception is if it is proved that your injury or illness is directly 
caused by the negligence of an Emory or sponsor employee.  “Negligence” is the failure to 
follow a standard duty of care.  
If you become ill or injured from being in this trial, your insurer will be billed for your 
treatment costs.  If you do not have insurance, or if your insurer does not pay, then you will 
have to pay these costs.   


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If you believe you have become ill or injured from this research, you should contact Dr. Ihab 
Hajjar at telephone number 404-686-5500 ID number (extension) 71988. You should also let 
any health care provider who treats you know that you are in a research study.  
Costs 
 
The study sponsor will pay for the tests that were described above as part of the study conduct. 
The study sponsor will also pay for certain items and services that you may receive if you take 
part in this study.   
 
You will have to pay for the items or services for which the study sponsor does not pay. The 
sponsor will not pay for your regular medical care. If you have insurance, Emory will submit 
claims to your insurance for items and services that the sponsor does not cover.  Emory will 
send in only those claims for items and services that it reasonably believes your insurance will 
pay and that the sponsor has not paid.  
 
The actual amount that you have to pay depends on whether or not you have health insurance 
and whether or not that insurance will pay for any research study costs. Generally, insurance 
companies will not pay for items and services that are required just for a research study. Some 
insurance companies will not pay for regular medical treatment or treatment for complications if 
you are in a study.  How much you will have to pay for any co-payments, deductibles or co-
insurance depends on your plan.  Emory and the sponsor will not pay for these costs.  
 
It is a good idea to contact your insurance provider and tell them you want to be in this research 
study.  Ask them what they will pay for and what they will not pay for.  You can also ask the 
study team for help in figuring out what you will have to pay.  
 
If you do not have insurance, Emory will review your case as part of its program for low-
income patient care.  The standard policies of that program will apply.  The program will figure 
out if you have to pay any costs for taking part in the study and what those costs will be. 
 
Withdrawal from the Study 
 
Your participation in this study is voluntary. Your decision whether or not to take part will not 
affect your current or future care at this institution. You are not giving up any legal claims or 
rights. If you do decide to take part in this study, you are free to change your mind and stop 
being in the study at any time. 
 
 For your safety, however, you should consider the study doctor’s advice about how to go off 
the study treatment.  If you leave the study before the final planned study visit, the researchers 
may ask you to have some of the final steps done.   


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The researchers also have the right to stop your participation in this study without your consent if: 
• They believe it is in your best interest; 
• You were to object to any future changes that may be made in the study plan; 
• If you fail to comply with the procedures of the study 
• Or for any other reason. 
 
Contact Information 
• Contact the study Doctor, Ihab Hajjar, at 404-7286959 or email ihajjar@emory.edu.  In case 
you need to reach him immediately you can page him at telephone number 404-6865500 
extension 71988:  
• if you have any questions about this study or your part in it,   
• if you feel you have had a research-related injury or a bad reaction to the study drug, or 
• if you have questions, concerns or complaints about the research 
 
• Contact the Emory Institutional Review Board at 404-712-0720 or 877-503-9797 or 
irb@emory.edu: 
• if you have questions about your rights as a research participant. 
• if you have questions, concerns or complaints about the research. 
• You may also let the IRB know about your experience as a research participant through our 
Research Participant Survey at http://www.surveymonkey.com/s/6ZDMW75. 
 
 


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Consent 
 
I have read (or someone has read to me) the information provided above.  I have been given a 
chance to ask questions.  All my questions were answered.  I have decided to sign this form in 
order to take part in this study. 
 
1) 
I agree to share my MRI and other data anonymously with other IRB-approved studies. 
 
 
 
 
 
 
Yes ______________ 
No ____________ 
 
 
2) 
I agree to be re-contacted in the future, if additional information or procedures are 
requested 
 
Yes ______________ No ____________ 
 
Please print your name and sign below if you agree to be screened and to participate in this 
study if you are eligible. By signing this consent form, you will not give up any of your legal 
rights. We will give you a copy of the signed consent to keep. 
 
 
 
Name of Subject  
 
 
 
 
 
  
Signature of Subject  
Date              Time 
 
 
 
 
 
Signature of Person Conducting Informed Consent Discussion 
Date              Time 
 
__________________________________________________________ 
Name of Person Conducting Informed Consent Discussion 
 
 
 
 
 
Signature of Legally Authorized Representative 
Date              Time 
with authority for research decisions 
 
 
 
Authority of Legally Authorized Representative or Relationship to Subject 
 
 


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STUDY PARTNER INFORMATION & CONSENT 
 
 
STUDY PARTNER INFORMATION AND CONSENT 
 
 
As the participant’s study partner, you have the important tasks of providing important 
assistance to the enrolled participant to complete the study accurately.   
 
These responsibilities include providing information about the participant’s physical and 
thinking abilities and informing the study personnel about any significant changes in these 
abilities. You also agree to come with the study participant for his or her exams and evaluations.  
If you cannot come to the study center, then you agree to be available by phone to discuss with 
the study personnel the participant’s physical and thinking abilities. 
 
If for some reason you become unable to carry out these responsibilities, please tell the study 
coordinator immediately.  You may be asked, if possible, to select a substitute who can take 
over your duties. 
 
AGREEMENT: 
I have read (or someone has read to me) all the preceding information which describes both the 
participant’s involvement in the study and my involvement as the participant’s study partner.  I 
have been given a chance to ask questions. All my questions have been answered. By signing 
this form, I am agreeing to take part in this study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
______ 
Name of Study Partner (print) 
Signature                                               Date 
 
 
 
 
I have personally explained the research to the research participant and answered all questions. I 
believe that he/she understands the information described in this informed consent and freely 
consents to participate.  
 
 
 
 
Name of Investigator/Person 
Obtaining Informed Consent (print) 
Signature 
Date