Intensive Versus Standard Blood Pressure Lowering to Prevent Functional Decline in Older People
Phase: NA
Conditions: Hypertension, Systolic, Cerebrovascular Disease
Sponsor: UConn Health

 
 
 
Intensive Versus Standard Blood Pressure Lowering to Prevent 
Functional Decline in Older People 
 
NCT01650402 
 
Protocol 
 
IRB Approval Version 4/16/2018 

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
1
PROTOCOL TITLE:
INFINITY: Intensive versus Standard Blood Pressure Lowering to 
Prevent Functional Decline in Older People
Principal Investigators:
William B. White, MD, Calhoun Cardiology Center
Leslie Wolfson, MD, Department of Neurology
University of Connecticut Health Center, Farmington
Supported by:
The National Institute on Aging
2R01AG022092-06A1
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
2
TABLE OF CONTENTS 
Page
PARTICIPATING STUDY SITES...............................................................................................9
PRÉCIS ..........................................................................................................................................9
1. Study objectives ...................................................................................................................11
1.1 Primary Objective .............................................................................................................11
1.2 Secondary Objectives......................................................................................................11
2. BACKGROUND AND RATIONALE....................................................................................12
2.1 Background on Condition, Disease, or Other Primary Study Focus........................12
2.2 Study Rationale ..................................................................................................................2
3. General STUDY DESIGN .......................................................................................................2
4. Study population.....................................................................................................................3
4.1 Inclusion Criteria.................................................................................................................3
4.2 Exclusion Criteria................................................................................................................1
4.3 Study Enrollment Procedures at University of Connecticut Health Center...............2
5. STUDY INTERVENTIONS ......................................................................................................3
5.1 Interventions, Administration, and Duration...................................................................3
5.2 Handling of Study Interventions.......................................................................................6
5.3 Concomitant Interventions ................................................................................................6
5.3.1
Allowed Interventions .............................................................................................6
5.3.2
Required Interventions  (discussed in Section 5.1)...........................................7
5.3.3
Prohibited Interventions .........................................................................................7
5.4 Adherence Assessment ....................................................................................................7
5.5 Schedule of Evaluations....................................................................................................8
5.6 Description of Evaluations ................................................................................................8
5.6.1
Screening Evaluation............................................................................................14
5.6.2
Enrollment, Baseline, and/or Randomization ...................................................16
5.6.3
Post-Randomization Follow-up Visits ................................................................18
5.6.4
Completion/Final Evaluation................................................................................22
6. SAFETY ASSESSMENTS ....................................................................................................23
6.1 Specification of Safety Parameters ...............................................................................23
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
3
6.2 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
...................................................................................................................................................24
6.3 Reporting Procedures......................................................................................................26
6.4 Follow-up for Adverse Events ........................................................................................27
6.5 Safety Monitoring..............................................................................................................28
7. INTERVENTION DISCONTINUATION...............................................................................28
8. STATISTICAL CONSIDERATIONS....................................................................................29
8.1 General Design Issues ....................................................................................................29
8.3  Sample Size and Randomization..................................................................................34
8.3.1 Treatment Assignment Procedures........................................................................35
8.3.2  Interim Analyses and Stopping Rules For Safety...............................................35
8.4 Outcomes ..........................................................................................................................36
9. DATA COLLECTION AND QUALITY ASSURANCE ......................................................36
9.1 Data Collection Forms.....................................................................................................36
9.2 Data Management............................................................................................................37
9.3 Quality Assurance ............................................................................................................37
9.3.1
Training.......................................................................................................................37
9.3.2
Quality Control Committee ......................................................................................37
9.3.3
Metrics ....................................................................................................................37
9.3.4
Protocol Deviations...............................................................................................37
9.3.5
Monitoring...............................................................................................................38
10. PARTICIPANT RIGHTS AND CONFIDENTIALITY .......................................................38
10.1 Institutional Review Board (IRB) Review....................................................................38
10.2 Informed Consent Forms (appendix II).......................................................................38
10.3 Participant Confidentiality .............................................................................................38
10.4 Study Discontinuation....................................................................................................39
11. COMMITTEES (not applicable – single center study)...............................................39
12. PUBLICATION OF RESEARCH FINDINGS ...................................................................39
13. REFERENCES......................................................................................................................39
14. SUPPLEMENTS/APPENDICES ............................................Error! Bookmark not defined.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
4
I. Procedures Schedule
II. Informed Consent Form (approved by UCHC IRB June 2011)
III. Other (add as many appendices as necessary)
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
5
PARTICIPATING STUDY SITES  
This is a single-site trial, taking place at the University of Connecticut Health Center, located at 
263 Farmington Avenue in Farmington, Connecticut.  
PRÉCIS 
Study Title 
Intensive versus Standard Blood Pressure Lowering to Prevent Functional Decline 
in Older People
Objectives 
The goal of this randomized clinical trial is to determine if lowering and maintaining 24-h 
ambulatory systolic BP (ABP) to <130 mmHg (intensive control) versus <145 mmHg 
(standard control) slows/halts progression of deterioration of mobility and cognitive 
function linked to white-matter disease (also known as white-matter hyperintensity or 
WMH) in patients with normal or mildly impaired mobility and cognition in subjects with 
detectable cerebrovascular disease (>0.5% WMH fraction of intracranial contents). 
Design and Outcomes  
The study is a single-site, prospective randomized, open-label trial with blinded 
endpoints (PROBE), in patients ages 75 and older with elevated 24-h systolic BP (>150 
mmHg in the untreated state) who do not have unstable cardiovascular disease, 
congestive heart failure or history of stroke. 
The key primary and secondary outcomes in the trial are: 
1) change from baseline in mobility parameters (self-paced walk and stance times) 
2) change from baseline in cognitive function (executive function, processing speed
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
6
3) Accrual of WMH over the course of the trial (36 months) including degeneration 
of tissue and tissue perfusion using an MRI technology known as diffusion tensor 
imaging (DTI)
Interventions and Duration 
The study patients will be enrolled and randomized to one of two levels of ambulatory 
BP control (intensive to achieve a goal 24-hour systolic BP of < 130 mmHg or standard 
to achieve a goal 24-hour systolic BP of < 145 mmHg) for a total of 36 months. Similar 
antihypertensive regimens will be used in both of the treatment groups with a general 
strategy of a renin-angiotensin blocking agent (ACE inhibitor or angiotensin blocker if 
ACE inhibitor not tolerated) along or in combination with a dihydropyridine calcium 
channel blocker and thiazide diuretics.  Titration of antihypertensive therapies will be 
performed at monthly intervals for the first 3 to 6 months post-randomization to achieve 
goal systolic BP. The primary and secondary outcomes will be evaluated at baseline, 
and following 18 months and 36 months of therapy. Adverse events, tolerability, and 
health-related quality of life will be evaluated as well. Study patients will be seen on an 
an ad hoc basis throughout the trial for any/all issues associated with blood pressure, 
the administered antihypertensive therapies, and adverse events. 
Sample Size and Population 
It is estimated that 400 potential patients will be screened with MRI of the brain to 
detect the presence or absence of WMH and hypertension. There will be 200 subjects 
with demonstrable tWMH (> 0.5% of intracranial volume) randomized into 2 groups of 
100 subjects with standard (24-h systolic BP<145 mmHg) or intensive (24-h systolic 
BP ≤130 mmHg) antihypertensive therapy strategies. No stratification is planned.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
7
1. STUDY OBJECTIVES
1.1 Primary Objective 
The primary objective of the study is to assess causality between 24-h systolic BP 
levels and preservation of mobility, cognitive and urinary function associated with 
lesser accrual of WMH in people over the age of 75 years. A key hypothesis of the trial 
is that intensive treatment of 24-hour systolic BP to levels of 130 mmHg or less will 
result in improved gait time, stair descent time, and maximal gait velocity compared to 
treatment of systolic BP to levels of 145 mmHg or less. This separation of ABP goals 
should achieve at least a ≥10 mmHg differences between groups. This difference has 
been shown to be responsible for the mobility decrements associated with WMH in 
older patients with systolic hypertension in our prospective cohort study.
1.2 Secondary Objectives
There are multiple secondary objectives of the trial:

To determine whether accrual in WMH over 36 months mediates changes from 
baseline in mobility parameters. 

To evaluate the changes from baseline in cognitive function parameters in 
patients undergoing intensive treatment of 24-hour systolic BP (< 130 mmHg) 
versus those with standard treatment of 24-hour systolic BP (< 145 mmHg). 

To determine whether accrual in WMH over 36 months mediates changes from 
baseline in cognitive function. 

To evaluate the changes from baseline in urinary function parameters in 
patients undergoing intensive treatment of 24-hour systolic BP (< 130 mmHg) 
versus those with standard treatment of 24-hour systolic BP (< 145 mmHg). 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
8

To determine whether accrual in WMH over 36 months mediates changes from 
baseline in urinary function 

To assess whether markers of tissue damage associated with microvascular 
disease of the brain (via diffusion tensor imaging) are linked to the functional 
measures (mobility, cognitive tests, and urinary function) at baseline and in the 
2 treatment groups of blood pressure levels.
2. BACKGROUND AND RATIONALE 
2.1 Background on Condition, Disease, or Other Primary Study Focus
White matter hyperintensities (WMHs), present in the magnetic resonance images 
(MRIs) of older people have been linked to hypertension and other vascular disease risk 
factors1. Evidence suggests that WMHs occur as a result of arteriosclerotic changes 
within the arteriolar wall and have been viewed as the manifestations of microvascular 
disease2. Large arterial and microvascular disease of the cerebral circulation share risk 
factors, (e.g., hypertension, diabetes) and may co-exist in an individual1 3 although given 
the differences noted in Table 1 below, it is unclear that they both produce tissue 
damage through similar mechanisms2 4. 
Table 1.   Comparison of the characteristics of stroke and microvascular disease 
Characteristic
Stroke (large artery)
Microvascular disease
Onset/progression
sudden/brief if any
ill-defined/gradual over years
Manifestations
focal neurologic deficit
functional limitations 
Location
vascular distribution
grow from head/tail-lateral ventricles
Size
stroke(cm)→lacune (mm)
<1 mm
Vessel
large to small artery 
Arteriolar
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
9
Pathophysiology
ischemic
Unclear
An increasing literature has associated WMHs to functional deterioration of mobility5 
6 urinary control7 and cognition8. The presence of WMH within brain pathways known 
to support mobility, cognition or voiding9 10 confirms the association between the 
functions and some of the proposed pathways. Detail seen on FLAIR and T2-
weighted sequences of MRIs has allowed localization and quantification of the 
disseminated WMHs.  Cross-sectional and prospective cohort studies have 
documented the relationships among WMH and neurologic function in older people 
and the distinctive nature of the distribution and volume of brain WMHs that are 
responsible for deterioration of these functions, particularly in the oldest groups.
2.2 Study Rationale
The BP in the clinic has been linked to brain WMH although predictors of quantitative 
WMH progression and their effect on the function of older persons are poorly 
understood. In our past work in this area, we evaluated the progression of WMH over 
2-years in a cohort of 95 patients 75-90 years (mean baseline age, 82 years) who 
had office and ABP and volumetric MRI11 Regression analyses were performed to 
assess the relations among changes in systolic BP, WMH, mobility and cognitive 
function. After 2 years, neither clinic BP nor change in clinic BP predicted 
progression of WMH whereas the 24-hour ambulatory BP and changes in 
ambulatory BP at 2 years significantly correlated with both WMH volume (p<0.04) 
and change in WMH (p<0.003).  To determine the thresholds of 24-hour ambulatory 
systolic BP that correlated with decline in function and progression of WMH, 
analyses of tertiles of 24-hour BP were conducted. This analysis demonstrated an 
association for WMH and mobility indexes with level of systolic BP. In the high (144 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
10
mmHg) ambulatory BP groups, WMH was increased and mobility slower compared 
to the middle tertile (ambulatory systolic BP = 130 mmHg). Cut-point ranges for 24-h 
systolic BP at 2 years that separated WMH volume, declines in mobility and 
measures of cognitive function were developed.  These data demonstrated that older 
subjects with 2-year 24-h systolic BP ≥140mmHg had significantly greater WMH, 
slower gait/stair descent times and a trend towards poorer executive 
function/processing speed than those with 24-h systolic BP <130mmHg.  Gait speed 
in the high BP group decreased 0.15m/sec more than that in the low BP group and 
while this difference appears small, it represents between group change after only 2-
years.  Mobility impairment linked to WMH occurs gradually so that this decrement 
may be part of a long-term process which compromises gait velocity over 10 or more 
years. Hence, our results demonstrated that ambulatory BP, not clinic BP predicts 
the progression of WMH volume in older people within 2 years and is associated with 
significant differences in mobility. These data suggest that an intervention using 
mean 24-hour systolic BP as the target could reduce progression of microvascular 
disease in the elderly and thus favorably impact function.
Data from Hypertension in the Very Elderly Trial (HYVET) demonstrate 
antihypertensive therapy decreases stroke mortality even in patients in their mid-
80s12. In HYVET, the goal of therapy was to reduce systolic BP to < 150 mmHg and 
this did result in a 39% reduction in stroke mortality linked to a 15 mmHg difference 
in systolic BP between active and placebo groups. To our knowledge, there is no 
other information on level of systolic BP and outcomes in a hypertensive population 
over the age of 80 years. Thus, the standard of care systolic BP is approximately 
145-150 mmHg. Further, no clinical trial in hypertensive patients has used 
ambulatory BP to guide therapy and to assess cerebrovascular outcomes. Our study 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
11
has been designed to evaluate the functional impact of a clinically relevant 
separation in ambulatory systolic BP in an older population (that is, <130 mmHg 
versus <145 mmHg). 
2.3 Hearing Sub-Study 
Hearing Sub-Study Introduction and Specific Aims: 
Small-vessel disease of the brain may cause white matter hyperintensities (WMHs) that 
are associated with the sequelae of uncontrolled hypertension and cardiovascular 
disease (Vermeer SE, Den Heijer 2003).  The total burden of WMHs and WMHs at 
specific loci of the brain are correlated with low mobility in the elderly and reduce speed 
of cognitive functioning (Moscufo et al., 2011; Kaplan et al, 2009).  Doctors White, 
Wolfson and colleagues at our institution show that WMHs are associated with increased 
ambulatory systolic blood pressure and reduced measures of executive function and 
cognitive processing (White et al., 2011). These data suggest that systolic blood 
pressure control may be a possible target for the reduction of microvascular disease in 
the brain and the functional sequelae of WMHs.  A prospective study, Intensive versus 
Standard Ambulatory Blood Pressure Lowering to Prevent Functional Decline in the 
Elderly (INFINITY) at UConn Health is ongoing to study the link between WMHs, systolic 
blood pressure control, and neurological function. 
The human brain coverts electrical impulses from the auditory nerve fibers and 
transforms them into meaningful auditory percepts and sensations (Willot, 1996). An 
individual’s ability to hear would not be possible without an appropriately functioning 
central auditory nervous system.  The central auditory nervous system is comprised of 
the auditory brainstem and the auditory cortex. The primary auditory cortex is located 
within the superior temporal gyrus of the temporal lobe and is composed of specialized 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
2
neurons that contribute significantly to hearing in noise performance (Musiek and Baran, 
2007). Therefore, WMHs at specific loci of the brain, such as the primary auditory cortex, 
and lesions at these locations may contribute to decreased hearing in noise performance 
and some forms of age related hearing loss, known as presbycusis.  
Presbycusis is described as sensorineural hearing loss that is associated with aging.  
Presbycusis is characterized by mild-to-moderate hearing loss in the high-frequency 
range with decreased speech understanding in background noise. Patients typically 
have slowed central processing of sounds and reduced ability to localize sounds.  
Presbycusis is present in approximately 50% of patients over the age of 70 (Fransen et
al., 2003).
Schuknecht  et al., categorized presbycusis based on findings from human temporal 
bone specimens (Schuknecht  et al., 1964).  He described 5 categories. 1) Sensory 
presbycusis was characterized by an abrupt change in the audiometric pattern is caused 
by the degeneration of hair cells. 2) Neural presbycusis was associated with a downward 
sloping pattern on the audiogram on pure-tone average testing  and loss of cochlear 
nerve cells and central neural pathways. 3) Metabolic presbycusis was associated with 
atrophy of the stria vascularis and a flat hearing curve on audiometric testing. 4) 
Cochlear presbycusis was illustrated by a gradual sloping pattern on the audiogram with 
no histological changes in organ of Corti and neural structures. 5) Mixed presbycusis 
was a combination of the other types of presbycusis. To date, WMHs have not been 
studied as a cause or a contributing factor to hearing loss such as presbycusis.  We 
propose to study the relative contribution of WMHs to presbycusis and hearing loss.  
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
3
Hypothesis: WMHs at specific loci of the brain are critical to hearing, such as the primary 
auditory cortex, and lesions at these locations may contribute to some forms of 
presbycusis.  A second hypothesis is that the global burden of WMHs may be 
associated with hearing loss, possibly as a marker of vascular changes in the cochlea. 
Specific Aim 1: Are WMHs at specific loci of the brain along the auditory ascending 
pathways associated with presbycusis?
Expected outcomes and implications
We expect to find anatomical correlates of WMHs at specific loci of the brain on MRI 
diffusion tensor imaging that correspond to poor performance on audiometric testing, 
particular for hearing in noise performance. Brain imaging analysis will be blinded to 
audiometric analysis. The relative contribution of different brain loci to hearing loss will 
be compared. 
Specific Aim 2: Is the global burden of WMHs in the brain associated with presbycusis?  
It remains a possibility that the global burden of white matter changes of the brain may 
be associated with presbycusis.  Friedland et al., demonstrate, through a retrospective 
analysis that  low-frequency hearing loss is associated with underlying cardiovascular 
disease, stroke and intracranial vascular pathology (Friedland et al., 2009). These 
authors hypothesize that this because vascular disease differentially impacts the apex of 
the cochlea, the area of the cochlea responsible for low frequency hearing. For this 
reason, we plan to study whether there is a correlation between WMHs in the brain 
associated with metabolic presbycusis, described by Schuknecht in histological 
specimens, that was associated with atrophy of the stria vascularis and a flat hearing 
curve on audiometric testing (Schuknecht et al., 1964). Such a correlation would allow 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
4
simple audiometric testing to be predictive of the presence of WMHs in the brain and the 
subsequent neurological sequelae.
Expected outcomes and implications
We expect to find a correlation of global burden WMHs to some forms of presbycusis. 
The pattern of hearing loss may be predictive of WHMs, which may have prognostic 
value for cardiovascular and neurological health.
Overall, a long-term goal of this sub-study is to understand the connection between 
WMHs in the brain, hearing loss, and possibly the connection between blood pressure 
control and hearing loss. The patient cohort in the INFINITY trial presents a unique
population to study these questions.
Hearing Sub-study Methods
Many of the participants may have already undergone audiometric testing in some 
capacity through UConn Health.  We will perform a retrospective analysis, specifically 
looking for audiometric testing in the past of patients who have completed the study (and 
the MRI) over one year ago. 
Participants who have completed the main study over one year ago will undergo a 
retrospective chart review of only their hearing test records at UConn (Group 1). These 
records will be compared to the results of MRI scans and patient demographics as part 
of the main study.  Only audiometric data will be collected as part of this retrospective 
review. Consent will not be obtained for this aspect of the study; a waiver of consent and 
HIPAA is submitted. These participants are all at least 78 and are no longer patients in 
the main study. Transportation may be difficult for many of them, some may have 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
5
moved, and some may have passed away. The waivers are necessary to avoid having 
these elderly participants who have completed the study over a year ago to return to 
UConn in order to only give permission to access hearing test records at UConn. 
Patients will not be contacted with the results of the retrospective study as they will not 
benefit from any further contact. Each patient would have already been counseled 
appropriately regarding medical management and possible rehabilitation strategies if 
hearing loss was demonstrated by a previous hearing test at UConn.
Participants who have completed the study/had an MRI in the past year will be contacted 
by mail with a letter explaining this sub-study and a phone number to call into if they are 
interested in participating (Group 2). Completed participants in Group 2 will only be 
contacted if they agreed to be contacted for future studies on the original study’s HIPAA 
sign off. Participants will receive a letter describing the study (see attached letter). If 
participants in Group 2 are interested in participating they will call in to learn more about 
the study and schedule a visit to consent and undergo hearing tests. 
Participants who are still active in the study will be given information (such as the ICF) 
about the hearing sub-study at their follow-up visits (Group 3). If interested in 
participating these participants will be consented at the main study follow-up or they 
schedule a consent visit and hearing test.  
Consent will be performed by Dr. Roberts, Dr. White and approved study staff.  All 
proposed audiometric testing will be performed by a licensed audiologist and are 
standard clinical metrics for hearing loss. Audiometric testing will include pure-tone 
audiometry, speech reception threshold testing, otoacoustic emmisions, and word 
recognition testing, AzBio sentence testing and ABR testing in some cases.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
6
Data will be collected with standard forms used at the University of Connecticut in the 
clinical setting, to measure audiometric performance (AzBio Sentence Test List 1, 
UConn Health Audiometric Scoring sheet, dichotic digits score) and levels of tinnitus 
(Tinnitus Handicap Inventory) (see attached data collections forms).   
All audiometric testing are standard clinical metrics for hearing loss and are routinely 
used in the clinical setting at the University of Connecticut.  Audiometric testing will 
include a comprehensive audiogram consisting of pure-tone audiometry, speech 
reception threshold testing, otoacoustic emmisions, and word recognition testing. 
Subjects will also undergo AzBio sentence testing to investigate speech in noise
performance. Pure-tone audiometry involves the presentation of soft tone stimuli, which 
requires a subject to indicate when a tone is heard. Speech reception/recognition testing 
requires the subject to repeat words presented at a decibel level adjusted for their 
hearing. Pure-tone audiometry and speech reception/word recognition testing takes 
place in an audiology sound booth and presented via headphones. Otoacoustic 
emissions are obtained by placing a soft probe in the ear canal and presenting soft tonal 
stimuli. The same probe will measure a response emitted back from the inner ear. 
Subjects will also undergo AzBio sentence testing to investigate speech in noise 
performance.  AzBio sentence testing involves the subject repeating sentences at a 
volume adjusted for their hearing in the presence of background noise. This first hearing 
test session will take approximately 1 hour to complete.
For patients who demonstrate abnormalities on audiometric testing and have findings on 
imaging that may be accounted for audiometric findings, dichotic digit testing (DDT) will 
be performed. The DDT is a widely used test to screen for central auditory dysfunction. 
25 sets of double-digit pairs (ie one, five) are presented for a total of 50 digits per ear. 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
7
The participant reports all digits heard for each presentation and a percent-correct score 
is calculated for each ear.  Testing takes place in an audiology sound booth and will take 
approximately 1 hour.
If hearing loss is demonstrated or referral to a physician is indicated based on testing, 
participants will be offered a medical evaluation and will be treated accordingly.  If a 
physician referral’s indicated by audiometric testing is needed, the participant or 
participants insurance will be billed. A referral will only be given if the participant agrees 
to the referral. The participant will sign a release of information form allowing results of 
the hearing tests to be released to the participant or to the doctor.
Audiometric data will be compared to correlates assessed on morphological (T1, T2, and 
FLAIR) MRI, as well as on diffusion tensor MRI (DT-MRI). Patient demographics and 
clinical data that have already been collected through the INFINITY trial will also be 
compared.
Hearing Sub-study Risks and minimizations 
A hearing test is safe with essentially no risks. At times, cerumen (ear wax) prevents the 
ability of an audiologist to perform a test. Should cerumen be present preventing testing, 
your ears will be cleaned by a physician prior to the hearing test. Confidentiality of the 
participant and the data collected is not guaranteed. To minimize this risk, data collection 
forms (see attached) will be coded and stored in a locked cabinet in a locked room. Only 
study staff will have access to this data.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
8
Intensive BP Treatment (N=100) 
Standard BP Treatment (N=100) 
Treatment Period (3 years)
Day -21
to -1
Month 1
Visits at
Months 2, 3, 
6 & 9
Month 12
Visits every 
6 months, with 
major evaluations
at 18 and 36 
months for 
primary and 
secondary 
endpoints
End of
Study
2-week 
Follow-up
Screening 
Visit
Day 1 
Baseline/
Randomization
3. GENERAL STUDY DESIGN 
The study is a prospective, randomized, parallel group, open-label trial with blinded 
endpoints (PROBE), in older patients who have untreated 24-h systolic BPs between 
150 and 180 mmHg mmHg) and evidence of at least 0.5% WMH volume on MRI. 
The key primary and secondary outcomes in the trial are change from baseline in 
mobility parameters (self-paced walk and stance times) and cognitive function 
(executive function, processing speed) with accrual of WMH providing the mediating 
mechanism for the functional decline. After baseline evaluation, patients will be 
randomized to the intensive group (goal 24-hour systolic BP < 130 mmHg) or to the 
standard group (goal 24-hour systolic BP < 145 mmHg) Assessments for the 
outcomes will be made at baseline and at 18 and 36 months post-randomization. 
Adverse events, tolerability, and health-related quality of life will be evaluated 
outcomes as well.  We will perform complete assessments at times zero (baseline) 
and after 18 and 36 months (see Study Design Figure) 
Figure. Design of Trial – Intensive BP Treatment – goal 24-hour ambulatory systolic BP < 130 
mmHg ; Standard BP Treatment – goal 24-hour systolic BP < 145 mmHg 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
9
4. STUDY POPULATION 
Three hundred men and women over the age of 75 years will be recruited and screened for 
the presence of systolic hypertension and WMH volume of > 0.5% on MRI. It is expected 
that 2 of 3 patients in this age group will have WMH. Of the screened patients, 200 will be 
randomized in a 1:1 ratio to either the intensive or standard treatment arms. Every attempt 
will be made to have a substantial representation of minorities who have hypertension. It is 
estimated that 15% of the study population will be African-American and 10% will have 
Hispanic/Latino ethnicity. The inclusion and exclusion criteria for study entry are as follows:
4.1 Inclusion Criteria 
To be included in the study, the following criteria must be met:
A. 75 years of age or older
B. Seated clinic systolic BP >150 mmHg in the untreated state 
C. At risk for cerebrovascular disease (history of smoking, dyslipidemia, type 2 
diabetes, longstanding hypertension, family history). Patients must have visible 
(0.5% WMH or more) white- matter hyperintensity lesions on screening magnetic 
resonsance imaging.
D. To achieve success in maintaining a 24-hour systolic BP of <140-145 mmHg in the 
standard treatment group or a systolic BP <125-130 mmHg in the intensive treatment 
group, patients will be eligible for inclusion if (1) their clinic systolic BP is 150-170 
mmHg, and they are taking 0 to 2 antihypertensives, (2) their systolic BP is > 170 
mmHg and they are taking 0 to 1 antihypertensive. 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
1
4.2 Exclusion Criteria 
All candidates meeting any of the following exclusion criteria at baseline will be 
excluded from study participation.
1) Uncontrolled diabetes mellitus (HBA1c >10%)
2) History of stroke, dementia or clinically impaired gait (Mini-mental status 
exam score (MMSE) <24, Short Physical Performance Battery for gait 
(SPPB)  < 9,)
3) Body Mass Index > 45 kg/m2 and/or arm circumference > 44 cm)
4) Poor kidney function (defined as estimated GFR <30 ml/minute)
5) Active liver disease or serum transaminases >3 times the upper limit of 
normal
6) Major cardiovascular event (e.g. myocardial infarction) or procedure (e.g. 
cardiac bypass surgery) in past 3 months; stroke with residual gait 
abnormality
7) Uncompensated congestive heart failure (NYHA class III or IV or documented 
ejection fraction <30%)
8) Chronic atrial fibrillation that disallows ambulatory BP monitoring to be 
successfully performed
9) Medical conditions that limit survival to < 3 years 
10) Non-dermatologic cancer diagnosed within 2 years
11) Organ transplantation requiring anti-rejection drug therapy
12) Severe and unexplained weight loss (>15%) in past 6 months
13) Medical need to undergo recurrent phlebotomy or blood transfusions
14) Current participation in another investigational trial
15) Unable to obtain informed consent
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
2
16) Factors limiting adherence to the interventions
17) MRI contraindications (including MRI-incompatible implants, severe 
claustrophobia).
18) Known carotid or intracranial arterial occlusive disease.
4.3 Study Enrollment Procedures at University of Connecticut Health Center
Study recruitment and enrollment. The study is a single-site randomized clinical trial 
that will be performed at the University of Connecticut Clinical Research Unit. Patients 
will be recruited from a variety of sources as described below. Three hundred patients 
will be enrolled into the trial in order to randomize 200 patients and complete 140 
patients at 3 years of randomized treatment. Based on our prior experience in studying 
patients in this age group with hypertension and mild mobility issues, we project a 3-
year attrition rate of approximately 30%.  Recruitment will be carried out by several 
mechanisms, Including: A) contacting former research participants from the Cardiology 
and Hypertension faculty practices, the Center on Aging, and Neurology who have 
agreed to be informed of future studies, B) publically posted advertisements in addition 
to advertisements on the internet, radio and newspapers, C) Recruitment 
presentations conducted at community health centers, faith-based organizations and 
senior centers in conjunction with BP community clinics. 
Recruitment will be extended into the greater Hartford region to improve minority 
participation. Advertisements will state that we are seeking volunteers for a treatment 
study aimed at older patients with hypertension willing to join a study involving the 
evaluation and treatment of high blood pressure, mobility and cognitive function. The 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
3
ads will state that antihypertensive medication, clinical visits, brain imaging, and other 
testing will be provided at no cost. 
Following voluntary assent, interested individuals will be screened by phone for 
inclusion/exclusion criteria. Those meeting initial screening criteria will be invited to a 
Consent/Evaluation Visit during which informed consent will be obtained, followed by a 
medical history, physical exam, and tests to determine eligibility. Those not meeting 
study criteria will be referred for medical care. Patients not able to read and 
understand the consent form will be excluded from the study.
5. STUDY INTERVENTIONS 
5.1 Interventions, Administration, and Duration 
REGIMENS, ADMINISTRATION, AND DURATION.  Similar types of antihypertensive regimens 
will be used in both the intensive and standard treatment groups. As noted above, the BP 
goal in the intensive group is a 24-hour systolic BP mean of < 130 mmHg and in the 
standard treatment group a 24-hour systolic BP mean of <145 mmHg.  The types of 
therapy chosen for this trial are highly evidenced based – recent results from the HYVET 
study, a 2 year trial in high-risk, hypertensive patients >80 years demonstrated that 
diuretic and ACE inhibitor treatment reduced the risk of stroke using 150 mmHg as the 
treatment goal.  In addition to efficacy and tolerability, ease of dosing plays a role in 
treatment adherence. Consideration of these issues as well as the finding from the 
ACCOMPLISH and ASCOT trials that use of an ACE inhibitor with a calcium antagonist 
were superior to a diuretic and ACE inhibitor are central to the proposed algorithms. 
At the baseline, post-screening visit, an urn randomization procedure2, 13  will be used to 
assign subjects to treatment conditions described below. There will be no stratification.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
4
TREATMENT STRATEGY FOR THE INTENSIVE THERAPY GROUP.  Patients in the intensive group 
will receive a low dose dihyropyridine calcium antagonist (amlodipine, 5 mg daily)14  and a 
low dose ACE inhibitor (lisinopril 10 mg daily) at the time of randomization. If there is a 
history of ACE inhibitor intolerance (e.g. angioedema or cough), an angiotensin receptor 
blocker (ARB) (e.g. losartan 50 mg daily) will be substituted. Intensive group subjects will 
be seen monthly for titration of the 2 agents (maximal doses: amlodipine 10 mg and/or 
lisinopril 40 mg once daily) until achieving a clinic systolic BP of <135 mmHg – at that 
time (average time, 3 months), we will verify the 24-hour mean systolic BP is <130 
mmHg. If the systolic BP has not reached goal on maximally tolerated doses of a calcium 
antagonist and an ACEi or ARB, low dose diuretic will be added (e.g., 
hydrochlorothiazide/12.5 mg daily or furosemide/20mg daily).  If the BP goal is not 
achieved with 3 drugs, addition of daily dosing of one of the following agents is allowed: 
1) beta-adrenergic blocker (first choice in a patient with known coronary disease), 2) 
alpha-adrenergic blocker (first choice in men with benign prostatic hyperplasia), 3) 
aldosterone antagonist (first choice in patients with low serum potassium levels). A loop 
diuretic may be substituted for a thiazide in patients whose estimated GFR is <50 
ml/minute.15 In subjects who had not reached the ABP goal at 3 months and who have 
further drug titration, the ABP will be repeated at 6 months to confirm that the 24-hour 
systolic BP goal has been achieved.
TREATMENT STRATEGY FOR THE STANDARD CARE GROUP.  This group’s goal of an ABP 
<145 mmHg is based on evidence from antihypertensive treatment strategies in older 
patients from HYVET12 161616 in which clinic systolic BP values of <150 mmHg were 
associated with clinical benefits. Of note, there is no evidence that clinic systolic BP 
values <150 mmHg reduce stroke events in patients over the age of 75 years. As the 24-
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
5
hour BP mean is typically 5 to 10 mmHg lower than the clinic BP due to the effects of 
sleep, the goal in this group was set at 145 mmHg.
Treatment in this group will start with the ACEi lisinopril (initial dose 10 mg daily and 
maximal dose of 40 mg once daily) (or ARB if there is a history of ACEi intolerance). 
Subjects will be seen monthly until achieving a clinic systolic BP <150 mmHg with 
subsequent confirmation that the 24-hour BP goal of <145 mmHg has been achieved.  If 
systolic BP does not reach the goal on maximally tolerated doses of an ACEi or ARB, a 
dihydropyridine calcium antagonist (e.g., amlodipine 5 mg up to 10 mg qd) will be added. 
Similarly, if the 24-hour systolic BP goal of <145 mmHg isn’t achieved with this regimen, a
diuretic will be added (e.g. hydrochlorothiazide/12.5 mg daily or furosemide/20mg daily).  
Similarly to the intensive BP group algorithm, a loop diuretic may be substituted for a 
thiazide in patients with chronic kidney disease. Finally, if goal BP is not achieved on 3 
drugs, daily dosing of: 1) beta-adrenergic blocker, 2) alpha-adrenergic blocker, 3) 
aldosterone antagonist may be added.  As in the intensive group, subjects not reaching 
their 24-hour systolic BP goal at 3 months and who have drug titration will have an ABP 
monitor performed at 6 months to confirm that goal 24-hour systolic BP has been 
reached.
DOWN-TITRATION OF ANTIHYPERTENSIVE THERAPY.  Since it is unknown if lowering 24-hour 
systolic BP to the more intensive goal of <130 mmHg is beneficial in this age group, a 
reduction in the dose or number of antihypertensive drugs is allowed for patients in both 
groups but is likely to be more common in the standard group. The criterion that permits 
down-titration of medications in the standard care group is a clinic systolic BP <140 
mmHg at 2 successive clinic visits or systolic BP <135 mmHg at a single visit 
accompanied by a 24-hour systolic BP value of <140 mmHg.  The goal of down-titration is 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
6
to produce a usual care group systolic BP of 140-145 mmHg thus producing at least a 10 
mmHg difference in ABP levels between the intensive and standard care groups. 
5.2 Handling of Study Interventions 
All study medications will be ordered and stored in the University of Connecticut 
Health Center Research Pharmacy (director, Ruth Lacasse, Pharm.D.) Clinical 
supplies will be ordered in bulk for both economical and practical reasons. The 
Research Pharmacy will prepare and dispense the labeled (study name and patient 
name are identified on the medication bottles) study medications to the research 
nurse as needed for individual patients. Unused study products will be returned to 
the pharmacy for disposal. 
Drug accountability records are kept on every case report form and all dispensed 
and returned medications are quantitated by pill counts and recorded (including date 
and time of dispensing to study patients) on this form. 
5.3 Concomitant Interventions 
5.3.1
Allowed Interventions
Any medication for the treatment of a comorbid condition is typically acceptable as 
long as it does not belong to an antihypertensive drug class. It will be recommended 
that drugs that are known to raise the blood pressure or interfere with 
antihypertensive drug effect be used judiciously (e.g. decongestants with 
sympathomimetic activity, or chronic high-dose nonsteroidal anti-inflammatory 
agents). Study physicians will monitor concomitant drug use carefully and at every 
visit. Patients will be asked to always contact the research nurse to report any new 
prescriptions by physicians outside of the study for review.   
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
7
5.3.2
Required Interventions  (discussed in Section 5.1)
5.3.3
Prohibited Interventions
See 5.3.1 – otherwise, there are no other prohibited interventions.
5.4 Adherence Assessment 
We will provide a prevention-oriented approach for adherence to study visits and 
medication compliance. Physicians and coordinators will be instructed on adherence 
issues as part of pre-trial training. Adherence will be monitored by self-report of each 
of the prescribed BP control medications at each visit. Pill counts of antihypertensive 
medications will be performed. In our experience as well as in the HYVET12 and 
ACCOMPLISH17 Trials with similar therapies those proposed in this trial, adherence 
to the regimen and study retention should be in excess of 75%.
Compliance to study medications is defined as taking 80 to 120% of prescribed 
medications based on pill counts.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
8
5.5 Schedule of Evaluations
Assessment during the randomized clinical trial of intensive versus standard ambulatory BP 
control
Baseline
MONTH
Screen
I
II
1
2
3
6
12
18
24
30
36
Post
Study
Med Hx-Phys Ex
X
X
X
X
Med Washout
(0 to 4 week period)
X
X
ECG
X
PRN* PRN
PRN
PRN
X
PRN
PRN
X
CBC, Chemistries
X
PRN
PRN
X
X
X
X
PRN
X
MRI
X
X
X
Gait/Mobility
X
X
X
Cognitive Tests
X
X
X
Urinary Function
X
X
X
Clinic BP,HR,BMI
X
X
X
X
X
X
X
X
X
X
X
X
X
Med Titration
X
X
PRN
X
PRN
PRN
PRN
PRN
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
ABPM (24hr)
X
R
A
N
D
O
M
I
Z
A
T
I
O
N
X
X**
X
X
HOME BP
X
X
X
X
X
X
*PRN laboratory testing for safety checks only (electrolytes, and renal function tests); note: due to the age of patients, 
medical staff and PIs will be available at all times for impromptu visits; ** - if needed based on 3 month ABPM and/or 
changes in clinic BP
5.6 Description of Evaluations 
Resting clinic BP:  Taken on a semi-automated digital device (Suntech TM2420, 
Morrisville, NC) with an appropriate cuff. After sitting 5 min, BP will be taken twice, 2-3 
minutes apart in the non-dominant arm and averaged.  BP readings will be taken 
between 8 and 11 am, before taking antihypertensive medication. 
24-hour ambulatory BP Monitoring (ABPM): conducted after antihypertensive 
washout and prior to initiation of investigative therapy using the Oscar II BP device 
(Suntech Medical Instruments, Morrisville, NC) which has been validated 
independently.18 The device is a light, comfortable automated BP recorder. Eighty BP 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
9
readings will be programmed during the 24-h study. Monitors will measure BP and heart 
rate every 15 min from 6 am to 10 pm, and every 30 min from 10 pm to 6 am. 19, 20.  
Follow-up ambulatory BP recordings will be made at 3 months to evaluate response to 
therapy and at 6 months if medications were adjusted at 3 months to ascertain if systolic 
BP goals were achieved.  Data will be transferred to Accuwin software program 
(Suntech Medical Instruments, Morrisville, NC) for analysis. Components of the ABPM 
for analysis will include the 24-hour mean systolic and diastolic BP, the awake and sleep 
BPs, and the early morning BP (the difference between the 2 hour post-awakening BP – 
the 2 hour pre-awakening BP) as previously described.20, 21.  
A baseline electrocardiogram (ECG): a standard 12-lead ECG will be obtained at
baseline, 18 months and end of study – these will be assessed by study physicians 
Marfatia and/or White.
Laboratory tests (safety): CBC, glucose, BUN, creatinine, liver enzymes and urinalysis, 
sodium and potassium.   Abnormal results will require further testing or referral for 
treatment before (or in lieu of) study participation. 
Laboratory tests (research): lipid profile (Total, HDL and LDL cholesterol, and 
triglycerides).
Mobility Measures:  Performance will be assessed primarily by timing.

walking-moving 

Gait Speed: Gait speed will be measured as participants walk at a comfortable 
pace over an 8-meter course with 1 meter for acceleration and deceleration.

Stair Ascent/Descent: stair ascent and descent will be used as a measure of 
walking-moving. We have previously shown stair descent time to be predicted by 
WMH22.  Ascent and descent of 4 steps at a comfortable pace will be timed 
separately.

changing-maintaining body position (3 with body position changes and 4 
requiring maintenance of position): 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
measure
IRB APPR
measure BP
OVA
BP and
L DA
and heart
TE: 04/
heart

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
10

Supine-to-sit will occur on a mat table toward the preferred side at normal pace 
(hand-use allowed). 

Sit-to-stand will be from the mat table adjusted to leg length. Five repetitions will 
be performed at maximal pace with arms folded across the chest.

Functional reach is measured in a forward direction using a wall-mounted meter 
stick.

Maintenance of 3 stance postures (side by side, semi-tandem, tandem) as 
described in the Short Physical Performance Battery will be timed to a maximum 
of 30 sec. Thereafter, single limb stance using the preferred limb will be timed to 
a maximum of 30 sec.
Neuropsychological test battery:  Testing will be performed in a quiet room by a 
trained technician using standardized procedures.

Hopkins Verbal Learning Test (HVLT-R)23 - provides an assessment of verbal 
learning and memory (immediate recall, delayed recall, and delayed recognition). 
There are 3 learning trials, in which a 12 word list is read aloud and subjects 
repeat the words immediately. Delayed recall uses a 20-25 minute delay after 
which, subjects repeat the set of words; it is because of the delay that this test 
must be given first. There is also a yes/no recognition trial in which subjects hear 
a randomized list that includes 12 words from the original list and 12 new words, 
6 of which come from semantic categories on the original list. Subjects must 
identify the 12 words from the original list.

Stroop Color- Word test23  - Stroop Color and Word tests how well an individual 
suppresses a habitual response in favor of an unusual one thus assessing 
complex processing speed. Slower Stroop performance correlates with WMH. 

Controlled Oral Word Association Test23 - Controlled Oral Word Association Test 
is a test of word generation from letters.  This type of word fluency is typically 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
side
IRB A
side at
PP
at normal
ROVAL D
normal pace
ATE: 0
pace

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
11
impaired in patients with frontal lobe lesions but spared in early Alzheimer’s 
disease.  

Trail making test23  - Trail Making tests speed of visual search, attention, mental 
flexibility and motor function.  Performance on Trail Making is sensitive to early 
stages of dementia. 

Symbol Digit Substitution Test23  - Symbol Digit Substitution evaluates 
processing speed. Subjects are asked to write the numbers corresponding to 
symbols in a Key at the top of the page. The Key shows the correct pairing of the 
symbols and numbers.  Subjects are given 90 seconds in which to complete as 
many pairings as possible.

Digit Span Test23  - Digit Span tests auditory attention, concentration and working 
memory. The 2 parts of Digit Span – Digits Forward and Digits Backward—are 
administered separately.  Digit Span number sequences are 2-8 random digits. 
Testing begins with 2 numbers that are read aloud at one digit per second. 
Subjects are asked to repeat the number sequence either as presented or 
reversed. 

California Computerized Assessment Package24 - Cal CAP consists of 3 
reaction time (RT) tests, a simple RT, a choice RT, and a serial RT.  Simple 
RT measures general motor slowing.  Choice RT is a go-no go paradigm, 
which measures response inhibition and processing speed. Serial RT 
measures divided attention and processing speed.

Geriatric Depression Scale25 was developed as a basic screening measure for 
depression in older adults.
Incontinence Assessment: Urinary incontinence (UI) will be measured by validated 
assessments.  A yes answer to the question, “During the last 3 months, have you leaked 
urine (even a small amount)?” will define participants as incontinent.  The type of UI will 
be evaluated by the 31Q questionnaire which uses 3 items to classify UI: presence of 
IRB Review
IRB NUMBER: IE-11-155S-2
APPROVAL DATE: 04/16/2018
early
IRB A
early Alzheimer s
APPROVAL DAT
Alzheimer s

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
12
leakage, situation of leakage (inability to reach toilet, physical activity, neither) and main 
type of UI (urge UI, stress UI, both, neither)26.  Urinary incontinence severity will be 
measured using the Urinary Incontinence Severity Index in which leakage is depicted as 
none, slight, moderate, severe based on frequency and amount.27  A brief version of the 
Urogenital Distress Inventory (UDI) will be used to measure the bother linked to urinary 
tract symptoms and UI based on a 4-point scale.28 The functional impact of UI will be 
evaluated using the IIQ-7 (e.g., social activities) with a 4 point scale.29  
Telephone Memory Impairment Screen. Death and study attrition are associated with 
age-related diseases. Failure to account for this informative censoring may result in 
biased estimates of dementia risk and cognitive decline. Hence, we will collect data by
telephone to assess the degree to which living participants who fail to appear for their 
final assessment differ from participants who complete the study. Specifically, we will 
use telephone administration of a validated mobility assessment30 to estimate mobility 
outcomes through multiple imputation or joint modeling that would have been observed 
had the participants appeared for their clinical assessment. We will use baseline and 18 
month mobility data along with the answers to the telephone mobility assessment at all 3 
time points to impute or jointly model the expected mobility outcomes, enabling us to 
predict the mobility outcomes that would likely have been observed at 36 months in 
subjects unable to appear for this assessment. While 18 month data are used in 
secondary analyses for major hypotheses, here the 18 month data are needed to 
estimate progression rate and the rate in patients not appearing for their final clinical 
assessment and are therefore essential for imputing the 36 month mobility outcome. 
MRI acquisition will be performed at the University of Connecticut Health Center on a 
1.5 Tesla Siemens Avanto scanner using the following parameters.  3D T1-weighted 
Magnetization Prepared Rapid Gradient Echo (MPRAGE): 120 contiguous 1.3 millimeter 
(mm)-thick sagittal slices, repetition time (TR)/echo time (TE)=2700/5 milliseconds (ms), 
IRB Review
IRB NUMBER: IE-11-155S-2
B APPROVAL DATE: 04/16/2018
ity,
IRB
ity, neither)
APPROVA
neither) and
L DA
and main
TE: 04
main

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
13
inversion time (TI)=950 ms, matrix size=192x256, field of view=230x310 mm2, in-plane 
resolution =1.21x1.21 mm2; 3D-T2: 120 contiguous 1.3 mm-thick sagittal slices, 
TR/TE=4300/349 ms, matrix size=190x256, field of view=230x310 mm2, in-plane 
resolution =1.21x1.21 mm2), and 3D-Fluid Attenuated Inversion Recovery (FLAIR): 120 
contiguous 1.3 mm-thick sagittal slices, TR/TE=6500/349 ms, TI=2200 ms, matrix 
size=190x256, field of view=230x310 mm2, in-plane resolution =1.21x1.21 mm2). Whole 
brain diffusion tensor imaging (DTI) will be performed utilizing syngo DTI parameters at a 
diffusion-weighting strength of b =1000 s/mm2; TR/TE = 2800/88 ms; 12-directions, 
matrix size=128x128 and FOV of 230 mm.
White matter lesion segmentation: Image pre-processing includes correction of
magnetic field signal in-homogeneities31, and linear affine registration of FLAIR and T2 
series to the MPRAGE series.32 Brain classification into normal WM, and T2-
hyperintense WMH will be done using semi-automated segmentation. The final 
segmentation map will be obtained after expert review. Total  WMH volume in milliliters 
(mL) will be calculated by multiplying voxel volume (mm3) by the number of WMH pixels 
and dividing by 1000. To account for head size variability, volumes will be normalized 
and expressed as fraction of intracranial cavity volume (ICC).
Assessment of brain structural integrity through diffusion tensor imaging (DTI): 
We will assess the integrity of brain WM microstructure using DTI.33 DTI will obtain 
measures of diffuse tissue damage, i.e. fractional anisotropy (FA) and mean diffusivity 
(MD), to complement WMH burden as additional MRI outcomes. While the WMH 
characterizes a volume of localized tissue damage, DTI measures aspects of tissue 
quality not otherwise available. Together the measures provide a more complete 
assessment that captures disease progress at different stages.  DTI measures will thus 
be used as outcome markers in the same way as WMH.  Specifically we will investigate 
1) whether microvascular disease causes damage in normal-appearing WM (NAWM) on 
conventional (T2-weighted) MRI; and 2) whether controlling BP slows accrual of tissue 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
0x310
IRB AP
0x310 mm
PROV
mm2VA
2,A, in-plane
L DATE: 0
in-plane

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
14
damage in the form of both NAWM as well as in WMH. Using the subject’s brain 
segmentation output 34  as mask, we will identify the NAWM areas and within them 
determine FA and MD. We will characterize the cross-sectional and longitudinal 
relationships of FA and MD with WMH at baseline and follow-up to determine: 1) 
presence and degree of association; 2) predictive value of FA and MD as early 
indicators of functional (cognitive and mobility) deterioration and/or WMH accrual; and 3) 
effect of anti-hypertensive intervention on these DTI markers.  Using this approach we 
will focus on WMH areas to quantitatively assess 1) the degree of structural integrity 
within areas of WMH compared to NAWM and 2) the change of FA and MD over time, to 
determine effectiveness of treatments in halting or slowing progress of fiber-tract
damage. 
The investigators performing mobility testing, cognitive testing, voiding function studies, 
and volumetric MRI will be blinded to treatment assignment until the T36 data are 
finalized and data lock has occurred.
MRI Reproducibility Sub-study
Ten to fifteen subjects will be scanned by a different technician to exam the 
reproducibility of the imaging protocol.  These subjects will be scanned two consecutive 
times on the same day followed by a short break, following the same sequencing 
protocol each time.  Recruitment of these subjects will occur at the 18-month and 36-
month follow-up visits. At the 18-month or 36-month visits, prior to the follow-up MRI, the 
study physician/consentor will invite subjects to participate in the sub-study and will 
review sub-study consent and HIPAA consented at that time.  
5.6.1
Screening Evaluation
Consenting Procedure
IRB Review
IRB NUMBER: IE-11-155S-2
ROVAL DATE: 04/16/2018
ubject s
IRB APPR
ubject s brain
OVAL
brain

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
15
Consent authorization will not be obtained prior to preliminary screening through 
telephone calls initiated by potential subjects or for those interested in completing 
a brief screening questionnaire in person at community presentations.  Those 
deemed eligible will sign a consent form at their first study visit.  
Patients will be given time in the interview room privately to read the study 
consent form.  After approximately 15-20 minutes, the study nurse or physician 
will review each section of the consent form together, taking time to answer any 
questions that arise.  After any questions have been answered the study nurse or 
physician will move to the next section of the document and repeat the process.  
After the last section has been reviewed the patient will be asked to review the
research project in his/her own words.  If the subject provides an accurate 
summary s/he will be asked if s/he would like more time to consider their decision 
to participate and whether s/he would like to sign and date the consent form. If 
the summary is not accurate the coordinator will go over the relevant sections 
again.  It is estimated that the informed consent discussion will take 30 to 45 
minutes.  
Signed consent forms will be stored securely in a locked file, separate from case 
report forms.  Should significant findings arise that might affect a patient’s 
willingness to continue to participate, the PI will submit a request for modification 
to the Informed Consent Form to the IRB and then, after obtaining approval, re-
consent the subjects at the next regularly scheduled visit.  If the updated consent 
form has not yet been approved by the IRB at the time of the visit a verbal 
explanation of the information will be provided to the patient and documentation 
of the explanation will be noted in the research record.  
If the investigator or IRB determine that patients need to be contacted 
immediately depending on the nature of the information and the level of risk it 
IRB Review
IRB NUMBER: IE-11-155S-2
B APPROVAL DATE: 04/16/2018
ary
IRB
ary screening
B APPROVAL
screening through
DATE: 04
through

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
16
presents to subjects, the PI will communicate the information to the patients in 
the study as soon as possible and will document the contact with the patients.
Screening Procedures  

Study overview and consent  

Medical history 

Physical exam 

Standardized Clinic BPs 

ECG 
5.6.2
Enrollment, Baseline, and/or Randomization 
A. Enrollment Period
Baseline visit 1

Fasting laboratory studies* 

Review and discussion of medication tapering if needed (by physician)

Brief exam and standardized blood pressures 

Medical history, including evaluation of concomitant medications, adverse events 
for baseline 

Laboratory Tests: includes complete blood count, serum creatinine and blood 
urea nitrogen, glucose, ALT, urinalysis, total cholesterol, LDL and HDL 
cholesterol and triglycerides (fasting)

Baseline MRI – (Radiology) Note: if patient has no WMH on baseline MRI, they 
will be excluded from further participation in the trial. No medication tapering will 
occur prior to the results of this study. 
Baseline visit 2– this visit will be the first assessment following taper of prior 
antihypertensive therapy for those patients demonstrating WMH on the screening MRI.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
on
IR
on to
B A
to the
APPR
the patients
OVAL DAT
patients in
E:in

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
17

Medical history (intercurrent illnesses, medication history, adverse events) 

Standardized clinic BPs* 
If patient is off antihypertensive agents at baseline or has been discontinued for 2 weeks 
with a mean clinic SBP > 150 mmHg, patient will proceed with various tests below. If SBP < 
150 mmHg, patient will return in 1 week to re-evaluate clinic BPs.

*Standardized clinic BP measurements will be taken using the validated Suntech 
Medical Instruments TM24/7 in the non-dominant arm, seated position in 
duplicate and 1 upon standing prior to dosing of morning BP medications.

Ambulatory BP monitoring

Home BP monitoring – self-monitoring with a portable digital device, obtaining BP 
readings twice-daily in duplicate (morning, evening) for seven days. Patients will 
receive training on proper use of the device and record readings on separate 
sheet.  Blood pressure readings will be obtained in the seated position prior to  
any morning and/or evening antihypertensive medications.

Mobility battery - Gait Speed, Stair ascent and descent, Supine-to-sit, Sit-to-
stand, Functional reach, Stance time, Single leg stance

Cognitive battery – HVLT, Trail Making Test, Digit Span Test (Forward and 
Backward), Digit Span, Stroop Color and Word Test, Symbol Digit Substitution, 
Controlled Oral Word Association Test, California Computerized Assessment 
Package (Cal CAP), Geriatric Depression Scale.

Incontinence questionnaires - UI 31Q, Urinary Incontinence Severity Index, 
Urogenital Distress Inventory (UDI), IIQ-7

Mini-mental status exam
At this point, if all inclusion and exclusion criteria have been met, patient will be 
randomized to either A) Intensive ABP reduction group or B) Standard ABP reduction 
group. Treatment initiation will be as outlined in Section 5.1.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
dverse
IRB APP
dverse events)
ROVAL DA
events)

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
18
5.6.3
Post-Randomization Follow-up Visits   
Visit 1 (1 month post-randomization) – At visit 1, patients will be evaluated for their clinic 
BP responses to assigned therapies. Procedures previously defined above will be repeated 
at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration as appropriate based on clinic systolic BP 
(goals are < 135 mmHg if assigned to the Intensive group and < 150 mmHg if 
assigned to the standard group)

Dispense medications for next month
Visit 2 (2 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate (goals are 
< 135 mmHg if assigned to the Intensive group and < 150 mmHg if assigned to 
the standard group; if the standard BP group patient has a systolic BP < 135 
mmHg, antihypertensive medications will be reduced by the study physician)

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary

Electrocardiogram if clinically necessary

Dispense medications for next month
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
19
Visit 3 (3 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate (goals are 
< 135 mmHg if assigned to the Intensive group and < 150 mmHg if assigned to 
the standard group; if the standard BP group patient has a systolic BP < 135 
mmHg, antihypertensive medications will be reduced by the study physician)

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary

Electrocardiogram if clinically necessary

Ambulatory blood pressure monitoring if clinic systolic BP has been stable for 
visits 2 and 3 according to treatment assignment. If not, patients will return in 2-
4 weeks for re-assessment of BP stability. Antihypertensive drug titration will be 
based on ambulatory BP from this point forward.

Dispense medications for next 3 months
Visit 4 (6 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate – ad hoc 
ambulatory BP can be performed here to address therapeutic goals and if 
deemed medically necessary.

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
uation
IRB AP
uation of
PR
of

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
20

Electrocardiogram if clinically necessary

Dispense medications for next 6 months
Visit 5 (12 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate; ad hoc 
ambulatory BP can be performed here to address therapeutic goals and if 
deemed medically necessary.

Laboratory studies (potassium, creatinine, BUN, glucose, ALT, cholesterol 
profile)

Electrocardiogram if clinically necessary

Home BP monitoring

Dispense medications for next 6 months
Visit 6 (18 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group and will 
have comprehensive testing for WMH, mobility, cognitive function as well as blood pressure 
control. Procedures previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate; 
ambulatory BP will be performed to evaluate achievement of therapeutic goals 
according to randomized treatment strategy.

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
21

Electrocardiogram 

MRI acquisition at UCONN neuroradiology

Mobility Testing

Cognitive Testing

Questionnaires related to urinary function, QOL

Home BP monitoring

Dispense medications for next 6 months
Visit 7 (24 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication titration or down-titration as appropriate; ad hoc 
ambulatory BP can be performed here to address therapeutic goals and/or if 
deemed medically necessary.

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary

Electrocardiogram if clinically necessary 

Home BP monitoring

Dispense medications for next 6 months
Visit 8 (30 months post-randomization) – Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group. Procedures 
previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
22

Antihypertensive medication titration or down-titration as appropriate; ad hoc 
ambulatory BP can be performed here to address therapeutic goals and/or if 
deemed medically necessary.

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary

Electrocardiogram if clinically necessary

Home BP monitoring

Dispense medications for next 6 months
5.6.4
Completion/Final Evaluation 
Visit 9 (36 months post-randomization) -  Patients will return for evaluation of 
antihypertensive response to therapy according to randomized treatment group and will 
have final research testing for WMH, mobility, cognitive function as well as blood pressure 
control. Procedures previously defined above will be done at this visit:

Medical history, concomitant medications, adverse events, medication 
compliance

Standardized clinic BP measurements, body weight and height

Antihypertensive medication will be prescribed/continued according to clinical 
goals for long-term management. Clinical follow-up will be arranged with either 
primary care physician, one of the study physicians, or both, depending on 
wishes of study patient.

Safety laboratory studies (potassium, creatinine, BUN) if clinically necessary

Electrocardiogram 

Ambulatory blood pressure monitoring 

MRI acquired at UCONN neuroradiology

Mobility Testing

Cognitive Testing

Questionnaires related to urinary function, QOL
IRB Review
IRB NUMBER: IE-11-155S-2
VAL DATE: 04/16/2018
ppropriate;
IRB APPROVA
ppropriate; ad
AL D
ad hoc
DATE
hoc

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
23

Home BP monitoring
Early termination patients who complete at least 18 months of randomized therapy will be 
considered completed study patients and all comprehensive tests will be completed that 
were designated for visit 9.
SAFETY ASSESSMENTS 
5.7 Specification of Safety Parameters
There are no experimental antihypertensive drugs in the trial. All medications that will be used 
are quite mature and have been in clinical use for > 15 years. Due to the age of the study 
patients, a number of serious and non-serious adverse events are expected and will be 
tabulated according to treatment assignment.  Should a study patient have symptoms 
suggestive of vertebrobasilar insufficiency, whether prior to enrollment or during follow-up, the 
patient will be evaluated by a neurologist.  All discontinuations due to serious and non-serious 
adverse events will be tabulated according to treatment assignment as well. These include:
Serious Adverse Events

Major adverse cardiovascular events: cardiovascular death, nonfatal myocardial 
infarction, nonfatal stroke, unstable angina with urgent revascularization.

Cardiac arrhythmias not associated with ischemia

Hospitalized congestive heart failure

Falls and/or syncope associated with injury (e.g fractures)

Non-cardiovascular death

Venous thromboembolic events (pulmonary embolism, deep venous thrombosis)

Aortic aneurysm rupture, surgery

Peripheral arterial surgery

Coronary and peripheral revascularization, elective

Major life-threatening infections 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
24
Non-Serious Adverse Events

Potential symptoms/signs of low systolic BP (recorded systolic BP < 90 mmHg, 
postural reduction in systolic BP > 20 mmHg, lightheadedness, near syncope, falls 
without injury)

Non-serious or non-severe adverse events according to body system: allergic, 
hematologic, gastrointestinal, pulmonary, renal, etc.) 
Safety laboratory parameters
The key safety laboratory studies in the trial will include: hematocrit, potassium, sodium, 
creatinine, blood urea nitrogen, glucose, and AST. Each laboratory parameter will be evaluated 
in context of the individual patient. In general, large changes (e.g. doubling of serum creatinine) 
will be evaluated immediately, whereas small changes (e.g. a 15% increase in serum 
creatinine from baseline) will be repeated in a convenient fashion for the patient.  Potassium 
supplements will be prescribed as needed.
5.8 Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters
Serious adverse events and deaths will be recorded and reported to the NIA and DSMB 
within 48 hours of occurrence (or when the clinical staff become aware of the occurrence). 
Full descriptions of the serious adverse event and deaths will be made as soon as complete 
dossiers on the clinical information can be accumulated. Source documents from 
hospitalizations will be obtained in every case unless patient does not consent to do this. All 
reference to the patient will be redacted (name, names of relatives, date of birth, etc).
Stopping rule. A decision to discontinue the study will be based primarily on serious 
adverse events (SAEs).  In discussion with the DSMB as it relates to timing of any decision 
making, the study will be stopped if unexpected and possibly study-related SAEs occur in 
20% or more of the study population, or if an imbalance of these SAEs occur in 15% or 
greater of those participating in either treatment arm.  We anticipate that unexpected and 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
25
possibly study-related SAEs will be rare, because participants will be receiving well tolerated 
antihypertensive therapies with substantial clinical safety oversight by the PI and research 
staff. Research nurses and staff who assist in the conduct of the trial will detect SAEs. In 
addition to the immediate disclosure, complete reports of SAEs will be reviewed at monthly 
staff meetings with the PIs, research nurses and physicians. 
The NIH/NIA Adverse Events Monitoring Form will be used to collect detailed information 
about all serious adverse events, how they were handled, and their potential relationship to 
study participation.  The procedures for SAE reporting also include written documentation 
using clinical notes related to the adverse event and specific forms detailing the event with a
sign-off by clinical hypertension research MDs. Communication of recommendations and 
decisions from all parties (DSMB members, investigators, IRB) will be made in a timely 
manner as noted above. All of these individuals will receive a copy of the expected Serious 
Adverse Events Monitoring Form within 10 business days or sooner (48 hours) in the case 
of deaths and study-related SAES, at which point a decision will be made whether to 
convene a meeting. 
Reviews of SAE and other safety data will be made at 4 month intervals by the DSMB 
members. Each DSMB member will vote on whether the study should: 1) continue as 
planned without changes; 2) continue after a protocol amendment; or 3) stop the trial 
pending further investigation. If, after this meeting, the DSMB votes to stop recruitment or 
requests a protocol modification due to concerns with patient safety, the IRB and NIH 
project officer will be informed immediately. 
Other adverse events, such as cardiovascular, neurologic or renal adverse events not 
requiring hospitalization, will also be reported within 48 hours to the PIs by the study nurse 
and/or project manager.  A determination of how to proceed will be made based on 
IRB Review
IRB NUMBER: IE-11-155S-2
ROVAL DATE: 04/16/2018
eceiving
IRB APPR
eceiving well
OVAL
well tolerated
DATE: 04/
tolerated

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
26
consultation with the physician investigators on the project, or the patient's own physician, 
provided a release of information has been obtained.  These adverse events will also be 
recorded on an Adverse Events Monitoring Form, which is similar to the SAE form.  
A database of all adverse events will be maintained by the project manager in conjunction 
with the study nurse coordinator. Once per month, in research team meetings, all adverse 
events will be reviewed that occurred over the prior month, as well as over the course of the 
trial.  In addition, the local IRB maintains records of all adverse events.  Deaths and study 
related serious adverse events are reviewed immediately, and data are sent to NIH per 
standard policy. Aggregate data on reports of adverse events are reviewed on at least an
annual basis by the IRB for study continuation, and at 4 month intervals by the external 
DSMB and study investigators. Any temporary of permanent suspension of patient accrual 
will be reported to the NIH project officer.
5.9  Reporting Procedures
Serious and non-serious adverse events will be documented as noted above and reported 
on a regular basis to the project director, the PI, the IRB, and NIA as indicated.  Every 4 
months, reports of aggregate data will be submitted to the data safety committee members 
that contain baseline demographics, retention data, adverse events and laboratory data, and 
any other data that will help in the assessment of the clinical trial. Based on this report, each 
DSM committee member will recommend on whether the study should: 1) continue 
recruitment unchanged; 2) continue with a protocol amendment; 3) stop recruiting pending 
further investigation. If, after this meeting, any DSM committee member votes to stop 
recruitment or requests a protocol modification, the IRB will be informed.
IRB Review
IRB NUMBER: IE-11-155S-2
APPROVAL DATE: 04/16/2018
ent s
IRB A
ent s own
APPRO
own physician,
VAL DATE: 
physician,

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
27
5.10 Follow-up for Adverse Events
Participants who experience a significant medical problem requiring an overnight 
hospitalization at an acute care facility will be defined as having experienced a serious AE, 
which are expected to occur fairly regularly in this age group. Types of SAEs in the 
hypertensive population with vascular disease are as follows: cardiovascular complications 
of hypertension including myocardial infarction, stroke, arrhythmias, and heart failure.  Other 
non-serious adverse events (AEs), such as shortness of breath, dizziness, or near syncope 
not requiring hospitalization, will also be reported. All SAEs and AEs result in the completion 
of an Adverse Events Monitoring Form within 2 days of discovery to the PI and/or study 
coordinator by the research nurses and/or research assistants.
The Adverse Events Monitoring Form is adapted from one being used in the NIH Clinical 
Trials Network and our other ongoing trials. This form collects detailed information about all 
adverse events, how they were handled, and their potential relationship to study 
participation. The procedures for adverse event reporting also include written documentation 
using clinical notes related to the adverse event and specific forms detailing the event with a 
sign-off by all appropriate supervisory personnel.
We anticipate that unexpected and possibly study-related SAEs will be rare, because 
participants will be receiving well-tolerated, FDA approved pharmacotherapy. None of the 
study procedures are associated with SAEs. 
As noted above, clinical research staff will review all past month and study cumulative AEs 
and SAEs at monthly meetings. All research staff members have completed required 
institutional training on research with Human Subjects.  Research staff are trained in 
adverse event reporting and understand that their responsibility is to document and report 
adverse events reported by study participants, independent of determinations made at the 
time or later of the relationship between the event and participation in the study. 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
28
Adverse events will be followed until they are resolved or considered stable by the clinical 
investigative team. We have an AE/SAE log in every case report form that will be updated 
as the disposition of the adverse event evolves. The categories include a) resolved, b) 
reduced, c) unchanged.
5.11 Safety Monitoring 
This study has a formal data safety monitoring plan and will be evaluated by an 
independent Data Safety Monitoring Board (DSMB) (see appended draft DSMB Charter). 
6. INTERVENTION DISCONTINUATION 
A. Patients will be discontinued from their antihypertensive intervention if it is deemed that the 
treatment(s) or blood pressure level is no longer safe or appropriate based on clinical 
condition (e.g. development of congestive heart failure that mandates a specific regimen or 
development of a terminal malignancy).
B. Potential reasons for discontinuation of the intensive treatment might include untoward 
symptoms associated with low blood pressure related to development of a new morbidity 
(e.g. blood loss, sepsis) or intolerance to therapy (e.g. lightheadedness/syncope. In rare 
cases, hyperkalemia or hyponatremia may develop that would be unmanageable under the 
constraints of the protocol-drive therapies. Hypokalemia will be managed with aggressive 
potassium replacement to maintain serum levels > 3.5 meql/L.
C. As this is an intention-to-treat trial, patients who discontinue treatment interventions will be 
invited to participate in clinical follow-up and all comprehensive outcome studies at months 
18 and 36 of the trial.
D. In the event of temporary discontinuation of antihypertensive treatment (e.g. need to 
withhold antihypertensive medications due to surgery, post-operative bleeding, infection or 
other causes  of low blood pressure), reassessment of these individual patients will be made 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
table
IRB A
table by
PPR
by the
OVA
the clinical
L DATE:
clinical

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
29
Decreased ABP
C
A
B
Decreased WMH Accrual
Increased Mobility Function
Preserved  WM Microstructure
D
E
The Figure shows graphically how our hypotheses relate to one another.  Hypothesis 1 tests the combined effects of 
paths A, B, C, D & E i.e., the total effect of BP on mobility. Hypothesis 2 tests path A, Hypothesis 3 tests path D,  
Hypothesis 4 tests path B+E; together Hypotheses 2, 3 and 4 together test the effect of BP on mobility mediated 
through BP’s effects on WMH and WM microstructure. Hypothesis 5 tests the relative importance of paths A and B to 
that of path C, i.e., the degree to which the effect of BP on mobility is explained by WMH. Hypothesis 6 tests the 
relative importance of paths D and E to that of path C, i.e., the degree to which the effect of BP on mobility is explained 
by changes in WM microstructure.
in the research clinic for a return of BP levels towards baseline, and study medications will 
then be resumed.
7. STATISTICAL CONSIDERATIONS 
7.1 General Design Issues 
General considerations: Predictor, covariate, and dependent variables will be examined for outliers 
and data beyond the range of human performance. We will analyze variables on the original 
measurement scale, or on a scale that allows meaningful interpretation e.g., when an inverse 
transformation on a time measure results in a speed interpretation. The primary analyses 
(hypotheses 1, 2 and 3) will be intention-to-treat.
Hypothesis models, analysis plan, and power estimates for primary outcomes were developed 
with PASS 200835  and SAS PROC POWER36 were used for estimation of power.
8.2 Hypotheses and Statistical Analyses
Hypothesis path diagram
Hypothesis 1: Intensively treating 24-h systolic BP to a goal of <130 mmHg versus standard BP 
control of <145 mmHg will lead to faster walking speeds at T36. (Paths A&B+C+D&E)
IRB Review
IRB NUMBER: IE-11-155S-2
APPROVAL DATE: 04/16/2018
udy
IRB 
udy medications
APPROVAL DAT
medications will
TE: 0
will

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
30
Hypothesis 2: Intensively treating 24-h systolic BP to a goal of <130 mmHg versus standard BP 
control <145 mmHg will lead to smaller total WMH volume. (Path A) 
Hypothesis 3: Intensively treating 24-h systolic BP to a goal of <130 mmHg versus standard BP 
control <145 mmHg will stabilize brain WM microstructural integrity (FA and MD) at T36. (Path 
D)  We will perform 3 sets of analyses for hypotheses 1, 2 & 3: 
a.
Multiple linear regression will be performed with treatment group (intensive vs. 
standard) as the predictor of interest. Gait velocity at T36 is the primary outcome for 
hypothesis 1, WMH at T36 is the primary outcome for hypothesis 2, and DTI indices 
(FA and MD) are the primary outcomes for hypothesis 3. The analysis will be 
intention-to-treat. Age, sex, and 24 hour SBP at T0 (baseline) will be included as
covariates, along with other demographic factors for which the treatment groups are 
not comparable. The analysis for hypothesis 1 is the proposal’s primary efficacy 
analysis and thus the proposal is powered to address this analysis (see 
Sample size estimation). 
b. We will repeat analyses 1a, 2a  and 3a but with gait velocity at T18, total WMH at T18, 
and DTI indices at T18 as the primary outcomes. A comparison of these analyses 
with analyses 1a and 1b will determine the time course of the intervention’s effects. 
In particular, it will be important to determine if these effects occur early (T18) or 
require a 3-year treatment period. In addition, for participants who are present at T18 
but not T36, the data from T18 will be used to estimate the effect of informative loss to 
follow-up. (See Missing Data)
c.
We will further examine the progression of mobility and WMH changes using a 
progression model using methods adapted from Diggle:36 










0
0
18
0
*
*
36
0
cross sectional covariates + residual error 
cross sectional covariates + longitudinal covariates + residual error
cross sectional covariates +
i
i
T
i
i
i
T
i
L
E
i
i
i
T
i
L
E
i
Y
b
X
Y
b
X
X
Y
b
X
X




















 longitudinal covariates + residual error
  
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
ersus
IRB AP
ersus standard
PROVAL DA
standard BP
TE:
BP

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
31
Here,
are the outcomes (mobility or imaging) at T0 T18 and T36 for study
0
18
36
,
, and
i
i
i
Y
Y
Y
participant 
 and
 is the treatment group assignment indicator for study participant 
 and 
,i
i
X
,i
is a random intercept used to account for the fact that repeated measurements on 
0
ib
individuals are not independent; the other 
are fixed effects in this example although we 
'
j s

will consider the possibility that treating them as random effects will add to the model fit. The 
model will be fit as a linear mixed model.37, 38  The parameters of interest are 
 the 
*
, and 
,
E
E


difference in the outcome progression rate (mobility or imaging) between the treatment groups 
at T18 and T36.  If the difference in the rate of progression is constant during follow-up, we 
would expect 
 to approximately equal 
This allows a more powerful and rigorous test 
*
E

2
.
E


of whether the intervention’s effects are manifested quickly or over the long-term. Additional 
secondary analyses will use the T18 data to determine temporal continuity of the trends and as 
a partial assessment of the effect of dropout. Additional secondary analyses will use logistic 
regression with severity of urinary incontinence at T36 and T18 as an ordinal outcome.
Other mobility measures will also be examined as secondary outcomes in models otherwise 
identical to those in a, b, and c.  The analyses will be repeated for cognition, with the speed 
obtained on Trailmaking B at T36 as the primary outcome and other cognitive measures as 
secondary outcomes. Additional secondary analyses will use logistic and ordinal models with 
the same predictors and incontinence presence and severity, respectively as outcomes; the 
progression model (c) will be fit as binary or ordinal generalized linear mixed models. 
Hypothesis 4: Reduced total WMH and decreased markers of tissue damage on DTI at T0 and 
at T36 are linked to better mobility at T36. (Paths B+E)  The same outcomes will be used for 
this hypothesis as in hypothesis 1, with identical analyses except that WMH, and DTI indices 
(FA and MD) as continuous variables will be the primary predictor of interest. The power for 
this hypothesis as expressed as increased in explained variability (R2) will be the same as for 
hypothesis 1: 85% power to achieve an increase in R2 of 0.0533; we actually observed an 
increase in R2 of 0.1658, to 0.2925, as the effect of tWMH, corresponding to a reduction in gait 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
dId T
RBT36
B A
36 for
PPR
for study
OVAL D
study

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
32
velocity of 0.0063 m./sec. for each 0.1% increase in tWMH. The analyses will be repeated for 
gait velocity at T18 with a model corresponding to analysis b, and for the following progression 
model replacing the model for analysis c: 










0
0
0
18
0
0
18
0
36
0
0
36
0
cross sectional covariates + residual error 
cross sectional covariates + longitudinal covariates + residual error
cross sectional covar
i
i
C
i
i
i
C
i
L
i
i
i
i
C
i
L
i
i
Y
b
X
Y
b
X
X
X
Y
b
X
X
X


















iates + longitudinal covariates + residual error
Here, 
are the outcomes (mobility or imaging) at T0, T18 and T36 for study 
0
18
36
,
, and 
i
i
i
Y
Y
Y
participant 
 
 the tWMH at T0 T18 and T36 for study participant 
 and 
is a 
,i
0
18
36
,
, and 
i
i
i
X
X
X
,i
0
ib
random intercept that is used to take into account the fact that repeated measurements on 
individuals are not independent. The model will be fit as a linear mixed model37.  Again the 
other 
are fixed effects although we will consider the possibility that treating them as 
'
j s

random effects will add to the model fit. The parameters of interest are 
 the cross-
 and 
, 
C
L


sectional and longitudinal effects of the imaging measures on mobility over the 36-month 
follow-up. As secondary analyses we will consider interactions with treatment group and 
nonlinear effects in time. Analyses will be repeated for the other mobility and cognitive 
measures, also as linear mixed models, and urinary incontinence presence/severity as binary 
and ordinal generalized linear mixed models. 
Hypothesis 5: Total WMH at T0 and at T36 mediate the effect of treatment group, showing that 
the mechanism by which reduced ABP is linked to better mobility occurs by reducing 
total WMH.(Paths C - A&B)   Mediation models allow the evaluation of hypotheses using 
biological mechanisms. In this case, we believe that much of the salutary effect of reduced 
ABP results from reduced WMH. Assessing mediation involves estimating direct effects (Path 
C, above) and indirect effects (Paths A and B, above) in multistage predictor models by 
adding potential mediators to models describing the effect of a predictor on the outcome. To 
the extent by which WMH mediates the effect of BP, the effect of BP will be reduced in the 
model that includes WMH compared to the model not including WMH.  We saw this in our 
observational study, as the adjusted effect of SBP in the pseudo-treatment group was reduced 
IRB Review
IRB NUMBER: IE-11-155S-2
RB APPROVAL DATE: 04/16/2018
sIR
s will
RB A
will be
PPR
be repeated
OVAL DATE
repeated for
: 04
for

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
33
from a .15 m/sec. to a .1 m/sec. difference in gait velocity when WMH was added as a model 
predictor. 
Product of coefficients methods35.36 will be used for formal statistical inference regarding the 
mediation. Specifically, we will estimate the product of the effect estimated for hypothesis 2 
corresponding to Path A (the effect of intervention group on total WMH at T36), and the effect 
estimated for hypothesis 3 corresponding to Path B (the effect of WMH at T36 on gait velocity 
at T36). The magnitude of this product turns out to be proportional to the change in the effect of 
intervention group on gait velocity at T36 when WMH at T36 is added to a regression model of 
gait velocity at T36 as a function of intervention group. Similar models will be used to assess 
outcomes at T18, and the cognitive outcomes. As formal tests for mediation using the product
of coefficients method require larger sample sizes than available in this study, we will treat 
results from analyses in Hypothesis 5 as preliminary, to be potentially verified by a larger 
study should the main effects in Hypotheses 1-3 be confirmed.
Hypothesis 6: Diffusion tensor imaging (DTI) indices (FA, MD) at T0 and at T36 mediate the 
effect of treatment group, showing that the mechanism by which reduced ABP is linked 
to better mobility occurs by preserving brain WM microstructural integrity (FA, MD). 
(Paths C – D&E)  The same analysis as used for hypothesis 5, except that the mediating 
effect of the DTI indices will be assessed.
Missing Data. 
Death and study attrition are associated with age-related diseases.  Failure to account for 
this informative censoring may result in biased estimates of dementia risk and cognitive 
decline.37 Hence, we will collect data by telephone to assess the degree to which living 
participants who fail to appear for their final assessment differ from participants who 
complete the study. As mentioned above, we will use telephone administration of a validated 
mobility assessment39 and the method developed by Dr. Hall and colleague30 to estimate 
mobility outcomes through multiple imputation or joint modeling that would have been 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
as
IR
as added
B APPRO
added as
VAL
as a
L D
a model
DATE: 0
model

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
34
observed had the participants appeared for their clinical assessment. While our primary 
efficacy outcome analysis will be limited to participants who complete the study, this will be 
the first trial in aging with the potential to assess the impact of informative dropout beyond 
usual sensitivity analyses.
8.3  Sample Size and Randomization
We conservatively estimate that at least 140 of the original 200 participants will complete 
assessments at 35 months. We analyzed a subset of participants in our earlier observational study 
in order to mimic the results of the two treatment groups we expect to see in the intervention study. 
for a standard care arm, we selected participants in the observational study who had 24 hour 
systolic BP between 140 and 150 mmHg, inclusive, at follow-up, and for the intensive treatment 
arm, we selected participants with 24 hour Systolic BP between 120 and 130 mmHg, inclusive, at 
follow-up. A regression of gait velocity over 8 feet on our covariates age, sex, and 24 hour systolic 
BP at baseline showed an r2 of 0.1267. If we see similar results in the intervention study, 140 
participants (70 in each group) will give us 85% power to observe an increase in r2 of 0.0533 to 
0.1800. In our prior observational study, we saw an increase in r2 of 0.1082 to 0.2349, with a 
difference in gait speed between the two simulated treatment groups of 0.15m./sec.  While the 
0.15m/sec gait speed difference between the low and high BP groups appears small, it represents 
only 2 years of observation.  Mobility impairment linked to WMH is a long-term decremental process 
that limits gait velocity over 10 or more years.  Thus a “small” 2-year differential is both believable 
and meaningful. We are therefore confident that the proposed study has ample power to find 
smaller yet clinically significant effects for our primary outcome. A regression of total WMH on 
covariates age, sex, and 24 hour systolic BP at baseline showed an r2 of 0.1162. Similar results in 
the intervention study imply 85% power to observe an increase in r2 of 0.0540 for the effect of the 
treatment arm, to 0.1702. We actually observed an increase of 0.0861, to 0.2023, in the prior 
observational study, corresponding to a difference between the two simulated treatment groups of 
0.93% total WMH. 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
While
IRB A
While our
PPRO
our primary
VAL DATE
primary

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
35
8.3.1 Treatment Assignment Procedures
This trial is an open-label PROBE design – clinical staff and investigators will be aware of 
treatment assignment for safety and management. Those observers performing outcome tests 
(WMH calculations, mobility testing, cognitive assessment, and urinary function testing) will 
remain blinded to individual treatment group assignments until the end of the trial. .Interim 
analyses and Stopping Rules
8.3.2  Interim Analyses and Stopping Rules For Safety 
No interim analysis is planned that would result in stopping the trial early. 
Stopping rule for safety. A decision to discontinue the study will be based primarily on serious 
adverse events (SAEs).  In discussion with the DSMB as it relates to timing of any decision 
making, the study will be stopped if unexpected and possibly study-related SAEs occur in 20% or 
more of the study population, or if an imbalance of these SAEs occur in 15% or greater of those 
participating in either treatment arm.  We anticipate that unexpected and possibly study-related 
SAEs will be rare, because participants will be receiving well tolerated antihypertensive therapies 
with substantial clinical safety oversight by the PI and research staff. Research nurses and staff 
who assist in the conduct of the trial will detect SAEs. In addition to the immediate disclosure, 
complete reports of SAEs will be reviewed at monthly staff meetings with the PIs, research 
nurses and physicians. 
7.4 Outcomes 
See Section 8.2 for analysis of outcomes.
8. DATA COLLECTION AND QUALITY ASSURANCE
8.1 Data Collection Forms 
Appended to the protocol are case report forms (CRF) that will be used for all other clinical 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
36
data. The patients name or other identifying information is never recorded on the CRF or 
recorded by those individuals involved in the outcome assessments. Rather a unique study 
code # is given to each patient without regard to randomization treatment group. Laboratory 
reports and informed consent forms that do identify the study patients are maintained with a 
key of unique study code # in a locked cabinet in the clinical research unit with a back up list 
in the PI’s office.
8.2 Data Management 
This is a single site study. Our data management procedures are mature and standardized. 
Data are entered from the CRFs and outcome assessment forms into ACCESS, which allows 
ranges to be defined a priori, minimizing data entry errors. Data will later be imported into
SPSS, and within- and cross-file checks are used for cleaning and checking anomalous 
values. Data files are backed-up regularly to a secure server. 
8.3 Quality Assurance 
8.3.1
Training
We use centralized training, certification, and reliability testing for consistency across 
projects. In addition, monthly staff meetings will be held to review and remind staff  on data 
collection, informed consent, adverse events, confidentiality, etc, to research staff to 
enhance fidelity. 
8.3.2
Quality Control Committee 
Not applicable.
8.3.3
Metrics 
We have developed reproducibility methods for all outcome assessments. These methods 
allow us to develop a range of coefficients of variation for the various measures over time.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
ed
IR
ed on
B A
on the
PPR
the CRF
OVAL D
CRF or
DAT
or

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
37
8.3.4
Protocol Deviations
The project manager of the study and project statistician will regularly be reviewing the 
individual case report forms for deviations from the protocol as data are entered into the 
ACCESS database. Protocol deviations will be minimized by effective communication 
among clinical staff and study participants. In all cases, the deviations will be documented in 
a separate study binder and those of important magnitude must be reported to the 
University of Connecticut Institutional Review Board for assessment. 
8.3.5
Monitoring
As this is a single center study, external monitoring will not be in place. The institution does 
have a voluntary (and random involuntary) auditing process in place for all Human Subjects 
Trials that is conducted by an officer of the Office of Clinical and Translational Research. In 
theses audits, a random sample of CRFs are evaluated for protocol violations, as well as 
assessment of regulatory documents, informed consent forms and pharmacy records.
9. PARTICIPANT RIGHTS AND CONFIDENTIALITY 
9.1 Institutional Review Board (IRB) Review 
The study protocol and the informed consent document has been reviewed and approved by 
the IRB committee responsible for oversight of the study (University of Connecticut Health 
Center IRB).  Any subsequent modifications will be reviewed and approved by the University 
of Connecticut Health Center IRB.
9.2 Informed Consent Forms (Appendix)
A signed informed consent form (ICF) will be obtained from each participant. The ICF 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 record. 
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
38
9.3 Participant Confidentiality 
Any data, forms, reports, and other records that leave the site will be identified only by a 
participant identification number (Participant ID) to maintain confidentiality.  All records will be 
kept in a locked file cabinet.  All computer entry and networking programs will be done using 
participant IDs only. Information will not be released without written permission of the 
participant, except as necessary for monitoring by IRB, the FDA, the NIA, and the OHRP.
9.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the NIA, the OHRP, the FDA, or other 
government agencies as part of their duties to ensure that research participants are protected. 
10. COMMITTEES (NOT APPLICABLE OTHER THAN DSMB – SINGLE CENTER STUDY)
11. PUBLICATION OF RESEARCH FINDINGS
Publication of research findings are under the direction of the Principal Investigators and other Key 
Personnel.
12. REFERENCES 
1.
Vermeer SE DHT, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Incidence and risk 
factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke. Feb 
2003;34(2):392-396.
2.
Wolfson L. Microalbuminurea as an index of brain microvascular dysfunction. J Neurol Sci. 
Sep 15 2008;272(1-2):34-35.
3.
Kuller LH LW, Jr., Arnold AM, Bernick C, Bryan RN, Beauchamp NJ, Jr. White matter 
hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke. Aug 
2004;35(8):1821-1825.
4.
Rosenberg G. Matrix metalloproteinases and their multiple roles in neurodegenerative 
diseases. Lancet Neurol. Feb 2009;8(2):205-216.
5.
Benson R GC, Wei X, et al. Older people with impaired mobility have specific loci of 
perventricular abnormality on MRI. . Neurology. 2002;58:48-55.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
39
6.
Baloh RW YQ, Socotch TM, Jacobson KM. White matter lesions and disequilibrium in older 
people. I. Case- control comparison. Arch Neurol. 1995;52(10):970-974.
7.
Sakakibara R HT, Uchiyama T, Yamanishi T. Urinary function in elderly people with and 
without leukoaraiosis: relation to cognitive and gait function. . J Neurol Neurosurg 
Psychiatry. Nov 1999;67(5):658-660.
8.
Junque C PJ, Vendrell P, et al. Leuko-araiosis on magnetic resonance imaging and speed of 
mental processing. . Arch Neurol. 1990;47(2):151-156.
9.
Kuchel GA MN, Guttmann CR, et al. Localization of brain white matter hyperintensities and 
urinary incontinence in community-dwelling older adults. J Gerontol A Biol Sci Med Sci. Aug 
2009;64(8):902-909.
10.
Kaplan RF CR, Moscufo N, et al. Demographic and biological influences on cognitive reserve. 
. J Clin Exp Neuropsychol. Mar 31 2009:1-9.
11.
White WB WL, Wakefield DB, Hall CB, Campbell P, Moscufo N, Schmidt J, Kaplan RF, 
Pearlson GP, Guttmann CR. Average Daily Blood Pressure, not Office Blood Pressure, 
Predicts Progression of Cerebrovascular Disease and Functional Decline in Older People. 
Circulation. 2011 (revised manuscript submitted).
12.
Beckett NS PR, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or 
older. . N Engl J Med. May 1 2008;358(18):1887-1898.
13.
Schulz KF GD. Generation of allocation sequences in randomised trials: chance, not choice.
Lancet. Feb 9 2002;359(9305):515-519.
14.
Group A. Effects of intensive blood pressure control in type 2 diabetes. New Engl J Med. 
2010;362(17):1575-1585.
15.
Brater D. Diuretic therapy. N Engl J Med. Aug 6 1998;339(6):387-395.
16.
Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of 
age or older. N Engl J Med. May 1 2008;358(18):1887-1898.
17.
Jamerson K WM, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for 
hypertension in high-risk patients. N Engl J Med. Dec 4 2008;359(23):2417-2428.
18.
Cameron JD SI, Reed E, McGrath BP, Dart AM, Kingwell BA. Accuracy of automated 
auscultatory blood pressure measurement during supine exercise and treadmill stress 
electrocardiogram-testing. . Blood Press Monit. Oct 2004;9(5):269-275.
19.
White W. Expanding the use of ambulatory blood pressure monitoring for the diagnosis and 
management of patients with hypertension. Hypertension. Jan 2006;47(1):14-15.
20.
White WB WC, Borer JS, et al. Risk of cardiovascular events in patients receiving celecoxib: a 
meta-analysis of randomized clinical trials. . Am J Cardiol. Jan 1 2007;99(1):91-98.
21.
Campbell P GN WD, Wolfson L, White WB. Long-term reproducibility of ambulatory blood 
pressure is superior to office pressure in the very elderly. J Hum Hypertens. 2010;24:749-
754.
22.
Wakefield DB MN, Guttmann CR, et al. White Matter Hyperintensities Predict Functional 
Decline in Voiding, Mobility and Cognition in Older Adults. J Am Geriatr Soc. 2010;58:275-
281.
23.
Strauss E SM, Strauss. . A compendium of neuropsychological tests. New York: Oxford; 2006.
24.
Miller EN SP, Visscher B. Computerized and conventional neuropsychological assessment of 
HIV-1- infected homosexual men [see comments]. Neurology. 1991;41(10):1608-1616.
25.
Yesavage JA BT, Rose TL, et al. Development and validation of a geriatric depression 
screening scale: a preliminary report. . J Psychiatr Res. 1982;17(1):37-49.
26.
Brown JS BC, Subak LL, et al. The sensitivity and specificity of a simple test to distinguish 
between urge and stress urinary incontinence. . Ann Intern Med. May 16 2006;144(10):715-
726.
27.
Hanley J CA, Hagen S. Validity study of the severity index, a simple measure of urinary 
incontinence in women. . BMJ. May 5 2001;322(7294).
28.
Uebersax JS WJ, Shumaker SA, McClish DK, Fantl JA. Short forms to assess life quality and 
symptom distress for urinary incontinence in women: the Incontinence Impact 
Questionnaire and the Urogenital Distress Inventory. Continence Program for Women 
Research Group. Neurourol Urodyn. 1995;14(2):131-139.
IRB Review
IRB NUMBER: IE-11-155S-2
AL DATE: 04/16/2018
equilibrium
IRB APPROVA
equilibrium in
ALin older
DATE:
older

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
40
29.
Harvey MA KB, Griffith D, Versi E. The Incontinence Impact Questionnaire and the Urogenital 
Distress Inventory: a revisit of their validity in women without a urodynamic diagnosis. . Am 
J Obstet Gynecol. jUL 2001;185(1):25-31.
30.
Verghese J, Katz MJ, Derby CA, Kuslansky G, Hall CB, Lipton RB. Reliability and validity of a 
telephone-based mobility assessment questionnaire. Age Ageing 2004; 33: 628-632.
31.
Sled JG ZA, Evans AC. A nonparametric method for automatic correction of intensity 
nonuniformity in MRI data. . IEEE Trans Med Imaging. Feb 1998;17(1):87-97.
32.
Jenkinson M SS. A global optimisation method for robust affine registration of brain images. . 
Med Image Anal. Jum 2001;5(2):143-156.
33.
Pierpaoli C JP, Basser PJ, Barnett A, Di Chiro G. Diffusion tensor MR imaging of the human 
brain. . Radiology. 1996;201(3):637-648.
34.
Moscufo N GC, Meier D, et al. Brain regional lesion burden and impaired mobility in the 
elderly. Neurobiol Aging. Apr 2011;32(4):646-654.
35.
PASS 2008 [computer program]. 2008.
36.
SAS PROC POWER [computer program]. Cary, NC: SAS Institute.
37.
Diggle PJ. An approach to the analysis of repeated measurements. Biometrics. 
1988;44(4):959-971.
38.
Laird NM WJ. Random-effects models for longitudinal data. . Biometrics. 1982;38(4):963-974.
39.
Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38(4):963-
974.
40.
Sliwinski MJ HS, Hall C, Buschke H, Lipton RB. Modeling memory decline in older adults: the 
importance of preclinical dementia, attrition, and chronological age. . Psychol Aging. Dec 
2003;18(4):658-671.
13. APPENDIXES
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018
re
IRB
re and
B APP
and the
ROV
the Urogenital
AL DATE: 04
Urogenital

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
41
Addendum to Protocol
11 – 01 - 2012
Sleep Assessment: 
The relationship between brain white matter disease and sleep will be evaluated using two 
different instruments which have both been validated in older individuals.  
The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire which has been 
shown to provide a measurement of the subject's general level of daytime sleepiness1;2. 
This   8-item instrument evaluates the extent of subject sleepiness during various normal 
daytime activities.  
The Pittsburgh Sleep Quality Index (PSQI) offers a quantitative assessment of subjective 
sleep difficulties experienced by each individual3;4. The instrument generates “component” 
scores: subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, 
sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of 
scores for these seven components yields one global score3;4.
The sleep assessments will be administered at baseline, 18- and 36- month timepoints.
Reference List
1.
Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. 
Sleep 1991;14:540-545.
2.
Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 
1992;15:376-381.
3.
Buysse DJ, Reynolds CF, III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality 
Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-
213.
4.
Buysse DJ, Reynolds CF, III, Monk TH, Hoch CC, Yeager AL, Kupfer DJ. Quantification of 
subjective sleep quality in healthy elderly men and women using the Pittsburgh Sleep Quality 
Index (PSQI). Sleep 1991;14:331-338.
Hearing Sub-study Bibliography
1. Fransen E, Lemkens N, Van Laer L, Van Camp G. Age-related hearing impairment (ARHI): 
environmental risk factors and genetic prospects. Exp Gerontol. 2003;38:353–359.
2. Friedland DR, Cederberg C, Tarima S. Audiometric pattern as a predictor of cardiovascular 
status: development of a model for assessment of risk. Laryngoscope. 2009 Mar;119(3):473-
86.
3. Kaplan RF, Cohen RA, Moscufo N, et al. Demographic and biological influences on 
cognitive reserve. J Clin Exp Neuropsychol 2009;31:868-76.
IRB Review
IRB NUMBER: IE-11-155S-2
IRB APPROVAL DATE: 04/16/2018

IBP Trial #11-155S-2
Protocol -  version 8/1/2017
42
4. Musiek, F.E., & Baran, J.A. (2007). The Auditory System: Its Anatomy, Physiology and 
Clinical Correlates. Boston, MA: Allyn & Bacon.
5. Moscufo, N., Guttmann, C.R., Meier, D., Csapo, I., Hildenbrand, P.G., Healy, B.C., Schmidt, 
J.A., Wolfson, L., 2011. Brain regional lesion burden and impaired mobility in the elderly. 
Neurobiology of Aging 32, 646–654.
6. Schuknecht HF. Further observations on the pathology of presbycusis. Arch Otolaryngol. 
1964;80:369–382.
7. Vermeer SE, Den Heijer T, Koudstaal PJ, Oudkerk M, Hofman A, Breteler MM. Incidence 
and risk factors of silent brain infarcts in the population-based Rotterdam Scan Study. Stroke. 
2003;34:392–396.
8. Willot, J.F. (1996), Anatomic and physiologic aging: A behavioral neuroscience perspective. 
Journal of the American Academy of Audiology, 7, 141-151.
9. White WB, Wolfson L, Wakefield DB, Hall CB, et al. Average daily blood pressure, not 
office blood pressure, predicts progression of cerebrovascular disease and functional decline 
in older people. Circulation 2011;124:2312-9.
IRB Review
IRB NUMBER: IE-11-155S-2
RB APPROVAL DATE: 04/16/2018
y,IR
y, Physiology
RB APPROVAL 
Physiology and
DATE
and