Sleep Quality and Mechanisms of Cardiovascular Risks in Adults With Hypertension
Phase: NA
Conditions: Hypertension, Insomnia
Sponsor: Duke University

 
 
 
 
 
 
 
 
 
 
Sleep Quality and Mechanisms of Cardiovascular Risk in Adults with Hypertension 
 
Document Date: 11/29/2023 
 
NCT04009447 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Purpose of the Study 
  
The objective of the study is to elucidate the potential mechanisms responsible for the increased risk of 
CVD among patients with hypertension and comorbid insomnia. To address this issue, we propose to 
utilize a behavioral intervention to manipulate sleep quality in 150 adults with hypertension and 
comorbid insomnia, who will receive a 6-week Cognitive Behavioral Therapy for Insomnia (CBT-I) 
intervention, which has been shown to markedly improve sleep quality and promote consolidated sleep 
in approximately 60% of those treated. Blunted nighttime blood pressure dipping is one of several 
proposed mechanisms to be examined. 
 
 
Background & Significance 
 
There is a growing body of evidence that insomnia is a CVD risk factor.  In a meta-analysis of 17 
observational cohort studies, with a combined sample size of 311,260 participants free of CVD at 
baseline, Li and colleagues found that insomnia was associated with a 41% increased risk of myocardial 
infarction (MI), coronary heart disease (CHD), stroke, or CVD mortality over a 1-year follow-up period.  
Similarly, in an analysis of 13 prospective cohort studies of adults with insomnia (N=122,501), but absent 
of documented CVD, Sofi and colleagues  found a 45% increased risk of developing or dying from CVD 
over a follow-up period of 3 years or more.  As the latter authors, concluded, “Insomnia is associated 
with an increased risk of developing and/or dying from cardiovascular disease. The evidence that low-
quality sleepers are at higher risk of myocardial infarction and other cardiovascular disease is extremely 
important for primary and secondary prevention.”  Even in the absence of an insomnia disorder 
diagnosis, poor sleep quality has been linked to CVD risk.  In a meta-analysis of 20,432 adults, aged 20-
65 years without history of CVD followed for 10-15 years, Hoevenaar-Blom et al.26 reported that poor 
sleep quality was associated with a 22% higher risk of developing CVD and a 34% higher risk of CHD 
incidence than those with good sleep quality.  Lo and colleagues18 also recently reported a meta-
analysis of studies including over 45,000 participants, spanning over 5 continents, showing that poor 
subjective sleep quality was associated with increased likelihood of hypertension.  Similarly, in a review 
of 17 observational cohorts studies, which included a total sample of 58,924 participants with at least 1 
year of follow-up data, Meng et al. found that insomnia was associated with an increased incidence of 
hypertension. 
  
Although the link between insomnia and hypertension has gained wide acceptance, recent reviews note 
that this evidence is based upon clinic BP.   However, clinic BP is markedly inferior to BP measured over 
24-hours using wearable ABPM technology.  In healthy adults, the normal circadian BP profile reveals 
that BP dips during the nighttime sleep period; importantly, a blunted nighttime BP dip (<10% dip in BP 
due to elevated nighttime BP) is the strongest BP predictor of CVD morbidity and mortality.  Blunted 
nighttime BP dipping is characteristic of 30-40% of patients with hypertension, and there has been 
growing interest in strategies to target and lower nighttime BP in the management of hypertension.   In 
patients with hypertension whose BP is managed using antihypertensive medications, there is 
compelling evidence that nighttime dosing of antihypertensive medications augments nighttime BP 
dipping.  Moreover, this pharmacological chronotherapy has been shown to reduce the risk of adverse 
CVD events, underscoring that blunted nighttime BP dipping is an important mechanism contributing to 

heightened CVD risk.  However, for patients with insomnia and hypertension, it is possible that 
behavioral treatment of their insomnia may be a non-pharmacologic approach that could also benefit 
their BP as well as overall CVD risk.  For example, current guidelines recommend consideration of non-
pharmacologic interventions that include weight loss for overweight or obese patients, together with a 
heart-healthy diet comprising reduced sodium, lower saturated fat and limited alcohol consumption, 
which may lower systolic blood pressure (SBP) by approximately 11 mm Hg.  Nonetheless, despite its 
association with hypertension and CVD risk, whether insomnia is a reversible CVD risk factor remains 
unknown. 
  
A.2. Mechanisms Underlying the Link between Insomnia and CVD risk 
 
Recent reviews and meta-analyses have emphasized that two critical kinds of studies are required in 
order to understand the link between insomnia, hypertension and increased CVD risk.  First, there is a 
need for studies focusing on the possible mechanisms by which insomnia and poor sleep quality may 
contribute to CVD risk.  Second, studies should determine if these mechanistic pathophysiological 
pathways can be modified if sleep quality is improved and/or insomnia successfully treated. As others 
also have noted, and as we have emphasized in a recently published commentary, the most conspicuous 
candidate mechanism by which poor sleep and insomnia are likely to contribute to CVD risk is by 
disrupting the normal circadian variation in BP, by blunting the extent to which BP falls during the 
nighttime sleep period. In the study proposed in this application, by evaluating whether nighttime BP 
dipping is modified when sleep quality is manipulated, we will help establish whether BP dipping is a 
mechanism by which insomnia contributes to CVD risk.   In this way, we also propose to evaluate other 
putative bio-behavioral mechanisms.  Our own work has documented that blunted nighttime BP dipping 
is related to nighttime SNS hyperactivity in men and women with hypertension.  The SNS has long been 
implicated in the pathogenesis of hypertension, and more recently in various manifestations of CVD, and 
is a potential mechanism related to insomnia.  In their systematic review of 32 studies, Aziz and 
colleagues reported that poor subjective sleep quality was associated with vascular abnormalities 
related to hypertension and CVD risk, including endothelial dysfunction and arterial stiffness.  Both of 
these potential sleep-related mechanisms have also been related to blunted nighttime BP dipping, with 
elevated nighttime SNS activity speculatively involved.  Recent evidence that blunted nighttime BP 
dipping is due to elevated nighttime systemic vasoconstriction is also consistent with the possibility that 
these vascular mechanisms contribute to CVD risk associated with insomnia. Indeed, vascular 
endothelial dysfunction is associated with blunted nighttime BP dipping in hypertension.  Carroll and 
colleagues found that improved sleep quality in men and women with insomnia resulted in an improved 
lipid profile, an additional mechanistic pathway that would exacerbate the progression of vascular 
disease and increase CVD risk.  Our conceptual model (Figure 1) illustrates how these candidate 
mechanisms may contribute to hypertension and CVD risk through their association with poor quality 
sleep and insomnia.  As illustrated by this conceptualization, the putative mechanisms by which 
insomnia is hypothesized to convey increased CVD risk are interrelated pathways, with elements of a 
cascading pathophysiology.  Improving sleep quality in those with hypertension and comorbid insomnia 
is therefore expected to result in favorable changes in these mechanistic pathways.  Because these CVD 
mechanisms are also related to hypertension, it is possible that improved sleep quality may have a 
broader antihypertensive effect.   Importantly, improvements in sleep quality that result from CBT-I are 
not transitory; a recent report documented that the improved sleep benefits are maintained for up to 

10 years after completion of treatment.  Sleep quality improvement following the CBT-I intervention 
may affect some mechanisms (e.g., augmented nighttime BP dipping) immediately, while other 
mechanisms (e.g., improved lipid profile) may emerge over several weeks, but could be sustained long 
term.  Thus, our study design includes complete 6-month follow-up assessments in order to examine the 
possibility of progressive improvements in CVD risk mechanisms, and overall CVD risk. 
  
In summary, the objective of this application is to further our understanding of the association between 
insomnia, hypertension, and CVD risk by focusing on the potential mechanisms involved.  We aim to 
ascertain whether these mechanisms are affected favorably when sleep quality is improved by a 
behavioral intervention in those with insomnia, thereby also importantly determining whether poor 
sleep quality is a modifiable CVD risk factor.  Exploratory aspects of this research study will include a 
focus on individual difference characteristics, with a particular interest in race, in view of extensive 
evidence that both poor sleep quality and nighttime BP non-dipping are especially common amongst 
African-American adults. Importantly, the study objectives are consistent with the call to consider 
nighttime BP a therapeutic target, and should help determine if interventions to improve sleep quality 
can favorably modify this characteristic of the circadian BP profile that appears to be a pathway leading 
to heightened CVD risk. 
  
RESEARCH STRATEGY: B. INNOVATION           
  
Insomnia and CVD Risk Mechanisms - To our knowledge, this is the first study that includes a sleep 
manipulation intervention as an approach to identifying the mechanisms that link insomnia to CVD risk.  
Several recent reviews and meta-analyses of this field have emphasized the need for studies designed to 
help identify these mechanisms.  Previous studies have been limited by their cross-sectional designs, 
whereas the study proposed in this application should yield evidence of several mechanisms whereby 
insomnia conveys increased CVD risk. 
 
The evidence that insomnia is a CVD risk factor has arisen from multiple observational studies, but 
whether it is a reversible risk factor is unknown - The proposed study will help establish whether those 
who respond to CBT-I with reduced insomnia symptoms and improved sleep quality are also likely to be 
characterized by ameliorated CVD risk. 
 
Interventions that can achieve sustained improvements in sleep quality have the potential to abate the 
putative mechanisms that link insomnia to increased CVD risk – Because the improvement in sleep 
quality in response to CBT-I has been shown to persist for at least 10 years, the mechanisms conveying 
CVD risk are also likely to remain favorably modified.  The proposed study includes a 6-month follow-up 
assessment to evaluate this possibility. 
 
The mechanisms of insomnia-related CVD risk will be studied in the context of adults with hypertension 
– The proposed study will focus on adults with hypertension (and comorbid insomnia) because the 
presence of these two CVD risk factors has been shown to be interrelated, with their associated 
mechanisms of CVD risk also potentially shared.  This patient population therefore affords the potential 
to show marked improvements in the mechanisms of CVD risk.  The study outcomes should pave the 

way for future research using CBT-I to target sleep in other medical conditions where insomnia is a 
common comorbidity. 
 
 
Design & Procedures 
 
The study design reflects our objective of identifying the mechanisms responsible for the increased risk 
of CVD among patients with hypertension and insomnia, and to determine if these mechanisms can be 
favorably altered by improving sleep quality. We propose to utilize a behavioral intervention to 
manipulate sleep quality in 150 adults with hypertension and comorbid insomnia.  This mechanistic 
clinical trial design will assign all 150 participants to a 6-week CBT-I intervention, which has been shown 
to markedly improve sleep quality and promote consolidated sleep in approximately 60% of those 
treated; whereas approximately 40% do not respond to CBT-I.30  While CBT-I is generally effective, the 
anticipated wide-ranging treatment response will provide the prerequisite variability in sleep quality 
changes that will afford us the opportunity to help identify the mechanisms by which insomnia conveys 
CVD risk and by which improved sleep may lower CVD risk.  Our design (see Figure 5 below) will include 
a 6-week run-in period, without treatment, to document the stability of sleep quality, ABP, and CVD risk 
mechanisms, which will serve as a basis of comparison following CBT-I treatment.  Assessments will be 
performed at baseline, after the 6-week run-in period, after the subsequent 6-week CBT-I intervention, 
and at 6-month follow-up.  Importantly, the study design will also establish whether these insomnia-
driven CVD risk mechanisms are modifiable by CBT-I for participants who show improved sleep following 
treatment.  
  
Screening Assessments. Initial telephone screening will be used to ascertain whether potential 
participants are likely to meet the study eligibility criteria, with a focus on previously observed clinic BPs 
and the presence of insomnia symptoms. For those who are likely eligible, the first of two screening 
sessions will be scheduled, at which informed consent will be first obtained. A medical history will be 
taken for eligible participants. For women, menopausal status will be documented by self-reported 
menstrual bleeding, using the criteria described by Tom and colleagues. Status categories are 
postmenopausal (natural or surgical), perimenopausal, and premenopausal. Menopausal status will be 
considered as a potential covariate in analytic models. 
 
ReScreening - If a participant fails to meet all eligibility criteria, but remains interested in participating in 
the study, they will  have the option to be rescreened at a future date.  If the rescreening occurs within 3 
months, only the eligibility criterion which made them ineligible initially will be reassessed in order to 
ascertain their eligibility at rescreening; if rescreening occurs after more than 3 months, then the full 
screening protocol will be repeated.  The participant will be re-consented at the time of rescreening.  
 
Office BP Screening Assessment. At the first lab screening session, BP will be determined by unattended  
automated office blood pressure (AOBP) measurement using the Omron HEM-907 Professional 
Intellisense BP Monitor. AOBP measurement minimizes the “white coat” effect and correlates more 
closely with ambulatory BP than do standard office measurement techniques. After seating the 
individual in a quiet room, a cuff of appropriate size will be wrapped around the individual’s non-
dominant upper-arm and the Omron HEM-907 will be operated in automated mode: After starting the 

monitor, the Research Assistant will leave the room, and after a lapsed time of 5 minutes, the monitor 
will take a total of three BP measurements, each 2 minutes apart; the average of these three readings 
will be used to define office BP at that visit. If BP meets the studies inclusion/exclusion criteria, a second 
screening session will be scheduled, and if BP continues to meet criteria, the individual will be enrolled 
as a study participant (assuming all other inclusion/exclusion criteria are also met). This method for 
office BP assessment also will be completed subsequently at all four laboratory assessment sessions. 
 
Sleep Apnea Screening and Exclusion Assessments. A previous diagnosis of obstructive sleep apnea 
(OSA) is an exclusion criterion. The Snoring, Tiredness, Observed apnea, high BP, BMI, Age, Neck 
circumference and male Gender (STOP-BANG) questionnaire will be used to screen potential study  
participants for OSA.88 Potential participants scoring >3 on this scale, who otherwise meet all study 
eligibility criteria, will be required to complete a further screening assessment by the WatchPat device 
(Itamar Medical, Caesarea, Israel). The WatchPat device is a convenient tool that is worn in the comfort 
of potential participants’ own bedroom and is found to be a sensitive and specific assessment for 
identifying the presence of OSA. Participants are given the option of using a Duke owned iPhone or their 
own smart phone that works with the WatchPat device.  Potential participants showing an apnea-
hypopnea index (AHI) > 15 will be notified that they are no longer eligible to continue, and will be 
encouraged to seek additional evaluation and treatment through their physician.  If someone has 
completed a polysomnography sleep test in the last 3 months, these results can be used instead of the 
Watchpat device. 
 
C.3. SLEEP MANIPULATION INTERVENTION 
 
Cognitive Behavior Therapy for Insomnia (CBT-I). CBT-I is a well-established behavioral treatment for  
insomnia that successfully reduces insomnia symptoms and improves both subjective and objective 
measures of sleep quality. The approach to CBT-I for the proposed study is based on CBT-I programs that 
have been practiced and studied by research team members.94,95 CBT-I is manualized in a session-by-
session guide. Our proposed study co-investigator, Dr. Christie Ulmer serves as a consultant and trainer 
on the nationwide dissemination of CBT-I (see biosketch). Dr. Ulmer will train study therapists to deliver 
CBT-I in accordance with the training approach adopted by the CBT-I dissemination effort. Further, our 
sleep consultant, Dr. Jack Edinger, will assist in the interventionist training and will oversee the fidelity 
measures and methods. CBT-I treatment will be delivered by Dr. Ulmer and one additional study 
therapist over 6 one-hour individual sessions. 
 
Intervention Training and Fidelity. A second study therapist will be trained by Dr. Ulmer, according to 
consensus guidelines. Initial didactic training (covering session-by-session procedures, core components 
of CBT-I) will last three days and be followed by training cases. The therapists will be allowed to provide 
the intervention once they have demonstrated 100% competence and adherence with all required 
treatment elements. The therapist will meet weekly for supervision throughout the trial. All therapy 
sessions will be recorded. A random selection of twenty percent will be rated for fidelity. In order to 
protect against drift, the frequency of fidelity checks will occur equally across the beginning, middle, and 
end of the intervention period. Dr. Edinger will rate therapist treatment fidelity/adherence for recorded 
sessions using the adapted version of the Yale Adherence and Competence Scale. Recordings will be 
rated on the presence/absence of CBT-I elements. In addition, recordings will be rated on the 

presence/absence of nonspecific treatment elements (e.g., therapeutic alliance, patient expectancies). 
Feedback from fidelity checks will be provided by Drs. Edinger and Ulmer. 
 
CBT-I Intervention Protocol Summary. The CBT-I intervention will be delivered individually and in person  
by one of the therapists, over six one-hour weekly sessions.  In circumstances where in-person visits 
prevent participation, the CBT-I intervention can be delivered via telephone.  The CBT-I protocol is 
summarized below: 
 
Session 1: Sleep Education and Introductions to CBT-I and Sleep Diaries. Participants will receive an 
overview of CBT-I treatment concepts and approach, in addition to education about sleep regulation 
processes and the cognitive and behavioral processes involved in the development of insomnia. At the 
end of the session, they will be instructed in establishing realistic treatment goals and the process for 
keeping weekly sleep diaries. 
 
Session 2: Introduction to Sleep Restriction Therapy and Stimulus Control. The therapist will introduce 
Stimulus Control and Sleep Restriction Therapy guidelines and rationale. Sleep Restriction Therapy (SRT) 
is designed to strengthen the homeostatic sleep drive by restricting time in bed to actual sleep time as 
determined by sleep diary. The sleep “prescription”, or allowable sleep window, is gradually increased 
over the course of treatment to extend sleep duration. Stimulus Control is a set of instructions designed 
to strengthen the association between the bed/bedroom and sleep, and to establish a consistent sleep–
wake schedule. Participants will receive education and intervention based on treatment targets 
identified in Session 1 in addition to the sleep pattern information gleaned from the sleep diary review. 
Sleep hygiene education will be provided for topics that are relevant to the participant (e.g., the effects 
of alcohol on sleep). An initial “sleep prescription” will be established and participants will be asked to 
follow this sleep schedule during the upcoming week. Cognitive therapy will be used, as needed, to 
address dysfunctional beliefs about sleep and to enhance adherence. 
 
Session 3: Introduction to Relaxation Therapy. Participants will be introduced to Relaxation Therapy. The  
therapist will review the sleep diary with the participant and modify the sleep prescription, as needed, in  
accordance with SRT99 principles. Participants will be reinforced for adherence and progress. Barriers to  
adherence will be discussed and addressed using education, motivational enhancement, and cognitive  
therapy. Participants will be asked to practice relaxation strategies, follow their sleep prescription, and 
continue to track their sleep on diary during the upcoming week. 
 
Sessions 4 and 5: Sleep Prescription Titration. The therapist will review the sleep diary with the 
participant and modify the sleep prescription, as needed, in accordance with SRT principles. Barriers to 
adherence will be discussed and addressed using education, motivational enhancement, and cognitive 
therapy. Participants will be asked to continue using relaxation strategies, follow their sleep 
prescription, and track their sleep on diary during the upcoming week. 
 
Session 6: Relapse Prevention. The therapist will review the sleep diary with the participant and provide 
instruction on adjusting their sleep schedule after treatment, as needed. Treatment gains will be 
reviewed, and the therapist and participant will jointly develop a plan for ensuring that treatment gains 
are maintained. 

 
C.4. ASSESSMENTS OF INSOMNIA AND SLEEP 
 
The following laboratory-based and ambulatory assessments will be completed at baseline and repeated 
following the 6-week run-in control period, following the 6-week CBT-I intervention, and at 6-month 
follow up.   
 
Insomnia and Sleep Assessments. Sleep will be assessed by both subjective and objective measures. 
Subjective measures will include sleep diaries, self-report measures of sleep quality, insomnia severity, 
and perceived daytime sleepiness. However, the primary measures of sleep quality and their anticipated 
changes following CBT-I will be actigraphy-based objective measures. 
 
Interview-Based Assessment of Sleep. The Duke Structured Interview for Sleep Disorders (DSISD) follows 
DSM-V and the International Classification of Sleep Disorders criteria, and will be administered to 
identify those with insomnia disorder at screening. The DSISD was developed by the proposed study 
consultant, Dr. Edinger, and has been shown to have good reliability and validity.  
 
Actigraphy Sleep Assessments. Sleep and daily physical activity will be recorded using an accelerometer 
(Actigraph GT9X Link, Actigraph, Pensacola, Florida), unobtrusively worn on the wrist of the non-
dominant arm. The Actigraph GT9X monitor is a small, lightweight device that utilizes a 3-axis MEMS 
accelerometer, with motion sampled at a frequency of 30-100 Hz, and has been utilized and validated in 
both healthy and patient populations.102,103 Participants will wear the Actigraph 24 hours/day for 7 
consecutive days, at baseline, upon completion of the 6-week run-in period, upon completion of the 
CBT-I intervention, and at 6-month followup. The actigraphy data will be processed using ActiLife and 
ActiLife+Sleep software (Actigraph, Pensacola, Florida), which was developed in collaboration with the 
US and international sleep and activity research community; scoring of actigraphy data will proceed in 
accordance with the guidelines of the Society of Behavioral Sleep Medicine. Recorded sleep log times, 
confirmed by an event marker, will be used to establish “lights out” and “out of bed” times.  
ActiLife+Sleep software will be used to derive our primary outcome measure of sleep quality, sleep 
efficiency (SE). Other sleep parameters of interest will be Time in Bed (TIB), total sleep time (TST), wake 
after sleep onset (WASO), and sleep fragmentation index (SFI). Sleep duration will be defined as TST 
(calculated by subtracting all periods of wakefulness from the time spent in bed). WASO is calculated by 
summing wakefulness periods after initial sleep onset and before final awakening. Sleep efficiency is 
defined as the ratio of total sleep time divided by TIB ((TST/TIB)*100). Sleep fragmentation is defined as 
the sum of percent mobile and percent immobile bouts less than 1-minute duration to the number of 
immobile bouts for a given interval. Actigraphy also provides reliable measurements of daily life physical 
activity and has been extensively validated against self-report, observational measures, and oxygen 
consumption estimates of physical activity. Therefore, the ActiLife software will also be utilized to derive 
daily cumulative step count and daily energy expenditure (kcal/d). All physical activity and sleep 
parameters derived using actigraphy will be based on the 8-consecutive-days monitoring protocol and 
represented as average daily activity/sleep values at each assessment phase (baseline, upon completion 
of the 6-week run-in period, upon completion of the CBT-I intervention, and at 6-month follow-up). 
 

Subjective Assessments of Sleep. Subjective insomnia severity will be evaluated utilizing the Insomnia 
Severity Index (ISI). The ISI provides a global measure of perceived insomnia severity. Total scores range 
from 0-28, with higher scores indicating higher severity. The ISI has excellent internal consistency 
(Cronbach alpha = 0.74) and temporal stability (r = 0.80). The ISI has been validated with sleep diaries 
and polysomnography (PSG). In clinical samples, a cut-off score of 11 was shown to have the greatest 
sensitivity and specificity for correctly identifying study participants meeting criteria for insomnia 
diagnosis. We also propose to use the Pittsburgh Sleep Quality Index (PSQI), a 19-item measure of sleep 
quality and disturbances over the past month, which has been shown to have internal consistency and 
validity. These subjective measures also will be used to document the extent to which the CBT-I 
intervention was effective at improving sleep quality in study participants, and are expected to show a 
strong association with changes in the objective actigraphy-based measures. Morningness Evenningness 
Questionniare will assess circadian rhythms. 
 
Daily Sleep Diaries. Subjective sleep estimates will be obtained concurrent with actigraphy. Participants 
will record their sleep using the recently developed consensus sleep diary to assure comparability across 
insomnia research studies. The sleep diary is considered the gold standard of self-reported sleep. 
 
C.5. ASSESSMENT OF MECHANISMS OF CARDIOVASCULAR RISK 
 
The following laboratory-based and ambulatory assessments will be completed at baseline and repeated 
following the 6-week run-in control period, following the 6-week CBT-I intervention, and at 6-month 
follow up. Assessors will be blinded to the study phase at which data are collected.  
 
Office BP Assessment. Automated office BP (AOBP) will be obtained using the Omron HEM-907 
 
Professional Intellisense BP Monitor. The office BP assessment protocol is described under “Office BP 
Screening Assessment” described earlier in this application. 
 
24-hour Ambulatory Blood Pressure (ABP) Monitoring. We will use the Oscar 2 ABP monitor (Suntech 
Medical Inc., Raleigh, NC), which has been validated previously according to US and International 
standards. Study participants will be instrumented with the ABP monitor between 6:00-10:00 am on a 
typical weekday (Mon-Fri), and the monitor will be programmed to take BP measurements every 20 
minutes throughout the waking hours and every 30 minutes during the nighttime sleep period. We have 
used this procedure with excellent participant acceptability and compliance in numerous previous 
studies. A successful 24-hour study will require at least 80% of the total readings to be valid, with no 
more than two consecutive hours lacking a valid reading, and at least one valid measurement per hour 
during the nighttime sleep period.119 Unsuccessful ABP studies will be repeated. Because a single 24-
hour ABPM record has been shown to be of greater prognostic value than multiple clinic BP readings, it 
has become an accepted gold standard for evaluating intervention effects on BP. In addition to mean 24-
hour ABP, mean waking and mean nighttime BP will be computed, with the nighttime sleep period 
defined by selfreported sleep logs, in accordance with the Society for Behavioral Sleep Medicine (SBSM) 
guidelines. Nighttime BP dipping will be defined as the percentage of the decline in nighttime SBP 
((mean daytime SBP - mean nighttime SBP/mean daytime SBP) × 100); SBP dipping defined in this way is 
a continuous variable that will be a primary outcome measure of sleep-related CVD risk mechanisms in 

the proposed study. In addition, for descriptive purposes, a SBP dip ≥ 10% will be classified as normal 
“dipper”, while <10% will be classified as “non-dipper”, with secondary analyses evaluating intervention 
effects on dipping status. As noted earlier in this application, the causes and consequences of blunted 
nighttime BP dipping has been a focus of our prior research. Importantly, our recent work shows that 
ABPM does not disturb sleep, and a single successful 24-hour ABP study provides adequate 
representation of the diurnal ABP profile in patients with hypertension.17,51 24-hour ABP assessments 
will be obtained.  
 
Echocardiogram 
 
Patients with insomnia are at increased risk of heart failure and of cardiovascular events.  A focused 
echocardiogram (2-D images of the heart in the parasternal long axis and apical 4-chmaber views, pulsed 
wave Doppler of mitral inflow, and tissue Doppler imaging of the mitral annulus) will be performed to 
examine echocardiographic predictors of cardiovascular morbidity and mortality.  Left ventricular mass, 
left ventricular global longitudinal strain (an index of systolic function), and measures of diastolic 
function of the left ventricle will be examined to determine if these parameters are modified by 
improved sleep quality. This will be performed pre-CBTI and at the 6 month follow-up. Dr. Hinderliter 
will read all the echocardiograms and will be sent these images using DukeBox. The images will only 
include the date, therefore a transfer of a limited dataset of PHI has been established.  
  
 
24-hour Urinary Catecholamines and Electrolytes. Patients will be asked to collect urine over a 24-hour 
period. Urine samples will be kept cold by storage in a portable cooler throughout each 24-hour sample 
period. Urine will be collected in two containers provided to each participant in a portable cooler, with 
careful instructions to collect daytime/awake urine in containers labeled accordingly, including the last 
collection before bedtime; any nighttime/sleep period urine collection will be collected in the container 
labelled “nighttime”, and participants will be instructed to void using that collection container as soon as 
they get up in the morning. Samples will be assayed for norepinephrine, epinephrine, and creatinine. 
Catecholamine levels will be expressed as urine concentration ( g/ml) per urine concentration of 
creatinine (mg/ml), yielding norepinephrine and epinephrine values of g per mg creatinine for each 
sample. This provides catecholamine excretion indices that are corrected for individual differences in 
body size and urine volume. We will also assay for sodium and potassium as dietary habit changes may 
be contributory mechanisms of BP change, worthy of exploration. In prior studies of circadian changes in 
sympathetic activity, urinary catecholamine data have proven informative, with low subject burden and 
excellent compliance.  The 24-hour urine collection will be done twice, before and after CBT-I.  
 
Vascular Endothelial Function - Flow Mediated Dilation (FMD). Our approach for assessing endothelial 
function conforms to the recently published guidelines for assessment of flow-mediated arterial 
vasodilatation. 
 
Longitudinal B-mode ultrasound images of the brachial artery, 4-6 cm proximal to the antecubital 
crease, will be obtained at end-diastole (ECG R-wave gated digital image capture) using a dedicated 
Acuson Sequoia ultrasound platform. All images will be acquired with participants supine, utilizing an 11 
MHz linear array probe with stereotactic holder in our temperature-controlled clinical research 

laboratory, by Michael Ellis, RDMS, RVT, who has over 20 years of experience performing the 
standardized image acquisition protocols for our ultrasound FMD assessments. In an unpublished 
evaluation of 20 healthy men and women who underwent our FMD assessment protocol on two 
consecutive days, repeat FMD values showed a correlation of r=0.81, p<.001, and a mean absolute 
difference of 0.64%. Images will be obtained and stored digitally at resting baseline, as well as during 
and following inflation to 220 mm Hg of an occlusion cuff placed around the forearm, 2 cm below the 
elbow. All arterial diameter measurements will be performed by the same experienced member of the 
research team, blinded to participant identity and the study phase at which the assessment was made, 
using edge detection software (Brachial Analyzer, MIA-LLC, Coralville, IA). FMD response will be assessed 
from 10-120 seconds post-deflation of the forearm cuff, with peak arterial diameter quantified using 
polynomial curve fitting, and FMD thereby defined as the maximum percent change in arterial diameter 
relative to pre-inflation resting baseline. As others have reported, using this rigorous standardization of 
FMD methodology, our FMD assessments will be obtained with optimal reproducibility, reflected in a 
coefficient of variation of approximately 10% or less. Peak hyperemic flow and shear stress will be 
derived by standard formulae based upon Doppler velocity measurements during the first 10 seconds 
following deflation of the occlusion cuff. 
 
Arterial Stiffness. Aortic pulse wave velocity (PWV), measured using the Complior system (Artech 
Medical, Pantin, France), will be our validated index of central arterial stiffness. Pulse pressure 
waveforms will be recorded from the right carotid and right femoral arteries, and PWV through the 
descending aorta, measured in meter/sec, is calculated from measurements of pulse transit time and 
the distance travelled by the pulse, derived from the distance between the two recording sites. The 
PWV assessment will be performed by Michael Ellis, RDMS, RVT, who has over 10 years of experience 
with this procedure. This will be performed pre-CBTI and at the 6 month follow-up. 
 
Blood Assays. Blood will be drawn and processed by our research phlebotomist between 8:00 am and 
10:00 am, after 12 hours of overnight fasting, on each of the four laboratory assessment visits, in order 
to measure: total cholesterol, HDL- and LDL-cholesterol, VLDL-cholesterol, and triglycerides; 
inflammatory activity measured by high sensitivity C-Reactive Protein (hsCRP);  At baseline assessment 
only, thyroid stimulating hormone (TSH) will be assayed to ascertain if hypertension is due to hyper- or 
hypothyroidism. 
 
Atherosclerotic Cardiovascular Disease (ASCVD) Risk. Although we are interested primarily in whether 
improved sleep quality will lower the mechanisms of insomnia-related CVD risk, we will also explore 
computed ASCVD risk (for participants aged ≥ 40 years) from the Pooled Cohort Equations recently 
validated and recommended by the clinical practice guideline expert panel of the American College of 
Cardiology/American Heart Association. These equations estimate the 10-year risk of a primary ASCVD 
event (including myocardial infarction and stroke) among patients without pre-existing CVD. Patients are 
considered to be at "elevated" risk if the Pooled Cohort Equations predicted risk is ≥ 7.5%. For example, 
a 50-year old white male smoker with a systolic BP of 130 mm Hg, no diabetes, and total cholesterol of 
200 mg/dL with HDL cholesterol 30 mg/dL would have a 10-year ASCVD risk of 13.2%. Lowering systolic 
BP to 120 mm Hg and raising HDL to 50 mg/dL, with total cholesterol remaining at 200 mg/dL, would 
almost half his risk, reducing it to 6.9%. Indeed, we also have recently shown that both pharmacological 
and behavioral interventions to treat depression can lower the calculated 10-year risk of an ASCVD 

event. Because several large population studies have shown that insomnia and short sleep duration are 
linked to hyperlipidemia,136 the CBT-I intervention holds promise for both lowering BP and improving 
lipid profiles, thereby reducing 10-year ASCVD risk. 
 
C.6. QUALITY OF LIFE (QOL) ASSESSMENTS 
 
CBT-I has been shown to result in marked improvements in QoL in medical patient populations where 
insomnia is commonly comorbid. In the present proposal, we will explore QoL changes that may 
accompany improved sleep quality following the CBT-I intervention. We will also explore QoL and 
psychosocial distress as potential moderators of the changes in CVD risk mechanisms accompanying 
sleep quality changes. A demographic information will be complete once and will be used to assess 
ethnicity, smoking, and alcohol use and menopausal status where applicable. The following assessments 
will be made at baseline, post-6-week run-in, post-CBT-I intervention, and at 6-month follow-up. 
 
Health-Related Quality of Life will be measured using the Short Form-36 Health Survey (SF-36), which 
provides a physical health and mental health QoL summary score. 
 
Depressive Symptoms. The Beck Depression Inventory II (BDI-II)139-141 will be used to assess 
depressive symptoms. It is a widely used self-report measure of depressive symptoms, consisting of 21 
items, each corresponding to a specific category of symptoms and attitudes. The inventory has been 
studied extensively since it was first developed in 1961. It has been shown to be both a reliable and valid 
measure of the severity of depressive symptoms. In cardiac populations, depressive symptoms assessed 
using the BDI and the revised BDI-II, as well as changes in BDI over time, have been related to clinical 
outcomes. It should be emphasized that the BDI-II is not a diagnostic instrument, but rather a method 
for determining the presence and severity of depressive symptoms. 
 
Anxiety Symptoms. Anxiety will be measured using the state and trait anxiety versions of the State-Trait 
Anxiety Inventory (STAI). The STAI consists of two separate 20-item self-report inventories, one 
measuring state anxiety and the other trait anxiety. The STAI has been shown to be associated 
prospectively with increased CVD risk and all-cause mortality.  
 
Perceived Stress will be measured by the Perceived Stress Scale (PSS). The PSS152 consists of 10 items  
that are evaluated on a 5-point Likert scale. 
 
Daytime Sleepiness will be assessed by the Epworth Sleepiness Scale (ESS), an 8-item measure of 
perceived daytime sleepiness. 
 
Socioeconomic Status (SES). SES will be measured by interview assessment of annual household income, 
occupation, and years of education. In addition, subjective SES will be assessed with the MacArthur 
Scale of Subjective Social Status. 
 
 
 
 

Selection of Subjects 
 
Inclusion Criteria.  Systolic BP ≥ 130 mm Hg based upon two standardized BP screening assessments  a 
current diagnosis of insomnia disorder as defined in the International Classification of Sleep Disorders 
(ICSD-3);84 or undiagnosed, but suspected, insomnia disorder that is confirmed at their screening lab 
visit; an age range of 30-60 years. 
  
Exclusion Criteria.  Uncontrolled hypertension (screening office BP > 160/100 mm Hg); antihypertensive 
medication use; cardiovascular medications; previously diagnosed moderate or severe obstructive sleep 
apnea; severe obesity defined by BMI>40 kg/m2; pacemakers; atrial fibrillation; acute coronary 
syndrome or coronary revascularization procedure within 6 months of enrollment; congestive heart 
failure; identifiable cause of hypertension (e.g., primary hyperaldosteronism, renal artery stenosis, 
untreated hyper- or hypothyroidism, chronic kidney disease, Cushing’s disease, pheochromocytoma, 
coarctation of the aorta); severe uncorrected valvular heart disease; current pregnancy; active diagnosis 
of psychosis, bipolar disorder, current treatment of PTSD with exposure based therapy; severely 
impaired hearing or speech; participation in another interventional study to address insomnia; rotating 
shift workers; diabetes; prominent suicidal or homicidal ideation (as assessed through a clinical 
interview); psychiatric hospitalization within the past 12 months; unstable comorbid sleep disorder 
requiring assessment and/or treatment outside of the study protocol; medical or psychiatric conditions 
judged to be the primary cause of insomnia; alcohol or drug abuse within 12 months; dementia; inability 
to comply with the assessment procedures or inability to provide informed consent. 
  
Identification.  The study coordinator and research associate will identify patients using the electronic 
medical records (Maestro).  A detailed description is below in Subject Recruitment. If a participant is 
interested and their electronic medical record (EMR) is not available, study staff can ask the participant 
the eligibility criteria that would have been collected in the EMR to collect the medical history necessary 
to determine eligibility. 
 
 
Subject Recruitment and Compensation 
 
A total of 150 men and women who meet systolic BP criteria for hypertension (SBP≥130 mm Hg) and 
have comorbid insomnia will comprise the study sample.  Participants will be recruited by various 
general mechanisms.  The primary approach will be through the new Recruitment and Engagement 
Policy at DUMC.  All internal staff have received training and will adhere to the new policy.  We will use 
DEDUCE within the PACE environment and screen potentially eligible patients in Maestro.  Once patients 
are identified, we will submit them to the honest broker to export name, address, email address and 
phone number so we can send them a letter or email and a brochure introducing the study to them.  
Potential patients will be called about a week later after they receive to letter or email to determine 
interest.  Per DOCR guidelines, no potential patients will not be contacted more than 3 times.  No 
patient who has opted out of research will be contacted. 
  
Another mechanism will be through the network of primary care clinics, led by co-investigator Dr. 
Anthony Viera, Chair of the Department of Family and Community Medicine, where we will enlist the 

support of primary care physicians in the Duke Health System.  Hypertension is one of the most common 
presentations in the primary care setting, with approximately 103 million American adults meeting the 
new ACC/AHA diagnostic criteria of 130/80 mm Hg,81 and approximately 40% of primary care patients 
reporting difficulty sleeping.  There are a currently 27 Duke Primary Care Clinics, with a total of 77,016 
patients diagnosed with hypertension, 29,951 with an insomnia diagnosis, and 16,980 patients with a 
diagnosis of both hypertension and insomnia.  Patients who meet our BP criteria and who have (or are 
suspected to have) comorbid insomnia, and have elected not to receive antihypertensive 
pharmacotherapy, will be informed by their primary care physician (PCP) about our study.  If interested, 
they will be given an information leaflet with our contact information.  
 
Facebook/Instagram Ads – We would like to use Facebook and Instagram to recruit and have added 
possible text and pictures for these ads in recruitment tools.  We would also like a Qualtrics survey for 
interested participants to enter their contact information. This Qualtrics survey will be delivered via our 
lab webpage, social media ads/posts, and QR codes on study fliers. Participants will fill in their name, 
phone number, email address, and best times to contact, and study coordinators will respond to 
requests. Identifying information for ineligible and uninterested participants will be destroyed. 
 
Maestro Care screening:  This study will use tools available in Maestro Care to help identify and recruit 
potential participants before consent is signed. Only key personnel who are delegated the task of 
patient identification/ recruitment will have access to information in Maestro Care.  Once identified and 
screened further to ensure they are qualified, letters, phone calls and emails will be used to recruit 
these participants.  Potential patients will be called about a week later after they receive to letter or 
email to determine interest.  Per DOCR guidelines, no potential patients will not be contacted more than 
3 times.  No patient who has opted out of research will be contacted. Patients may be associated with a 
pre-consent status of “Declined” or “No Longer a Candidate” in Maestro Care prior to consent, if 
necessary. The association with the study cannot be removed from Maestro Care. 
 
Maestro Care MyChart messaging:  This study will use a MaestroCare MyChart recruitment invitation to 
help identify potential participants pre-consent. Potential subjects are identified via a report generated 
within Maestro Care by the DOCR Maestro Care Analyst team. A recruitment invitation will be sent by a 
DOCR analyst to potential subjects via MyChart. The patient will indicate if they are interested or not 
interested and the study coordinator will be sent an Inbasket message (Maestro Care internal message) 
indicating the response. Only key personnel who are delegated the task of patient 
identification/recruitment will have access to the Inbasket messages. Only patients who express interest 
will be contacted by key personnel, who will then follow the recruitment process approved by the IRB 
for this study.  If a patient expresses interest and the study team determines the patient is not qualified 
for the study prior to contacting them, they will be sent an approved email letting them know.  If a 
patient does not open their MyChart message, the Maestro or Epic Analyst can send up to two 
additional "tickler" notifications, at least a week apart, to let the patient know they have an unread 
message.   
 
The final recruitment strategy will be advertising in local newspapers, posting flyers at area community 
centers (e.g., churches), and using hospital TV screens to display approved flyers.  As for previous 
studies, we also will set up a BP and insomnia screening booth at area health fairs and community 

events.  These methods have proven very successful at recruiting large samples of men and women with 
the early stages of untreated hypertension in our previous studies.16,83  Initial phone screening will 
establish whether potential participants are likely to meet the study’s eligibility criteria.  If appropriate, 
the first screening session will be scheduled, which will include office blood pressure measurements, 
medical history, and physical examination.  Because the study demands a series of four lab visits, plus 
screening visits, and a total of four 24-hour ABP monitoring assessments, we are proposing $300 
reimbursement per participant, $200 post CBT-I and $100 at follow-up.  Partial reimbursement will be 
available for participants who do not finish the study.  Our previous studies of unmedicated patients 
with hypertension indicate that adequate subject reimbursement is ultimately cost-effective.  A further 
and very significant incentive in the currently proposed study is that all eligible participants will receive a 
state-of-the-art intervention for their insomnia to improve their sleep quality. 
 
UNC-Chapel Hill was added as a recruitment site and will use these recruitment mechanisms as well.  
The UNC IRB is relying on the Duke IRB and the IAA is attached.  
  
  
Study Interventions 
 
SLEEP MANIPULATION INTERVENTION 
 
Cognitive Behavior Therapy for Insomnia (CBT-I). CBT-I is a well-established behavioral treatment for 
insomnia that successfully reduces insomnia symptoms and improves both subjective and objective 
measures of sleep quality.  The approach to CBT-I for the proposed study is based on CBT-I programs 
that have been practiced and studied by research team members. CBT-I is manualized in a session-by-
session guide. Our proposed study co-investigator, Dr. Christie Ulmer serves as a consultant and trainer 
on the nationwide dissemination of CBT-I (see biosketch). Dr. Ulmer will train study therapists to deliver 
CBT-I in accordance with the training approach adopted by the CBT-I dissemination effort. Further, our 
sleep consultant, Dr. Jack Edinger, will assist in the interventionist training and will oversee the fidelity 
measures and methods. CBT-I treatment will be delivered by Dr. Ulmer and one additional study 
therapist over 6 one-hour individual sessions. 
  
Intervention Training and Fidelity. A second study therapist will be trained by Dr. Ulmer, according to 
consensus guidelines. Initial didactic training (covering session-by-session procedures, core components 
of CBT-I) will last three days and be followed by training cases. The therapists will be allowed to provide 
the intervention once they have demonstrated 100% competence and adherence with all required 
treatment elements. The therapist will meet weekly for supervision throughout the trial.  All therapy 
sessions will be recorded.  A random selection of twenty percent will be rated for fidelity. In order to 
protect against drift, the frequency of fidelity checks will occur equally across the beginning, middle, and 
end of the intervention period. Dr. Edinger will rate therapist treatment fidelity/adherence for recorded 
sessions using the adapted version of the Yale Adherence and Competence Scale.98 Recordngs will be 
rated on the presence/absence of CBT-I elements. In addition, recordings will be rated on the 
presence/absence of nonspecific treatment elements (e.g., therapeutic alliance, patient expectancies). 
Feedback from fidelity checks will be provided by Drs. Edinger and Ulmer. 
  

CBT-I Intervention Protocol Summary.  The CBT-I intervention will be delivered individually and in person 
by one of the therapists, over six one-hour weekly sessions, as summarized by the CBT-I protocol below: 
Session 1: Sleep Education and Introductions to CBT-I and Sleep Diaries.  Participants will receive an 
overview of CBT-I treatment concepts and approach, in addition to education about sleep regulation 
processes and the cognitive and behavioral processes involved in the development of insomnia. At the 
end of the session, they will be instructed in establishing realistic treatment goals and the process for 
keeping weekly sleep diaries. 
 
Session 2: Introduction to Sleep Restriction Therapy and Stimulus Control.  The therapist will introduce 
Stimulus Control and Sleep Restriction Therapy guidelines and rationale. Sleep Restriction Therapy (SRT) 
is designed to strengthen the homeostatic sleep drive by restricting time in bed to actual sleep time as 
determined by sleep diary. The sleep “prescription”, or allowable sleep window, is gradually increased 
over the course of treatment to extend sleep duration. Stimulus Control is a set of instructions designed 
to strengthen the association between the bed/bedroom and sleep, and to establish a consistent sleep–
wake schedule. Participants will receive education and intervention based on treatment targets 
identified in Session 1 in addition to the sleep pattern information gleaned from the sleep diary review. 
Sleep hygiene education will be provided for topics that are relevant to the participant (e.g., the effects 
of alcohol on sleep). An initial “sleep prescription” will be established and participants will be asked to 
follow this sleep schedule during the upcoming week. Cognitive therapy will be used, as needed, to 
address dysfunctional beliefs about sleep and to enhance adherence. 
 
Session 3: Introduction to Relaxation Therapy.  Participants will be introduced to Relaxation Therapy. 
The therapist will review the sleep diary with the participant and modify the sleep prescription, as 
needed, in accordance with SRT principles. Participants will be reinforced for adherence and progress. 
Barriers to adherence will be discussed and addressed using education, motivational enhancement, and 
cognitive therapy. Participants will be asked to practice relaxation strategies, follow their sleep 
prescription, and continue to track their sleep on diary during the upcoming week.  
 
Sessions 4 and 5: Sleep Prescription Titration.  The therapist will review the sleep diary with the 
participant and modify the sleep prescription, as needed, in accordance with SRT principles. Barriers to 
adherence will be discussed and addressed using education, motivational enhancement, and cognitive 
therapy. Participants will be asked to continue using relaxation strategies, follow their sleep 
prescription, and track their sleep on diary during the upcoming week. 
 
Session 6: Relapse Prevention.  The therapist will review the sleep diary with the participant and provide 
instruction on adjusting their sleep schedule after treatment, as needed. Treatment gains will be 
reviewed, and the therapist and participant will jointly develop a plan for ensuring that treatment gains 
are maintained.  
 
 
Risk/Benefit Assessment 
 
The primary risks of this study are minimal and are primarily associated with confidentiality. There is 
some risk attendant to confidentiality of self-report data.  In order to ensure confidentiality of data, all 

records will be identified by the patient's identification number, not by name.  All raw data will be kept 
in a locked file cabinet. Although several previous psychosocial interventions may be associated with 
increased risk, we believe that it is unlikely that this treatment will be harmful to patients.  Nevertheless, 
we will carefully monitor symptoms and refer those patients with high levels of depression or distress 
for treatment.  We also will include a Study Advisory Committee (SAC) to monitor study progress and 
adverse events. 
  
With the blood draw, there is a risk of bruising at the site of the draw and rarely, fainting and/or 
infection. The Oscar 2 ABPM has built in safeguards to avoid over-inflation or prolonged inflation of the 
cuff, as well as a measurement abort key that can be activated by the participant. The participant could 
experience mild disomfort as the cuff inflates and rarely, mild skin irrataion and bruising. The FMD 
assessment will include blood pressure cuff inflation for 5 minutes, which has the risk of causing tingling 
and discomfort in the arm. The sublingual glyceryl trinitrate used during the FMD procedure can cause a 
headache or a sensation of flushing. Because of this, participants with a history of migraines will be 
allowed to do the FMD procedure without taking nitroglycerin. There are no known risks associated with 
use of the actigraphy. 
  
The risk of serious injury due to study participation is negligible.  All measurement techniques have been 
used extensively by the investigative team without a single adverse event.   Procedures for protecting 
subjects against potential risks include screening procedures. Patients will be referred to their local 
physicians when needed.  We also will take special precautions to ensure the safety of patients with 
clinically significant depression, i.e., patients with BDI-II scores >29 (moderate-severe depression) or 
who are actively suicidal.  Although we are not pre-selecting patients with hypertension and comorbid 
insomnia based upon their level of distress or depressive symptoms, our assessments may determine 
the presence of significant clinical depression.  In the unlikely event that patients are determined to be 
actively suicidal, they will be queried for suicidal plans, intent and past suicidal behaviors.  Those with 
current active suicidal ideation, history of suicidal acts within the past 12 months, or bipolar disorder or 
psychosis will not be enrolled in the study and appropriate referral or admission procedures will be 
initiated.  If a patient exhibits moderate-severe depression (e.g., BDI-II >29) at baseline, we will inform 
the participant and, with his or her permission, notify their primary care physician.  Any participant who 
is determined to be actively suicidal over the course of the study will be referred for psychiatric 
evaluation and possible hospital admission. If they are found to be at immediate risk, emergency 
procedures will be followed including requesting an ambulance to take the patient to the emergency 
department (ED) for immediate evaluation and treatment.  Patients who score >29 on the BDI-II and are 
not actively suicidal will be informed about the results of our assessment, and with their consent, we 
will inform their physicians for further evaluation and possible treatment.  In this manner, we believe 
that risk will be minimized.  Any enrolled patient who becomes actively suicidal (i.e., who scores >1 on 
item 9 of BDI-II) will be immediately evaluated by our study psychologist for suicidal plans and intent.  If 
a patient is considered acutely suicidal, he or she will be dropped from further participation and will be 
referred for either urgent evaluation by a psychiatrist or prompt ED evaluation.   Our medical director or 
PI will contact the patient within 24 hours after the referral to ensure that the patient has followed 
through with the referral.  We also have referral sources in place to provide psychiatric treatment if 
necessary. This protocol has been used successfully in our previous work, including studies of patients 
with major depression. 

If a patient scores >29 on the BDI-II at the time of the post-treatment assessment, he or she will be 
informed of the results and, with the patient’s permission, we will notify their primary care physician so 
that further evaluation, referral or treatment can be initiated as appropriate.  
  
Adequacy of Protection Against Risks 
 
a. Informed Consent and Assent 
 
Consecutive patients in Duke University Medical Center Primary Care Clinics, who meet the study 
eligibility criteria will be offered the opportunity to participate in the study. The recruitment process will 
involve an initial screening by the research study staff under an IRB-approved waiver of HIPAA 
Authorization (by conforming with the Duke IRB’s federally mandated conditions for granting such a 
waiver - http://irb.duhs.duke.edu/). If a patient appears to qualify, a letter will be mailed to them 
introducing the study. For patients interested in participating in the study, full details of the procedures 
involved, risks and benefits will be provided in written and oral form. Enrollment in the study will 
require potential participants to read and sign a written informed consent form, approved by the Duke 
Medical Center IRB. It will be made clear to subjects that they may withdraw at any time without 
penalty, and that they may contact the IRB chairman (at a phone number provided) if for any reason 
they believe that their privacy or health have been compromised.  
  
b. Protections Against Risk 
 
As noted earlier, the primary risks for participants are those associated with confidentiality.  To ensure 
that confidentiality is maintained, we will store our non-electronic patient records in locked cabinets 
within a locked area, with access limited to study staff.  Electronic records will be maintained in a secure 
network setting, with access available only to selected study personnel.  In addition to network security, 
individual workstations for data entry and analysis will be accessible only by password.  Also as noted 
earlier, all electronic records will be identified only by a study identification number.  
 
All project staff will have fulfilled Duke University mandatory HIPAA training requirements.  All aspects 
of the study protocol will meet HIPAA requirements specified by the Human Studies Committee and the 
Privacy Office at Duke University.  
 
The protocol will be approved by the Duke University Medical Center IRB before it is implemented.  All 
investigators have completed the required education and certification in the protection of human 
research subjects. 
 
In the unlikely event of an adverse medical event during assessment or any other on-site phase of study 
participation, the patient’s attending physician and/or the emergency services at DUMC will be 
contacted immediately.  In addition, the principal investigators and medical director of the study will be 
notified of all such events.  
  
Potential Benefits:  This study has several potential benefits.  First, patients receiving CBT-I are likely to 
benefit from marked reductions in their insomnia symptoms and improvement in their sleep quality; 

these benefits have been documented to persist for many years after completion of the 6-week CBT-I 
intervention.  Study participants will also receive state-of-the-art evaluation of their blood pressure 
observed over 24-hours on four occasions, thereby providing themselves and their primary care 
physicians the most appropriate and valuable information on which hypertension management can be 
based.  Our comprehensive assessments of CVD risk mechanisms will also be made available to 
participants’ physicians upon completion of the study, again helping optimize their medical 
management. 
 
Potential Benefits of the Proposed Research to Research Participants and Others 
While most participants should benefit from improved sleep and/or reduced insomnia complaints, as 
well as a comprehensive evaluation of their blood pressure and possible lowering thereof, there are no 
guaranteed benefits to the individual participant and no immediate benefits of the proposed research to 
others. 
 
Information gathered from participants may help us to establish a link between sleep impairment and 
how insomnia has adverse effects on CVD risk. In our opinion, the anticipated benefits of this study 
outweigh the potential risks. 
  
ANALYSIS PLAN 
 
Data will be entered into a secure Microsoft Access database. Entry to the database is limited to key 
personnel and is password protected at the point of the workstation and the application. Standard 
double-entry and data checking approaches will be performed for all measures.  
  
General Analytic Approach:  Descriptive statistics will be performed on all study variables. In order to 
mitigate potential bias due to transient improvements in either sleep or BP dipping, we will utilize a 6-
wk run-in phase after which participants will have their sleep efficiency and BP dipping markers re-
assessed to ensure stability. Although we do not anticipate significant variation in either sleep or BP 
parameters during this pre-treatment phase, we will exclude participants who no longer meet inclusion 
criteria following the 6-wk run-in period. This practice has been shown to result in an increased 
magnitude of treatment improvements and therefore may improve the statistical power and potential 
precision of the proposed analyses.155-158 Markers of sleep efficiency and BP dipping collected after 
our run-in phase will therefore be used as our baseline assessment measures. 
 
Regression-based analytic approaches will be used to examine associations between improved sleep 
efficiency, ABP indices, and mechanisms of CVD risk. In order to minimize potential confounding of 
treatment improvements due to either misdiagnosis or transient fluctuations in sleep, we will use 
assessments collected after the run-in period as our baseline time point. For our 6-week outcomes, 
improvements in sleep efficiency and ABP will be examined using simple regression analyses as detailed 
below. In contrast, our 6-month outcomes will be examined using repeated measures mixed models 
with an unstructured covariance matrix, using both 6-week and 6-month levels of the outcome modeled 
jointly. Incorporating both outcomes into a unified, mixed modeling approach will allow us to examine 
improvements in sleep as they associate with trajectories of BP dipping improvements and also allows 
for more robust handling of missing data. 

For our primary aim examining improvements in sleep efficiency and ABP, we will focus on nighttime BP 
dipping as the outcome of interest with a prespecified significance level of P = .05. Because other ABP 
outcomes could plausibly be improved with CBT-I and will partially reflect improvements in nighttime 
dipping, we will conduct parallel analyses of nighttime average BP and 24-hour BP levels. Consistent 
with contemporary recommendations examining secondary outcome measures as supportive and/or 
explanatory, we will maintain a P = .05 for all for secondary outcome measures. Patterns of missing data 
will be characterized using Rubin’scriteria and managed accordingly using Harrell’s multiple imputation 
(mult.impute) procedure in R. We will carefully examine all model assumptions and reparameterize as 
indicated. All analyses will be carried out using SAS (Cary, NC) or R (http://cran.r-project.org/) software. 
  
AIM 1: Determine whether the circadian BP profile contributes CVD risk associated with poor sleep by 
evaluating whether it is modified by changes in sleep quality in men and women with hypertension and 
comorbid insomnia  
 
Hypothesis 1: Improved sleep quality will be accompanied by: (i) enhanced nighttime BP dipping; (ii) 
lower average nighttime BP; (iii) lower average 24-hour BP. 
 
Analysis Plan: General linear models will be used to examine the associations between improvements in 
sleep quality on improvements in BP dipping, controlling for age, gender, race, baseline sleep efficiency, 
baseline mean 24-hour BP, and pretreatment BP dipping, with post-treatment BP dipping as the 
criterion. Significance will a priori be set at P = .05. For follow-up analyses of 6-mo BP dipping, linear 
repeated measures mixed models will be examined in which 6-wk and 6-mo BP dipping both serve as 
outcome variables using the same covariates above. As an a priori explanatory analysis for our follow-up 
analyses, we will examine potential time X sleep efficiency interactions in order to examine the extent to 
which the association between sleep efficiency and BP dipping at six weeks differs from that at six-
months. In addition, we will conduct an area under the curve analysis to examine overall associations 
that apply to both 6-wk and 6-mo in order to determine whether larger improvements in sleep are 
associated with larger improvements in BP outcomes in an overall sense.165-167 Because other ABP 
outcomes could plausibly be improved by CBT-I and also will reflect improved nighttime dipping, we will 
conduct parallel analyses of nighttime average BP and 24-hour BP levels. 
  
AIM 2: Evaluate candidate mechanisms of CVD risk related to sleep quality in patients with hypertension 
and comorbid insomnia 
 
Hypothesis 2: Improved sleep quality will be accompanied by: (i) reduced nighttime SNS activity; (ii) 
enhanced vascular endothelial function; (iii) reduced arterial stiffness, and; (iv) improved lipid profile. 
Analysis Plan: General linear models will be used to examine the associations between improved sleep 
efficiency and improvements in mechanisms of CVD risk, controlling for age, gender, race, baseline sleep 
efficiency, and the pre-treatment (post run-in) level of the outcome. For our analyses of vascular 
endothelial function only, we also will adjust for baseline arterial diameter, consistent with our prior 
work. Follow-up analyses will follow the same approach as in Hypothesis 1, using linear repeated 
measures mixed models with 6-wk and 6-mo levels serving as the outcome variables. 
  

Exploration of Mechanistic Relationships: For additional explanatory purposes in relation to our 
mechanistic conceptual model (Figure 1), we propose to conduct mediation analyses using the more 
commonly known Baron and Kenny approach as well as the newer MacArthur approach.170 By the 
MacArthur definition, the potential mediator must be during or post-treatment; therefore, changes in 
mechanisms of CVD risk occurring between baseline and 6-wk will be considered as potential mediators.  
The outcome then will be participants' post-treatment change in BP dipping, which will be assessed at 6-
month follow-up. We will first fit a model to examine the relationship between changes in sleep 
efficiency and the mediator (C) (i.e., changes in mechanisms of CVD risk), as noted for Hypothesis 2.  We 
will then fit a model examining the relationship between the mediator and post-treatment change in BP 
dipping.  Finally, we will test for mediation using an extension of the Sobel first-order test, which 
examines the extent to which the associations between improved sleep efficiency and BP dipping are 
attributable to improvements in mechanisms of CVD risk. To fully understand these relationships, we 
will also investigate the MacArthur approach which is less restrictive in its assumptions, where 
improvements in BP dipping are attributable to improvements in mechanisms of CVD risk if there is 
evidence of a non-zero association between sleep efficiency and mechanisms of CVD risk, and either 1) 
mechanisms of CVD risk or 2) their interaction with changes in sleep efficiency also are non-zero. 
  
Power and Sample Size Considerations: Our power estimates were derived from prior data assessing 
sleep efficiency and nighttime BP dipping among individuals with HTN using the following assumptions: 
an initial sample size of 150 individuals, attrition of 15%, an alpha of 0.05, and a correlation of r = 0.30 
between sleep efficiency and BP dipping. Using these assumptions, we will have 80% power to detect 
correlations of r>=0.25 between improvements in sleep efficiency and BP outcomes, suggesting that we 
will have adequate power to test the proposed hypotheses.  In a more conservative scenario for 
comparing the worst 1/3 of the sample in terms of sleep efficiency change to the best 1/3, and assuming 
50 participants in each group, there is 0.85 power at the two-sided 0.05 significance level for the 
detectable effect size theta=0.6 via the following equation: (n per group) = 50 = 2*(((1.96 + 1.04) / 
0.6)**2). In the present proposal, this corresponds to a difference of 2.2% in SBP dipping between high 
and low sleep efficiency groups. 
  
Exploratory Analyses of Effect Modification: In addition to our formal analyses, we will conduct 
exploratory analyses of effect modification, which will be interpreted as hypothesis generating. 
Candidate markers for effect modification will include background and clinical characteristics, such as 
race, gender, baseline insomnia severity, baseline anxiety, and the presence of elevated depressive 
symptoms (BDI > 14). Specifically, we will examine the interaction terms between these candidate 
moderators, changes in sleep efficiency and mechanisms of CVD risk using the same general linear 
modeling approach noted for Hypothesis 2. 
  
D.2. METHODOLOGICAL ISSUES 
 
For this mechanistic study, we considered several alternative designs, including a cross-sectional 
observational study and a two-group randomized design. A cross-sectional design was rejected because 
differences in CVD risk factors between patients with poor sleep quality and good sleep quality could be 
due to other factors besides their sleep.  However, because the study objective was mechanistic, with 
the (favorable) manipulation of sleep quality of primary interest as the independent variable, and 

because CBT-I has emerged as the gold standard for treating insomnia, we could not uphold the 
principle of equipoise in a design that randomized participants to an intervention that would likely be 
markedly less effective in treating their insomnia (e.g., sleep hygiene, no treatment, wait-list control).  
Moreover, the study objective is not to ascertain the efficacy of CBT-I, so a randomized design and 
comparison group is not required.  Indeed, with the efficacy of CBT-I at approximately 60%,30 the more 
ethically defensible design was considered to be that all participants should receive the CBT-I 
intervention, with a time-equivalent run-in phase serving as a within-participant control phase to help 
establish that more marked alterations in sleep quality (60%) should be attributed to the CBT-I 
intervention, with an estimated 40% showing minimal to clinically insignificant changes.  
  
A second aspect of our methodologic considerations was the selection of a primary measurement to 
serve as a manipulation check for sleep quality changes associated with the CBT-I intervention.  We 
selected sleep efficiency, determined from actigraphy, because it is an objective and continuous 
measurement of sleep quality that: (i) has been shown to improve markedly following CBT-I; (ii) has 
been shown to be related to the development of hypertension, and; (iii) from our pilot studies, it is the 
index of sleep quality that was most clearly related to nighttime BP dipping and vascular endothelial 
function.  Therefore, while sleep efficiency will serve as the primary index of sleep quality changes, we 
will also explore effects on other actigraphy-based sleep parameters, including total sleep time (TST), 
wake after sleep onset (WASO), and sleep fragmentation index (SFI).  Insomnia aside, the evidence 
showing that poor sleep quality is a CVD risk factor has been based on large-scale meta-analytic studies 
of subjective measures of sleep quality and duration; this is because such data are widespread, and 
studies incorporating objective measures are relatively few.  However, the available evidence shows 
that in smaller scale studies, objective measures of sleep quality show more robust associations with 
CVD risk. Nonetheless, we have included two important subjective measures of sleep, the ISI110 and the 
widely used PSQI, which we will use to provide supportive evidence of sleep quality changes and their 
association with changes in putative mechanisms relating sleep to CVD risk. 
  
With respect to participant inclusion/exclusion criteria, we chose to focus on hypertension with 
comorbid insomnia because of the putative mechanisms of CVD risk, including blunted nighttime BP 
dipping, heightened sympathetic activity, arterial stiffness, and endothelial dysfunction being evident in 
this population, and therefore affording the opportunity for their improvement following CBT-I as a 
manifestation of sleep-related mechanisms of CVD risk.  We also adopted the new ACC/AHA guidelines 
for defining hypertension at lower BP levels, with our selection of systolic BP≥130 mm Hg as the 
inclusion criterion.  We also excluded antihypertensive medication use, as different classes of 
medications have different half-lives and may distort the patient’s normal circadian BP profile.  Many 
individuals with recently diagnosed hypertension refuse antihypertensive therapy in favor of attempting 
lifestyle changes first; for those with comorbid insomnia, enrolling in our proposed study will provide 
them an opportunity to help control their BP, as well as improve their sleep.  We also elected to exclude 
sleep apnea because of its association with hypertension presenting a potential confounding of our 
observations.  Interestingly, a recent review and meta-analysis failed to find conclusive evidence that 
continuous positive airway pressure (CPAP) reduced the risk of CVD events in sleep apnea patients. 
However, in addition to compliance with CPAP therapy being difficult to ascertain, sleep apnea is 
frequently comorbid with insomnia, and when sleep apnea is diagnosed, comorbid insomnia is rarely 
treated, further complicating our understanding of sleep apnea and its treatment effect on BP. 

  
  
 
Data & Safety Monitoring 
Summarize safety concerns, and describe the methods to monitor research subjects and their data to 
ensure their safety, including who will monitor the data, and the frequency of such monitoring. If a data 
monitoring committee will be used, describe its operation, including stopping rules and frequency of 
review, and if it is independent of the sponsor (per 45 CFR 46.111(a) (6)). 
 
Safety Monitoring 
 
Although blood pressure will be monitored by research staff during the study, blood pressure 
management will continue to be up to participants’ health care providers (HCPs). Patients who exhibit 
screening “office” averaged BP greater than 160/100 mm Hg across the two screening sessions will not 
be eligible to participate in the study and will be provided their screening BPs with the recommendation 
that they provide this information to their HCP within 72 hours.   For participants already enrolled in the 
study, if “office” averaged BP values exceed 160/100 mm Hg, the participant will be provided those BP 
readings at that time, and will be encouraged to share the results with their HCP within 72 hours; with 
patient written consent, we also will provide the BP readings to their HCP.  All eligible participants will 
have completed the CBT-I intervention within approximately 3 months from study enrollment.  Both 
pre- and post-treatment ambulatory blood pressure records and study-assessed “office” blood 
pressures will be provided to participants at that time (i.e., after ~12 weeks), and with their consent 
(using a Redcap electronic medical authorization or paper authorization form), also will be provided to 
their HCP for follow-up as needed.  In the event that participants do not have a HCP, a list of local family 
HCPs who are accepting new patients will be provided to them. 
 
Participants will undergo follow-up assessments 6 months after the CBT-I intervention. Any intervening 
treatments including antihypertensive medications, will be documented. It should be emphasized that 
participants will not be prohibited from initiating pharmacologic treatment for high blood pressure at 
any time during the study. At all assessment phases, participants’ medications will be documented.  
Upon completion of their participation in the study (approximately 9 months after initial screening 
assessments confirmed their eligibility), for participants who exhibit no improvement in their insomnia 
symptoms, we will refer them back to their HCP for consideration of alternative approaches to treating 
their insomnia. 
 
Potential participants suspected by questionnaire and diagnostic sleep interview to have obstructive 
sleep apnea will also have an overnight sleep apnea screening assessment using the WatchPAT One 
(Itamar Medical) system.  Moderate to severe sleep apnea is an exclusion criterion, as defined by an 
apnea-hypopnea index (AHI) >15.  Potential participants excluded due to an elevated AHI will be 
provided a letter indicating their AHI and invited to share this information, indicating suspected sleep 
apnea, with their HCP. 
 
Although we are not selecting, or excluding, hypertensive patients based upon their level of distress or 
depression, our assessments may determine the presence of severe depression.  If patients are acutely 

suicidal, they will be evaluated by our licensed study clinical psychologist (Dr. Blumenthal); appropriate 
referral or admission procedures will be initiated, and they will be dropped from further study. 
Specifically, should participants become acutely suicidal [if they endorse a response of 2 or 3 on item 9 
(suicide item) on the BDI-II at the end of the 6-week run-in or after the 6-week CBT-I treatment 
program] they will be evaluated by our study psychologist within 24 hours and will be referred for 
treatment as needed.   
 
Reporting Mechanisms of AEs/SAEs to the IRB, FDA, DSMB and/or NIH:  
 
Any adverse events (AEs) will be reported to the DUMC IRB in accordance with the local Human 
Research Protection Program’s Standards of Practice. These guidelines require immediate reporting of 
any serious adverse events (SAEs) that are potentially study-related.  Any SAEs that are potentially 
study-related will be reported to the DSMB within 48 hours via Duke’s secured email system.  Consistent 
with NHLBI policy  (NHLBI Adverse Events and Unanticipated Problems Reporting) , any SAEs and 
unanticipated problems (UPs) will be reported to NHLBI.  All research projects conducted at DUMC are 
required to have annual IRB review. Reports of non-serious AEs or unanticipated problems that may 
increase risk for study participants or others are required as part of the annual progress reports.  
Additionally, any changes to the project between review periods must be approved by the IRB prior to 
implementation.  Because there are no study medications involved in this project, we do not expect any 
reporting to the Food and Drug Administration (FDA). Additional reports will be made to the NIH in 
accordance with the institute’s standards of practice. 
 
Plans for Interim Analysis of Efficacy Data and Stopping Rules:   At present, there are no planned interim 
analyses of outcome data. 
 
Trial Stopping Rules:  We do not anticipate that the proposed study will be stopped for any reason other 
than completion of study enrollment and procedures.  
 
HIPAA Compliance: All project staff will have fulfilled the Duke University's mandatory HIPAA training 
requirements.  All aspects of the study protocol will meet HIPAA requirements specified by the Human 
Studies Committee and the Privacy Office at Duke University.    
 
IRB Review and Investigator Certification: The protocol will be approved by the Duke University Medical 
Center IRB before it is implemented.  All investigators have completed the required education and 
certification in the protection of human research subjects. 
 
ClinicalTrials.gov Requirements:  The clinical trial is registered with ClinicalTrials.gov as recommended by 
NIH.