Electronic Tools to Increase Recognition and Improve Primary Care Management for Hypertension in Chronic Kidney Disease
Phase: NA
Conditions: Chronic Kidney Diseases, Hypertension
Sponsor: Brigham and Women's Hospital

 
06/22/2020 
1 
PARTNERS HUMAN RESEARCH COMMITTEE 
DETAILED PROTOCOL 
 
Electronic Tools to Increase Recognition and Improve Primary Care Management 
for Hypertension in Chronic Kidney Disease 
 
P.I.: Lipika Samal M.D., M.P.H.  
 
 
I. 
BACKGROUND AND SIGNIFIGANCE 
 
Prevalence, Outcomes and Cost of Chronic Kidney Disease: Chronic kidney disease 
(CKD) is prevalent, afflicting 26 million Americans, and is a condition associated with 
high morbidity and mortality. In addition, CKD is costly. The average cost per person per 
year is about $20,000 and Medicare costs for ESRD total $26.8 billion. CKD Diagnosis, 
Monitoring, and Treatment Must Be Improved in Primary Care Clinics: There are 
effective approaches to monitoring and treatment that must be disseminated broadly in 
order to cut costs and to save lives. Dissemination efforts must focus on primary care 
clinics because 95% of patients with CKD have early disease and are cared for by 
primary care physicians (PCPs). Only 15% of patients whose estimated glomerular 
filtration rate (eGFR) is less than 60 mL/min/1.73m2 are aware that they have CKD, so it 
is especially important that PCPs become aware of the diagnosis early.5-9 Furthermore, 
there is evidence that CKD is under-diagnosed by PCPs. Data from our 15 primary care 
clinics showed that only 15% of patients with CKD had a documented diagnosis of CKD 
and only 40% had a urine albumin test. Hypertension Control in CKD Improves 
Outcomes: Hypertension (HTN) is one of the most, if not the most, important risk factor 
for long-term outcomes such as kidney failure, cardiovascular events, and death. A met 
analysis of three large cohorts of CKD patients without diabetes concluded that 
maintaining blood pressure below 140/90 mmHg decreases risk of these outcomes 
significantly.11 Several guidelines have been issued to emphasize the importance of HTN 
control in CKD. Evidence-based Management by PCPs for HTN in CKD: Many effective 
approaches for recognition of CKD and treatment of uncontrolled HTN in CKD are 
appropriate for the primary care setting. Lifestyle Change Counseling: Lifestyle change 
is recommended for all patients with uncontrolled HTN. The role of the PCP as 
counselor for lifestyle change is accepted and welcomed by both patients and PCPs.15,16 
Lack of time is a common barrier, but when PCPs perform brief counseling it tends to be 
successful, as shown in the literature on tobacco cessation.  Anti-hypertensive 
Medication Initiation and Intensification: Evidence-based guidelines recommend certain 
anti-hypertensive agents in CKD, either an angiotensin converting enzyme inhibitor or 
angiotensin receptor blocker (ACE/ARB). The UK NICE guidelines specify a protocol for 
initiation and intensification of medications based on demographic characteristics.20 
Efforts to simplify patients’ medication regimens and provide patient education are 
proven to be effective in reducing blood pressure HTN in CKD Is Under-recognized and 
Suboptimally Managed, but CDS Has Shown Potential in Clinical Trials of the Non-CKD 
HTN Population: Nationally representative data show that 52% of CKD patients have 
diagnosed HTN, 19% have preHTN, and 16% have undiagnosed HTN. Treatment rates 
are suboptimal given the fact that less than 40% of CKD patients with uncontrolled HTN 
are prescribed anti-hypertensive medications. HTN control rates, cited as 48% to 72% 
across studies, are also suboptimal. A large meta-analysis of clinical decision support 
(CDS) for HTN in a non-CKD population showed a positive result, but with a small 

 
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average effect size of just 1 mmHg.26 An intervention in a managed care organization 
that incorporated CDS improved HTN control rates with an institution-wide adoption of a 
titration protocol and follow-up visits with a medical assistant. A multi-arm study 
combined CDS that recommended specific medication titration and quarterly 
performance reports with nurse counseling. BP control and SBP improved in all groups, 
but there was no significant difference between intervention groups and the control 
group. Another study in a non-CKD population showed a strongly positive result. The 
investigators tested CDS that synthesized data on the patient’s current anti-hypertensive 
regimen and made a recommendation to intensify treatment. There was a positive result 
in mean BP in the arm which combined CDS with provider education and patient 
education (138/75 mmHg), as compared to CDS plus provider education (146/76 
mmHg), and as compared to provider education alone (145/78 mmHg).  Several recent 
trials of CDS have shown improvement in urine albumin monitoring and ACE/ARB 
prescription rates in CKD. However, no studies of CDS have shown an improvement in 
HTN management in CKD. In one pre-post study in which provider education was 
delivered along with multiple EHR-delivered recommendations, a flowsheet containing 
CKD-relevant data, and a registry, there were significant effects on diagnosis and 
monitoring, but no significant change in BP. 31 Another study used CDS for PCPs and 
nephrologists in conjunction with patient education letters and the option of a self-
management outreach support program. There was no impact on BP outcomes. 
[Sequist, personal communication] Another study compared CDS alone to CDS along 
with a practice improvement effort to implement the Chronic Care Model. The study 
found no significant effect on BP outcomes, [Fox, personal communication] The 
proposed study, if successful, would be the first to improve HTN in CKD patients through 
an intervention that incorporates CDS. 
 
 
II. 
SPECIFIC AIMS 
 
Hypothesis: The mean systolic blood pressure of the CKD population can be decreased 
by an intervention with three innovative features: 1) methods to synthesize EHR data in 
order to identify under-diagnosed chronic conditions, 2) iterative improvement in CDS 
content through human factors methods to maximize the “informativeness” of the CDS, 
and 3) the use of behavioral economic principles to create behavioral “nudges” internal 
and external to the CDS. 
Specific Aim 1: To develop and validate the intervention. 
 
Specific Aim 1a: To develop and validate the CDS that will: 1) synthesize existing 
laboratory tests, medication orders, and vital sign data; 2) increase recognition of CKD, 
3) increase recognition of uncontrolled HTN in CKD patients; and 4) deliver evidence-
based CKD and HTN management recommendations. 
 
Specific Aim 1b: To improve the design and content of the CDS using human factors 
methods, specifically usability testing.  
 
Specific Aim 1c: To develop a “wrap-around” intervention including two behavioral 
“nudges”: 1) pre-checked default orders, and 2) an email to obtain commitment from 
PCPs to obtain their commitment to follow the CDS recommendations.  
 
Specific Aim 2: To test the effectiveness of the intervention. 

 
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Specific Aim 2a: To evaluate whether the intervention developed in Aim 1 significantly 
decreases mean systolic blood pressure in a population of CKD patients with blood 
pressure > 140/90, N=2,350 (N derived from EHR data about primary care patients at 15 
clinics). We will evaluate the effectiveness of the intervention in a pragmatic, cluster-
randomized controlled trial, randomized at the level of the physician (185 PCPs). 
Secondary outcomes will include hypertension-specific process measures, such as 
treatment intensification. 
 
Specific Aim 2b: To evaluate whether the intervention improves process measures for 
quality of CKD care including: documented CKD diagnosis, annual serum creatinine test, 
and annual urine albumin test. We will also examine process measures related to CKD 
care. We will use multivariable logistic regression to account for clustering by PCP using 
a multilevel statistical regression model, as implemented in the SAS package through 
the GLIMMIX procedure. 
 
Specific Aim 2c: To perform a cross-over study in order to evaluate the effect of the 
intervention on PCP behavior and PCPs’ intention to change behavior, as measured by 
a validated 12-item questionnaire. 
 
 
III. 
SUBJECT SELECTION 
 
Subjects: All patients over the age of 18 who have a visit with a PCP at one of the 
intervention practices during the 2 years preceding the study period will be eligible. We 
are able to utilize data from the past 2 years stored in the EHR to identify CKD patients 
with uncontrolled HTN. The first inclusion criteria will be CKD, defined as two prior eGFR 
16-59 mL/min/1.73m2 separated by 90 days, as calculated by CKD-EPI, or two prior 
UACR >30mg/g. The second inclusion criteria will be uncontrolled hypertension, defined 
as at least one SBP >140 mmHg within the 2 years preceding the enrollment visit, as 
well as SBP >140 mmHg at the enrollment visit. Our objective was to include PCPs who 
have a consistent panel of primary care patients. We obtained a list of currently 
employed physicians, physicians assistants and nurse practitioners in our primary care 
network of 15 practices. We excluded residents in training, as well as physicians who 
were only seeing urgent care and walk-in patients.  
 
Inclusion of Women and Minorities 
Women will be represented in this study, reflecting the patient population of the BWH 
primary care practices and the physician population of BWH; women comprise over 50% 
of patients in these practices. Minorities also are fully represented in this study in 
proportion to their presence in these primary care practices and in proportion to their 
presence in the BWH physician and specialist community. The practices serve an 
ethnically and socioeconomically diverse patient population. Approximately 16% percent 
of BWH patients are Latino and 29% are Black. About 1.5% of BWH patients are Asian. 
Definitions of patients’ race and ethnicity will be based on self-report at the time of 
hospital registration. By promoting uniformly high standards of patient care, our 
interventions may lessen disparities in care. 
 
 
IV. 
SUBJECT ENROLLMENT 
 

 
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Randomization and Enrollment: This study will utilize a matched-pair cluster randomized 
design with the intervention on the cluster level, and the main outcome (6 month minus 
baseline change in SBP) measured at the patient level.  We will have 174 clusters 
(made up of 185 clinicians) in the study.  We will match pairs of clusters with similar 
number of patients and prior year mean blood pressure of patients in the cluster.  One 
cluster in each pair with be randomized to the intervention and unit one to usual care. 
Patients will be electronically identified and included in the study over the course of 12 
months. Patients seen by PCPs during the pilot study will be excluded. Retrospective 
data indicates that 70% of patients have a follow-up around 6 months. Outcomes 
assessment will occur at 180 days (+/- 60 days). After the 12-month enrollment period 
ends, data collection will continue for 6 months so that those enrolled toward the end of 
the enrollment period will have a full 6 months to complete any interventions ordered by 
the PCP. A small subset of PCPs will be enrolled in a pilot study for approximately one 
month, as described below in study procedures Aim 1b. Clinical outcomes will be 
recorded and reviewed every month over the course of the trial. 
 
 
V. 
STUDY PROCEDURES 
 
Aim 1, and 1a Study Procedures:  
 
Modify Rules for Automated Diagnosis of CKD and Uncontrolled HTN: Dr. Samal is a 
participant in the NKDEP Health Information Technology care plan working group.80 She 
has contributed to their efforts to new national standards for diagnosis of patients with 
CKD using EHR data. We will modify the rules from the MAPLE study in order to align 
them with this new national standard. Then, we will create rules for automated diagnosis 
of uncontrolled hypertension. We will implement the BPA in “silent mode” for the control 
arm. This means that we will identify control patients in real time according to the same 
inclusion criteria as intervention patients, excluding all patients who are pregnant.  
 
Develop Rules for Evidence-based Recommendations for HTN in CKD: We will leverage 
past work that we have done in a study that delivered recommendations based on 
JNC7.73 An example of one of the rules is to determine whether anti-hypertensive agents 
have been prescribed but are not at highest potency. If so, the CDS will deliver a 
recommendation to increase the dosage. Or, if multiple agents have been prescribed at 
maximum potency, the CDS will access the patient’s refill record. If the patient has not 
been refilling medications on schedule, the tool will recommend a medication adherence 
discussion. We will also include one-click access to documentation and orders relevant 
for CKD. For example, a message that gives a specific diagnosis, “This patient has 
stage 3b CKD with unknown level of albuminuria”), as well as an actionable order, “Click 
here to order a urine microalbumin to creatinine ratio test.” The BPA will include a BP 
entry field in which a PCP can record a repeat BP reading.83,84 If the PCP enters a BP 
reading, it will automatically be recorded in the vital signs flowsheet and vice versa. We 
will include appropriate laboratory monitoring test orders. Confirmatory testing is 
appropriate for an abnormal urine albumin level, so we will include an order if the prior 
result was abnormal.85 We will also provide one-click access to print patient handouts. In 
order to minimize cognitive overload and improve self-efficacy we will only deliver three 
messages at one time. We will develop a ranked list to drive the choice of 
recommendations. For example, in patients with CKD and HTN who smoke, tobacco 
cessation would be the highest priority.  

 
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Implementation of CDS in Epic: The next step is implementation in Epic as a BPA. Each 
of the rules will be added to the Epic database. The BPAs appear in an area of the 
screen that is visible when orders are being entered. Currently, there are several cancer 
screening BPAs and a seasonal influenza BPA. The CDS will be moved to the 
Production environment in “silent mode” before the scheduled start date of the trial, 
where it will record when it would fire, but it will not be displayed to the user. This step 
will allow us to validate that the rules are accurately identifying patients and producing 
the correct recommendations through a chart review. We will review 10 charts of 
patients with CKD and uncontrolled HTN per clinic for a total of 150 charts. The CDS will 
be activated in the Production environment on the start date of the clinical trial in Aim 2. 
 
Validation of Hypertension-specific Process Measures: In preparation for the clinical trial 
in Aim 2, we will validate three process measures. Two of the measures will reflect 
treatment intensification by the PCP, 1) an increase in dosage or 2) addition of a new 
anti-hypertensive agent. The third measure will reflect medication adherence by the 
patient using data from a pharmacy benefits manager. We will perform a retrospective 
chart review of 150 charts to calculate the sensitivity and specificity of each rule. 
 
Aim 1b Procedure: 
 
Task Scenario Development and Pilot Test: Usability testing clinical scenarios will be 
developed by two subject matter experts (Dr. Samal and Dr. Bates). Tasks will include 
adding CKD to the problem list, placing lab and/or medication orders, and printing 
patient education handouts. We will also include a test scenario that could lead 
the PCP to decide not to follow the CDS recommendation and we will see if they are 
able to enter a justification without assistance (see “accountable justification” section 
below). The scenarios will be reviewed by the research team to ensure that the content, 
format, and presentation are representative of real expected use and address the major 
components of the CDS. Then we will pre-load test patients with the data necessary for 
these scenarios and prepare the usability test procedure (described below). The usability 
test will be piloted with a PCP and we will ask for feedback on the usability test process, 
as well as content and wording of test scenarios. 
 
Usability Test Procedure: A usability test plan will be developed that includes details on 
the testing procedure, tasks, usability metrics, usability goals, and appendices containing 
the test scenarios, pre-test instructions, and post-test interview questions. A moderator 
and observer from the research team will both attend each session. First, the moderator 
will describe the usability test procedure using scripted pre-test instructions to ensure 
that all participants receive the same instruction. The participant will be informed of the 
goal of evaluating the CDS and that the session will be video-taped. The moderator will 
describe the “think-aloud” process, asking the participant to share their thought process 
and expectations while completing the tasks.87 An example of think aloud will be 
demonstrated. Then, the moderator will begin recording the session using Morae 
software. The participant will read each task aloud, attempt the task, and inform the 
moderator when the task is complete. The moderator will record task success or failure 
based on the intended outcome as described in the test plan. If a participant is having 
trouble completing a task, he or she will be given an assist at the moderator’s discretion. 
The observer will make note of assists and other usability or comprehension issues that 
arise. After all tasks are complete, the moderator will administer a verbal post-test 
interview. The moderator will ask questions like, “How did you interpret this?”, “Why did 

 
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you do X?” and “What would you change about the content of the CDS?” The moderator 
and observer will manually record observations during the testing session. In addition to 
the comments and data recorded during the session, usability metrics will be coded after 
the session using Morae software. Usability metrics are measurements collected to 
determine to what extent usability goals have been met. The metrics will include task 
completion success rates, time-on-task, error rates, and assists by the moderator. We 
will be able to compare these measurements to those gathered from subsequent tests to 
determine whether iterative changes to the CDS have improved the usability of the CDS. 
Qualitative analysis: Qualitative methods will be employed to analyze the data. The 
research assistant will review the video recordings to identify usability issues based on 
observations of the participants during the task and the participants’ think-aloud 
comments. Video recordings will be transcribed verbatim, and subject identifiers will be 
removed from the transcripts. The transcripts will be organized by task and participant 
and then quotes will be identified that illustrate a user expectation, frustration, or 
misinterpretation of content or functionality. 
 
Pilot Study: Prior to the clinical trial, a pilot study will be conducted in live clinical 
settings. A subgroup of PCPs will be selected an the BPAs will be turned on for 
approximately one month. Interaction with the BPAs will be monitored. Each time a BPA 
fires the research team will contact the PCP by email to gather feedback through 
surveys and/or interviews. Iterative refinement of BPAs may be undertaken. 
 
Aim 1c Procedure: 
1) Pre-checked, no-action default: The first nudge will be part of the CDS. We will 
display the CDS with certain options pre-selected. We plan to include addition of the 
CKD diagnosis to the problem list and addition of a patient education handout to the 
after-visit summary. 
 
2) Pledge email to obtain commitment from PCPs to follow the CDS recommendations: 
As a starting point, we need to ensure that PCPs are aware of the clinical practice 
guidelines. At the beginning of the study, we will send an advertisement email to all 
PCPs in the network. In addition, as part of the intervention, we will ask PCPs to commit 
to following the recommendations presented to them in the BPA, or writing their rationale 
in the CDS if they choose not to. The PI will send an email via REDCap to intervention 
PCPs giving a brief overview of the CDS content. By clicking a link in the email, the 
intervention PCP will come to a REDCap survey asking them to type their name to 
pledge to consider the CDS recommendations provided in our BPAs. The control PCPs 
will receive a similar email without the specific details about our study and without the 
REDCap link. 
 
Behavioral Science Methods Review Committee: Though the research team does 
include co-investigators with expertise in behavioral science methods, we have decided 
to convene an advisory group consisting of three experts in behavioral science as 
applied in interventions for both PCPs and patients. We have chosen the members of 
this committee based upon their familiarity with chronic disease management 
interventions and EHR-based interventions. We have limited the group to three 
members because we plan to meet on a monthly basis during the first two years of the 
study. This group will give advice to the research team on elements of 
Aim 1 and the roll-out of the clinical trial. 
 

 
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Specific Aim 2 & 2a Procedures: 
Setting: The Brigham and Women's Primary Care Practice-Based Research Network 
(BWPC PBRN) is one of 155 PBRNs nationally certified by the Agency for Healthcare 
Research and Quality (AHRQ). The BWPC PBRN is a network of 15 practices which 
includes hospital-based practices, community-based practices, and community health 
centers affiliated with Brigham and Women’s Hospital. The network includes 185 primary 
care physicians that care for approximately 150,000 patients. 
 
Subjects: All patients over the age of 18 who have a visit with a PCP at one of the 
intervention practices during the 2 years preceding the study period will be eligible. We 
are able to utilize data from the past five years stored in the EHR to identify CKD 
patients with uncontrolled HTN. The first inclusion criteria will be CKD, defined as two 
prior eGFR 16-59 mL/min/1.73m2 separated by 90 days, as calculated by CKD-EPI, or 
two prior UACR >30mg/g. The second inclusion criteria will be uncontrolled 
hypertension, defined as at least two SBP >140 mmHg within the 2 years preceding the 
study period. We will exclude all patients who are currently pregnant. The CDS will 
review lab data starting five years before the visit to determine whether the patient has 
CKD using the logic described above. If the patient has CKD, the CDS will search BP 
data starting one year before the visit to determine whether the patient has had at least 
two SBP > 140 mmHg. 
 
Specific Aim 2b Procedure:  
Outcomes: We will analyze the actual use of the CDS, defined as interaction with the 
BPA, signing of orders, or accountable justification documentation within the BPA.  
 
 
VI. 
BIOSTATISTICAL ANALYSIS 
 
Data collected during the pilot study will not be included in the final analysis. Patients 
enrolled in the pilot study will not be enrolled in the final analysis. However, PCPs in the 
pilot study will be included in the intervention arm of the main clinical trial. A subgroup 
analysis will be performed on patients of these PCPs. 
 
Table 1. Outcome Variables and Measures for Both Arms 
Measurement 
Variable 
Form of Variable 
Analysis Metric 
Time Point 
Primary 
Mean SBP 
Continuous 
Change from baseline 
6 months, 12 
months, 18 months 
Secondary 
Controlled SBP 
Rate 
Dichotomous 
Proportion of patients with 
controlled SBP rate 
6 months, 12 
months, 18 months 
Urine Albumin to 
Creatinine Ratio 
Continuous 
Urine Albumin to Creatinine 
Ratio 
6 months, 12 
months, 18 months 
Serum Creatinine > 
2.0 
Dichotomous 
Proportion of patients with 
Creatinine > 2.0 
Monthly 
eGFR 
Continuous 
eGFR 
6 months, 12 
months, 18 months 

 
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Medication ordered Dichotomous 
Proportion of patients with 
recommended medication 
ordered 
6 months 
Basic metabolic 
panel ordered 
Dichotomous 
Proportion of patients with 
basic metabolic panel ordered 6 months 
Referral to e-
consults 
Dichotomous 
Proportion of patients with 
referral to e-consults  
6 months 
BPA acceptance 
Dichotomous 
Proportion of patients where 
BPA was accepted 
6 months 
Mean SBP of less 
than 110 
Dichotomous 
Proportion of patients with 
mean SBP of less than 110 
Monthly 
Newly documented 
allergy 
Dichotomous 
Proportion of patients with 
newly documented allergy due 
to adverse drug events 
Monthly 
K+ > 5.2 
Dichotomous 
Proportion of patients with K+ 
> 5.2 
Monthly 
K+ < 3.6 
Dichotomous 
Proportion of patients with K+ 
< 3.6 
Monthly 
Mean SBP intent-
to-intervene 
analysis with 
imputation of 
missing 6-month BP 
measurement 
Dichotomous 
Proportion of patients with 
missing 6-month BP 
measurement 
6 months 
Controlled SBP 
Rate intent-to-
intervene analysis 
with imputation of 
missing 6-month BP 
measurement 
Dichotomous 
Proportion of patients with 
missing 6-month BP 
measurement 
6 months 
 
Table 2. Outcome Variables and Measures for Intervention Arm Only 
Measurement 
Variable 
Form of Variable 
Analysis Metric 
Time Point 
Acknowledgment 
reason entered 
Dichotomous 
Proportion of patients with 
acknowledgment reason 
entered 
6 months 
Feedback button 
clicked 
Dichotomous 
Proportion of patients with 
feedback button clicked 
6 months 
PCP participation 
on pledge email 
survey 
Dichotomous 
Proportion of patients whose 
PCPs participated in pledge 
email survey 
6 months 
Guideline accessed Dichotomous 
Proportion of patients with 
guideline accessed 
6 months 
 
 
VII. 
RISKS AND DISCOMFORTS 
 

 
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There are minimal risks to physicians or patients as a result of the intervention. For 
clinicians, there is a risk that the decision support and other tools could have unexpected 
adverse consequences such as creation of more work, unfavorable workflow issues, and 
overdependence on technology. Although important to consider, these risks are 
balanced by evidence suggesting the effectiveness of computerized clinical decision 
support to improve the quality of patient care. For patients, the risks are those that are 
typically undertaken in the receipt of general medical care. That is, it is conceivable that 
the intervention could result in a change in management (e.g., ordering more tests, 
referral), but in the case of chronic kidney disease this may in fact lead to a clinical 
benefit. There also is the possibility of psychological risk to patients associated with 
being labeled as having chronic kidney disease; however, this risk is outweighed by the 
potential benefits associated with better evaluation and treatment of the disease. Finally, 
there is a risk of overtreatment of hypertension which may cause hypotension or an 
acute decrease in kidney function. The intervention is delivered to the primary care 
physician, who will weigh the risk and benefit of treatment intensification. However, this 
risk is expected to be low since we only recommend treatment intensification within 
consensus guidelines. 
 
 
VIII. POTENTIAL BENEFITS 
 
This research has the potential benefit of improving the quality of care for patients in the 
intervention practices, which ultimately could prevent disease progression and death. 
There are no potential benefits to the control subjects, who will receive current standard 
of care. 
 
 
IX. 
MONITORING AND QUALITY ASSURANCE 
 
The investigators will establish an independent Data Safety Monitoring Board (DSMB), 
which will serve as an independent group to monitor participant safety, study burden and 
scientific validity of the clinical data. The PI will ensure that the research is conducted in 
an ethical manner in accordance with good clinical practice and meets all applicable 
regulatory laws and policies. In addition to meeting the responsibilities for protecting the 
rights, safety, and welfare of the subjects enrolled in the research, the PI will review 
safety data, study conduct, procedural safety enrollment, adverse events, and other 
study-related information. The PI and co-investigators will review enrollment, adverse 
events and any recent literature that may be relevant to the research on a quarterly 
basis. Formal minutes with discussion points and remediation/actions plans (e.g. 
changes to protocol and consent documents) will be created, maintained, and relayed to 
the DSMB. The DSMB will convene in person or by teleconference once per year. At this 
meeting, the board will review any cases where systolic blood pressure was found to be 
below 110 mmHg, any reported adverse events, and deaths of enrolled patients. 
 
 
X. 
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