Association Between a Pharmacogenetic Algorithm to Predict Blood Pressure Therapy With Blood Pressure Response to Anti-Hypertensive Therapy
Conditions: Hypertension
Sponsor: Geneticure, LLC

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 1 of 20 
Revised: September 22, 2017 
PROTOCOL TITLE: 
 
Association between a Pharmacogenetic Algorithm to Predict Blood Pressure 
Therapy with Blood Pressure Response to Anti-Hypertensive Therapy.  
 
PRINCIPAL INVESTIGATOR or FACULTY ADVISOR: 
Pamela Phelps, PharmD 
Pharmacy 
612-672-5149 
Pphelps2@fairview.org 
 
STUDENT INVESTIGATOR: 
N/A 
 
VERSION NUMBER/DATE: 
1: 9.22.17 
 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 2 of 20 
Revised: September 22, 2017 
REVISION HISTORY 
 
Revision 
# 
Version 
Date 
Summary of Changes 
Consent 
Change? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 3 of 20 
Revised: September 22, 2017 
Table of Contents 
After completing your protocol, right click on the Table of Contents below and 
select “Update Field.” If prompted, select “Update entire table.” This will 
automatically update the protocol sections and page numbers for you. Do this 
also each time you modify your protocol after initial approval. 
 
1.0 
Objectives ................................................................................................... 6 
2.0 
Background ................................................................................................. 6 
3.0 
Study Endpoints/Events/Outcomes ............................................................. 9 
4.0 
Study Intervention(s)/Investigational Agent(s) ............................................. 9 
5.0 
Procedures Involved ................................................................................. 10 
6.0 
Data and Specimen Banking ..................................................................... 13 
7.0 
Sharing of Results with Participants .......................................................... 13 
8.0 
Study Duration .......................................................................................... 13 
9.0 
Study Population ....................................................................................... 13 
10.0 Vulnerable Populations ............................................................................. 14 
11.0 Local Number of Participants .................................................................... 15 
12.0 Local Recruitment Methods ...................................................................... 15 
13.0 Withdrawal of Participants ......................................................................... 16 
14.0 Risks to Participants .................................................................................. 16 
15.0 Potential Benefits to Participants .............................................................. 16 
16.0 Data Management..................................................................................... 16 
17.0 Confidentiality ........................................................................................... 18 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants ......... 18 
19.0 Provisions to Protect the Privacy Interests of Participants ........................ 18 
20.0 Compensation for Research-Related Injury .............................................. 19 
21.0 Consent Process ....................................................................................... 19 
22.0 Setting ....................................................................................................... 19 
23.0 Multi-Site Research ................................................................................... 19 
24.0 Resources Available ................................................................................. 19 
25.0 References ................................................................................................ 20 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 4 of 20 
Revised: September 22, 2017 
ABBREVIATIONS/DEFINITIONS 
BP/Blood Pressure 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 5 of 20 
Revised: September 22, 2017 
STUDY SUMMARY 
 
Study Title 
Association between a Pharmacogenetic 
Algorithm to Predict Blood Pressure 
Therapy with Blood Pressure Response 
to Anti-Hypertensive Therapy.  
 
Study Design 
Retrospective Association Study 
Primary Objective 
To retrospectively assess the effectiveness 
of the use of a patient’s genes to predict 
which hypertension therapy is successful: 
1.  Level of blood pressure control 
(<140/<90) 
2. Change in blood pressure from 
baseline to control 
 
Secondary Objective(s) 
1. Number of medications needed to 
obtain control 
2. Time to control 
3. Number of office visits to control 
4. Side effects from hypertension 
therapy 
5. Hypertension associated adverse 
events during the course of treatment 
 
Research 
Intervention(s)/Investigational 
Agents 
Association between blood pressure control 
and genetic variants important in blood 
pressure regulation.  
IND/IDE # (if applicable) 
 
Investigational Drug Services 
# (if applicable) 
 
Study Population 
Hypertensive patients who have achieved 
BP control 
Sample Size (number of 
participants) 
Up to 2000 
Study Duration for Individual 
Participants 
Less than one day 
 
 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 6 of 20 
Revised: September 22, 2017 
1.0 
Objectives 
Purpose: To assess the effectiveness of the use of a patient’s genes to predict 
which hypertension therapy is successful, as measured by: 
 
1. 
Level of blood pressure control (<140/<90) 
2. 
Change in blood pressure from baseline to control 
3. 
Number of medications needed to obtain control 
4. 
Time to control 
5. 
Number of office visits to control 
6. 
Side effects from hypertension therapy 
7. 
Hypertension associated adverse events during the course of 
treatment 
 
2.0 
 
Background 
1. Significance of Research Question/Purpose:  
Hypertension is known to have a strong heritable component. Previous work has 
demonstrated that sons of hypertensive patients are more likely to be 
hypertensive when compared to sons of normotensive individuals. Additionally, 
monozygotic twins are more likely to share hypertension than dizygotic twins who 
are more likely than non-twin siblings to share hypertension. Each of these 
previous studies demonstrate that genetics plays a role in the development of 
hypertension. For each major class of drugs (diuretic, vasodilator, and β-blocker) 
the effectiveness rate ranges from 40-60%. Contrary to common belief, even a 
small ~10-20% of patients have an increase in blood pressure with a given anti-
hypertensive medication. These effectiveness rates go far beyond adherence in 
that these previous trials have controlled for medication adherence. In addition to 
this controlled studies, epidemiologic data has demonstrated that 40% of patients 
who take their medication, as prescribed by their clinician, do not have their 
blood pressure under control.  
 
Unfortunately, despite a significant impulse in the medical community to move 
towards an “individualized medicine” approach to patient centered treatment, the 
current clinical treatment strategy is based on a set algorithm which does not 
take into account individual patient differences. Rather, physicians are guided to 
choose a drug (one out of many options) in a given class of drugs and use that 
specific drug as a “first line therapy” (typically initiating with the diuretic class) and 
titrate that specific drug of choice to therapeutic dosage regardless of efficacy2. It 
is only after a prolonged course of treatment with that specific class of drug that 
clinical efficacy is determined (typically three months).  At this stage, if clinical 
guideline goals for blood pressure have not been met, it is often recommended 
that the patient remain on the “first line therapy” whilst an additional drug from a 
different class of drugs (typically an Angiotensin converting enzyme inhibitor 
(ACE inhibitor) or Angiotensin II receptor blocker (ARB)) is added to the 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 7 of 20 
Revised: September 22, 2017 
pharmacologic regimen. Again, this drug is titrated to recommended therapeutic 
dosage and another prolonged course of treatment is initiated before clinical 
efficacy is determined (an additional three months – six months since initiation of 
treatment). If at this point, clinical guideline goals for blood pressure have not 
been met, a third drug from a third class of drugs (typically a beta-blocker) is 
added and the process is repeated (another three months – nine months from 
initiation of treatment). Further, if clinical guideline goals have continued to be 
elusive, the diagnosis of refractory hypertension is added and the process is 
reinitiated with a different combination of drugs, different classes of drugs, 
different drug options within a given class of drugs, different dosages, or all of the 
above. Thus, from the time of initial diagnosis and the start of treatment to the 
point in which blood pressure is adequately controlled may take anywhere from 
three months to well over one year. This trial-and-error standard of care is clearly 
not optimal. 
 
The blood pressure panel created by Geneticure has been created to 
comprehensively assess seventeen common genetic variants in the liver (drug 
metabolizing enzyme) cardiac, vascular, and renal systems that can improve 
therapeutic guidance for the clinician based on known functional alterations of 
the protein through these genetic changes, as well as demonstrated effects of 
certain drug classes on these various genotypes. Based on this information, a 
clinician can guide therapy with knowledge specific to their patient, rather than 
“trial-and-error” based on population data and using drugs with least side effects 
initially.   
 
1. 
Preliminary Data: N/A 
2. 
Existing Literature:  
 
Background 
 
Hypertension (high blood pressure) is one of the most important preventable 
contributors to disease and death in the United States and represents the most 
common condition seen in the primary care setting1,2. According to the American 
Heart Association, approximately 78 million adults (1 in 3) living in the United 
States have hypertension with more than 5 million new diagnoses made each 
year3,4. Of these individuals, 82% are aware they have it, 75% are currently being 
treated for it, but only 52% have their blood pressure under control (thus, ~48% 
do not have adequate blood pressure control). Hypertension is known to lead to 
myocardial infarction, stroke, renal failure, and death if not detected early and 
treated appropriately. In fact, in 2009, high blood pressure was listed as a 
primary or contributing cause of death in ~350,000 of the ~2.4 million U.S. deaths 
(14% of all deaths). From 1999-2009 the number of deaths attributable to 
hypertension increased by 44%. In 2009, the direct and indirect economic burden 
on the United States health care system associated with hypertension was 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 8 of 20 
Revised: September 22, 2017 
estimated at $51 billion. With the advent of improved diagnostic techniques, 
increased rates of health care utilization and screening, and the increasing age of 
the population, a continual upward trend in this expenditure is expected. Because 
nearly two-thirds of the people living with hypertension worldwide reside in 
developing countries, providing optimal treatment at the lowest cost is critically 
important. 
 
 
Hypertension is known to have a strong heritable component. Previous work has 
demonstrated that sons of hypertensive patients are more likely to be 
hypertensive when compared to sons of normotensive individuals. Additionally, 
monozygotic twins are more likely to share hypertension than dizygotic twins who 
are more likely than non twin siblings to share hypertension. Each of these 
previous studies demonstrate that genetics plays a role in the development of 
hypertension. For each major class of drugs (diuretic, vasodilator, and β-blocker) 
the effectiveness rate ranges from 40-60%. Contrary to common belief, even a 
small ~10-20% of patients have an increase in blood pressure with a given anti-
hypertensive medication. These effectiveness rates go far beyond adherence in 
that these previous trials have controlled for medication adherence. In addition to 
this controlled studies, epidemiologic data has demonstrated that 40% of patients 
who take their medication, as prescribed by their clinician, do not have their 
blood pressure under control.  
 
Unfortunately, despite a significant impulse in the medical community to move 
towards an “individualized medicine” approach to patient centered treatment, the 
current clinical treatment strategy is based on a set algorithm which does not 
take into account individual patient differences. Rather, physicians are guided to 
choose a drug (one out of many options) in a given class of drugs and use that 
specific drug as a “first line therapy” (typically initiating with the diuretic class) and 
titrate that specific drug of choice to therapeutic dosage regardless of efficacy2. It 
is only after a prolonged course of treatment with that specific class of drug that 
clinical efficacy is determined (typically three months).  At this stage, if clinical 
guideline goals for blood pressure have not been met, it is often recommended 
that the patient remain on the “first line therapy” whilst an additional drug from a 
different class of drugs (typically an Angiotensin converting enzyme inhibitor 
(ACE inhibitor) or Angiotensin II receptor blocker (ARB)) is added to the 
pharmacologic regimen. Again, this drug is titrated to recommended therapeutic 
dosage and another prolonged course of treatment is initiated before clinical 
efficacy is determined (an additional three months – six months since initiation of 
treatment). If at this point, clinical guideline goals for blood pressure have not 
been met, a third drug from a third class of drugs (typically a beta-blocker) is 
added and the process is repeated (another three months – nine months from 
initiation of treatment). Further, if clinical guideline goals have continued to be 
elusive, the diagnosis of refractory hypertension is added and the process is 
reinitiated with a different combination of drugs, different classes of drugs, 
different drug options within a given class of drugs, different dosages, or all of the 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 9 of 20 
Revised: September 22, 2017 
above. Thus, from the time of initial diagnosis and the start of treatment to the 
point in which blood pressure is adequately controlled may take anywhere from 
three months to well over one year. This trial-and-error standard of care is clearly 
not optimal. 
 
The blood pressure panel created by Geneticure has been created to 
comprehensively assess seventeen common genetic variants in the liver (drug 
metabolizing enzyme) cardiac, vascular, and renal systems that is being studied 
to see if it can improve therapeutic guidance for the clinician based on known 
functional alterations of the protein through these genetic changes, as well as 
demonstrated effects of certain drug classes on these various genotypes. Based 
on this information, a clinician can guide therapy with knowledge specific to their 
patient, rather than “trial-and-error” based on population data and using drugs 
with least side effects initially.   
 
3.0 
Study Endpoints/Events/Outcomes 
1. 
Primary Endpoint/Event/Outcome:  
To assess the effectiveness of the use of a patient’s genes to predict which 
hypertension therapy is successful, as measured by: 
 
1. Level of blood pressure control (<140/<90) 
2. Change in blood pressure from baseline to control 
 
2. 
Secondary Endpoint(s)/Event(s)/Outcome(s):  
Blood Pressure control with respect to: 
1. 
Number of medications needed to obtain control 
2. 
Time to control 
3. 
Number of office visits to control 
4. 
Side effects from hypertension therapy 
5. 
Hypertension associated adverse events during the course 
of treatment 
4.0 
Study Intervention(s)/Investigational Agent(s) 
1. 
Description: A multigene panel comprised of genes with known 
functionality in the heart, vasculature, and kidney, that are known to 
influence BP. This study will be performed as a retrospective study 
on patients within the Fairview Health System. Patients will be those 
who have been previously diagnosed with hypertension and have a 
history of blood pressure control (<140/<90 for two consecutive office 
measures. The study will involve collection of a buccal swab (can be 
done at the patient’s home, by the patient) and a clinical chart review 
of the patient’s hypertension and medication history. From the buccal 
swab we will assess 18 SNPs in 11 genes  (2) SNPs in ADRB1, (2) 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 10 of 20 
Revised: September 22, 2017 
SNPS in ADRB2, (1) in SCNN1A, (1) in ADD1, (2) in SLC12A3, (3) in 
WNK1, (1) in ACE, (3) in AGT, and (1) each in AGTR1, CYP2D6*4 
and REN) with known functionality in the liver, heart, vasculature, 
and kidney.  
 
2. 
Drug/Device Handling: The device used for sample collection is a 
buccal swab kit that gently removes cells from the inside of the 
cheek. The Geneticure kit contains two buccal brushes and two 
tubes of lysis buffer. The patient swabs their left cheek and deposits 
the end of the swab in the lysis buffer, then does the same for the 
right cheek. This swab is placed (by the patient) in lysis buffer (a 
small tube) and shipped to the study site, if collected off site. The 
swab is then shipped to the University of Arizona Genomics core 
facility for DNA extraction, quantification, and assessment of the 
genes listed above. The study is retrospective in nature and the DNA 
assessment will not influence prescribing, i.e. no drugs will be 
changed based on this analysis for the patients. No identifying 
information will EVER accompany the kit to the genetic testing 
facility.  
3. 
IND/IDE: In-vitro diagnostic device and exempt from IDE. 
4. 
Biosafety: N/A  
5. 
N/A 
 
5.0 
Procedures Involved 
1. 
Study Design: Retrospective analysis of association with DNA 
variants with pharmacotherapy used to achieve BP control.  
General Flow of Activities: 
1.      Patients identified via UMN AHC-IE and sent recruitment letter, consent, 
survey and buccal swab kit via FRA’s recruitment mailing process.  
a.       An E-mail, Letter, survey information, are included along with this 
submission.  
2.     Subject collects buccal swab: 
Using the collection kit consisting of two buccal swabs and two uniquely 
barcoded tubes the investigator, patient, or designee will remove the first buccal 
brush and scrape the brush end across the inside of a Subject’s right cheek 
repeatedly (for five seconds using moderate pressure).  The investigator, patient, 
or designee will place the brush end over the open buffer vial and press the 
opposite end of the swab stick to release the brush into the buffer and then close 
the vial.  The process will be repeated on the left cheek. Each of the right and left 
cheek vial numbers must be recorded on the clinical review form and 
accountability log as right (R), or left (L). 
 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 11 of 20 
Revised: September 22, 2017 
3.       The patients return completed consent, buccal kit, to Geneticure for 
sorting. 
4.      The signed consent form is sent to the PI (Dr. Pamela Phelps) and the 
buccal swab in lysis buffer is sent to the University of Arizona Genomics core 
facility for Genotyping.     
 
- All genotyping is performed in a blinded manner looking at 19 single 
nucleotide polymorphisms.  
5.      $30 sent to participant at the time the Geneticure team receives the buccal 
swab, consent, etc. The Geneticure team will perform any follow-up needed for 
participants who do not receive their payment, additional questions. Clinical 
questions will be forwarded to Dr. Phelps as the PI  
6.      Research team (Fairview pharmacy residents Danielle Walla and Krista 
Weaver) conducts chart review and abstracts data onto CRFs 
7.      CRFs sent to Geneticure 
 
Specific Study procedures:  
 
Screening 
 Identify Potential Study Subjects through AHC.  Refer to the 
Inclusion and Exclusion Criteria sections of this protocol for a 
complete list of eligibility criteria. 
 Obtain Written Informed Consent either in-person or via mail.  
Each potential study participant must be given time to review the 
IRB-approved informed consent form, have his/her questions 
answered to their satisfaction and sign the form prior to any study 
procedures being performed. A subject will be given a copy of the 
informed consent form.  
 Review Inclusion/Exclusion Criteria. The investigator and/or 
designee will review all criteria to determine if the subject is eligible 
for enrolment. Eligibility of all subjects must personally be 
confirmed by the Investigator and will be documented on the CRF.  
Enrollment 
 Assign Identification Number to Eligible Subjects.   
Chart Review 
 Record demographics, antihypertensive medical history and most 
recent blood Pressure.  Data will be documented in the source 
document and recorded on the patient demographic form, including but 
not limited to the following: 
o Age 
o Sex 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 12 of 20 
Revised: September 22, 2017 
o Height 
o Weight 
o Race 
o Ethnicity 
(additional data for collection is included in the attachment entitled 
“metrics”) 
 
Specimen Collection 
 Collect Buccal Specimen.   
 
Subject Numbering 
Subjects meeting the criteria for enrollment (and their specimens) will be 
identified by unique numbers that will be assigned sequentially by order of 
enrollment. The pre-assigned investigational site number will be prefixed with 
GCE and the identification number and separated by a hyphen (e.g., GCE-
001etc.). Throughout the descriptions within the protocol the A swab will be 
referring to the swab that has originated from the right cheek, while the B swab 
will be that that has originated from the left cheek. To further clarify. Subject 
GCE-001 will be given two barcoded tubes. These barcode numbers should be 
recorded for each patient. These will also be recorded as originating from the 
right cheek (A) or left cheek (B).  
At no time should any study paperwork or specimens be marked with the 
subject’s name or any other traceable identifier except for the informed consent 
form, which is signed by the subject and kept at the site. At no time should the 
original (signed) or a copy of this form be collected by the Sponsor or its 
representative. 
 
2. 
Follow-Up: Data will be collected for up to one year.  
3. 
Individually Identifiable Health Information: a chart review will be 
performed to assess a patient’s BP medication history. No personally 
identifiable information (Name, Address, date of birth) will be kept 
with the study document. The only individuals who will have access 
to a patient’s chart will be Fairview clinical employees who also have 
IRB approval to be involved with this study. The linking information 
(from consent) will be kept in the PI (Dr. Pamela Phelps) office in a 
locked cabinet. No patient data with identifying information will be 
transmitted outside of the Fairview system. Additionally, no de-

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 13 of 20 
Revised: September 22, 2017 
identified PHI will be transmitted to any individual who does not have 
IRB approval to be involved with this research study.  
 
4. 
Use of radiation: N/A  
5. 
Use of Center for Magnetic Resonance Research: N/A 
6.0 
Data and Specimen Banking 
If this study does not involve data or specimen banking for future use, type 
“N/A” and delete the sub-headings below. Otherwise, complete all items 
below. 
1. 
Storage and Access: Data will be stored on secure, password-
protected Fairview Health Services Servers.  
2. 
Data: BP control history and relevant cardiovascular and side-effect 
data will be collected. We will not be banking any of this information 
for other studies, this is for the present study only.  
3. 
Release/Sharing: No individual data or patient information will be 
released or shared with any individual who is not approved to 
participate in this research study.  
7.0 
Sharing of Results with Participants 
1. 
We will share patient’s genetic results, if requested. None of the 
genes are known to be major cancer causing genes. If we share the 
genetic results with the patient this will be done by a Fairview 
clinician on our research team. We will offer genetic counseling 
services, if the patient requests such a service. The laboratory where 
the genetic testing is performed (the University of Arizona Genomics 
core) is a CLIA-certified genetic laboratory.  
8.0 
Study Duration 
1. 
Describe: 
 
An individual will just need to provide two buccal swabs and 
complete a BP medication survey. This will take less than one 
hour.  
 
We anticipate it will take approximately 6 months to recruit our 
subjects.  
 
We anticipate it will take one year in total from beginning of 
study for data to be presented in abstract for and submitted as a 
manuscript.  
9.0 
Study Population 
1. 
Inclusion Criteria:  
1. 
Subject is able and willing to provide informed consent  
2. 
Subject is ≥ 20 and ≤ 85 years of age 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 14 of 20 
Revised: September 22, 2017 
3. 
Subject with diagnosis of Hypertension for a minimum of 1 
year 
4. 
Subject has been on the same class/classes of blood 
pressure medication for a minimum of 6 months.  Note: A change in 
dosage, frequency, or specific medication is acceptable as long as 
there have been no changes to the class/classes of medications 
prescribed. 
5. 
Subject with a Body Mass Index (BMI)  ≥ 19 and ≤ 45  
6. 
Subject is currently prescribed and taking one of the 
following classes of medications alone or in combination with each 
other.   
o 
Diuretics (thiazide or thiazide-like) 
o 
ACE Inhibitors 
o 
Angiotensin Receptor Blocker (ARB) 
o 
Beta-blockers 
o 
Ca+ Channel Blockers 
2. Exclusion Criteria:  
1. 
Subject has a diagnosis of secondary hypertension or is 
experiencing a complication of pregnancy. 
2. 
Subject is currently prescribed and taking any additional 
class of medication(s) for high blood pressure not included in the list 
above 
3. 
Subject has Systolic BP > 190 or Diastolic BP > 120 
documented within the six months prior to visit.  
4. 
Any other reason that the subject is inappropriate for study 
enrollment in the opinion of the Investigator.   
2. 
Screening:  
Because this is a retrospective chart review study, subjects will be 
screened by a Fairview employee (or AHC personnel) for eligibility. 
Only subjects who have opted in (or who have not opted out) of 
research will be contacted.  
10.0 Vulnerable Populations 
1. 
Vulnerable Populations:  
☐ Children 
☐ Pregnant women/Fetuses/Neonates 
☐ Prisoners 
☐ Adults lacking capacity to consent and/or adults with diminished 
capacity to consent, including, but not limited to, those with acute 
medical conditions, psychiatric disorders, neurologic disorders, 
developmental disorders, and behavioral disorders 
☐ Approached for participation in research during a stressful 
situation such as emergency room setting, childbirth (labor), etc. 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 15 of 20 
Revised: September 22, 2017 
☐ Disadvantaged in the distribution of social goods and services 
such as income, housing, or healthcare 
☐ Serious health condition for which there are no satisfactory 
standard treatments 
☐ Fear of negative consequences for not participating in the 
research (e.g. institutionalization, deportation, disclosure of 
stigmatizing behavior) 
☐ Any other circumstance/dynamic that could increase vulnerability 
to coercion or exploitation that might influence consent to research 
or decision to continue in research 
☐ Undervalued or disenfranchised social group 
☐ Members of the military 
☐ Non-English speakers 
☐ Those unable to read (illiterate) 
☐ Employees of the researcher 
☐ Students of the researcher 
☒ None of the above 
2. 
Adults lacking capacity to consent and/or adults with diminished 
capacity to consent: 
 
N/A 
3. 
Additional Safeguards: If the research involves individuals Checked 
in Section 10.1 above, provide justification for their inclusion and 
describe additional safeguards included to protect their rights and 
welfare. 
 
N/A 
11.0 Local Number of Participants 
1. 
Local Number of Participants to be Consented: Up to 2000 subjects 
may participate in the study. 600 subjects are ideal for statistical 
analysis but given possible co-morbidities, we aim to consent up to 
2000 individuals.  
12.0 Local Recruitment Methods 
1. 
Recruitment Process: Subjects will be recruited via letter, phone call, 
and e-mail (drafts of each are attached to the IRB ETHOS “smart” 
form) 
2. 
Source of Participants: Medical record review 
3. 
Identification of Potential Participants: Recruited based on 
inclusion/exclusion criteria, Fairview participation, and willing to 
participate in a research study. Participants will primarily be identified 
via AHC-CTSI data that is gathered daily for Fairview participants 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 16 of 20 
Revised: September 22, 2017 
who have not opted-out of research. In addition, we may also use the 
following reach-out methods: 
 
Dr. Phelps is a Fairview clinician 
 
Dr. Phelps via mailer.  
 
In the mailer (attached to the IRB) we ask the patient regarding 
approval of use of medical records. In addition to this we will not 
use any patient who has opted out of research within the 
Fairview system.  
4. 
Recruitment Materials: Attached 
5. 
Payment: 30 dollars for completion of the buccal collection and BP 
history survey (which is attached) 
13.0 Withdrawal of Participants 
1. 
Withdrawal Circumstances: The researchers may withdraw a subject 
if they have inadequate DNA yield, they have a severe co-morbidity 
that was not previously flagged, or if the participant does not submit 
their buccal swab.  
2. 
Withdrawal Procedures: If a participant withdraws no data will be 
gathered after this time and no data from this participant will be used 
in the research. It is the patient’s right to withdraw at any time.  
3. 
Termination Procedures: N/A 
14.0 Risks to Participants 
For each risk or set of risks below, include the procedures to be performed 
to lessen the probability, magnitude, duration, or reversibility of those 
risks. 
1. 
Foreseeable Risks: Although unlikely, there is a possible risk of 
knowledge of genetic information. Given that none of the genes we 
are assessing are severe disease causing genes we find this highly 
unlikely.  
2. 
Reproduction Risks: N/A 
3. 
Risks to Others: It is possible that family members will try to infer 
their genetic results based on those of the participant.  
15.0 Potential Benefits to Participants 
1. 
Potential Benefits: There are no direct benefits to the participants.  
16.0 Data Management 
1. 
Data Analysis Plan:  
The Investigator is responsible to ensure the accuracy, completeness, and 
timeliness of reported data. 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 17 of 20 
Revised: September 22, 2017 
All data will be compiled within the Fairview system on secure servers. De-
identified final data may be sent to Geneticure using a secure, password-
protected Excel spreadsheet on a server that is only accessible to IRB-approved 
personnel and is fully auditable.  The database will be validated prior to use in 
the study. All required data will be recorded on CRFs or paper facsimiles. Data 
collected within the CRFs will be supported by source documents as appropriate 
and may be updated to reflect the latest observations on the subjects 
participating in the study. Corrections to the source documentation will be made 
in a manner that does not obscure the original entry and will be dated and 
initialed by the Investigator or assigned designee. It is important for data entry to 
occur in a timely manner, therefore, data collected on source documents should 
be transferred into CRFs as soon as possible following study visits. 
All data will be coded for statistical analysis (i.e. drug classes will be coded 
numerically and genotypes will be coded numerically). Subject’s raw genetic data 
will be entered into the Geneticure for Hypertension algorithm. All data will be 
analyzed with SPSS v.20. Normality of the data will be assessed using Levene’s 
test prior to statistical analysis and any correction for non-normal data distribution 
will be used. Descriptive statistics will be computed (average time for blood 
pressure control, average number of visits to the clinician for blood pressure 
control, age, height, weight, BMI, etc.).  
 
Data will be initially analysed following the collection of samples/data from up to 
600 subjects. Statistical tests will be corrected for the number of tests run 
(preservation of alpha). Ordinary least squares regression via univariate 
modelling will be used to estimate the magnitude of linearity between drug class 
that yielded the best blood pressure control and genetic profile of the subject. 
Multiple regression analysis will be performed to determine the impact of 
confounding variables (height, weight, age, race) on blood pressure control. For 
all statistical analyses an alpha level of 0.05 will be used to determine statistical 
significance.  
 
Missing Data 
All patients with available data will be included in the analyses of the study 
objectives.  No patients will be directly contacted to retrieve missing data, and no 
sensitivity analyses will be performed on missing data.  
 
2. 
Power Analysis:  
Power Calculation and Sample Size:  
Given the unique study design and pilot/feasibility nature of this proposal, highly 
accurate preliminary data are not available to generate detailed power 
calculations on the impact of the Geneticure panel for hypertension therapy. This 
is due to the lack of studies that have been performed in a prospective manner 
on genetic guidance for hypertension. However, previous work from our group 
utilizing a relatively small sample size and chart review have yielded data on all 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 18 of 20 
Revised: September 22, 2017 
17 genes that are contained within the Geneticure panel for hypertension 
treatment. Several of the genes with large effects can demonstrate statistical 
differences at relatively small sample sizes. For instance position 49 of the beta-1 
adrenergic receptor demonstrates a functional genotype mean arterial blood 
pressure of 97mmHg (SD of 12.4mmHg) with beta-blocker therapy and the non-
functional genotype demonstrates a mean arterial blood pressure of 102mmHg 
(SD of 11.5mmHg) with this same therapy. A power calculation based on this site 
of the beta-1 adrenergic receptor would yield a sample size per group needed of 
109 for an alpha level of 0.05 and a power of 0.80 (not correcting for multiple 
comparisons) (table 1). Based on these results we can determine that the gene 
with the smallest effect from this previous smaller study (specifically that 
encoding WNK-1, rs2107614) will determine the approximate sample size 
needed to observe an effect, if an effect exists, for the panel as a whole in this 
prospective trial. Data from our phase-I trial demonstrates a mean arterial blood 
pressure of 97.6mmHg  with diuretic therapy in the functional genotype group of 
WNK-1 and a mean arterial blood pressure of 100.8mmHg (Pooled SD = 12) with 
diuretic therapy in the non-functional genotype group for this site of WNK-1. 
Without correcting for multiple comparisons, one can determine that a per-group 
sample size of 162 individuals would be needed for 80% power with an alpha of 
0.01. Using an alpha of 0.05 and a power of 0.80 we have estimated that we will 
need 300 subjects per group to observe a significant difference, where one 
exists. Based on possible retention of 70% of subjects who initially enroll, we will 
seek to recruit up to 2000 subjects for the study.  
 
Concomitant Medications/Treatment/Procedures 
This study protocol does not require change to any existing treatments or those 
prescribed during the course of the study by the Investigator or any other 
provider whom the subject sees for any medical reason. Outside of eligibility 
screening, there are no clinical evaluations planned as part of this study. 
 
17.0 Confidentiality 
1. 
Data Security: As mentioned previously, all data will be de-identified 
and stored on pass-word protected Fairview Health servers. The only 
linking information (the consent) will be kept in a locked cabinet in Dr. 
Pam Phelps office.  
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
 
N/A 
19.0 Provisions to Protect the Privacy Interests of Participants 
1. 
Protecting Privacy: No identifiable information wil be kept, other than 
the consent document (which serves as the linking identifier) which 
will be kept in a locked cabinet in Dr. Pamela Phelps’ office. We will 
only reach out to patients who have not opted-out of research within 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 19 of 20 
Revised: September 22, 2017 
the Fairview system. Only IRB-approved personnel with appropriate 
training (CITI, biomedical, etc.) will be interacting with these patients.  
2. 
Access to Participants: If the subjects agree to participate in the 
study, have not opted out of research within the Fairview system, and 
the study is approved for us to access patients in the manner by 
which we propose in this IRB form and attached documents, we will 
have access to the patients using the techniques detailed herein.  
20.0 Compensation for Research-Related Injury 
1. 
Compensation for Research-Related Injury: N/A 
2. 
Contract Language: N/A 
21.0 Consent Process 
1. 
Consent Process (when consent will be obtained): 
The investigator will prepare an informed consent form in accordance with this 
study protocol and all regulatory requirements (21 CFR Part 50) using the 
template informed consent form provided by the sponsor.  The informed consent 
form must be submitted to the IRB and a copy of the final IRB-approved consent 
form must be submitted to the investigative team prior to the start of the study at 
that investigational site. 
Prior to any study procedures, all subjects must document their consent for study 
participation and authorization for use and disclosure of health information by 
signing the IRB-approved Informed Consent Form.  As part of the consent 
process, the subject will have the opportunity to ask questions of, and receive 
answers from the personnel conducting the study.   
The investigator will notify the investigative team and the IRB within 5 working 
days if device use occurs without subject informed consent.  
 
2. 
Non-English Speaking Participants: N/A 
22.0 Setting 
1. 
Research Sites: Fairview Health System, Kasota Center (virtual 
study: i.e. patients will not be coming in for visits) 
23.0 Multi-Site Research 
 
N/A 
24.0 Resources Available 
1. 
Resources Available:  
 
We have the full capability to complete this research. This is an 
accomplished research and clinical team that consists of 
experts in clinical care, physiology, pathophysiology, and 

PROTOCOL TITLE: 
VERSION DATE: 
 
Page 20 of 20 
Revised: September 22, 2017 
statistics. In addition, as needed, medical residents may help 
with data extraction if they are approved by the IRB.  
25.0 References 
1. 
The sixth report of the Joint National Committee on prevention, detection, 
evaluation, and treatment of high blood pressure. Arch Intern Med 
1997;157:2413-46. 
2. 
Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the 
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of 
High Blood Pressure: the JNC 7 report. Jama 2003;289:2560-72. 
3. 
American Heart Association. Heart and Stroke Statistics - 2004 Update. 
In: Dallas: American Heart Association; 2004; 2004. 
4. 
Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke 
statistics--2012 update: a report from the American Heart Association. Circulation 
2012;125:e2-e220. 
5. 
Akpunonu BE, Mulrow PJ, Hoffman EA. Secondary hypertension: 
evaluation and treatment. Disease-a-month : DM 1996;42:609-722. 
6. 
Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, 
evaluation, and treatment: a scientific statement from the American Heart 
Association Professional Education Committee of the Council for High Blood 
Pressure Research. Circulation 2008;117:e510-26. 
7. 
Johnson JA, Turner ST. Hypertension pharmacogenomics: current status 
and future directions. Curr Opin Mol Ther 2005;7:218-25.