Cilostazol for HFpEF (Heart Failure With a Preserved Ejection Fraction)
Phase: PHASE2
Conditions: Heart Failure With Preserved Ejection Fraction
Sponsor: University of Minnesota

MEDICAL PROTOCOL (HRP-590) 
PROTOCOL TITLE: Cilostazol for HFpEF 
 
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ANCILLARY REVIEWS 
 
Which ancillary reviews do I need and when do I need them? 
Refer to HRP-309 for more information about these ancillary reviews. 
Select yes or 
no 
Does your study… 
If yes… 
Impact on 
IRB Review 
☐ Yes 
☒ No 
 
Include Gillette resources, staff 
or locations 
Gillette Scientific review and Gillette 
Research Administration approval is 
required.  Contact: 
research@gillettechildrens.com   
Required 
prior to IRB 
submission 
☒ Yes 
☐ No 
Involve Epic, or Fairview 
patients, staff, locations, or 
resources? 
The Fairview ancillary review will be 
assigned to your study by IRB staff 
Contact: ancillaryreview@Fairview.org 
Approval 
must be 
received 
prior to IRB 
committee/ 
designated 
review.   
 
Consider 
seeking 
approval 
prior to IRB 
submission. 
☒ Yes 
☐ No 
Include evaluation of drugs, 
devices, biologics, tobacco, or 
dietary supplements or data 
subject to FDA inspection? 
The regulatory ancillary review will be 
assigned to your study by IRB staff 
Contact: medreg@umn.edu  
 
See: 
https://policy.umn.edu/research/indide  
☒ Yes 
☐ No 
Require Scientific Review? Not 
sure? See guidance on next 
page. 
 
Documentation of scientific merit must 
be provided.   
Contact: hrpp@umn.edu  
☐ Yes 
☒ No 
Relate to cancer patients, 
cancer treatments, cancer 
screening/prevention, or 
tobacco? 
Complete the CPRC application process.  
Contact: ccprc@umn.edu  
☐ Yes 
☒ No 
Include the use of radiation? 
(x-ray imaging, 
radiopharmaceuticals, external 
beam or brachytherapy) 
Complete the AURPC Human Use 
Application and follow instructions on 
the form for submission to the AURPC 
committee. 
Contact: barmstro@umn.edu  
Approval 
from these 
committees 
must be 
received 
prior to IRB 
approval;  
 
These 
groups 
each have 
their own 
☐ Yes 
☒ No 
Use the Center for Magnetic 
Resonance Research (CMRR) 
as a study location? 
Complete the CMRR pre-IRB ancillary 
review  
Contact: ande2445@umn.edu  
☐ Yes 
☒ No 
Include the use of 
recombinant or synthetic 
nucleic acids, toxins, or 
infectious agents? 
Complete the IBC application via 
eprotocol.umn.edu 
Contact: 

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☐ Yes 
☒ No 
Include the use of human fetal 
tissue, human embryos, or 
embryonic stem cells? 
Contact OBAO for submission 
instructions and guidance 
application 
process.  
☒ Yes 
☐ No 
Include PHI or are you 
requesting a HIPAA waiver? 
If yes, HIPCO will conduct a review of 
this protocol. 
Contact: privacy@umn.edu  
☐ Yes 
☒ No 
Use data from the Information 
Exchange (IE)? 
The Information Exchange ancillary 
review will be assigned to your study by 
IRB staff 
Contact: ics@umn.edu  
Approval 
must be 
received 
prior to IRB 
approval. 
 
These 
groups do 
not have a 
separate 
application 
process but 
additional 
information 
from the 
study team 
may be 
required. 
 
☐ Yes 
☒ No 
Use the Biorepository and 
Laboratory Services to collect 
tissue for research? 
The BLS ancillary review will be 
assigned to your study by IRB staff. 
Contact: cdrifka@umn.edu  
☐ Yes 
☒ No 
Have a PI or study team 
member with a conflict of 
interest? 
The CoI ancillary review will be 
assigned to your study by IRB staff 
Contact: becca002@umn.edu  
☒ Yes 
☐ No 
Need to be registered on 
clinicaltrials.gov? 
If you select “No” in ETHOS, the 
clinicaltrials.gov ancillary review will be 
assigned to your study by IRB staff 
Contact: kmmccorm@umn.edu  
☒ Yes 
☐ No 
Require registration in 
OnCore? 
If you select “No” or “I Don’t Know” in 
ETHOS, the OnCore ancillary review will 
be assigned to your study by IRB staff 
Contact: oncore@umn.edu  
Does not 
affect IRB 
approval. 
 
 
 
 

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PROTOCOL COVER PAGE 
 
 
 
Protocol Title 
Cilostazol for HFpEF 
Principal 
Investigator/Faculty 
Advisor 
Name: Markus Meyer, MD  
Department: Cardiology 
Telephone Number: 802 922-0656 
Email Address: meye3249@umn.edu 
Student 
Investigator 
Name: N/A 
Current Academic Status (Student, Fellow, Resident): N/A 
Department: 
Telephone Number: 
Institutional Email Address: 
Scientific 
Assessment 
HRPP facilitated scientific assessment 
IND/IDE # 
N/A 
IND/IDE Holder 
N/A 
IDS # 
5773 
Version 
Number/Date: 
1.0 – 11.00.2020 

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REVISION HISTORY 
 
Revision # 
Version Date 
Summary of Changes 
Consent Change? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NOTE: Leave this section blank for the initial submission. The revision history should be 
documented for modifications to approved studies. 
 
 

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Table of Contents 
 
1.0 
Objectives 
7 
2.0 
Background 
7 
3.0 
Study Endpoints/Events/Outcomes 
8 
4.0 
Study Intervention(s)/Investigational Agent(s) 
8 
5.0 
Procedures Involved 
11 
6.0 
Data and Specimen Banking 
11 
7.0 
Sharing of Results with Participants 
12 
8.0 
Study Population 
12 
10.0 Local Number of Participants 
15 
11.0 Local Recruitment Methods 
15 
12.0 Withdrawal of Participants 
16 
13.0 Risks to Participants 
16 
14.0 Potential Benefits to Participants 
17 
15.0 Statistical Considerations 
17 
16.0 Health Information and Privacy Compliance 
18 
17.0 Confidentiality 
21 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
21 
19.0 Provisions to Protect the Privacy Interests of Participants 
22 
20.0 Compensation for Research-Related Injury 
22 
21.0 Consent Process 
22 
22.0 Setting 
23 
23.0 Multi-Site Research 
23 
24.0 Coordinating Center Research 
23 
25.0 Resources Available 
23 
26.0 References 
23 
 

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ABBREVIATIONS/DEFINITIONS 
Include any abbreviations or definitions for key or technical terms you use in your 
protocol. 
 
● HFpEF  
 
Heart Failure with a preserved ejection fraction 
● NTproBNP  
N-terminal B-type natriuretic protein (heart failure blood marker)  
 
 

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1.0 
Objectives 
1.1 Purpose:  
Determine if cilostazol improves symptoms and NTproBNP levels (heart failure 
blood marker) in heart failure with preserved ejection fraction (HFpEF) – a 
prevalent syndrome without evidence-based treatment.  
This will be assessed in a prospective 1-month single blinded study with 2 cross-
overs (n-of-1 study design with placebo and cilostazol) 
 
1.2 Primary outcome:  
1. standardized heart failure questionnaire  
(sample provided at the end of the consent document) 
1.3 Secondary outcome: 
2. NTproBNP  
2.0 
Background 
2.1 Significance of Research Question/Purpose:  
 
Heart failure (HF) is the #1 reason for hospital admissions. About half of the 
patients with HF have a preserved ejection fraction (HFpEF). There is no evidence-
based treatment for HFpEF. We recently reported that beta-blockers increase the 
risk for HF admissions in HFpEF, in part by their heart rate lowering effects (1-3). 
On the contrary, we found that elevating the heart rate with pacemakers conveys 
significant clinical benefits e.g. reduction in heart failure symptoms, lowering 
filling pressures and an increase in walk distance (4-6). Cilostazol increases the 
heart rate by about 5-8 beats per minute and has other potentially beneficial 
HFpEF effects such as peripheral vasodilation, lusiotropic effects (acceleration of 
relaxation) and dromotropic effects (improved cardiac electrical conduction). By 
activating proteinkinase A, cilostazol may also phosphorylate titin, which would 
reduce myocardial stiffness (6). 
  
2.2 Preliminary Data:  
 
Cilostazol is approved for the use in peripheral artery disease and has been used  
in patients with diastolic dysfunction-induced atrial fibrillation and HFpEF. This 
results in a symptomatic relief and significant reductions in the heart failure blood 
marker BNP (7,8). In our own clinical experience, cilostazol reduces HFpEF 
symptoms and lowers NTproBNP by about 25% to suggest a clinical benefit that is 
in line with the cilostazol-induced changes in BNP in patients with atrial 
fibrillation (7,8). No adverse effects were noted in our own HFpEF patients that 
chronically take cilostazol.  

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2.3 
Existing Literature:  
 
1. Meyer M, LeWinter M Heart Rate and Heart Failure with Preserved Ejection Fraction. Time to Slow β-
Blocker Use? Circ Heart Fail. 2019 
2. Silverman DN, Plante TB, Infeld M, Callas PW, Juraschek SP, Dougherty GB, Meyer M. Association of β-
Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients 
With Heart Failure With a Preserved Ejection Fraction: A Secondary Analysis of the TOPCAT Trial. JAMA 
Netw Open. 2019 Dec 2;2(12):e1916598. doi: 10.1001/jamanetworkopen.2019.16598. 
3. Nambiar L, Silverman D, Vanburen P, LeWinter M, Meyer M. Beta-Blocker Cessation in Stable 
Outpatients With Heart Failure With a Preserved Ejection Fraction. J Card Fail. 2019 Aug 31. pii: S1071-
9164(19)30616-5. doi: 10.1016/j.cardfail.2019.08.020. [Epub ahead of print] 
4. Wahlberg K, Arnold ME, Lustgarten D, Meyer M.  Effects of a Higher Heart Rate on Quality of Life and 
Functional Capacity in Patients with Left Ventricular     Diastolic Dysfunction American Journal of 
Cardiology 2019 
5. Silverman DN, Rambod M, Lustgarten DL, Lobel R, LeWinter MM, Meyer M. Heart Rate-Induced 
Myocardial Ca2+ Retention and Left Ventricular Volume Loss in Patients With Heart Failure With 
Preserved Ejection Fraction. J Am Heart Assoc. 2020 Sep;9(17):e017215. doi: 10.1161/JAHA.120.017215. 
Epub 2020 Aug 28. PMID: 32856526. 
6. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren 
P, Meyer M, Redfield MM, Bull DA, Granzier HL, LeWinter MM. Myocardial stiffness in patients with 
heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015 Apr 
7;131(14):1247-59. doi: 10.1161/CIRCULATIONAHA.114.013215. Epub 2015 Jan 30. 
7. Kishida M, Watanabe K, Tsuruoka T. Effects of cilostazol in patients with bradycardiac atrial fibrillation. 
J Cardiol. 2001 Jan;37(1):27-33. 
8. Atarashi H, Endoh Y, Saitoh H, Kishida H, Hayakawa H. Chronotropic effects of cilostazol, a new 
antithrombotic agent, in patients with bradyarrhythmias. J Cardiovasc Pharmacol. 1998 Apr;31(4):534-9. 
9. Nanayakkara S, Byrne M, Mak V, Carter K, Dean E, Kaye DM. Extended-release oral milrinone for the 
treatment of heart failure with preserved ejection fraction. J Am Heart Assoc. 2020; 9:e015026. DOI: 
10.1161/JAHA.119.015026. 
10. Burkhoff D, Borlaug BA, Shah SJ, et al. Levosimendan Improves Hemodynamics and Exercise 
Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial. JACC Heart Fail 2021 
doi: 10.1016/j.jchf.2021.01.015 [published Online First: 2021/04/03 
 
 
3.0 
Study Endpoints/Events/Outcomes 
Endpoint/Event/Outcomes:  
1. standardized heart failure questionnaire 
2. NTproBNP 
 
4.0 
Study Intervention(s) 
4.1 
Description: 
We propose a n-of-1 study design using the standard dose cilostazol formulation of 
100mg twice a day approved in peripheral vascular disease. The patients will be blinded 
and serve as their own controls with two crossovers (cilostazol – placebo – cilostazol - 
placebo). This exploratory study is neither designed nor powered to seek a change in 

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the drug approval and thereby does not require an FDA investigational new drug (IND) 
application (see section 4.1). The study aims to minimize in-person visits during the 
ongoing COVID-19 pandemic. 
 
Study Flow: 
1. Screening of clinic patients 
2. Informed Consent 
3. Study drugs distribution by the pharmacy 
4. Study start (1st of month) 
5. Interventions (see below) 
6. Study end (end of month) 
Cilostazol 100mg BID (white) versus Placebo BID  
(colored or different shape – to confirm adherence)  
 
 
 
The cilostazol and placebo pills are in a preloaded pill-organizer box (see below).   
- study start at first day of the month (to facilitate adherence)  
- two in person study visits on day 5-7 and day 25-28 for blood draw and vital signs 
- four scheduled phone calls (days: 7, 14, 21 and 28) : heart failure questionnaires  
  
4.2 Cilostazol Adverse Effects  
 
For cilostazol’s relationship to milrinone (PDE3 inhibitor inotrope) a theoretical 
concern was raised that cilostazol may increase the risk for sudden death or may 
worsen congestive heart failure with reduced ejection fraction as detailed below: 
However, in the studies that led to FDA approval in 1999, cilostazol was 
determined to have a  good safety profile. In a randomized study of 1,439 
patients that included recovered ejection fraction heart failure patients, the 36 
months cumulative mortality rates were 6.8% in the placebo group and 5.6% in 
the cilostazol group, a non-significant difference. Despite an absence of adverse 
outcomes, a precautionary safety warning for patients with reduced ejection 
fraction congestive heart failure was included in the drug label. Nevertheless, 

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cilostazol is sometime used as a modestly effective inotrope (agent that increases 
cardiac contractility) in end-stage heart failure with a reduced ejection fraction.   
The most common cilostazol adverse effect is a headache (+20% over placebo), 
abdominal symptoms and diarrhea (+12% over placebo) and palpitations (+9% 
over placebo). 
 
The aforementioned milrinone, which is more potent than cilostazol, was recently 
reported to improve HFpEF. In the US, milrinone is only approved as an 
intravenous agent (9). Similarly, levosimendan was recently reported to provide 
hemodynamic and symptomatic benefits (10).   
The package insert includes the risk of left ventricular outflow tract obstruction, 
any type of heart failure, bleeding dyscrasias, blood dyscrasias and drug 
interactions 
Source: https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020863s021lbl.pdf 
 
Detail the FDA exemption:  
After reviewing the information contained in your submission, we have concluded 
that your study, “Cilostazol for HFpEF,” meets all of the requirements for 
exemption from the investigational new drug (IND) regulations and, therefore, an 
IND is not required to conduct your investigation.  
The IND regulations [21 CFR 312.2(b)] state that the clinical investigation of a drug 
product, including a biological product, that is lawfully marketed in the United 
States, is exempt from the requirements for an IND if all of the following apply: 
(1) The investigation is not intended to be reported to FDA as a well-controlled 
study in support of a new indication for use, nor intended to be used to support 
any other significant change in the labeling for the drug. 
(2) The investigation is not intended to support a significant change in the 
advertising for a prescription drug product. 
(3) The investigation does not involve a change in route of administration, dosage  
level, or patient population, or other factor that significantly increases the risks 
(or decreases the acceptability of risks) associated with use of the drug product. 
(4) The investigation is conducted in compliance with the requirements for 
institutional review (21 CFR 56) and informed consent (21 CFR 50). 
(5) The investigation is conducted in compliance with the requirements of 21 CFR 
312.7, i.e., the drug may not be represented as safe or effective, nor may it be 
commercially distributed, for the purposes for which it is under investigation. 
 

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4.3 
Drug storage/ handling and administration: 
 
Cilostazol and placebos will be provided by the Fairview IDS pharmacy and preloaded 
into the 1 month pill box and given or shipped to the patient after consent is obtained.  
The pill box has 31 removable medication vials for each day of the month to simplify 
the administration schedule and increase adherence. The study always starts at the 
first day of a month. 
 
4.4 
Biosafety: N/A  
 
4.5 
Stem Cells: N/A 
4.6 
Fetal Tissue: N/A 
 
5.0 
Procedures Involved 
5.1 Study Design: prospective single blind placebo controlled n=1 study with 2 cross-
overs 
5.2 Study Procedures:  
● 
NTproBNP on cilostazol and on placebo (see flow diagram) 
day 5 to 7 (5mL’s) and day 25 to 28 (5 mL’s) at any Fairview Lab site. 
● 
Kansas City Heart Failure Questionnaire (KCCQ-12)  
will be administered by PI phone call day 7, 14, 21 and 28  
● 
Baseline patient characteristics collected from Fairview EPIC 
5.3 Study Duration: 1 month 
● 
The duration anticipated to complete all study procedures, including any 
long-term follow-up, and data analysis: 12 months 
 
5.4   Use of radiation: N/A 
5.5 Use of Center for Magnetic Resonance Research: N/A  
6.0 
Data and Specimen Banking 
6.1 Storage and Access: The primary data collected and stored a password protected 
UMN PCs as outlined later. In addition the data file will be encrypted and 
password protected. All computer equipment is in a locked office of the PI at the 
UMN. Data exported for analysis will only be shared as a de-identified file. The 
primary identifying data file will be deleted after publication. 
6.2 Data:   
baseline clinical patient characteristics e.g. age, gender, medications. 

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dates of study and results 
 
6.3 Release/Sharing: No directly identifying PHI will be released outside the 
University of Minnesota. 
7.0 
Sharing of Results with Participants 
7.1 Patient will be informed of their personal results: benefit – no benefit.  
If requested by the participant the treating provider will be contacted to discuss 
the potential benefits of a cilostazol prescription.   
7.2 Sharing of genetic testing: N/A 
8.0 
Study Population 
 
Patients with HFpEF are typically >55y/o with an equal gender distribution 
Inclusion Criteria:  
>18 yrs 
LVEF ≥ 50% (on last assessment, <2 years) 
Diagnosis of HFpEF or Shortness of breath and NYHA Class ≥ 2 and one of the following: 
  
1. pulmonary edema on chest imaging or documented on exam or on loop diuretics 
  
2. NTproBNP >400 ng/ml in the last 24 months 
  
3. HFpEF>50% hospitalization in the last 3 years 
  
4. Qualitative echo:  > mild diastolic dysfunction on echo report and > mild left 
  
ventricular hypertrophy and left atrial dilation or quantitative echo: left ventricular 
  
hypertrophy [men ≥115 g/m², women ≥95 g/m² or relative wall thickness >0.42 or any  
  
LV wall thickness >1.2cm and has LA dilation (>28ml/m2) 
 
Exclusion Criteria: 
<18yo  
resting heart rate >100/min (assessed by pulse or ECG recorded in EPIC)  
patients with LVEF <50% and advanced end-stage heart failure (NYHA 3 and 4) 
symptomatic COPD on home O2 
uncontrolled severe HTN as defined by BP >160/100 mmHg on two checks ≥15 minutes apart  
patients with life expectancy <6 months 
end-stage liver cirrhosis 
more than moderate valve disease 
infiltrative myocardial disease (e.g. amyloidosis) or constrictive pericarditis or myocarditis 
patients unable to participate in follow up  
patients without baseline LVEF data > 2 years 
pregnant patients or patients without reliable contraceptive agent (intra-uterine device, birth 
control implant, compliance with contraception injections or contraception pills) for the 
duration of study participation) 
left ventricular outflow tract obstruction 

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bleeding dyscrasias, blood dyscrasias 
Patients that take: ketoconazole, itraconazole, fluconazole, miconazole, fluvoxamine, 
fluoxetine, nefazodone, sertraline, erythromycin, clarithromycin or azithromycin 
 
 
 
 
Screening:  
Individuals will be screened or assessed for eligibility during a hospital admission at the UMN 
Medical Center or in the UMP cardiology outpatient clinics.  
9.0 
Vulnerable Populations 
9.1 
Vulnerable Populations:  
 
Population / Group 
Identify whether any of the 
following populations will be 
targeted, included (not necessarily 
targeted) or excluded from 
participation in the study.  
Children 
Excluded from Participation 
Pregnant women/fetuses/neonates 
Excluded from Participation 
Prisoners 
Excluded from Participation 
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 
Excluded from Participation 
Non-English speakers 
Excluded from Participation 
Those unable to read (illiterate) 
Included/Allowed to Participate 
Employees of the researcher 
Excluded from Participation 

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Students of the researcher 
Excluded from Participation 
Undervalued or disenfranchised 
social group 
Included/Allowed to Participate 
Active members of the military 
(service members), DoD personnel 
(including civilian employees) 
Included/Allowed to Participate 
Individual or group that is 
approached for participation in 
research during a stressful situation 
such as emergency room setting, 
childbirth (labor), etc. 
Excluded from Participation 
Individual or group that is 
disadvantaged in the distribution of 
social goods and services such as 
income, housing, or healthcare. 
Included/Allowed to Participate 
Individual or group with a serious 
health condition for which there are 
no satisfactory standard treatments. 
Included/Allowed to Participate 
Individual or group with a fear of 
negative consequences for not 
participating in the research (e.g. 
institutionalization, deportation, 
disclosure of stigmatizing behavior). 
Excluded from Participation 
Any other circumstance/dynamic 
that could increase vulnerability to 
coercion or exploitation that might 
influence consent to research or 
decision to continue in research. 
Excluded from Participation 
 
9.2  Additional Safeguards:  
Individuals who are ethnic minorities would not be excluded from this study if 
they were so inclined to participate. Subjects would be taken through the consent 
process as per usual if subject is an ethnic minority who is English speaking. 
Individuals who are illiterate, would go through the consent as per usual; a 
witness would sign the consent form, documenting the consent process.  

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Undervalued or disenfranchised social group (transgender, LGBTQIA+ etc, person 
of color, etc.) would not be targeted but could be incidentally included if they met 
criteria and wanted to participate. 
Individual or group that is disadvantaged in the distribution of social goods and 
services such as income, housing, or healthcare are not targeted but could be 
included. No compensation is provided for participating in this study; thus, 
subjects from these groups would not feel coerced to participate in order to 
obtain monetary compensation.   
A subject might incidentally be a person with a military background, active or 
inactive duty. We do not see them in a setting where rank could operate to 
coerce them into participating. 
Risks are minimized through compliance with the study protocol, adherence to 
the guidelines for selection of subjects, close monitoring of the subject status 
during the study and follow-up procedures. The sponsor provides training for 
research staff on this study protocol. This training, extensive knowledge of the 
protocol along with investigator and research staff experience aid in minimizing 
risks to subjects. 
10.0 Local Number of Participants 
10.1 Local Number of Participants to be Consented: 25  
11.0 Local Recruitment Methods 
11.1 Recruitment Process: Potential patients determined to be possible candidates will 
be approached in the clinic and/or Hospital. The environment will be conducive to 
discussion as the patient will be seen privately in a clinic exam room, or in a 
private exam room. Distractions are kept to a minimum. The visit will occur in a 
relaxed and open atmosphere conducive for private conversation. 
Subjects will be given time to think over whether or not they want to participate 
in the study. Subjects are free to discuss their options with their primary care or 
physician and their family members before making their decision. 
11.2 Identification of Potential Participants: Potential subjects will be recruited based 
on information contained in private/protected records (medical records, student 
records). This also includes subjects who will be recruited from the PI or Co-I’s 
patient population. The PI and Co-Investigators have legitimate access to records 
per their employment with UMP heart and Fairview hospitals/clinics. Research 
staff checks for opt-outs and does not review records if the patient has opted out.  
Research team members have legitimate access to records by virtue of their 
employment. Study team members, such as coordinators, are allocated this 
authority per the Delegation of Authority log. Please note, all involved research 
staff member have undergone required PHI and Human Subjects training for the 

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UMN, MHEALTH and Fairview in order to safely, correctly and legitimately access 
medical records.  
Initial contact with potential participants would be made by the treating 
cardiology providers followed by PI or Co-investigators. A physician or care 
provider in the cardiology clinic or on the cardiology service will briefly tell the 
patient about the study and ask if they would like to discuss it further with a 
member of the research staff (one of the investigators or coordinators). If the 
patient agrees, a member of the study staff will meet with the patient and discuss 
the study in more detail.  
Potential subjects will come from the UMP Cardiology Clinic/Cardiology 
Inpatient/Outpatient service where the cardiology provider practice, PI and Co-
Investigators clinically manage these patients.  
Private/protected records will include MEDICAL records. Research staff will 
ensure the patient has not opted out of research on the Consent for Treatment 
and Registration form. 
11.3 Recruitment Materials: N/A 
11.4 Payment: N/A 
12.0 Withdrawal of Participants 
12.1 Withdrawal Circumstances: 
 
Patients can withdraw at any time. 
 
Patient can be withdrawn without consent by the PI and key personnel for 
unexpected adverse events (AEs) or unanticipated problem (UAPs) that could be 
study related. This would be discussed with Cindy Martin MD, director of heart 
failure, and reported to the IRB within 48h. 
 
12.2 Withdrawal Procedures:  
No continued data collection after withdrawal  
12.3 Termination Procedures:  
The data will be used for AE and UAP reporting to the IRB and in a publication 
13.0 Risks to Participants 
13.1 Foreseeable Risks:  
Headaches 34% (+20% over placebo) 
Palpitations 10% (+9% over placebo) 
Diarrhea 19% (+12% over placebo) 
 
Additional Risks: 
left ventricular outflow tract obstruction, any type of heart failure, bleeding 

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dyscrasias, blood dyscrasias and drug interactions. 
 
13.2 Reproduction Risks:  
minimal, HFpEF is a disease outside the typical reproductive ages 
13.3 Risks to Others:  
N/A 
14.0 Potential Benefits to Participants 
14.1 Potential Benefits:  
moderate chance (>30%) at improving heart failure symptoms within 48h after 
first dose of cilostazol 
 
15.0 Statistical Considerations 
15.1 
Data Analysis Plan:  
Primary outcomes 
 
KCCQ heart failure questionnaire: paired parametric test (t-test) of placebo average 
composite score and the cilostazol average composite score. 
 
NTproBNP: Relative changes in NTproBNP level (placebo versus cilostazol) will be 
compared by paired parametric testing (t-test). 
 
15.2 
Power Analysis:  
In a recent large HFpEF clinical trial of sacubitril/valsartan the baseline KCCQ score was 
71 ± 19. A sample size of 18 would provide us with 80% power to detect a 25% relative 
difference using a 2-sided test. We propose a sample size of 25 participants to ascertain 
18 or greater completed studies. In a recently completed pacemaker study that leads 
to a similar increase in heart rate we found a beneficial outcome in a heart failure 
questionnaire in n=22 participants (see reference #4, Wahlberg et al.).  
 
15.3 Statistical Analysis:  
Linear mixed-effect models determine the effect of cilostazol on the primary outcome, 
accounting for inter-patient differences and treatment assignment and sequences. For 
the primary endpoint, the KCCQ total score at the end of each week (week 1 to 4) is the 
dependent variable, while the treatment (cilostazol versus placebo) is the independent 
variable. Patient identifier and treatment sequence (binary variable marking the start 
of the treatment with placebo or cilostazol) are entered as random effects. The same 
approach was taken to assess the effect of cilostazol on NT-proBNP levels, after log-
transforming NT-proBNP values given their skewed distribution. To determine the 

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treatment effect paired analyses of subsequent treatment periods will be performed 
(Wilcoxon test) to match weeks and the days within the treatment period.  
 
15.4 Data Integrity: 
The de-identified data will be available to all key personnel to yield a fully transparent 
data analysis. 
 
16.0 Health Information and Privacy Compliance 
 
16.1 
Select which of the following is applicable to your research: 
☐ My research does not require access to individual health information and 
therefore assert HIPAA does not apply.   
 
☒ I am requesting that all research participants sign a HIPCO approved HIPAA 
Disclosure Authorization to participate in the research (combined consent 
and HIPAA Authorization). 
☐ I am requesting the IRB to approve a Waiver or an alteration of research 
participant authorization to participate in the research. 
Appropriate Use for Research:  
☐ An external IRB (e.g. Advarra) is reviewing and we are requesting use of the 
authorization language embedded in the template consent form in lieu of the 
U of M stand-alone HIPAA Authorization.  Note: External IRB must be serving 
as the privacy board for this option. 
 
16.2 
Identify the source of Private Health Information you will be using for your 
research (Check all that apply)   
☐ I will use the Informatics Consulting Services (ICS) available through CTSI 
(also referred to as the University's Information Exchange (IE) or data 
shelter) to pull records for me 
☒ I will collect information directly from research participants. 
☐ I will use University services to access and retrieve records from the Bone 
Marrow Transplant (BMPT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) database. 
☒ I will pull records directly from EPIC. 
☐ I will retrieve record directly from axiUm / MiPACS 
☐ I will receive data from the Center for Medicare/Medicaid Services  

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☐ I will receive a limited data set from another institution  
☐ Other.  Describe:  
16.3 
Explain how you will ensure that only records of patients who have agreed to 
have their information used for research will be reviewed. 
 
patients who do not agree to have their PHI assessed cannot be enrolled. 
 
16.4 
Approximate number of records required for review: 25 
16.5 
Please describe how you will communicate with research participants during 
the course of this research.  Check all applicable boxes 
☐ This research involves record review only. There will be no communication 
with research participants. 
☒ Communication with research participants will take place in the course of 
treatment, through MyChart, or other similar forms of communication used 
with patients receiving treatment.  
☐ Communication with research participants will take place outside of 
treatment settings. If this box is selected, please describe the type of 
communication and how it will be received by participants. 
 
16.6 
Explain how the research team has legitimate access to patients/potential 
participants: 
Subjects will have signed a consent including a HIPAA authorization.  
Patients are from cardiology group where PI and Co-Investigators have 
legitimate access to these records. 
16.7 Location(s) of storage, sharing and analysis of research data, including any links to 
research data (check all that apply).   
☐ In the data shelter of the Information Exchange (IE)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In the Bone Marrow Transplant (BMT) database, also known as the HSCT 
(Hematopoietic Stem Cell Transplant) Database  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In REDCap (recap.ahc.umn.edu)  
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In Qualtrics (qualtrics.umn.edu) 
 ☐ Store 
☐ Analyze 
☐ Share 

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☒ In OnCore (oncore.umn.edu)  
 ☒ Store 
☐ Analyze 
☒ Share 
☒ In the University’s Box Secure Storage (box.umn.edu) 
 ☒ Store 
☒ Analyze 
☒ Share 
☐ In an AHC-IS supported server. Provide folder path, location of server and IT 
Support Contact: 
The path should be in the form of “\\vp.ahc.umn.edu\vp\Research\Study0004” 
HIPCO requires this information to verify the data are in a properly encrypted 
server. 
 ☐ Store 
☐ Analyze 
☐ Share 
☐ In an AHC-IS supported desktop or laptop.  
Provide UMN device numbers of all devices:  
PI #20191597 = password protected PC in locked office PC (PI) 
encrypted Excel file  
 ☒ Store 
☒ Analyze 
☐ Share 
☐ Other. Describe:  N/A 
Indicate if  data will be collected, downloaded, accessed, shared or stored using a 
server, desktop, laptop, external drive or mobile device (including a tablet 
computer such as an iPad or a smartform (iPhone or Android devices) that you 
have not already identified in the preceding questions 
☐I will use a server not previously listed to collect/download research data 
☐I will use a desktop or laptop not previously listed 
☐I will use an external hard drive or USB drive (“flash” or “thumb” drives) not 
previously listed  
☐I will use a mobile device such as an tablet or smartphone not previously listed 
16.8 Consultants. Vendors. Third Parties. N/A  
16.9 Links to identifiable data: OnCore is the CTMS used to link patients to their study 
IDs.  Information will be destroyed after the completion of the study in 
compliance with the University of Minnesota’s documentation destruction policy 
(https://policy.umn.edu/operations/recordretention-proc02) and HIPAA law.  
 
16.10 Sharing of Data with Research Team Members.  
UMN BOX and de-identified data via e-mail 
 

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16.11 Storage and Disposal of Paper Documents: The information will be destroyed in 
accordance with the University of Minnesota’s documentation destruction 
policy (https://policy.umn.edu/operations/recordretention-proc02). The 
department of Cardiology utilizes established contracts with shredding vendors. 
 
17.0 Confidentiality 
17.1 Data Security:  De-identified data will be stored in UMN Box. Box Secure Storage 
is a secure environment delivered by the Center of Excellence for HIPAA Data 
intended for storing, sharing and accessing sensitive and private-highly restricted 
files. 
Data and samples shared outside the institution: N/A 
The consent documents and other documents may be in physical files housed in 
the PI’s secured office. Subjects will be assigned a unique code, which will be 
included on the associated study data. Only trained members of the research 
team affiliated with this study will have access to the study information 
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Participants 
18.1 Data Integrity Monitoring. Describe the following: 
● 
The PI will personally oversee the progress of the study and to ensure that it 
is conducted, recorded, and reported in accordance with the protocol, 
standard operating procedures, and applicable regulatory requirements. 
Maintenance of, and the assurance of, data accuracy and consistency over 
its entire life-cycle will be monitored by the principle investigator and Dr. 
Tamas Alexy. NTproBNP and heart failure scores data integrity will be 
assessed and verified by both investigators.    
● 
CTSI monitoring service will be utilized to provide regular monitoring visits 
every 6 month or if there is any concern that data integrity is compromised 
to assure that the study is conducted, recorded, and reported in compliance 
with Good Clinical Practice. Monitoring is provided at no cost to PIs. 
18.2 Data Safety Monitoring.  
There is no formal DSMB. AEs and UOPs will be reported to the clinical director of 
heart failure Dr. Cindy Martin MD.  If she recommends a change in protocol this 
will be directly communicated to the IRB and enrollment will be halted until the 
changes are approved. 
 
The data will be continuously monitored by the PI and shared in a de-identified 
file amongst key personnel. 
 

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19.0 Provisions to Protect the Privacy Interests of Participants 
19.1 Protecting Privacy:  
Only affiliated research team member will interact or obtain personal or sensitive 
information from study subjects. 
We do anticipate any of the standard inquiries would make subjects feel 
uncomfortable; however, subjects do not have to answer questions that might 
make them feel uncomfortable. 
19.2 Access to Participants: Subjects will have signed the consent form including HIPAA 
allowing this access. 
20.0 Compensation for Research-Related Injury 
20.1 Compensation for Research-Related Injury: We will use the following UMN HRPP 
template language: 
“In the event that this research activity results in an injury, treatment will be 
available, including first aid, emergency treatment and follow-up care as needed.  
Care for such injuries will be billed in the ordinary manner, to you or your 
insurance company.  If you think that you have suffered a research related injury 
let the study physicians know right away.” 
20.2 Contract Language: N/A 
21.0 Consent Process 
21.1 Consent Process (when consent will be obtained): The consent process could take 
place: University of Minnesota Medical Center (UMMC), Clinics and Surgery 
Center (CSC) and Lillehei Clinical Research Unit (LCRU). 
We will allow patients as much time as possible to consider participation in the 
study. A physician or care provider in the cardiology clinic or on the cardiology 
service will briefly tell the patient about the study and ask if they would like to 
discuss it further with a member of the research staff. If the patient agrees, a 
member of the study staff will meet with the patient and discuss the study in 
more detail. Potential subjects will come from the UMP Cardiology 
Clinic/Cardiology Inpatient/Outpatient service where PI and Co-Investigators 
clinically manage these patients. 
Trained and affiliated members of the research team will determined that a 
potential participant understands the information during the consent process and 
discussion. Continued consent is accessed at each follow-up visit to ensure 
subject understanding and continued willingness to participate. 
Documentation is comprised of a note in the subject file. The free text note 
outlines the consent process and discussion; any questions that arose and how 
the research team addressed those questions. 

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21.2 Waiver or Alteration of Consent Process (when consent will not be obtained): N/A 
21.3 Waiver of Written/Signed Documentation of Consent (when written/signed 
consent will not be obtained): N/A 
21.4 Non-English Speaking Participants: N/A 
21.5 Participants Who Are Not Yet Adults (infants, children, teenagers under 18 years 
of age): N/A 
21.6 Cognitively Impaired Adults, or adults with fluctuating or diminished capacity to 
consent: N/A 
21.7 Adults Unable to Consent: N/A 
● 
Permission: N/A 
● 
Assent: N/A 
● 
Dissent: N/A  
22.0 Setting 
22.1 Research Sites: This information is already provided above in section 11 and 25 of 
this form; location information is provided in the ETHOS SmartForm. 
22.2 International Research: N/A  
23.0 Multi-Site Research 
N/A 
24.0 Coordinating Center Research 
N/A 
25.0 Resources Available 
25.1 Resources Available:  
● Sample size is addressed above in section 15 above. 
● We will take as much time is required to safety and appropriately 
conduct the study in compliance with the approved B&I protocol. 
● University of Minnesota Medical Center (UMMC), Clinics and Surgery 
Center (CSC), Fairview outpatient laboratories (any Fairview location), 
Lillehei Clinical Research Unit (LCRU) 
● Affiliated research team is comprised of doctors and nurses with 
extensive clinical and research experience. 
● Everyone obtaining consent has undergone IRB required research 
training. The PI and Co-PI are established researchers and clinicians with 
many years of experience in research. The study coordinators and 
research staff involved are experienced personnel who understand the 
tenets of good clinical practices.  
 
26.0 References 

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1. Meyer M, LeWinter M Heart Rate and Heart Failure with Preserved Ejection Fraction. Time to Slow β-
Blocker Use? Circ Heart Fail. 2019 
2. Silverman DN, Plante TB, Infeld M, Callas PW, Juraschek SP, Dougherty GB, Meyer M. Association of β-
Blocker Use With Heart Failure Hospitalizations and Cardiovascular Disease Mortality Among Patients 
With Heart Failure With a Preserved Ejection Fraction: A Secondary Analysis of the TOPCAT Trial. JAMA 
Netw Open. 2019 Dec 2;2(12):e1916598. doi: 10.1001/jamanetworkopen.2019.16598. 
3. Nambiar L, Silverman D, Vanburen P, LeWinter M, Meyer M. Beta-Blocker Cessation in Stable 
Outpatients With Heart Failure With a Preserved Ejection Fraction. J Card Fail. 2019 Aug 31. pii: S1071-
9164(19)30616-5. doi: 10.1016/j.cardfail.2019.08.020. [Epub ahead of print] 
4. Wahlberg K, Arnold ME, Lustgarten D, Meyer M.  Effects of a Higher Heart Rate on Quality of Life and 
Functional Capacity in Patients with Left Ventricular     Diastolic Dysfunction American Journal of 
Cardiology 2019 
5. Silverman DN, Rambod M, Lustgarten DL, Lobel R, LeWinter MM, Meyer M. Heart Rate-Induced 
Myocardial Ca2+ Retention and Left Ventricular Volume Loss in Patients With Heart Failure With 
Preserved Ejection Fraction. J Am Heart Assoc. 2020 Sep;9(17):e017215. doi: 10.1161/JAHA.120.017215. 
Epub 2020 Aug 28. PMID: 32856526. 
6. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren 
P, Meyer M, Redfield MM, Bull DA, Granzier HL, LeWinter MM. Myocardial stiffness in patients with 
heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation. 2015 Apr 
7;131(14):1247-59. doi: 10.1161/CIRCULATIONAHA.114.013215. Epub 2015 Jan 30. 
7. Kishida M, Watanabe K, Tsuruoka T. Effects of cilostazol in patients with bradycardiac atrial fibrillation. 
J Cardiol. 2001 Jan;37(1):27-33. 
8. Atarashi H, Endoh Y, Saitoh H, Kishida H, Hayakawa H. Chronotropic effects of cilostazol, a new 
antithrombotic agent, in patients with bradyarrhythmias. J Cardiovasc Pharmacol. 1998 Apr;31(4):534-9. 
9. Nanayakkara S, Byrne M, Mak V, Carter K, Dean E, Kaye DM. Extended-release oral milrinone for the 
treatment of heart failure with preserved ejection fraction. J Am Heart Assoc. 2020; 9:e015026. DOI: 
10.1161/JAHA.119.015026. 
10. Burkhoff D, Borlaug BA, Shah SJ, et al. Levosimendan Improves Hemodynamics and Exercise 
Tolerance in PH-HFpEF: Results of the Randomized Placebo-Controlled HELP Trial. JACC Heart Fail 2021 
doi: 10.1016/j.jchf.2021.01.015 [published Online First: 2021/04/03