Reducing Symptom Burden in Patients With Heart Failure With Preserved Ejection Fraction Using Ubiquinol and/or D-ribose
Phase: PHASE2
Conditions: Heart Failure, Diastolic
Sponsor: University of Kansas Medical Center

 
 
 
 
 
Study Protocol and Statistical Analysis Plan Cover Page 
 
 
Official title of study: Reducing Symptom Burden in Patients With Heart Failure With Preserved Ejection 
Fraction Using Ubiquinol and/or D-ribose 
 
 
Protocol ID: STUDY00140741 
 
 
NCT Number: NCT03133793 
 
 
Document Date: 22 January 2020 
 
 
 
 

 
 
 
 
RESEARCH STRATEGY 
A. SIGNIFICANCE 
A.1. Lack of Effective Treatment for Heart Failure with Preserved Ejection Fraction (HFpEF) Symptoms. 
The public burden of heart failure (HF) is manifested by its staggering cost ($39.2 billion in healthcare-related 
costs/year) in the US,1 while the personal burden of HF includes debilitating symptoms.2 It is estimated that 
there is a 20% lifetime risk of developing HF at age 40 and that 870,000 new cases will be diagnosed yearly in 
adults who are 55 years of age or older.3 In 2014, the Food and Drug Administration reported that “the burden 
of HFpEF was considerable and is projected to worsen” and “there are no approved therapies available for 
reducing symptoms.”4 Beginning January 2012, the Centers for Medicare and Medicaid Services began 
reducing payments to hospitals for HF patients readmitted within 30 days of hospital discharge. Of the patients 
hospitalized with HF, more than 50% have diastolic HF, which is termed heart failure with preserved ejection 
fraction.5 These patients have a left ventricular ejection fraction (LVEF) of more than 45 to 50% and symptoms 
that include lack of energy (fatigue), shortness of breath, peripheral edema, and reduced quality of life.6, 7 The 
most recent American College of Cardiology (ACC)/American Heart Association (AHA) HF guidelines for 
HFpEF acknowledge “huge gaps” in understanding effective treatments for patients with HFpEF.8 This study 
will provide an opportunity to evaluate the comparative effectiveness of alternative approaches for reducing 
symptom burden in patients with HFpEF. 
 
A.2. Improved Scientific Knowledge and Clinical Practice in Measuring HFpEF. This study of ubiquinol 
(CoQ10, a type of coenzyme Q10) and D-ribose in patients with HFpEF will significantly improve scientific 
understanding of myocardial bioenergetics. Ubiquinol and D-ribose are naturally produced in the body.9-11 One 
of the main functions of these products is to promote 
cardiac energy metabolism by increasing 
mitochondrial adenosine triphosphate (ATP) 
production (Figure 1).12 Ubiquinol and D-ribose exert 
this physiological benefit of enhancing cardiac 
function via two different bioenergetic pathways.13-15 
As an efficient electron carrier, ubiquinol plays an 
important role in transporting electrons in the 
electron transport chain (ETC), which produces the 
proton gradient needed for phosphorylation of ADP 
and creating ATP. In contrast, D-ribose provides a 
source for synthesis of adenosine monophosphate 
(AMP) to ensure there is sufficient ADP to form 
ATP.16-18 Therefore, administering these supplements should augment ATP synthesis, increasing both cellular 
and behavioral energy. The potential benefits of administering ubiquinol and/or D-ribose to patients with 
HFpEF are increased myocardial energy and diastolic relaxation, which would significantly reduce their cardiac 
symptoms. We plan to measure HFpEF symptoms using the Kansas City Cardiomyopathy Questionnaire 
(KCCQ), Vigor scale, and 6-minute walk test (6MWT). Biological measures will include myocardial wall motion, 
lactate/ATP ratio, and B-type natriuretic peptides (BNP). 
 
A.3. Using Biobehavioral Symptom Science. Novel discoveries in biobehavioral symptom science require 
integration of information from the patient's biologic processes, physiologic pathways, and behaviors to treat 
and manage symptoms of diseases such as HFpEF.19, 20 We plan to use biobehavioral symptom science to 
identify complex symptoms that can be characterized with biological and clinical data. In this study, symptoms 
of HFpEF patients that result in a person’s feeling a lack of energy will be measured using a questionnaire to 
evaluate the patient’s level of vigor and overall health status. We will also measure their lactate/ATP ratio, 
cardiac performance, B-type natrieutric peptides, and conduct a 6MWT. This study could assist in illuminating 
a therapeutic clinical intervention (ubiquinol and/or D-ribose) for patients with HFpEF by quantifying subjective 
symptom experiences and measuring biologic and physiologic underpinnings of the symptoms. 
 
A.4. Technologies and Treatments That Could Reduce the Symptoms of HFpEF. We plan to use a 
sophisticated echocardiographic software program called speckle tracking to measure myocardial wall tension 
and motion to evaluate diastolic function. In addition, we will quantify our term “energy” using point-of-contact 
instrumentation to measure lactate/ATP ratio and BNP concentration. The two important outcomes for patients 
with HFpEF are improved heart function and patient energy. If a patient with HFpEF takes ubiquinol and/or D-
Figure 1. Ubiquinol and D-ribose in ATP Production. 
Ubiquinol     Ubiquinol 
D-ribose 

 
 
 
 
ribose, we hypothesize that the increased cellular bioenergetics would decrease myocardial stiffness, resulting 
in improved cardiac output and level of vigor. With more energy, the patient should have improved health 
status in the five KCCQ domains (i.e., clinical summary, functional status, self-efficacy, social interactions, 
quality of life). Thus, if the aims are achieved, patients with HFpEF will have successful symptom management 
and improved assessment of diastolic function. In addition, we will determine whether the comparative 
effectiveness of the treatments will maintain or increase ATP levels, prevent additional stiffness of the heart, 
and thus improve cardiac function, thereby reducing symptoms. A reduced myocardial tissue content of CoQ10 
has been demonstrated in patients with HF, correlating with the severity of symptoms and the degree of left 
ventricular dysfunction.21 According to Sharma (2016), the pathophysiological rationale for the use of CoQ10 in 
HFpEF exists, and well-conducted clinical trials will be required to demonstrate how CoQ10 decreases the 
signs and symptoms in this population.22 This study will produce new knowledge that will provide information 
about comparative benefits and outcomes that is significant to patients with HFpEF and that will help these 
patients make informed critical decisions about using ubiquinol and/or D-ribose. 
 
B. INNOVATION 
B.1. New Applications of Theoretical Concepts to Address HFpEF Symptoms. This study is a novel 
design to compare ubiquinol and/or D-ribose as supplemental treatments for HFpEF using a biobehavioral 
model (Figure 2). A deficiency in ubiquinol and/or D-ribose is an underlying pathophysiologic mechanism that 
results in cellular energetic impairment that diminishes ATP 
production and decreases sarcoplasmic reticulum Ca2+-
ATPase.23 This results in decreased actin-myosin cross-
bridge detachment, which is reflected in increased diastolic 
stiffness and decreased ventricular compliance. In addition, 
increased free radical production in HFpEF can result in 
damage to mitochondria and nuclei.24 We will examine the 
bioenergetics of ubiquinol and/or D-ribose in patients with 
HFpEF both behaviorally (health status per KCCQ and 
Vigor scale) and biologically (6-minute walk test, 
echocardiographic imaging, lactate/ATP ratio, and BNP 
measurements). With emphasis on patient-centered care, it 
is important to assess patient perception of changes in 
health status and level of vigor as ubiquinol and/or D-ribose 
is administered. To our knowledge, the effects of combining 
ubiquinol and D-ribose in HFpEF patients have not been 
published and thus are innovative because of their 
synergistic potential. 
 
B.2. Patient-centered Perspective. Since HFpEF is related to changes in cellular bioenergetics, it is important 
to evaluate behavioral measures of energy such as the Vigor scale as well as biological clinical outcomes. 
After meeting with 30 HFpEF patients and 10 caregivers, we found they were extremely interested in the 
question of whether ubiquinol, D-ribose, or both could improve their health status (i.e., reduce their shortness 
of breath, increase their ability to perform daily activities, etc.) and their energy levels. With the advanced 
speckle tracking echocardiogram images, lactate/ATP ratio, and BNP measurements, we can answer that 
question. Our data will help us compare the effectiveness of ubiquinol and D-ribose with usual treatment in this 
patient population. 
 
B.3. Potential Impact of Racial/Ethnic and Cultural Differences. Studies raised concerns that the incidence 
of HF might vary among different racial/ethnic groups.25, 26 Thus, in this study we will oversample minorities as 
reviewers suggested, which will enable us to examine the relationship between HFpEF and racial/ethnic 
differences. Most of the data regarding treatments for HFpEF are derived from White populations,27 and 
therefore it is important to include other racial/ethnic groups and examine whether the effects of ubiquinol 
and/or D-ribose follow similar patterns to those among whites. 
 
B.4. Translational Research. This is our opportunity to translate what we have observed in the laboratory and 
in the cardiovascular clinic to decrease patients’ debilitating symptoms of HFpEF. In a rat model, we have 
observed a significant decrease in myocardial nuclear damage (apoptosis) and mitochondrial superoxide 
Figure 2.  Biobehavioral Model. 
Diastolic Dysfunction 
HFpEF 
Placebo
Ubiquinol + D-ribose 
AIM 2  
Hypotheses #3, #4, #5, #6 
Ubiquinol 
D-ribose 
    AIM 1 
Hypotheses #1, #2 
Echocardiogram, 6-minute walk test (6MWT),   
BNP, lactate/ATP ratio  
Cellular Energetics 
Impairment 
KCCQ and Vigor Scale 

 
 
 
 
production associated with ubiquinol administration during an acute oxidative stress condition. Mitochondrial 
damage as assessed by electron microscopy was greatly reduced with the administration of ubiquinol. In the 
clinic setting, we have observed significant improvements in cardiac function leading to improved symptoms in 
patients with HFpEF who received ubiquinol and/or D-ribose. Translating these significant findings via a human 
study will provide essential data to support the use of these supplements in clinical practice. 
 
B.5. Advanced Echocardiographic Imaging. In this study we will use a novel software program termed 
speckle tracking with an echocardiographic instrument to assess cardiac function in HFpEF patients with and 
without administered ubiquinol and/or D-ribose. Speckle tracking echocardiography is an innovative technique 
that measures myocardial velocities and deformation parameters such as strain, strain rate, and torsion. These 
parameters provide superior assessment of diastolic function relative to conventional echocardiography. Using 
this advanced echocardiographic imaging method to objectively measure the effectiveness of ubiquinol and/or 
D-ribose in HFpEF patients is innovative and provides highly specific data for clinicians and researchers. 
 
B.6. Use of Biomarkers with Imaging. Our study is innovative because of its unique strategy of evaluating 
biomarkers (BNP, lactate/ATP ratio) with advanced cardiovascular imaging (speckle tracking echocardiogram) 
to assess a treatment (usual care, ubiquinol, and/or D-ribose) for a major healthcare problem (HFpEF). We will 
use biomarkers to evaluate the comparative effects of usual care, ubiquinol, and/or D-ribose. Our use of 
handheld on-site measurement of lactate/ATP ratio in patients with HFpEF is pioneering because it provides 
an assessment of cellular energy, the major mechanism for HFpEF, available in 5 minutes. The rapid ATP 
method is an innovative approach that is not a conventional technique and has not been used in assessing 
bioenergetics in patients with HF. 
C. APPROACH 
C.1. Study Population and Environment. The research protocol will first be approved by the Institutional 
Review Board, and all subjects will be provided with a written informed consent. The subject population, > 50 
years of age, male and female with HFpEF, will be enrolled from the University of Kansas Medical Center 
(KUMC) Healthcare Enterprise Repository for Ontological Narration (HERON) database, Pioneers Recruitment 
Registry (Pioneers), and chronic HF clinic at the University of Kansas Hospital (KUH): 69 in the control 
(placebo) group; 69 in the ubiquinol group; 69 in the D-ribose group; and 69 in the ubiquinol plus D-ribose 
group, (total = 276). HERON provides clinical/translational investigators with the numbers of patients at KUH 
who meet the inclusion criteria for clinical trials and contact information for patients who sign up with KUMC’s 
Frontiers participant registry. Based on the HERON, there will be approximately 7,100 subjects with HFpEF 
available to be screened for enrollment in this study. As suggested by the reviewers, we will oversample 
minority populations to increase the generalizability of data for minority groups (30% Black/African Americans 
(AA), 30% Hispanic/Latino, 30% White, and 10% American Indian/Alaska Native, Asian, Native 
Hawaiian/Pacific Islander). In addition, two nurse practitioners and a cardiologist on this application who work 
in the outpatient HF clinics will refer patients to the research team. All patients included in this study will: be 50 
years old or older; have left ventricular ejection fraction (EF) ≥ 50% documented by an echocardiogram within 
12 months of enrollment; be diagnosed with HFpEF within a 12-month period;, have symptoms of dyspnea and 
New York Heart Association (NYHA) Classification II or greater symptoms, have a diagnosis of  HFpEF defined 
by one of the following: (1) previous hospitalization for HF with radiographic evidence (pulmonary venous 
hypertension, vascular congestion, interstitial edema, or pleural effusion) of pulmonary congestion, (2) invasive 
hemodynamics, (3) echocardiographic evidence of diastolic dysfunction, (4) elevated NT-pro (>400 pg/ml) or 
BNP (>200 pg/ml), or (5) no use of intermittent sublingual nitroglycerin within 12 months; have willingness to 
provide informed consent; have a telephone or reliable phone contact; and have their own means of 
transportation to the study site. Patients will be excluded based on any of the following criteria: (1) acute 
coronary syndrome in the past 12 weeks; (2) significant valvular heart disease;(3) severe cardiac fibrosis 
(galectin-3 level > 26 ng/ml); (4) constrictive pericardium; (5) pulmonary fibrosis; (6) congenital heart disease; 
(7) hypertrophic or infiltrative cardiomyopathy; (8) heart transplant; (9) left ventricular assist device; (10) HF 
associated hospital admission or emergency room visit within past 30 days; (11) recent percutaneous coronary 
intervention; (12) significant renal and/or hepatic dysfunction; (13) severe cognitive impairment; or (14) 
consumption of any CoQ10 (ubiquinol) or D-ribose supplements. Hepatic and renal dysfunction will be defined 
as an ICD-10 code with diagnosis of renal and/or hepatic failure in the patient’s healthcare record. For 
retention we will schedule the sessions at a convenient time for each participant. Part of the recruitment plan 
includes subjects’ preferences for conducting telephone calls and collecting data. All subjects will be asked to 

 
 
 
 
come to the Clinical and Translational Science Unit (CTSU), a newly renovated facility with private examination 
rooms, pharmaceutical rooms, and storage area (for echocardiogram, i-stat instrument, etc.), and computer 
access to the Velos eResearch for patient data. The facility has plentiful free/close parking. 
 
C.2. Study Design and Materials. Both HFpEF patients and stakeholders had a meaningful influence on the 
study design. We held focus groups, made individual phone calls, and had in-person meetings with patients 
with HFpEF. Our Stakeholder Advisory Panel (SAP) consists of diverse individuals including patients, 
caregivers, clinicians, and hospital administrators (Appendix 1) who have met three times. The patients and 
caregivers were particularly interested in whether ubiquinol, D-ribose, or both could enhance health status, 
decrease symptoms, and improve energy levels. We invited 30 HFpEF patients and their caregivers to provide 
input and feedback regarding the development of our research hypotheses and methods. We found their 
opinions extremely valuable in designing this patient-centered study. 
 
Study Design, Including Screening, Enrollment, Visits, and Phone Follow-up (Figure 3). 
 
 
 
Based on the power analyses (see C.5.), this randomized, double-blind, controlled trial will have a total sample 
size of (N) = 276. All participants will receive usual care for HFpEF. Efforts will be made to recruit 50% 
females, which is the actual proportion of HFpEF patients in Kansas City. 
N1 = 69 subjects: Control, receive no ubiquinol and no D-ribose; placebo capsules & powder per day. 
N2 = 69 subjects: Ubiquinol group, receive 600 mg of ubiquinol/day, D-ribose placebo powder per day. 
N3 = 69 subjects: D-ribose group, receive 15 g of D-ribose/day, placebo capsules for ubiquinol per day. 
N4 = 69 subjects: Ubiquinol + D-ribose group, receive 600 mg ubiquinol and 15 g D-ribose per day. 
Initially, potential subjects from HERON, Pioneers, and KUH outpatient HF clinics will be interviewed by phone 
for potential recruitment in the study. Two nurse practitioners and a cardiologist on our research team work in 
the outpatient HF clinics and will refer patients to us. Patients will be required to speak English, and the 
informed consent and patient information will be written at the 8th grade level. We will collaborate with our 
Human Subject Protection Program to ensure our consent form complies with the US Department of Health 
and Human Services (HHS) federal guidelines and obtain informed consent from eligible patients (Appendix 
10).  Patients that have consented will be provided a 1-week supply of placebo ubiquinol pills (instructed to 
take 2 pills/day) and placebo D-ribose powder (instructed to take 3 scoops/day) as a pre-randomization run-in 
period to evaluate compliance to the supplements.  Patients will be scheduled for an appointment at the CTSU 
in 1 week following the run-in period.  Patients that demonstrate an 80% compliance rate of ubiquinol intake 
(as evidenced by pill count) and an 80% compliance rate of D-ribose powder intake (as evidenced by weight of 
the containers) will be eligible to be randomized into a group assignment. The enrolled patients with 80% 
compliance will then be randomized into four groups (69 subjects in each group) to receive ubiquinol (600 mg 
daily), D-ribose (15 g daily), ubiquinol plus D-ribose, or placebo for a period lasting 12 weeks. Both the 
ubiquinol and the D-ribose supplements used in the study will have a certificate of analysis from the 
manufacturer (Appendix 9). The Project Director will receive the identified list of recruited subjects from the 
Principal Investigator (PI) and will randomly assign subjects to one of the groups using a list created by a 
computer-based random number generator. All supplements and the placebo will be indistinguishable in 
packaging and will be distributed by the Project Director independent of the PI so that the allocation of subjects 
to a treatment or placebo group will be concealed from both subjects and research personnel. 
 
Screening of 
Eligible 
Participants 
Enrollment & 
Randomization 
of Eligible 
Participants 
Ubiquinol 
Visit 1
Control 
Aims #1, #2 
  3 weeks             6 weeks            9 weeks       12 weeks    
16 weeks 
Baseline 
Participants Recruitment  
& Enrollment 
Phone 
Follow-up 
Figure 3. Study Design. 
D-ribose 
Ubiquinol +  
D-ribose 
Phone  
Follow-up 
Visit 2  
Aims #1, #2 
Phone  
Follow-up 

 
 
 
 
All subjects will complete the demographic form at baseline. The KCCQ (Appendix 2) and Vigor scale from the 
Profile of Mood States (POMS) will be completed in CTSU visits at baseline and 12 weeks (Appendix 3) along 
with the subject’s height and weight. The patient will be escorted to a private room and asked to remove 
clothing above the waist. A disposable gown will be provided and the patient will lay supine on the bed while an 
echocardiogram is completed. Approximately 0.5 ml of blood will be collected via finger stick to measure 
lactate, ATP, and BNP. Next, the subject will complete a 6MWT (Appendix 4, Borg scale). Approximately 2 
hours will be required for each subject’s visit to the CTSU. Follow-up calls will occur at 3, 6, and 9 weeks 
during the trial. 
 
Potential Problem and Alternative Solutions. Serum CoQ10 and D-ribose values in some of the treatment 
patients might be below threshold levels at 6 weeks, possibly due to subject non-adherence. If this occurs, the 
Project Director, who is not blinded to the list of placebo and treatment subjects, will call and ask if there are 
any problems with consuming the ubiquinol and/or D-ribose. The Project Director and Research Associate will 
conduct a phone follow-up interview at 3, 6, and 9 weeks during the trial using a structured interview. 
Questions asked will relate to any side effects and compliance history in taking their capsules or powder. 
 
Various cardiovascular risk factors will be recorded such as tobacco usage, diabetes mellitus, 
hypercholesterolemia, hypertension, and family history of cardiovascular disease. Smoking status will be 
recorded as either smoker or non-smoker. Patients who use tobacco will be given contact information for a 
tobacco/smoking cessation program. Diabetes mellitus will be determined by a history of the disease or use of 
medication for diabetes. Hypercholesterolemia will be defined as a fasting total serum cholesterol level ≥ 4.9 
mmol/l or use of medication. Hypertension will be defined as either systolic or diastolic blood pressure ≥ 140/90 
mmHg or use of hypertensive medications. 
 
C.3. Aims and Hypotheses. 
 
AIM #1: To determine the effects of oral ubiquinol, D-ribose, or a combination of the two administered during      
12 weeks on symptoms accompanying low bioenergetics in patients with HFpEF. 
 
Hypothesis #1. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will enhance the 
health status of patients with HFpEF as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). 
 
Primary outcomes of the study are patient-centered, thus the measurement of health status will be a priority. 
Bioenergetics has both biological and behavioral components. The biological component (i.e., improved heart 
function) and its measurement will be discussed below (Aim #2). In this section we will discuss the behavioral 
component that relates to patients’ perceptions of their health status (i.e., symptoms) and the impact of their 
health status on daily functioning (e.g., hobbies, work, and energy). 
 
We will assess patients’ perceptions of their symptoms using the KCCQ, a self-administered questionnaire that 
measures patients’ perceptions of five domains of their health status relevant to HFpEF.28 These domains are: 
(1) physical limitations, (2) symptoms, (3) self-efficacy, (4) quality of life, and (5) social interference. The KCCQ 
consists of 24 items to which patients respond on a scale indicating limitations due to HF. For example, for 
activities such as dressing, doing yard work, or climbing a flight of stairs, patients are asked to check a 
response that indicates the degree to which HF has limited their ability: “Extremely Limited,” “Quite a bit 
Limited,” “Moderately Limited,” “Slightly Limited,” “Not at all Limited,” or “Limited for other reasons or did not do 
the activity.” Another item is: “Over the past 2 weeks, how many times has shortness of breath limited your 
ability to do what you wanted?” Response alternatives are: “All of the time,” “Several times,” “At least once a 
day,” “3 or more times per week but not every day,” “1-2 times per week,” “Less than once a week,” and “Never 
over the past 2 weeks.” The KCCQ takes only 4 to 6 minutes to complete and has been used in more than a 
hundred studies. It has excellent psychometric properties and clinical usefulness including: (1) high test-retest 
reliability; (2) high internal consistency within each area (e.g., Cronbach’s alpha ranged from 0.78 to 0.90); (3) 
patients’ scores concerning their health status correlate well with objective measurements of their functional 
capacities; and (4) the scale’s sensitivity for detecting clinical changes in HF patients is significantly greater 
than that of the Minnesota Living with Heart Failure Scale.  We will use the KCCQ to compare the changes in 
health status of patients with HFpEF taking ubiquinol, D-ribose, ubiquinol + D-ribose, or placebo. 
 

 
 
 
 
Hypothesis #2. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will increase the 
level of vigor in patients with HFpEF as measured by the Vigor subscale of the Profile of Mood States (POMS). 
 
Using the Vigor subscale from the POMS questionnaire,29-31 patients will rate themselves on eight adjectives 
(lively, active, energetic, cheerful, alert, full of pep, carefree, and vigorous) on a five-point scale (0 = not at all, 
1 = a little, 2 = moderately, 3 = quite a bit, and 4 = extremely). The Vigor scale has very high internal 
consistency (Cronbach’s alpha = 0.90), and it takes only 1 minute to complete. In many studies it has been 
found to be effective for assessing vigor changes associated with exercise.32-34 The KCCQ and POMS Vigor 
scale will be administered to patients after they have been sitting quietly for 10 minutes at the beginning of 
each visit (baseline and 12 weeks). The total time for patients to complete both questionnaires will be 5 to10 
minutes. We anticipate that during the course of treatment the patients taking these supplements will report 
increasingly greater improvements in health status, daily functioning, and levels of energy. 
 
Potential Problem and Alternative Solutions. Some older subjects may have difficulty reading the KCCQ or 
the POMS Vigor scale due to visual problems. We will have copies of both items in LARGE font available for 
those subjects.  If that is not sufficient to solve the problem, we will read each item to the subject and complete 
the KCCQ and POMS Vigor scale for them if given verbal consent. 
 
AIM #2: To determine the effects of oral ubiquinol, D-ribose, or a combination of the two over 12 weeks on 
biological measures in patients with HFpEF. 
 
Hypothesis #3. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will improve left 
ventricular diastolic function measured by advanced echocardiographic imaging in patients with HFpEF. 
 
HFpEF is characterized by a stiff left ventricle (decreased compliance) that results from impaired relaxation. 
This decreased compliance leads to increased end-diastolic pressures. Signs and symptoms of diastolic HF 
are similar to those of patients with systolic dysfunction.35 One difference is that the pathophysiologic 
underpinning of HFpEF is decreased myocardial ATP.36 The 2013 ACC/AHA Guidelines for treatment of 
patients with chronic HFpEF include beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin 
II receptor blockers.8 These agents have been shown to be effective in systolic HF; however, clinical trials have 
failed to demonstrate decreased morbidity and mortality in HFpEF.37 These data support the need for studies 
that target different and novel mechanisms in HFpEF.38, 39 Thus, we believe our proposal will address the 
pathophysiology underlying HFpEF with a treatment that would reduce its signs and symptoms. 
 
Diastole is the phase in the cardiac cycle when the left ventricle fills and prepares for systole. At normal heart 
rates, diastole comprises two-thirds of the cardiac cycle.40 Diastolic filling is influenced by passive elastic 
properties of the left ventricle, by the highly energy-dependent process of active relaxation, and atrial systole.36 
Relaxation of cardiac muscle requires higher amounts of ATP than systole.41, 42 Diastolic dysfunction is the 
major pathological mechanism of HFpEF, in which there is impairment in left ventricular relaxation because of 
increased stiffness and decreased compliance. Higher left ventricular end-diastolic pressure results in 
increased pulmonary pressures, pulmonary congestion (dyspnea), elevated plasma BNP, and subsequent 
heart failure.43 The increased ventricular stiffness is attributable to the increase in cytoplasmic calcium resulting 
from decreased sarcoplasmic reticulum calcium ATPase. The elevated cytoplasmic calcium results in 
impairment of detachment of the actin/myosin cross bridges.44, 45 The decreased end-diastolic volume (EDV) 
reduces stroke volume (SV) resulting in a compensatory increase in heart rate to maintain an adequate cardiac 
output (CO). Thus, the degree to which CO can be increased with activity (e.g., exercise) is limited. 
 
Two-dimensional Doppler echocardiography is a safe imaging technique frequently used to assess HFpEF. 
However, LV diastolic dysfunction is difficult to assess using standard echocardiography.46 Speckle tracking 
echocardiography is a novel, objective, and non-invasive advanced imaging technology that provides an 
accurate and precise way to assess diastolic ventricular function.47, 48 This technology has been systematically 
validated by sonomicrometry, tagged cMR, and color-coded tissue Doppler echocardiography. Speckle 
tracking echocardiography is superior to Doppler imaging in measuring left ventricular deformation as it 
overcomes limitations such as angle-dependent high frame rates and tethering effects. It allows investigators 
to easily calculate and assess myocardial deformation (rotation, torsion, and strain) and tissue velocity, which 
are important parameters for left ventricular diastolic function.49 Studies using speckle tracking 

 
 
 
 
echocardiography on patients with HFpEF have demonstrated more sensitive measurements of changes of LV 
structure than regular echocardiography. Speckle tracking consistently showed early diastolic strain rate, 
reduced peak strain, and fibrosis as evidenced by increased myocardial reflectivity, which parallels the degree 
of diastolic dysfunction.50-52 In this study, a speckle tracking echocardiography technician will perform the 
echocardiograms during each visit (baseline and 12 weeks). Drs. Shah (an expert in speckle tracking 
research), Vacek, and Hiebert (cardiologists) will determine EF and the ratio of mitral peak velocity of early 
filling (E) to early diastolic mitral annular velocity (eꞌ) (E/eꞌ ratio) (SV, EDV, EF) from the echocardiogram. Using 
speckle tracking software, we will measure myocardial deformation, rotation, torsion, strain, strain rate, and 
tissue velocity. Changes in the early apical diastolic untwisting rate (rotR) and negativity of time from apical 
peak diastolic untwist (trotR) to mitral valve opening (MVO) are two major variables that reflect diastolic 
function. Decreases in rotR and trotR are indications of diastolic dysfunction.53 Speckle tracking analysis with 
two-dimensional imaging will be performed as previously described by Leitman et al. at high frame rate 
parasternal short-axis images at the level of the mitral valve to generate rotation and rotation rate data.47 
Frame-by-frame rotation and rotation rate will be exported in Excel, and the temporal data will be normalized to 
the percentage duration of systole and diastole separately as previously described by Nakai et al.54 We 
anticipate that ubiquinol and/or D-ribose will change rotR, trotR, strain, strain rate, and tissue velocity. 
 
Potential Problem and Alternative Solutions. One issue that might arise relates to scheduling the 
echocardiographic technician when the subject is available to come to the CTSU. A solution is to utilize an 
additional on-call echocardiographic technician should scheduling issues occur. 
 
Hypothesis #4. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will increase the 
distance that patients with HFpEF can walk in 6 minutes. 
 
Exercise-based testing is essential in evaluating the functional capacity and response to therapy and prognosis 
of patients with HF.55 The 6-minute walking test (6MWT) is a simple clinical tool which has been shown to be 
linearly related to oxygen uptake.56 The ease and cost of the 6MWT gives it advantages compared to other 
tests.57 Mortality and morbidity in chronic HF have been predicted with the 6MWT. It was found that patients 
with a walking distance of less than 300 meters (325 yards) had 50% mortality at 1 year; the mortality of those 
walking more than 450 meters was less at 1 year. In addition, there was an inverse relationship between 
distance walked and hospitalization rates.58 
 
We will examine the effects of ubiquinol and/or D-ribose on the 6MWT at baseline and 12 weeks. Participants 
will be asked to wear appropriate clothes and shoes and walk the longest distance possible in 6 minutes. Prior 
to exercising, there will be a 10-minute rest period during which heart rate and blood pressure will be recorded. 
Subjects will walk indoors on a flat, straight 30-meter path marked every 3 meters, and they will be informed 
that they can slow down or stop at any time. A one-lap demonstration will be completed before the test begins. 
The distance walked will be recorded. Following the 6MWT, a 0.02 ml blood sample will be obtained for lactate 
measurement. Lactate provides a measure of the oxygen debt occurring during exercise and correlates directly 
with reported dyspnea and fatigue. The patient will also record perceived dyspnea and fatigue at baseline and 
at the end of each walk by using the Borg scale, where 0 = nothing at all, 5 = severe, and 10 = very severe. 
Words of encouragement will be offered during the walk and water provided afterward. 
 
Hypothesis #5. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will decrease 
venous blood B-type natriuretic peptide (BNP) levels in patients with HFpEF. 
 
B-type natriuretic peptides are a cardiac neurohormone secreted from the atria and ventricles in response to 
volume expansion. This natriuretic peptide system assists in regulating extracellular volume by inducing renal 
diuresis.59 Serum levels of BNP increase in cardiac disease conditions associated with increased atrial and 
ventricular stretch and left ventricular diastolic filling pressures. Miller et al. found that BNP concentrations 
were increased in outpatients with HF and were directly correlated with the magnitude of HF.60 In one study of 
1,653 subjects, the BNP levels increased as left ventricular dysfunction increased.61 Ruskoaho found that in 
the outpatient setting serum BNP values had a sensitivity of 97% and a negative predictive value of 98%.62 
Increased BNP concentrations with diastolic dysfunction have been strongly related to left ventricular 
hypertrophy.63 HF recommendations were updated in 2010 to include natriuretic peptides (i.e., BNP) in the 
urgent-care setting when the clinical diagnosis of HF is uncertain.64 In HF patients with EF > 40%, natriuretic 

 
 
 
 
peptides were the strongest independent predictor of diastolic dysfunction.65  At time of discharge, a BNP level 
of 400 pg/ml was 89% sensitive for events, and the negative predictive value was 96%.66 Independent of other 
prognostic variables, BNP levels have been shown to predict mortality in patients with HF.67 
 
BNP concentration will be measured using a portable i-STAT handheld analyzer. A blood sample (20 μl) will be 
obtained from a finger stick after the subjects have completed the questionnaires at baseline and 12 weeks. 
We will measure BNP concentration at each visit. Prior to running the BNP test, the cartridge initiates a series 
of preset quality control diagnostics, from monitoring the quality of the sample to validating the reagent. The i-
STAT can detect BNP levels ranging between 5 and 5000 pg/ml, with results available in 10 minutes. 
 
Hypothesis #6. Ubiquinol (600 mg daily), D-ribose (15 g daily), or a combination of the two will decrease the 
lactate/ATP ratio in patients with HFpEF. 
 
CoQ10 is a key component in mitochondrial bioenergy transfer.14, 68 Its enzymatic processes facilitate electron 
transfer in the generation of ATP. CoQ10 functions in electron transfer chain (ETC) from enzyme complex I 
and enzyme complex II to complex III.69 Thus, CoQ10 is critical in ATP generation because 95% of ATP 
generation is via ETC.70 D-ribose is a naturally occurring compound and a simple sugar molecule that has 
been shown to increase cellular energy synthesis in the heart. The myocardium’s ability to resynthesize ATP is 
then limited by the supply of D-ribose,71, 72 and supplementing D-ribose would increase ATP production. We 
plan to measure the effects of ubiquinol and/or D-ribose on mitochondrial ATP production by using an indirect 
measure (serum lactate/ATP ratio). Several studies have measured the effects of CoQ10 on mitochondrial 
function.68, 73-75  In HFpEF, ATP production is limited due to myocardial mitochondrial dysfunction, which results 
in anaerobic metabolism and increased lactate production. When exercise intolerance occurs, fatigue and lack 
of energy ensue.76, 77 Pyruvate is the principal substance used in the production of energy. In a series of 
reactions, glucose is converted to pyruvate, which in the presence of adequate oxygen leads to mitochondrial 
ATP production. Insufficient oxygen supply results in pyruvate being converted to lactate. When mitochondrial 
function is impaired (e.g., CoQ10 deficiency) the pyruvate to ATP pathway is compromised resulting in 
pyruvate being converted to lactate.78-81 There have been studies measuring the lactate/pyruvate ratio in HF 
patients receiving ubiquinone.75, 82 In most studies, ubiquinone decreased this ratio. Dai et al. found that 
ubiquinone supplementation in patients with HF significantly lowered plasma lactate/pyruvate ratio.75 However, 
our review found only one case history that examined lactate/pyruvate ratios and ubiquinol deficiency.83 A 
direct measure of lactate and pyruvate levels from cardiac myocytes would be optimal; however, it is not 
feasible in an outpatient clinic setting. The pyruvate measurement takes approximately 3 hours to complete 
and requires reservation of instrumentation at a location other than the CTSU. We found a new reliable ATP 
test system called the EnSURETM, which is a handheld instrument that is sensitive to detect down to 0.1 fmol of 
ATP in 15 seconds. Chida et al. used serum lactate/ATP ratio as a new real-time biomarker in patients to 
assess changes in energy with impaired mitochondria, the lactate/ATP ratio is elevated.84 
 
A capillary finger stick blood sample (1.0 ml) will be obtained after subjects have completed the questionnaires 
and echocardiograms. Lactate concentration will be measured with a portable i-STAT handheld instrument 
using a CG4+ cartridge that requires 0.5 ml blood and takes 2 minutes to complete. Quality control tests will be 
performed on the i-STAT instrument each time prior to sampling. The lactate cartridge initiates a series of 
preset quality control diagnostics, from monitoring the quality of the sample to validating the reagent. The 
lactate cartridge contains sensitive biosensors on a silicon chip that is configured to perform that specific test. 
We will use 0.5 ml of venous blood for the ATP measurements and place it in 10 ml of distilled water. Using a 
probe called the AquaSnap Total system, ATP in solution will be measured. The specifically designed tip will 
collect 100 µl of solution, and then we will place the probe into the EnSURETM instrument (ATP Test System). 
The EnSURETM quality monitoring system detects real-time ATP down to 0.1 fmol within 15 seconds. 
 
C.4. Preliminary Data. Dr. Hiebert, our senior cardiologist, has more than 10 years of clinical experience in 
prescribing CoQ10, and for the past 4 years has prescribed the combination of ubiquinol (600 mg/day) and D-
ribose (15 g/day) for patients with HFpEF. He has observed significant improvement in the health status of 
these patients using this combination of supplements. All subjects in our preliminary study reported that they 
complied with these doses by taking all daily required supplements in the morning with breakfast (compliance). 
Each subject tolerated these doses without any reported side effects (tolerance). 
 

 
 
 
 
Table 1 summarizes the results of this preliminary study. Patients with HFpEF were given the KCCQ and the 
POMS Vigor subscale before and after 12 weeks of taking ubiquinol or ubiquinol plus D-ribose. We observed 
significant improvements (paired samples t-tests, p < 0.05) in the KCCQ clinical summary, functional status, 
self-efficacy, social interactions, quality of life, symptoms, and physical limitation scores as well as significant 
improvements in POMS Vigor scores. The increase in self-efficacy and social interactions was not a direct 
change but may have resulted from the improved level of vigor and reduced signs and symptoms of HF. 
 
 
Table 2 presents a summary of echocardiographic data from a retrospective chart review of patients with 
HFpEF: E/eꞌ; pulmonary artery pressure; and B-type natriuretic peptide (BNP) levels. Variables were retrieved 
from charts before and 12 weeks after taking the supplements (ubiquinol 600 mg/day, D-ribose 15 grams/day). 
 
Table 2 
No Ubiquinol 
With Ubiquinol 
With Ubiquinol + 
D-ribose 
 
 
Variable 
Baseline 
Change after 
12 weeksa 
Baseline 
Change 
after 12 
weeksb 
Baseline 
Change after 
12 weeksc 
Observed 
Effect Size 
Ubiquinol 
Observed 
Effect Size 
Ubiquinol+
D-ribosee 
E/eꞌ ratio 
9.3 ± 2.4 
(N=6) 
+5.5 ± 2.4 
17.9 ± 6.1 
(N=8) 
−7.7 ± 4.6 
18.2 ± 4.2 
(N=8) 
−6.5 ± 2.9 
−3.5 
−4.4 
Pulmonary 
Artery      
Pressure 
32.1 ± 5.4 
(N=12) 
+13.2 ± 8.6 
37.8 ± 5.8 
(N=10) 
−13.6 ± 10.3 41.1 ± 5.9 
(N=8) 
−10.4 ± 6.0 
−2.8 
−3.3 
BNP 
(pg/ml) 
1892 ± 2381 
(N=13) 
+4598 ± 4986 
2194 ± 1806 
(N=8) 
−1494 ± 
1641 
2122±116.
5 (N=4) 
−1262.8±92.7 
−1.5 
–1.3 
Values are mean ± standard deviation. a: For each patient, a change in a variable was computed by subtracting the baseline variable measure from 
a measure taken at the end of 12 weeks. b: In this nonrandomized pilot study, all changes after 12 weeks on ubiquinol were significantly different 
from their corresponding changes without ubiquinol, according to independent-samples t-tests (p<0.05). c: In this nonrandomized pilot study, 
changes after 12 weeks on ubiquinol + D-ribose were significantly different from their corresponding changes without ubiquinol, according to 
independent-samples t-tests (p<0.05). d: Cohen effect size comparing mean change on ubiquinol vs without ubiquinol was computed. e: Cohen 
effect size comparing mean change on ubiquinol + D-ribose versus without ubiquinol was computed. 
 
Comparative data were also reviewed from a group of patients who were not taking ubiquinol. These data 
indicate that E/eꞌ ratio, PAP, and BNP levels significantly deteriorated among patients who did not take 
ubiquinol. In contrast, 12 weeks of ubiquinol (or ubiquinol + D-ribose) supplementation resulted in a marked 
improvement of left ventricular function, as reflected by significant decreases in E/eꞌ ratio, PAP, and BNP. 
 
In another study we investigated the effects of ubiquinol on heart nuclear membrane damage (apoptosis) and 
mitochondrial structure injury during severe oxidative stress in anesthetized rats (Figure 4). 
 
 
Table 1 
Ubiquinol Only (N = 5) 
Ubiquinol + D-ribose (N = 5) 
Variables 
Baseline 
Change after  12 
weeksa 
Baseline 
Change after 12 
weeksa 
KCCQ Clinical 
Summary Score 
48.0 ± 21.9 
+16.3 ± 7.0 
42.2 ± 28.3 
+30.0 ± 13.2 
Functional Status 
46.6 ± 22.6 
+16.3 ± 8.5 
39.4 ± 29.3 
+31.7 ± 12.3 
Self-efficacy 
57.5 ± 16.8 
+15.0 ± 10.5 
62.5 ±16.3 
+12.5 ± 8.8 
Social Interactions 
56.0 ± 20.1 
+12.0 ± 7.6 
53.0 ± 22.0 
+22.0 ± 17.5 
Quality of Life 
43.3 ± 29.7 
+23.3 ± 12.4 
40.0 ± 34.1 
+33.3 ± 13.2 
Symptoms 
46.0 ± 25.1 
+16.0 ± 10.7 
39.0 ± 29.3 
+38.5 ± 12.9 
Physical Limitation 
47.3 ±19.6 
+16.7 ± 6.2 
40.0 ± 29.7 
+22.7 ± 13.6 
Vigor Score (POMS) 
15.2 ± 10.7 
+7.6 ± 4.2 
8.8 ± 9.3 
+9.6 ± 3.0 
Values are mean ± standard deviation. a: For each patient, a change in a variable was computed by subtracting 
the baseline variable measure from a measure taken at the end of 12 weeks. 

 
 
 
 
4A.   No Ubiquinol 
 
 
 
                       4B.   Ubiquinol-treated 
 
 
Oxidative stress was produced by removing 40% of the rat’s total blood volume and sustaining shock for 1 
hour, after which the blood and lactated Ringers were re-infused. One group received ubiquinol and monitored 
for 2 hours, after which the animals were euthanized and the heart excised for analysis. The findings indicate 
that ubiquinol significantly attenuated myocardial oxidative stress damage, which is implicated in the 
pathophysiology of HFpEF. In summary, a commonality between our preliminary data in rats and HFpEF 
patients is impaired mitochondrial energetics and oxidative stress. The proposed measurements in HFpEF 
patients will enhance our understanding of how ubiquinol and D-ribose is beneficial at the cellular level to 
improve cardiac performance and reduce HF symptoms. 
 
C.5. Statistical Analyses. 
 
Groups and Number of Subjects (69 per group/Total = 276 subjects).  The power analyses require 
62 subjects/group, but there will be 69 subjects/group based on the expected 10% attrition. 
1.  Control Group (Usual Care) 
N1  = 69 subjects: Receive no ubiquinol and 
no D-ribose; placebo capsules and powder per day. 
2.  Ubiquinol Group 
N2 = 69 subjects: Receive 600 mg of ubiquinol per day; 
D-ribose placebo powder per day. 
3.  D-ribose Group 
N3 = 69 subjects: Receive 15 g of D-ribose per day; 
placebo capsules for ubiquinol per day. 
4.  Ubiquinol + D-ribose Group 
N4 = 69 subjects: Receive 600 mg ubiquinol and 15 g of 
D-ribose per day. 
 
Power and Statistical Analyses. Our power computations described below suggest including 62 subjects in 
each of the four study groups (ubiquinol, D-ribose, ubiquinol + D-ribose, and placebo). Since we expect about 
a 10% attrition rate, we will include 69 subjects in each group for a total of 276 subjects who will be 
randomized to one of the four groups. Efforts will be made to recruit 50% females. As suggested by the 
reviewers, we will oversample minority populations to increase the generalizability of data for minority groups 
(30% Black/AA, 30% Hispanic/Latino, 30% White, and 10% Other). In each group there will be Black/AA = 21, 
Hispanic/Latino = 21, White = 21, American Indian/Alaska Native, Asian, Native Hawaiian/Pacific Islander = 6 
(Total = 69). A 10% attrition rate is anticipated since this is the approximate rate Dr. Carol Smith (Co-PI) has 
experienced with her heart failure clinical trials at the same locations. Reasons for the subject’s attrition were 
that they did not want to continue in the study, change in geographic location, or illnesses. 
 
Hypotheses #1 and #2. The change in the KCCQ Clinical Summary score from baseline to the end of the 12 
weeks of treatment will be computed for each patient as KCCQ score at 12 weeks minus KCCQ score at 
baseline. A two-tailed independent samples t-test will test the null hypothesis of no difference in mean change 
between patients on ubiquinol and patients on placebo. Similar tests will be used to compare D-ribose with 
placebo, ubiquinol + D-ribose with placebo, and ubiquinol versus ubiquinol + D-ribose.  Next, we state and 
justify the assumptions underlying our proposed sample size.  Soto et al. (2004) conducted a study of 1516 
patients and found that a 10-point decline in KCCQ scores had an important prognostic significance, in that 
patients whose KCCQ Clinical Summary scores declined by ≥ 10 points had a 107%  increased risk of dying or 
being hospitalized during the next 12 weeks (event rate = 11.4% vs. 5.5%, p<0.001).85 Thus, we believe that 
an increase of at least 10 points with use of ubiquinol will be clinically important. In addition, our pilot study with 
ten subjects also found that, after 12 weeks of treatment, all subjects with ubiquinol or ubiquinol + D-ribose had 
an increase in the KCCQ Clinical Summary score of at least 10 points, which is consistent with the study 
findings of Soto et al. (2004). The combined estimated standard deviation for the increase was 12.3 points. 

 
 
 
 
This implies that Cohen effect sizes of at least 0.81 (= 10/12.3) are clinically important. Therefore, a sample 
size of 62 subjects per group will provide at least 98% power to detect this or larger effect sizes at a nominal 
significance level of 0.05 (with Bonferroni correction for four comparisons). 
 
Analogous two-tailed independent samples t-tests will be used to compare changes in POMS scores. 
According to a linear regression of changes in POMS Vigor scores versus changes in the KCCQ Clinical 
Summary scores using our pilot data, a 10-point increase in KCCQ Clinical Summary scores predicted about a 
6.5 point increase in Vigor scores. Thus, we believe that a 6.5-point increase in vigor in our subjects will be of 
clinical importance. Our pilot study also yielded an estimated standard deviation of 3.6 for 12 week changes in 
Vigor score, which implies that Cohen effect sizes of at least 1.8 are clinically important. Our sample sizes will 
provide 99% power to detect this or larger effect sizes at a nominal 0.05 significance level with Bonferroni 
correction for four comparisons. If assumptions of the t-test are not satisfied, transformations or the Mann-
Whitney test will be applied. The five subjects of our pilot study who received ubiquinol showed a significant 
increase of 16.3 points in KCCQ Clinical Summary scores with respect to baseline (t=5.23, df=4, two-tailed 
paired samples p=0.0064). Similarly, the other five subjects of our pilot study who received ubiquinol + D-
ribose showed a significant increase of 30 points with respect to baseline (t=5.10, df=4, two-tailed paired 
samples p=0.007). The 13.7-point increase produced by the independent effect of D-ribose was borderline 
significant (t=2.06, df=9, two-tailed independent samples p=0.08). These results from our small pilot study 
suggest a high likelihood that ubiquinol, and probably D-ribose, will produce clinically important increases of 10 
points in KCCQ scores, which gives additional confidence in the success of our proposed study and in the 
potential clinical applications of ubiquinol. 
 
Hypothesis #3. The change in the E/eꞌ ratio from baseline to the end of 12 weeks of treatment will be 
computed for each patient as E/eꞌ ratio at 12 weeks minus E/eꞌ ratio at baseline. A two-tailed independent 
samples t-test will be used to test the null hypothesis of no difference in mean E/eꞌ ratio change between 
patients on ubiquinol and patients on placebo. Our pilot data (Table 2) showed a substantially strong and 
clinically important Cohen effect size of ubiquinol on E/eꞌ ratio (−3.5). With 62 subjects per group, our t-test will 
have a very large power of 99% to detect this or larger effect sizes with a 0.05 level of significance (with 
Bonferroni correction for 4 comparisons, since both D-ribose alone and combined with ubiquinol will 
additionally be compared with placebo, and ubiquinol will be compared with ubiquinol + D-ribose). There are 
no studies comparing E/eꞌ ratio on D-ribose versus placebo or on the combination of ubiquinol and D-ribose 
versus placebo. However, our sample sizes will be able to detect effect sizes of at least 0.7 in absolute value 
with at least 90% power. A study comparing D-ribose with dextrose found a significant improvement in atrial 
velocity with D-ribose, reporting means and SDs that suggest an effect size of about 0.85.9 Thus we are 
confident that our study will have sufficient power to investigate this other proxy of left ventricular diastolic 
function. Analogous computations and tests will be made to examine the effects of ubiquinol, D-ribose, and the 
combination of ubiquinol with D-ribose on PAP changes. The large and clearly clinically important effect size of 
ubiquinol on PAP observed in our pilot study (−2.8; Table 2) suggests that our sample sizes will provide 99% 
power for at least the ubiquinol-placebo comparison. 
 
Hypothesis #4. A two-tailed independent samples t-test will be used to test the null hypothesis that the mean 
change in the 6MWT from baseline to the end of 12 weeks in patients taking ubiquinol is different from the 
mean change for placebo. Comparisons of D-ribose versus placebo, of ubiquinol + D-ribose versus placebo, 
and of ubiquinol versus ubiquinol + D-ribose will likewise be made. Our proposed sample sizes (62 per group) 
will allow detecting Cohen effect sizes on the 6MWT of at least 0.7 with at least 90% power at a nominal 0.05 
level of significance with Bonferroni correction for four comparisons. Published data86 suggest the possibility of 
a much larger effect size of ubiquinol on a 6-minute walk (3.9), giving us confidence in our design for at least 
the ubiquinol vs. placebo comparison. 
 
Hypothesis #5. Our pilot data suggested that ubiquinol has a large effect size on BNP (−1.5; Table 2). Thus, 
two-tailed independent samples t-tests comparing changes in BNP from baseline to the end of 12 weeks will 
have a large power (99%) for investigating Hypothesis #5 using Bonferroni corrections. In general, our sample 
sizes will be able to detect effect sizes of at least 0.7 in absolute value with at least 90% power. 
 
Hypothesis #6. The change in lactate/ATP ratio from baseline to 12 weeks will be computed for each patient. 
A one-tailed independent samples t-test will examine the null hypothesis of no differences in mean changes 

 
 
 
 
between ubiquinol and placebo groups against the alternative that the mean change in patients on ubiquinol 
will be numerically smaller, which includes the possibility of a negative change. Similar tests will compare D-
ribose versus placebo, the combination of ubiquinol + D-ribose versus placebo, and ubiquinol versus ubiquinol 
+ D-ribose. Our sample sizes will give us a power of at least 90% to detect effect sizes of at least 0.7 in 
absolute value by using a 0.05 significance level and Bonferroni correction for the four comparisons. 
 
Statistical Analyses of Interaction. The study will give us an opportunity to examine whether there is an 
interactive effect with synergism on KCCQ scores when simultaneously administering ubiquinol and D-ribose. 
To investigate whether ubiquinol and D-ribose interact synergistically, a linear regression model of KCCQ 
score change from baseline to week 12 will be built. The model will include indicators for ubiquinol and D-
ribose treatment as independent variables, as well as the product of these two indicators (the interaction term), 
gender, and race/ethnicity demographics. Analogous regressions will be conducted with KCCQ subscales, with 
the POMS Vigor score, as well as with indicators of left ventricular diastolic function. In addition, this study will 
give us an unparalleled opportunity to: (1) examine the mediating role of the lactate/ATP ratio in the effect of 
ubiquinol on left ventricular diastolic function in patients; and (2) examine whether there is an interactive effect 
with synergism on this function when simultaneously administering ubiquinol and D-ribose. A structural 
equation model will be built to explore our mechanistic87 hypothesis that a reduction in lactate/ATP ratio 
mediates the association between ubiquinol treatment and reduction in E/eꞌ ratio.  We will control for potential 
confounders such as demographics, baseline lactate/ATP ratio, and baseline E/eꞌ ratio. This modeling 
approach will take full advantage of the fact that subjects will provide measures of lactate/ATP and E/eꞌ ratios 
at two time points (baseline and 12 weeks), which will allow disentangling the dynamic effects of time, a crucial 
variable in causality analyses. In a published article, Dr. Diaz has described the use of structural equations in 
examining mechanistic pharmacological hypotheses of mediation.88 Similar models will be built by using the 
other indicators of left ventricular diastolic function in place of E/eꞌ. To investigate whether ubiquinol and D-
ribose interact synergistically, a linear regression model of E/eꞌ change from baseline to week 12 will be built 
that will also include as independent variables indicators for ubiquinol and D-ribose treatment, as well as the 
product of these two indicators (the interaction term), gender, and race/ethnicity. Analogous regressions will be 
conducted with other indicators of left ventricular diastolic function. If necessary, transformations will be 
performed to achieve the assumptions of regression models. 
 
Statistical Analysis of Effect of Treatment Duration. The effect of ubiquinol treatment duration on KCCQ 
Clinical Summary changes will be further investigated by fitting a random intercept linear model that will use 
the repeated measures provided by the subjects. Each subject will contribute to the model if any of the 
following two measures of the dependent variable are available: (1) a change in KCCQ score from baseline to 
the end of the 6th week, and (2) a change from baseline to the end of the 12th week. One dummy variable 
indicating whether the change corresponds to a treatment duration of 6 weeks (dummy=0) or 12 weeks 
(dummy=1) will be included as an independent variable as well as an indicator of ubiquinol treatment, gender, 
and race/ethnicity. This analysis will include subjects with complete or incomplete data. A positive and 
significant regression coefficient for the treatment duration dummy will signal that 6 weeks are not sufficient to 
obtain a change in KCCQ score equivalent to the change obtained after 12 weeks of treatment. Further, a 
significant regression coefficient for the ubiquinol treatment indicator will provide additional evidence of 
differences in KCCQ score changes between ubiquinol and placebo groups. To explore whether there is 
heterogeneity of ubiquinol effects across subjects, an additional random effects linear model will treat the 
regression coefficient of the ubiquinol indicator as a random coefficient. Analogous analyses will be made with 
the other continuous variables: POMS Vigor scale, E/eꞌ ratio, PAP, and BNP and with D-ribose in place of 
ubiquinol. Random effects linear models use the information provided by participants with incomplete data 
such as participants discontinuing treatment. These models are robust to the presence of missing values under 
a missing-at-random assumption. To explore the sensitivity of the models to the presence of possible non-
ignorable missing data, such as missing data caused by informative drop-out, a joint random intercept linear 
model will be fitted that will simultaneously model the KCCQ score and the missingness process.89 
 
C.6. Project Milestones and Timeline. This research proposal is designed to be completed within a 3-year time 
period (Figure 5). After the arrival of equipment and supplies and hiring of personnel, we will start screening, 
recruitment, and enrollment of subjects. We will simultaneously collect data on Aims 1 and 2 until we reach the 
sample size. Data analyses and publication of the findings will then follow. 

 
 
 
 
 
Figure 5:  General timeline for the proposed study. 
 
Our research team is a diverse group of clinicians, scientists, and HFpEF patients who have the ability and 
experience to gain new knowledge by addressing each of the study aims. We have added a cardiovascular 
researcher (Dr. Shah, Director of HF at Northwestern University) who is world renowned for HF and speckle 
tracking analysis. We also have a large Stakeholder Advisory Panel (SAP) that will meet every 6 months 
(Appendix 1) to provide guidance related to our research. The SAP consists of 13 stakeholders including 
patients, caregivers, clinicians, and hospital administrators. Our novel approach addresses the use of ubiquinol 
and/or D-ribose to manage adverse symptoms (lack of energy, shortness breath, fatigue, leg edema) in    
patients with HFpEF, thus reducing their symptoms and improving quality of life. 
 
 
 
•Personnel recruitment, 
purchase equipment & 
supplies.  
• Screening, 
recruitment & 
enrollment of subjects. 
• Clean data, data 
analyses. 
• Prepare manuscripts 
for publication. 
• Presentations at 
national and regional 
conferences. 
Year 1 
Year 2 
Year 3 
AIM #1: To determine the effects of oral ubiquinol, D-ribose, or a 
combination of the two administered during 12 weeks on symptoms 
accompanying low bioenergetics in patients with HFpEF. 
AIM #2: To determine the effects of oral ubiquinol, D-ribose, or a 
combination of the two over 12 weeks on biological measures in patients 
with HFpEF. 

 
 
 
 
PARTICIPATION OF HUMAN SUBJECTS 
 
The University’s Institutional Review Board (IRB) will review and approve this study prior to implementation. 
Recruitment of subjects (patients with diastolic heart failure, or HFpEF) will be conducted by the Principal 
Investigator (PI) and research staff including Project Director and Research Associate in Kansas City, Kansas, 
and through the University of Kansas Hospital. Patients with HFpEF will be asked for permission to be 
contacted, have the study explained, be invited to participate, and will be provided written informed consent. 
The potential subjects will be informed that the purpose of the study is to examine the effects of oral ubiquinol, 
D-ribose, or a combination of the two in treating patients with HFpEF. Consent forms and Health Insurance 
Portability and Accountability Act (HIPAA) disclosure information per IRB will be given to all subjects and their 
signatures will be obtained and witnessed, if they agree to participate. The consent forms will include a 
description of the study, nature of the data collection, the potential benefits and adverse reactions anticipated, 
and the methods used to ensure confidentiality. The standard care of subjects will not be changed, withdrawn, 
or reduced for any subject in this study. The research team personnel will abide by all tenets of the University 
confidentiality policies as well as the Privacy Protection for Research Subjects. All research staff will keep their 
required Human Subjects Protection and HIPAA certification current. 
 
The University of Kansas Medical Center (KUMC) Tutorial for Human Subjects’ Protection program examines 
the historical context for human subjects’ protection; the foundational principles that govern the ethical conduct 
of research; policies and practices that promote the welfare of research volunteers; and the collective 
responsibilities shared by the institution, faculty, and staff. The KUMC Tutorial for HIPAA provides legal and 
ethical information about protected healthcare information. Research regulations are reviewed by the KUMC 
HIPAA Compliance Program Office. Training on HIPAA regulations will be conducted for project staff by R. 
Spaniol, PhD, who directs HIPAA Compliance at the University. 
 
1. Risks to Human Subjects. 
1.1. Human Subjects Involvement, Characteristics, and Design. The involvement of human subjects in the 
work outlined in the Research Strategy includes two visits to the Clinical and Translational Scientific Unit 
(CTSU), obtaining echocardiograms and digital punctures (finger sticks), completing questionnaires, and 
receiving three follow-up phone calls by research staff. As suggested by the reviewers, we will oversample 
minority populations to increase the generalizability of data for minority groups (30% African American (AA), 
30% Hispanic/Latino, 30% White, and 10% American Indian/Alaska Native, Asian, Native Hawaiian/Pacific 
Islander. All patients included in this study will: be 50 years old or older; have left ventricular ejection fraction 
(EF) ≥ 50% documented by an echocardiogram within 12 months of enrollment; be diagnosed with HFpEF 
within a 12-month period; HFpEF, have symptoms of dyspnea and New York Heart Association (NYHA) 
Classification II or greater symptoms, have a diagnosis of  HFpEF defined by one of the following: (1) previous 
hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, 
interstitial edema, or pleural effusion) of pulmonary congestion, (2) invasive hemodynamics, (3) 
echocardiographic evidence of diastolic dysfunction, (4) elevated NT-pro (>400 pg/ml) or BNP (>200 pg/ml), or 
(5) no use of intermittent sublingual nitroglycerin within 12 months; be 50 years old or older; have left 
ventricular ejection fraction (EF) ≥ 50% documented by an echocardiogram; are diagnosed with HFpEF within 
a 6-month period; have willingness to provide informed consent; have a telephone or reliable phone contact; 
and have their own means of transportation to the study site. Patients will be excluded based on any of the 
following criteria: (1) acute coronary syndrome in the past 12 weeks; (2) significant valvular heart disease; (3) 
severe cardiac fibrosis (galectin-3 level > 26 ng/ml); (4) constrictive pericardium; (5) pulmonary fibrosis; (6) 
congenital heart disease; (7) hypertrophic or infiltrative cardiomyopathy; (8) heart transplant; (9) left ventricular 
assist device; (10) HF associated hospital admission or emergency room visit within past 30 days; (11) recent 
percutaneous coronary intervention; (12) significant renal and/or hepatic dysfunction; (13) severe cognitive 
impairment; or (14) consumption of any CoQ10 (ubiquinol) or D-ribose supplements. Hepatic and renal 
dysfunction will be defined as an ICD-10 code with diagnosis of renal and/or hepatic failure in the patient’s 
healthcare record. For retention we will schedule the sessions at a convenient time for each participant. Two 
nurse practitioners and a cardiologist on this application who work in the outpatient HF clinics will refer patients 
to the research team.  Also, potential patients with HFpEF who are in the Frontiers participant registry will be 
contacted, screened, and enrolled in the study. In this randomized, double-blind, placebo-controlled trial, 
eligible subjects will be randomized to receive either ubiquinol (600 mg daily po), D-ribose (15 g daily po), a 

 
 
 
 
combination of the two, or matched placebo for a period of 12 weeks, using a randomly generated number 
from a statistical software package. 
 
1.2. Sources of Materials. Research material or data collected will be from clinical measurements 
(echocardiograph with speckle tracking software, 6-minute walk test), laboratory testing (lactate, ATP, and b- 
natriuretic peptides (BNP)), and questionnaires (Kansas City Cardiomyopathy Questionnaire, Profile of Mood 
States, and Demographic Questionnaire). Existing patient medical records of current diagnosis, drug list, and 
hospitalization history will be obtained with the patient’s permission. All data will be gathered for the explicit 
purposes of this study using procedures to ensure confidentiality. All personal data will be identified by code 
number only. A list that links the assigned code number to the subject’s name will be kept separately in a 
locked file. Only the Project Director and Research Associate will have the access to individually identifiable 
private information about study subjects. All subjects will be encouraged to contact the Human Subjects 
Committee with any concerns in the informed consent document. 
 
1.3. Potential Risks. No appreciable risk of physical, psychological, financial, legal, or other harm to the study 
subjects is expected. Ubiquinol is naturally produced in the human body, and the safety of high doses of orally-
ingested CoQ10 for long periods is well established.90-92 Specifically with ubiquinol, Hosoe et al. found that it 
was safe, tolerable, and bioavailable at various oral dosages. They also found effectiveness of oral ubiquinol in 
just 4 weeks.91 No serious adverse events were observed and no significant safety concern was raised. Thus, 
ubiquinol was found to have an acceptable safety profile as a dietary supplement with multiple daily doses. 
Only mild gastrointestinal symptoms have been reported in a small number of subjects; these were not dose-
related and occurred in both ubiquinol and placebo groups.91 D-ribose is a simple sugar that is also naturally 
produced in the human body and used for energy production. Extended toxicity studies have shown that oral 
administration of D-ribose up to 15 g/kg/d is safe. Only minor side effects were reported, including diarrhea, 
gastrointestinal discomfort, and nausea.93-95 The time and efforts required for two visits to the CTSU may be an 
inconvenience to patients with HFpEF, especially when they are experiencing symptoms. Subjects may 
experience minimal pain/discomfort from digital puncture, or possible bruising and swelling around the 
puncture site, especially for subjects who are taking anticoagulant therapy; uncommonly, faintness is 
associated with the procedure. Although the potential risks for subjects participating in the 6-minute walk test 
(6MWT) may be changes in blood pressure, heart rate, and lightheadedness, it is often well tolerated and 
without reported complications.96 
 
2. Adequacy of Risk Protection. 
The CTSU visits will be scheduled at a convenient time when patients with HFpEF feel comfortable to travel. 
The follow-up telephone calls made by the Project Director or Research Associate will include structured 
questions that are brief (less than 5 minutes), between the hours of 9 a.m. and 6 p.m. (or other times if 
specified by the subject), and are neutral in voice and tone. 
 
2.1. Recruitment and Informed Consent.  All recruitment, consent, and data forms for the study proposal will 
be submitted to the University’s IRB prior to subject enrollment. Informed consent will be obtained by a trained 
research team member (either the Project Director or Research Associate) who has completed an approved 
Human Subjects’ protection certification program. Consent includes the standard elements: Study description, 
potential risks, benefits, and options for non-participation. Prior to proceeding with enrollment, personnel will 
ask the subjects to confirm that they know what components of the study involve. Consent will be documented 
as a signed form and will be kept in a locked file cabinet in a locked study office at the CTSU. In this study, 
recruitment materials will target subjects with HFpEF. Invitation letters and advertisement flyers about the 
study will be sent by the research team at the University of Kansas Medical Center (KUMC). Using this 
process, the PI will not have any knowledge or contact with a potential study participant without permission. A 
list of potential subjects who enrolled in the Frontier Participant Registry will also be obtained upon approval by 
HERON. In addition, the Pioneers Recruitment Registry (Pioneers) will be used to assist with recruiting 
Black/AA, Hispanic/Latino, American Indian/Alaska Native, Asian, and Native Hawaiian/Pacific Islander 
subjects. The Pioneers Registry has an agreement with Swope Health Services to recruit minorities for studies. 
The two nurse practitioners and Dr. Vacek at MidAmerica Cardiology will also provide potential HFpEF patients 
for the research team to approach for participation in the study. Following permission, the Project Director or 
Research Associate will contact the potential participant and use a scripted approach to discuss the consent 
for the study and to answer all the participant’s questions. If individuals agree to participate in the study, they 

 
 
 
 
must verbally indicate that they understand the purpose of the study and their rights as participants. The 
returned, signed consent forms will be considered indicative of informed consent for this study. Due to time 
commitment to the study, subjects will be compensated for their time at each visit to the CTSU. A bonus 
incentive will be paid to subjects that complete two CTSU visits. 
 
2.2. Risk Protection. Although no appreciable risk of physical or mental harm is expected to result from the 
proposed protocol, procedures for dealing with adverse effects are established. Participants will be instructed 
to take the supplements (ubiquinol, D-ribose, a combination, or placebo) with a meal to prevent or minimize 
gastrointestinal symptoms. The procedures listed below will be followed to avert negative reactions to 
procedures or questions posed during the CTSU visits or the follow-up telephone calls: (1) all subjects will be 
informed that they are free to skip questions, (2) end data collection, (3) not participate in any component of 
clinical evaluation and laboratory testing, or (4) withdraw from the study without changes in their standard or 
usual medical or nursing care. Subjects will be instructed to report immediately to the PI, Project Director, 
Research Associate, or the cardiologists (consultants) any negative side effects when consuming the 
supplements. Appointments will be cancelled and rescheduled if subjects express an inability to travel for 
scheduled CTSU visits. Furthermore, personnel are trained to discontinue any data collection in which the 
participant becomes emotionally upset or notes discomfort. The Research Associate or the PI will refer that 
person to our cardiologists or call 911 if immediate medical assistance is required. Subjects who express worry 
or distress from perceived loss of privacy or have concerns about inconvenience or rights as a research 
subject (explained in the consent form) will be assured that they do not have to participate, that their medical 
care will not be affected, or, if already enrolled in the study, that they may withdraw at any time without 
prejudice. In addition, any such concerns will be documented and reported to IRB. 
 
We will use several procedures to protect subjects against the risk of compromising their confidentiality. First is 
the decoupling of all subjects’ names from all study materials. All forms will make use of a subject code 
number only, and informed consent forms that include the subject’s signature will be stored separately in 
locked file cabinets. Methods chosen will ensure that patient identifiers and study data are uncoupled. Only 
selected research staff (the Project Director and Research Associate) will have access to the subjects’ data.  
Information protection procedures are in place specific to the data/communications, Internet computer 
environment. All subjects and staff are informed that subjects’ names and patient medical treatment are not to 
be discussed or placed on the Internet so that incidental disclosure does not occur. 
 
Privacy and security under the HIPAA standards requires six basic concepts; (i) notice, (ii) permission, (iii) 
access, (iv) security, (v) responsibility, and (vi) oversight.97 Subjects’ informed consent includes the HIPAA 
compliance documentation approved by IRB. These documents and privacy concepts were used to develop 
and deliver interventions in other studies without untoward events.98 The research team personnel will abide by 
all tenets of the University confidentiality policies as well as the Privacy Protection for Research Subjects. 
 
3. Potential Benefits of the Proposed Research to Human Subjects and Others. 
The administration of oral ubiquinol, D-ribose, or a combination of both to patients with HFpEF will potentially 
reduce the signs and symptoms of heart failure. This would occur by ubiquinol and/or D-ribose enhancing 
cellular energetics in cardiac muscle, thus improving diastolic function and enhancing the health status and 
vigor of patients with HFpEF. The study will generate scientific data that will provide evidence to support 
expanded use of ubiquinol, D-ribose, or a combination in the clinical management of patients with HFpEF. This 
study addresses major problems related to lack of effective treatments for HFpEF in order to reduce morbidity 
and mortality and strives to improve HFpEF clinical outcomes. With the suggestions of the reviewers, we will 
have more generalizability of data for minorities since there will be oversampling of minority populations. 
 
4. Importance of the Knowledge To Be Gained. 
One benefit of gaining knowledge from this proposed study is to present valid and reliable data from these 
subjects with HFpEF in abstracts and full-length publications so that healthcare practitioners will have a better 
understanding of the effectiveness of oral ubiquinol, D-ribose, or both in treating patients with HFpEF. This 
would potentially change the clinical practice of cardiologists and healthcare practitioners in managing HFpEF 
and have a significant impact on implementing new changes in clinical guidelines for HFpEF. 
 
 

 
 
 
 
5. Racial/Ethnic Data for Kansans. 
Wyandotte County, Kansas - where the University of Kansas Medical Center is located - is profiled as multi-
cultural, urban-centered, and medically underserved. The 163,369 residents make it one of the most densely 
populated counties in Kansas (1,039 persons per square mile). Females comprise 50.4% of the population in 
the county. Culturally, over 24.3% of the population is Black/AA; 27.8% Hispanic/Latino; 40.8% White; 1.3% 
Native American; 4.1% Asian; and 1.7% Alaskan Native, Native Hawaiian/Pacific Islander.99  Kansas City, 
Kansas, is the largest city in the county; comprising 92.6% of the county population; 18.9% of residents (all 
ages) are Medicaid enrolled.  The state of Kansas has 105 counties with a population of 2,911,641 with a 
racial/ethnic designation of 6.3% Black/AA, 11.6% Hispanic/Latino, 77.1% White, 1.2% American Indian, 2.9% 
Asian, and 0.9% Alaskan Native, Native Hawaiian/Pacific Islander. Out of 25,731 annual deaths (both sexes) in 
Kansas, 21.2% were due to heart disease. KU Hospital/KUMC is only 30 feet from the Kansas City, Missouri 
state line. The ethnicity of Kansas City, Missouri, includes: Black/AA 29.7%, Hispanic/Latino 10.1%, White 
57.1%, American Indian 0.5%, Asian 2.4%, and 0.2% Alaskan Native, Native Hawaiian/Pacific Islander. KUMC 
receives referrals related to heart failure from both Kansas and Missouri. Data sources that document these 
data are: Kansas: Burden of Chronic Disease; CDC, 2012; Kansas Cancer Registry of The Kansas 
Department of Health and Environment (2000-2014); Kansas Department of Health & Environment, 2014; US 
Census Bureau (2015). 
 
6. Recruitment Is from Sites Related to the PI’s Community Involvement. 
This includes the University of Kansas Hospital, Institute for Community Engagement and Frontiers: Heartland 
Institute of Clinical and Translational Research (HERON), Pioneers Community Registry, all of which have HF 
patients signed up to volunteer to participate in HF research. In addition, the Pioneers group has an agreement 
with Swope Health Services which is an inner city clinic that is over 60% Black/AA, 30% Hispanic/Latino, and 
10% other races/ethnicity. Thus, we will screen at least 900 patients with HF across the 3-year study timeline. 
Of these 900 from various sources, we expect 600 patients will be eligible to enroll. Based on Dr. Smith’s 
recent HF trial, enrolling patients (N=276) from various registries and lists should be feasible. 
 
7. We Proposed Several Research Plans to Overcome Any Problems. 
Potential participants will be identified prospectively by the Mid-America Cardiology nurse study coordinator 
who reviews electronic medical records for 40 cardiologists. During recruitment, we will explain the various 
required time periods for testing and the different potential groups to which patients might be assigned. Our 
Project Director will assist us in recruiting subjects. Further, several previous study participants from Dr. 
Smith’s grant have volunteered to become involved in this study. 
 
8. Investigators Involvement in Human Subjects Training. 
The PI will assure that all members of the investigative team have completed and adhere to all requirements 
for the protection of human subjects.  The PI will be involved in providing discussion and on-going education 
on the ethical conduct of research for the research team. The five NIH required instructional components 
(format, subject matter, faculty participation, duration, and frequency) are discussed herein.  At each team 
quarterly meeting (duration and frequency) a standing agenda item will be core conduct of research topics. NIH 
recommends including conflict of interest, policies regarding human and animal subjects, research team 
members’ responsibilities in collaborative research, peer review processes, quality data acquisition, and coding 
(subject matter). Samples of research misconduct and policies on responsible authorship and publication 
(subject matter) are reviewed. In the past meetings, formats of instruction have included report readings of NIH 
human subjects concerns, case study reviews, discussions regarding any current study issues arising from 
consultant input or collaborative work (format). We will invite our KUMC faculty leading the KUMC monthly 
ethics seminar/discussions to lead (faculty participation) some of these discussions on human and data safety 
and monitoring of scientific rigor and human safety.  All staff members undertake the required human subjects 
research training, pledge to maintain the highest levels of scientific quality, and strive for meaningful 
translational influence of findings. 
 
Data and Safety Monitoring Plan (DSMP). 
The DSMP for this study follows the NIH policies and also policies of the University of Kansas Medical Center 
(KUMC) Office of Sponsored Projects, written by our Director of Research Compliance and Director of 
Research Administration. This plan will be approved and annually recertified by the Institutional Review Board 
(IRB) at the KUMC and carried out by an advisory group of reviewers that will be called the Data Safety 

 
 
 
 
Monitoring Board (DSMB). This plan will be completed by the DSMB members, following review of the National 
Institute of Aging (NIA) Policy (if funded by this agency). The DSMB chairperson will send all reports to NIH 
and to our KUMC IRB. 
 
1.0 Participants Safety 
1.1. Potential Risks and Benefits for Participants 
Ubiquinol has been found to have an acceptable safety profile as a dietary supplement with multiple daily 
doses. The potential risk to study participants for ubiquinol includes mild gastrointestinal symptoms at high 
doses around 1000 mg/day.  For D-ribose oral administration of D-ribose up to 15 g/kg/d is safe. Minor side 
effects include diarrhea, gastrointestinal discomfort, and slight nausea. Subjects may experience minimal 
pain/discomfort from digital puncture, possible bruising and swelling around the puncture site, especially for 
subjects who are taking anticoagulant therapy; uncommonly faintness is associated with the procedure. 
Although the potential risks for subjects participating in the 6-minute walk test (6MWT) may be changes in 
blood pressure, heart rate, and lightheadedness, it is often well tolerated and without reported complications. 
 
The potential benefits to study participants include improved energy level, increased overall health status 
(reduced physical limitations, less symptoms of heart failure with preserved ejection fraction (HFpEF), 
increased self-efficacy, expanded social interactions, and improved quality of life), and enhanced cardiac 
performance. 
 
1.2. Adverse Event and Serious Adverse Event Collection and Reporting 
Adverse occurrences or unanticipated problems reported by a subject during the course of their participation in 
the study will be immediately documented according to study protocol. A report will be sent to IRB if the 
adverse events is serious, unexpected, and related to the study. We will report to the DSMB and the National 
Institute on Aging (NIA) administrator all serious adverse events. For each occurrence, the PI or the 
designated Co-I will evaluate independently to determine severity, expectedness, and attribution of the 
occurrence to the study protocol or not and report to NIA, IRB, and DSMB if required per policy. 
Determinations regarding adverse and serious adverse events will be made by James Vacek, MD who is the 
designated cardiologist on the study who is unblinded. After Dr. Vacek makes this final determination, the 
adverse event will be reported by Dr. Janet Pierce (PI) or Dr. Qiuhua Shen (Co-PI) to the NIA and Chair of the 
DSMB (Dr. Pete Miller). All DSMB members are available in real time to review and recommend appropriate 
actions regarding any adverse or unanticipated events or other safety issues. Any action taken to suspend or 
terminate the project will be reported immediately to KUMC IRB, NIH Office of Sponsored Projects, and the 
study Program Officer at NIA. 
 
1.3. Protection Against Study Risks 
Informed Consent Process: The consent process will inform a volunteer about the study, indicating the 
participation is voluntary and he/she has the right to stop at any time. Risks will be enumerated in the informed 
consent form and described orally during the consent process. 
 
Protection Against Risks: Although no appreciable risk of physical or mental harm is expected to result from 
the proposed protocol, procedures for dealing with adverse effects are established. Participants will be 
instructed to take the supplements (ubiquinol, D-ribose, a combination, or placebo) with a meal to prevent or 
minimize gastrointestinal symptoms. The procedures listed below will be followed to avert negative reactions to 
procedures or questions posed during the CTSU visits or the follow-up telephone calls: 1) all subjects will be 
informed that they are free to skip questions, 2) end data collection, 3) not participate in any component of 
clinical evaluation and laboratory testing, or 4) withdraw from the study without changes in their standard or 
usual medical or nursing care. Subjects will be instructed to report immediately to the PI, Project Director, 
Research Associate or the cardiologists (consultants) any negative side effects when consuming the 
supplements. Appointments will be cancelled and rescheduled if subjects express an inability to travel for 
scheduled CTSU visits. Furthermore, personnel are trained to discontinue any data collection in which the 
participant becomes emotionally upset or notes discomfort. The Research Associate or the PI will refer that 
person to our cardiologists or call 911, if immediate medical assistance is required. Subjects who express 
worry or distress from perceived loss of privacy, have concerns about inconvenience or rights as a research 
subject (explained in the consent form), will be assured that they do not have to participate, that their medical 

 
 
 
 
care will not be affected, or if already enrolled in the study that they may withdraw at any time without 
prejudice. In addition, any such concerns will be documented and reported to IRB. 
 
2.0 Interim Analysis 
There are no advance plans for interim and/or futility analysis at this time. 
 
3.0 Data and Safety Monitoring 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a daily basis. The DSMB 
will act in an advisory capacity to the NIA Director to monitor participant safety, evaluate the progress of the 
study, to review procedures for maintaining the confidentiality of data, the quality of data collection, 
management, and analyses. 
 
3.1. Frequency of Data and Safety Monitoring 
The DSMB will meet annually to evaluate the study progress, either in-person or by teleconference call to 
review study progress, data quality, and participants safety. The PI (Dr. Pierce) will be informed of serious 
adverse events as soon as they occur and will notify the NIA and the DSMB within 2 business days of 
notification. 
 
3.2. Content of Data and Safety Monitoring Report 
The content of the data and safety monitoring report will include:  study status, participant descriptive 
information, safety information, and study quality. Prior to subject recruitment, the members of the DSMB will 
read the written study protocols, informed consent procedures, Data Safety Monitoring (DSM) policies, and 
plan.100 Members of the DSMB will initially discuss the plan for clarification of their responsibilities, the board 
structure, and organization and rules of operation, as noted in the policies. All trial progress and DSMB advice 
on continuation, modification, or termination are reported to the Principal Investigator (Dr. Janet Pierce), IRB, 
and the NIA Program Officer. 
 
3.3. DSMB Membership and Affiliation 
Each of the individuals will formally accept the position as part of the DSMB and the DSMB membership will be 
reviewed and approved by the NIA. Should there be any questions regarding the independence of the DSMB, 
it will be addressed and corrected if necessary at that time. This DSMB will include external scientists 
(cardiologist, supplemental specialist, and a biostatistician) selected and chosen by NIA. 
 
3.4. Conflict of Interest for DSMB’s 
DSMB members will have no direct involvement with the study investigators or intervention. Each DSMB 
member will sign a Conflict of Interest Statement which includes current affiliations, if any, with pharmaceutical 
and biotechnology companies (e.g., stockholder, consultant), and any other relationship that could be 
perceived as a conflict of interest related to the study and/or associated with commercial interests pertinent to 
study objectives. 
 
3.5. Protection of Confidentiality 
Data will be presented in a blinded manner during the open sessions of the DSMB. At DSMB meetings, data 
and discussion are confidential. Participant identities will not be known to the DSMB members. 
 
3.6. DSMB Responsibilities 
If approved by NIA, the DSMB Charter responsibilities will include: 
• 
Review the research protocol, informed consent documents and plans for data safety and 
monitoring; 
• 
Recommend subject recruitment be initiated after receipt of a satisfactory protocol; 
• 
Evaluate the progress of the trial, including periodic assessments of data quality and timeliness, 
recruitment, accrual and retention, participant risk versus benefit, performance of the trial sites, and 
other factors that can affect study outcome; 
• 
Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants or 
the ethics of the trial; 

 
 
 
 
• 
Review study performance, make recommendations and assist in the resolution of problems 
reported by the Principal Investigator (Dr. Janet Pierce); 
• 
Protect the safety of the study participants; 
• 
Report to NIA on the safety and  progress of the trial; 
• 
Make recommendations to the NIA and the Principal Investigator concerning continuation, 
termination or other modifications of the trial based on the observed beneficial or adverse effects of 
the treatment under study; 
• 
If appropriate, review interim analyses in accordance with stopping rules, which are clearly defined 
in advance of data analysis and have the approval of the DSMB; 
• 
Ensure the confidentiality of the study data and the results of monitoring; and, 
• 
Assist the NIA by commenting on any problems with study conduct, enrollment, sample size, and/or 
data collection. 
• 
The DSMB will evaluate the final study manuscripts and final reports to assure results are fairly 
presented and conclusions are appropriate.101 
 
 
 

 
 
 
 
Inclusion of Women and Minorities. 
Subjects may participate regardless of gender, socioeconomic level, or ethnic background. All subjects will be 
50 years or over, as HFpEF is more prevalent in older adults. National statistics show the prevalence of heart 
failure to be divided roughly equally between males and females.102 Efforts will be made to recruit 50% 
females, which is the actual proportion of HFpEF patients in Kansas City. 
 
The regional HF statistics indicate are: 10% Black/African Americans (AA), 13% Hispanic/Latino, 76% White, 
and 1% Asian, Native American/Alaskan Native, Native Hawaiian/Pacific Islander. The racial and ethnic 
population distribution planned coincides with these national and regional figures. The Kansas City 
Metropolitan Statistical Area confirms these percentages in the general population.99 In this study, we will 
oversample minorities (reviewer’s suggestion), which will enable us to examine the relationship between 
HFpEF and racial/ethnic differences. Most of the data regarding treatments for HFpEF are derived from white 
populations,27 and therefore it is important to include other racial/ethnic groups and examine whether the 
effects of ubiquinol and/or D-ribose follow similar patterns to those among whites. For this study, a total of 276 
subjects will be randomized to one of the four groups. As suggested by the reviewers, we will oversample 
minority populations to increase the generalizability of data for minority groups (30% Black/AA, 30% 
Hispanic/Latino, 30% White, and 10% Other). Each group will be Black/AA = 21, Hispanic/Latino = 21, White = 
21, American Indian/Alaska Native, Asian, Native Hawaiian/Pacific Islander = 6 (Total = 69). The University of 
Kansas Medical Center (KUMC) Healthcare Enterprise Repository for Ontological Narration (HERON) 
database, Pioneers Recruitment Registry (Pioneers), and chronic HF clinic at the University of Kansas Hospital 
(KUH) will be used to recruit subjects. These registries provide clinical/translational investigators with the 
numbers of patients at KUH who meet the inclusion criteria for clinical trials and contact information for patients 
who sign up with KUMC’s Frontiers participant registry. Based on the HERON, there will be approximately 
7,100 subjects with HFpEF available to be screened for enrollment in this study. The Swope Health Services in 
Kansas City, Missouri has a large Black/AA and Hispanic/Latino population. The Pioneers Registry has a 
relationship with Swope Health Services and can assist us with electronic informed consent forms, email 
verification, and subject recruitment at this site. 
 
 
 

 
 
 
 
Inclusion of Children. 
All subjects will be 50 years or over, as HFpEF is more prevalent in older adults. Children (the age to 18 years 
and younger) will not be included in this study because diastolic heart failure is very rare in the pediatric 
population. 
 
 
 

 
 
 
 
Ubiquinol 
D-ribose 
Appendix 9: Safety and Efficacy of Ubiquinol (CoQ10) and D-ribose 
 
 
Ubiquinol 
 
Safety 
 
• 
CoQ10 is generally well tolerated at doses not exceeding 1000 mg/day.11, 103, 104 
• 
Occasionally, a side effect is gastrointestinal upset, which is significantly reduced if CoQ10 is taken with 
food. Several studies have reported that patients tolerated ubiquinol well and that they had no adverse 
side effects.105-107 
• 
For this study, we will use Kaneka ubiquinol which is the only ubiquinol ingredient made in the USA. 
The Kaneka ubiquinol will have pure ubiquinol and be free of the following (does NOT contain): sugar, 
starch, salt, preservatives, corn, soy, wheat, dairy, gluten, mold, or metals. The ubiquinol will be Kosher 
and Vegan/Vegetarian. 
• 
Kaneka ubiquinol has a Current Good Manufacturing Practice (CGMP) certification by US Food and 
Drug administration (FDA).  This assures proper design, monitoring, and control of manufacturing 
processes, and facilities at Kaneka.  They also have a certificate of analysis for the ubiquinol product. 
• 
Kaneka QH has the National Safety Foundation (NSF) certification to be 100% pure without fillers or 
additives. The NSF is a Public Health and Safety Organization that certifies dietary supplements to 
ensure through testing and evaluations that a product is safe. 
• 
There are no established toxic effects of CoQ10 supplementation in humans, and CoQ10 has an 
excellent safety profile.11 
• 
Administration of 300 mg of ubiquinol (Kaneka QH) has significant absorption of ubiquinol from the 
gastrointestinal tract, and no safety concerns on standard laboratory tests for safety or on assessment 
of adverse events.91 
• 
In our study, we shall advise subjects to take ubiquinol with food to reduce the potential for 
gastrointestinal upset.108 
• 
Ubiquinol needs to be protected from extreme heat and light. It should be stored in a cool and dry 
place. 
• 
The ubiquinol dosage of 600 mg/day is well within the clinically recommended range. Several studies 
have indicated that CoQ10 produced no adverse effects or drug interactions.109-112 
 
Efficacy 
 
• 
Low serum CoQ10 levels may result from excessive use, impairment of biosynthesis, insufficient 
dietary intake, or any combination of the three.113, 114 
• 
In heart failure patients, it is necessary to increase serum CoQ10 levels to a minimum of 3.5 mcg/mL to 
achieve clinical benefits.115 
• 
Administering ubiquinone in some studies resulted in poor gastrointestinal absorption. In addition, the 
ability to convert ubiquinone to ubiquinol (active form) was decreased.116-119  This conversion is not an 
issue for individuals in the 20-40 year age range120, 121 but it becomes increasing difficult for individuals 
older than the age of 40.122, 123 
• 
With the use of ubiquinol, there is no impairment of absorption in patients of any age. With the 
introduction of ubiquinol the efficacy has greatly increased in many diseases105, 124, 125 including 
congestive heart failure.126, 127 
 
 
 
 
Safety 
 
• 
D-ribose is safe and well tolerated in the daily doses smaller than 20 grams.128-130 In this study, subjects 
will be consuming 15 grams/day. Subjects may experience loose stools. This effect can be 

 
 
 
 
Placebo Products – Capsules and Powder  
circumvented by avoiding D-ribose ingestion on an empty stomach or by taking three 5 gram doses at 
various times of the day. 
• 
For the study, we will use Dual Health 100% Pure D-Ribose Powder. It is a pharmaceutical USP Grade 
D-Ribose that is a white to slightly yellow crystalline powder, characterized by a fruity sweet odor and 
slightly sweet taste. 
• 
The Dual Health D-ribose is produced in the USA and from a CGMP manufacturer and has a certificate 
of analysis for the product. 
• 
The D-ribose from Dual Health is United States Pharmacopeia (USP) and Food Chemical Codex (FCC) 
graded and is 100% pure without fillers or additives. Thus, it is a certified dietary supplement that 
through testing and evaluations is a safe product for human consumption. 
• 
D-ribose readily dissolves in water, juice, milk, and other cold liquids and has been determined to be 
safe with few adverse side effects.131 
• 
D-ribose may lower blood pressures 132 
 
Efficacy 
 
• 
Impairment of adenosine triphosphate (ATP) synthesis results in energy demand exceeding energy 
supply, which results in depletion of ATP accompanied by diastolic dysfunction. Research has shown 
that supplementing exogenous D-ribose accelerated synthesis of ATP by six-fold.133 
• 
Increased ATP levels by D-ribose improved cardiac energy metabolism and contributed to significant 
recovery of myocardial contractility.134,135 
• 
D-ribose significantly improved diastolic function and patients’ exercise tolerance, which enhanced 
patients’ quality of life.71 
 
 
Combined Regimen of Ubiquinol and D-ribose 
 
 
• 
Reports have shown no evidence for adverse interactions between CoQ10 and D-ribose.136 They 
reported these supplements enhanced low and high-intensity exercise. There were no side effects in 
animal studies using these supplements thus investigators stated that they were safe for human 
consumption.137 
• 
Several studies have used the combination of antioxidants together for the treatment of patients with 
mitochondrial dysfunction. They found that D-ribose or ubiquinol with other antioxidants such as vitamin 
C, methylcobalamin, and N-acetyl-L-cysteine resulted in significant improvement with no accompanying 
side effects.138-140 
• 
The combination of these supplements has contributed to the cardiac function by maintaining cardiac 
energy by preserving ATP substrates. 
 
 
 
 
Safety 
 
• 
To reduce the risk of allergic reaction, all the placebo products (capsules and/or powder) will be free-
from the eight most common food allergens in the United States, as declared by the US Food and Drug 
Administration (FDA).141 
• 
Both the placebo capsules and powder will contain no wheat, no gluten, no soybeans, no dairy, no egg, 
no fish/shellfish, and no peanuts/tree nuts. 
• 
All placebo products will be manufactured at a pharmaceutical packaging facility that is certified by the 
Good Manufacturing Practice (CGMP) facilities and also FDA registered and inspected. This company 
will produce placebos to match our comparators (both the ubiquinol and D-ribose). Stark pharmacy in 
Overland Park, KS will prepare, package, and label the placebo capsules and powder. 
 
 

 
 
 
 
Placebo Products – Capsules and Powder 
Label Information from Stark Pharmacy 
Efficacy 
 
• 
The inactive ingredients within the placebo capsule will have microcrystalline cellulose in each capsule. 
The capsules will be the same color and size and in the same type of plastic container. 
• 
The ubiquinol and placebo capsules will both be non-marked light brown color, oval shape capsules. 
The study product and placebo capsules will be similar in capsule odor, texture, hardness, and 
packaging. 
• 
The D-ribose powder will be a pure product that has no inactive ingredients. Thus, the placebo powder 
will also not have inactive ingredients and consist of only microcrystalline cellulose.  Both powders will 
be white in color, similar consistency, and in the same type of plastic container. 
 
 
 
 
 
Below are examples of the bottle labels that will be provided by Stark Pharmacy. The first label (#1) will be 
used for the ubiquinol or placebo capsules. The second label (#2) will be used for either the D-ribose or 
placebo powder. 
 
Ubiquinol, D-ribose, or Placebo Sample Labels 
 
#1 
University of Kansas Medical Center 
3901 Rainbow Blvd., KCKS 66160 
913-588-5000 
Participant Number: ____________ 
Date: ________________________ 
Medication: Ubiquinol 300 mg capsule or Placebo 
Directions: Take 2 capsules daily for 12 weeks. 
Lot Number: ____________________ 
 
 
#2 
University of Kansas Medical Center 
3901 Rainbow Blvd., KCKS 66160 
913-588-5000 
Participant Number: ____________ 
Date: ________________________ 
Medication: D-Ribose powder or Placebo 
Directions: Take 3 scoops daily mixed in water for 12 weeks. 
Lot Number: ___________________ 
 
 
 
 
 

 
 
 
 
 
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