Clinical trial NCT03133793: CoQ10 and D-ribose in Patients With Diastolic Heart Failure
Official title: Reducing Symptom Burden in Patients With Heart Failure With Preserved Ejection Fraction Using Ubiquinol and/or D-ribose
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Heart Failure, Diastolic
Keywords: heart failure with preserved ejection fraction
Lead sponsor: University of Kansas Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2017-04-28
Enrollment: 216
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the clinical benefits of CoQ10 and D-ribose taken by patients who have diastolic heart failure, or heart failure with preserved ejection fraction (HFpEF).

Detailed description: This study used a novel design to compare ubiquinol and/or D-ribose as supplemental treatments for HFpEF using a biobehavioral model. This was a randomized, double-blind, controlled trial with a total sample size of (N) = 216 All participants received usual care for HFpEF. Efforts were made to recruit 50% females which is the actual proportion of HFpEF patients in Kansas City area. There were 63 subjects that did not make the 7 day enrollment which dropped our participants to 153.

Participants in this study were randomized into 4 study groups (total n = 153):

N1 = 39 subjects: Control, receive no ubiquinol and no D-ribose; placebo capsules \& powder per day.

N2 = 39 subjects: Ubiquinol group, receive 600 mg of ubiquinol/day, D-ribose placebo powder per day.

N3 = 37 subjects: D-ribose group, receive 15 g of D-ribose/day, placebo capsules for ubiquinol per day.

N4 = 38 subjects: Ubiquinol + D-ribose group, receive 600 mg ubiquinol and 15 g D-ribose per day.

The enrolled patients were randomized into four groups 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 had a certificate of analysis from the manufacturer. The Project Manager reviewed the electronic health records at the University of Kansas Health System (TUKHS) to identify subjects that met the study criteria and were approached to study inclusion. Once the subject signed the informed consent and successfully completed the 7-day run-in, they were randomly assigned to one of the four groups using a list created by a computer-based random number generator. All supplements and the placebo were indistinguishable in packaging and were distributed by the Project Manager or Research Associate independent of the PI so that the allocation of subjects to a treatment or placebo group were concealed from both subjects and key research personnel.

All subjects arrived at the Clinical and Translational Science Unit (CTSU) and escorted to a private exam room. They completed the demographic form at baseline. The KCCQ and Vigor scale from the Profile of Mood States (POMS) were completed in CTSU visits at baseline, and 12 weeks along with the subject's blood pressure, heart rate, height, and weight. The patient was given privacy and asked to remove clothing above the waist. A disposable gown was provided, and the patient laid supine on the bed while an echocardiogram was completed. Approximately, 1 ml of blood was drawn to measure lactate. adenosine triphosphate (ATP), and B-type natriuretic peptide (BNP). The blood samples were measured with point-of-contact instruments within 5 minutes at the CTSU. After the echocardiogram, questionnaires, BNP, and ATP measurements, the subjects completed the six-minute walk test (6MWT) with the Borg scale. The entire data collection period was approximately 2 hours for each subject's visit to the CTSU. Follow-up calls occurred at 3, 6, and 9 weeks during the trial.

Various cardiovascular risk factors were recorded such as tobacco usage, diabetes mellitus, hypercholesterolemia, hypertension, and family history of cardiovascular disease. Smoking status was recorded as either smoker or non-smoker. Diabetes mellitus was also determined by a history of the disease or use of medication for diabetes. Hypercholesterolemia was defined as a fasting total serum cholesterol level ≥ 4.9 mmol/l or use of medication. Hypertension was defined as either systolic or diastolic blood pressure ≥ 140/90 mmHg or use of hypertensive medications.

Aims and Hypotheses.

There were 2 aims and 6 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 were patient-centered; thus the measurement of health status was a priority. Bioenergetics has both biological and behavioral components. The biological component (i.e., improved heart function) and its measurement was discussed in Aim #2.

Investigators assessed 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. 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 were 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. Investigators used 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, patients rated 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. The KCCQ and POMS Vigor scale were administered to patients after they have been sitting quietly for 10 minutes at the beginning of each visit (baseline, 12 weeks). The total time for patients to complete both questionnaires was 5 to10 minutes.

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.

Two-dimensional Doppler echocardiography was used for myocardial imaging to assess cardiac function in patients with HFpEF. In this study, a echocardiography technician performed the echocardiograms during each visit (baseline and 12 weeks). Dr. Hiebert (cardiologists) determine ejection fraction (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.

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.

Investigators examined the effects of ubiquinol and/or D-ribose on the 6MWT at baseline and 12 weeks. Participants were asked to wear appropriate clothes and shoes and walk the longest distance possible in 6 minutes. Prior to exercising, there was a 10-minute rest period during which heart rate and blood pressure were recorded. Subjects walked indoors on a flat, straight 30-meter path marked every 3 meters, and they were informed that they could slow down or stop at any time. A one-lap demonstration was completed before the test began. The distance walked was recorded. Following the 6MWT, a 0.5 ml blood sample was 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 also recorded 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.

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.

BNP concentration was measured using a portable i-STAT handheld analyzer. A blood sample (20 μl) was obtained from a finger stick after the subjects have completed the questionnaires at baseline and 12 weeks. Investigators measured BNP concentration at each visit.

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.

0.1 ml blood sample obtained by finger stick was used for ATP measurements (AquaSnap Total system) after the subject had completed the questionnaires and echocardiograms. Lactate concentration was measured after the 6MWT with a portable i-STAT handheld instrument and requires 0.5 ml blood.

Eligibility criteria: Inclusion Criteria:

* Diagnosed with HFpEF within a 6-month period
* New York Heart Association (NYHA) Classification II-III HF
* Have left ventricular ejection fraction (EF) ≥ 50% documented by an echocardiogram
* Have a telephone or reliable phone contact
* Have their own means of transportation to the study site

Exclusion Criteria:

* Acute coronary syndrome in the past 12 weeks
* Significant valvular heart disease
* Severe cardiac fibrosis (galectin-3 level \> 26 ng/ml)
* Constrictive pericardium
* Pulmonary fibrosis
* Congenital heart disease
* Hypertrophic or infiltrative cardiomyopathy
* Heart transplant
* Left ventricular assist device
* Heart failure (HF) associated hospital admission or emergency room visit within past 30 days
* Recent percutaneous coronary intervention
* Significant renal and/or hepatic dysfunction
* Severe cognitive impairment
* Consumption of any CoQ10 (ubiquinol) or D-ribose supplements

Primary outcomes:
measure: Change in Health Status of Patients With HFpEF
timeFrame: Change from Baseline to Week 12
Secondary outcomes:
measure: Change in Vigor
timeFrame: Change from Baseline to Week 12
measure: Change in Ejection Fraction (EF)
timeFrame: Change from Baseline to Week 12
measure: Change in Septal E/e'
timeFrame: Change from Baseline to Week 12
measure: Change in 6 Minute Walk Test (6MWT)
timeFrame: Change from Baseline to Week 12
measure: Change in Venous Blood B-type Natriuretic Peptide (BNP) Levels
timeFrame: Change from Baseline to Week 12
measure: Change in Lactate
timeFrame: Change from Baseline to Week 12
measure: Change in Adenosine Triphosphate (ATP)
timeFrame: Change from Baseline to Week 12
Other outcomes:
Locations:
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
Study officials:
affiliation: University of Kansas Medical Center
name: Janet Pierce, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pierce JD, Shen Q, Mahoney DE, Rahman F, Krueger KJ, Diaz FJ, Clark L, Smith C, Vacek J, Hiebert JB. Effects of Ubiquinol and/or D-ribose in Patients With Heart Failure With Preserved Ejection Fraction. Am J Cardiol. 2022 Aug 1;176:79-88. doi: 10.1016/j.amjcard.2022.04.031. Epub 2022 May 27.
citation: Pierce JD, Mahoney DE, Hiebert JB, Thimmesch AR, Diaz FJ, Smith C, Shen Q, Mudaranthakam DP, Clancy RL. Study protocol, randomized controlled trial: reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D-ribose. BMC Cardiovasc Disord. 2018 Apr 2;18(1):57. doi: 10.1186/s12872-018-0796-2.