Heart Failure With Normal Ejection FractionPhase 2NCT01919177
Effect of Inorganic Nitrates (Beetroot Juice) on Arterial Hemodynamics and Exercise Capacity
A Phase 2 study testing Nitrate rich beetroot juice and Nitrate depleted beetroot juice in people with Heart Failure With Normal Ejection Fraction, run by Corporal Michael J. Crescenz VA Medical Center at 1 site in United States.
Trial summary
The main objective is to test the hypothesis that inorganic nitrate supplementation will: (1) Improve exercise efficiency and performance; (2) Enhance the systemic vasodilator reserve during exercise and specifically, the vasodilator response in exercising muscle; (3) Reduce arterial wave reflections and arterial… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Heart Failure With Normal Ejection Fraction
- What is being tested?
- Nitrate rich beetroot juice and Nitrate depleted beetroot juice
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 17 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2013to Nov 2014
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- The investigators will enroll 20 subjects >18 years of age who have a diagnosis of heart failure with preserved ejection fraction (>50%) by 2d echocardiography, with current New York Heart Association Class II-IV symptoms.
- In addition, subjects with heart failure must meet the following inclusion criteria:
- Chronic treatment with a loop diuretic for control of HF symptoms.
- If EF is normal, subjects must demonstrate elevated filling pressures as evidenced by at least one of the following: a) left atrial enlargement (LAVI > 32 mL/m2); b) at least stage II diastolic dysfunction; c) Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.
- Stable medical therapy as defined by: (I) No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days. (II) No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days. (III) No change in diuretic dose for 10 days.
Who cannot join
- Rhythm other than sinus rhythm (i.e., atrial fibrillation).
- Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from exercising.
- Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation).
- Hypertrophic cardiomyopathy.
- Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
- Pericardial disease.
Show all 19Show fewer
- Primary pulmonary arteriopathy.
- Have experienced a myocardial infarction or unstable angina, or have undergone percutaneous transluminal coronary angiography (PTCA) or coronary artery bypass grafting (CABG) within 60 days prior to consent, or requires either PTCA or CABG at the time of consent.
- Other clinically important causes of dyspnea such as morbid obesity or significant lung disease defined by clinical judgment or use of steroids or oxygen for lung disease within the past 6 months.
- Systolic blood pressure < 110 mmHg or > 180 mm Hg.
- Diastolic blood pressure < 40 mmHg or > 100 mmHg.
- Resting heart rate (HR) > 100 bpm.
- Hemoglobin <10 g/dL.
- Patients with known severe liver disease (AST > 3x normal, alkaline phosphatase or bilirubin > 2x normal).
- Patients with a clinically indicated stress test demonstrating significant ischemia within a year of enrollment which was not followed by percutaneous or surgical revascularization.
- Current therapy with phosphodiesterase inhibitors, such as sildenafil, vardanafil or tadalafil.
- Known allergies to beetroot or lemon juice.
- Current use of organic nitrates or phosphodiesterase inhibitors.
- Pregnancy. Although beetroot juice has not knows teratogenic effects, we feel that not enough data exist in this regard. Therefore, all females patients of reproductive age will be required to undergo a pregnancy test prior to enrollment.
Trial locations and contacts
1 site in 1 country.
United States1 site
Philadelphia Veterans Affairs Medical Center
Philadelphia, Pennsylvania, 19104
About this study
Official title: Effect of Inorganic Nitrates on Arterial Hemodynamics and Exercise Capacity
The main objective is to test the hypothesis that inorganic nitrate supplementation will: (1) Improve exercise efficiency and performance; (2) Enhance the systemic vasodilator reserve during exercise and specifically, the vasodilator response in exercising muscle; (3) Reduce arterial wave reflections and arterial load; (4) Improve skeletal muscle mitochondrial function in subjects with heart failure with preserved ejection fraction.
Read the detailed description
This represents a series of double-blind, controlled pilot randomized studies in which the effects of nitrate-rich beetroot juice and nitrate-depleted beetroot juice will be assessed in patients with heart failure and preserved ejection fraction (n=20). A total of 20 subjects will be enrolled over a 1.5 year period and randomized in a cross-over design to a single dose of nitrate-rich beetroot juice and nitrate-depleted beetroot juice. The order of the interventions will be randomized; thus, all subjects will receive the nitrate-rich and nitrate-depleted juice, with a 4-7 day washout period in-between studies.
- Being tested
- Nitrate rich beetroot juice, Nitrate depleted beetroot juice
- Keywords
- Heart Failure, Arterial hemodynamics, Exercise capacity, Mitochondrial oxidative capacity
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Nitrate rich beetroot juiceDietary supplement
Also called Beet It Stamina Sports shots
Subjects will receive 140 mL of Nitrate-rich concentrated beetroot juice.
Nitrate depleted beetroot juiceDietary supplement
Also called Beet It nitrate extracted (depleted) placebo shots
Subjects will receive 140 mL of nitrate-depleted beetroot juice.
| Study group | Role | What they receive |
|---|---|---|
| Nitrate rich beetroot juice | Active comparator | Subjects with heart failure with preserved ejection fraction will receive 140 mL of Nitrate-rich concentrated beetroot juice (containing 12 mmol of NO-3). This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. Receives: Dietary Supplement: Nitrate rich beetroot juice |
| Nitrate depleted beetroot juice | Placebo comparator | Subjects with heart failure with preserved ejection fraction will receive 140 mL of nitrate-depleted beetroot juice (containing <0.01 mmol of NO-3).This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. Receives: Dietary Supplement: Nitrate depleted beetroot juice |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test
We will assess the relationship between total power output and total O2 consumption (VO2, assessed via expired gas analysis) during a maximal-effort supine bicycle exercise test.
Measured: Baseline study, repeat study 4-7 days later
Secondary outcomes (7)
Change in Arterial wave reflection magnitude
Reflection wave magnitude will be assessed using arterial tonometry to arrive at the augmentation index. The data will also be processed using custom designed software for wave separation analysis to quantify the magnitude and timing of the reflected waves.
Measured: Baseline study, repeat study 4-7 days later
Change in Peripheral vascular resistance, total arterial compliance and reflection magnitude during supine bicycle peak exercise
Measured: Baseline study, repeat study 4-7 days later
Change in lower extremity exercise vasodilator reserve (change in femoral vascular resistance between rest and maximal effort supine-bicycle exercise)
Measured: Baseline study, repeat study 4-7 days later
Change in lower extremity blood flow reserve (change in femoral artery blood flow between rest and maximal effort supine-bicycle exercise)
Measured: Baseline study, repeat study 4-7 days later
Change in submaximal exercise efficiency (O2 consumption per power output during submaximal exercise and standardized handgrip exercise)
Measured: Baseline study, repeat study 4-7 days later
Change in Skeletal Muscle Mitochondrial Oxidative Capacity
The investigators will assess the oxygen consumption recovery kinetics after moderate forearm exercise, using repeated cuff brachial artery occlusions and near-infrared spectroscopy.
Measured: Baseline study, repeat study 4-7 days later
Change in post-ischemic vasodilatory response
The investigators will assess the post-ischemic vasodilatory response in the forearm using brachial artery pulsed wave Doppler interrogations before and after inflation of a brachial cuff at 200 mmHg for 5 minutes. The investigators will also assess forearm microvascular skeletal muscle flow with near-infrared spectroscopy and forearm skin microvascular flow using laser Doppler.
Measured: Baseline study, repeat study 4-7 days later
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Aug 2013 (estimated)
- Study startJan 2013
- Primary completionSep 2014
- Study completionNov 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Heart Failure With Normal Ejection FractionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 17 participants (actual)
Sponsor and investigators
- Lead sponsor
- Corporal Michael J. Crescenz VA Medical Center
- Sponsor type
- US federal agency
- Responsible party
- Principal investigator, Julio A.Chirinos, Corporal Michael J. Crescenz VA Medical Center
- Investigators
- Julio A Chirinos, MD, PhD, Principal investigator, Philadelphia VA Medical Center & University of Pennsylvania
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01919177
- Sponsor's protocol ID
- 01415
- Status last verified
- Apr 2015
- First submitted
- 22 Jul 2013
- Last updated
- 28 Apr 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
American Thoracic Society; American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003 Jan 15;167(2):211-77. doi: 10.1164/rccm.167.2.211. No abstract available.
PubMed 12524257Manetos C, Dimopoulos S, Tzanis G, Vakrou S, Tasoulis A, Kapelios C, Agapitou V, Ntalianis A, Terrovitis J, Nanas S. Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure. J Heart Lung Transplant. 2011 Dec;30(12):1403-8. doi: 10.1016/j.healun.2011.08.020. Epub 2011 Oct 7.
PubMed 21982360Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22.
PubMed 25533966
Study at a glance
From the registry record, last updated by the sponsor on 28 Apr 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Inorganic Nitrates on Arterial Hemodynamics and Exercise Capacity
- ClinicalTrials.gov ID
- NCT01919177
- Acronym / sponsor ID
- 01415
- Keywords
- Heart Failure, Arterial hemodynamics, Exercise capacity, Mitochondrial oxidative capacity
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 17 participants (actual)
- Lead sponsor
- Corporal Michael J. Crescenz VA Medical CenterUS federal agency
- Study start
- Jan 2013
- Primary completion
- Sep 2014 (actual)
- Study completion
- Nov 2014 (actual)
- First posted
- 8 Aug 2013 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The main objective is to test the hypothesis that inorganic nitrate supplementation will: (1) Improve exercise efficiency and performance; (2) Enhance the systemic vasodilator reserve during exercise and specifically, the vasodilator response in exercising muscle; (3) Reduce arterial wave reflections and arterial load; (4) Improve skeletal muscle mitochondrial function in subjects with heart failure with preserved ejection fraction.
Detailed description
This represents a series of double-blind, controlled pilot randomized studies in which the effects of nitrate-rich beetroot juice and nitrate-depleted beetroot juice will be assessed in patients with heart failure and preserved ejection fraction (n=20). A total of 20 subjects will be enrolled over a 1.5 year period and randomized in a cross-over design to a single dose of nitrate-rich beetroot juice and nitrate-depleted beetroot juice. The order of the interventions will be randomized; thus, all subjects will receive the nitrate-rich and nitrate-depleted juice, with a 4-7 day washout period in-between studies.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitrate rich beetroot juice | Active comparator | Dietary Supplement: Nitrate rich beetroot juiceSubjects with heart failure with preserved ejection fraction will receive 140 mL of Nitrate-rich concentrated beetroot juice (containing 12 mmol of NO-3). This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. |
| Nitrate depleted beetroot juice | Placebo comparator | Dietary Supplement: Nitrate depleted beetroot juiceSubjects with heart failure with preserved ejection fraction will receive 140 mL of nitrate-depleted beetroot juice (containing <0.01 mmol of NO-3).This will be a cross-over study. Therefore all subjects will receive both interventions, but the order of the interventions will be randomized. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- The investigators will enroll 20 subjects >18 years of age who have a diagnosis of heart failure with preserved ejection fraction (>50%) by 2d echocardiography, with current New York Heart Association Class II-IV symptoms.
- Chronic treatment with a loop diuretic for control of HF symptoms.
- If EF is normal, subjects must demonstrate elevated filling pressures as evidenced by at least one of the following: a) left atrial enlargement (LAVI > 32 mL/m2); b) at least stage II diastolic dysfunction; c) Documentation of elevated NT-pro BNP levels or other natriuretic peptide marker (BNP, ANP) according to the laboratory and assay upper limit of normal in the previous year.
- Stable medical therapy as defined by: (I) No addition or removal of ACE, ARB, beta-blockers, or calcium channel blockers (CCBs) for 30 days. (II) No change in dosage of ACE, ARBs, beta-blockers or CCBs of more than 100% for 30 days. (III) No change in diuretic dose for 10 days.
Key exclusion criteria (19 listed)
- Rhythm other than sinus rhythm (i.e., atrial fibrillation).
- Neuromuscular, orthopedic or other non-cardiac condition that prevents patient from exercising.
- Valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation).
- Hypertrophic cardiomyopathy.
- Known infiltrative or inflammatory myocardial disease (amyloid, sarcoid).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Nitrate rich beetroot juiceAlso: Beet It Stamina Sports shotsSubjects will receive 140 mL of Nitrate-rich concentrated beetroot juice. | Dietary supplement | Nitrate rich beetroot juice |
| Nitrate depleted beetroot juiceAlso: Beet It nitrate extracted (depleted) placebo shotsSubjects will receive 140 mL of nitrate-depleted beetroot juice. | Dietary supplement | Nitrate depleted beetroot juice |
Primary outcome
Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test
Time frame: Baseline study, repeat study 4-7 days later
We will assess the relationship between total power output and total O2 consumption (VO2, assessed via expired gas analysis) during a maximal-effort supine bicycle exercise test.
7 secondary outcomes
Change in Arterial wave reflection magnitude
Time frame: Baseline study, repeat study 4-7 days later
Change in Peripheral vascular resistance, total arterial compliance and reflection magnitude during supine bicycle peak exercise
Time frame: Baseline study, repeat study 4-7 days later
Change in lower extremity exercise vasodilator reserve (change in femoral vascular resistance between rest and maximal effort supine-bicycle exercise)
Time frame: Baseline study, repeat study 4-7 days later
Change in lower extremity blood flow reserve (change in femoral artery blood flow between rest and maximal effort supine-bicycle exercise)
Time frame: Baseline study, repeat study 4-7 days later
Change in submaximal exercise efficiency (O2 consumption per power output during submaximal exercise and standardized handgrip exercise)
Time frame: Baseline study, repeat study 4-7 days later
Change in Skeletal Muscle Mitochondrial Oxidative Capacity
Time frame: Baseline study, repeat study 4-7 days later
Change in post-ischemic vasodilatory response
Time frame: Baseline study, repeat study 4-7 days later
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Apr 2015.
- Background: PubMed 12524257American Thoracic Society; American College of Chest Physicians. ATS/ACCP Statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med. 2003 Jan 15;167(2):211-77. doi: 10.1164/rccm.167.2.211. No abstract available.
- Background: PubMed 21982360Manetos C, Dimopoulos S, Tzanis G, Vakrou S, Tasoulis A, Kapelios C, Agapitou V, Ntalianis A, Terrovitis J, Nanas S. Skeletal muscle microcirculatory abnormalities are associated with exercise intolerance, ventilatory inefficiency, and impaired autonomic control in heart failure. J Heart Lung Transplant. 2011 Dec;30(12):1403-8. doi: 10.1016/j.healun.2011.08.020. Epub 2011 Oct 7.
- Results publication: PubMed 25533966Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Julio A Chirinos, MD, PhD principal investigator
Philadelphia VA Medical Center & University of Pennsylvania
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Nitrate rich beetroot juice and Nitrate depleted beetroot juice in people with Heart Failure With Normal Ejection Fraction, run by Corporal Michael J. Crescenz VA Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Apr 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Peak exercise efficiency during maximal effort supine-bicycle exercise and peak oxygen consumption (VO2) during a maximal effort supine-bicycle exercise test (time frame: Baseline study, repeat study 4-7 days later). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01919177, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Apr 2015.