Heart Failure With Normal Ejection FractionEarly Phase 1NCT03289481
Treatment of HFpEF With Nitrate Supplement
A Early Phase 1 study testing Active lozenge in people with Heart Failure With Normal Ejection Fraction, run by MaineHealth at 1 site in United States.
Trial summary
The objective of this project is to determine if Neo40, a nitric oxide generating lozenge, when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease symptoms and improve quality of life for patients. 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?
- Active lozenge
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 13 participants
- Where
- 1 siteUnited States
- Study dates
- 29 Jun 2017to 22 Aug 2018
- Phase
- Early Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Diagnosis of HFpEF, defined as:
- symptomatic with one of more of the following: orthopnea, paroxysmal nocturnal dyspnea, lower-extremity edema, dyspnea on exertion; AND
- ejection fraction >50%
- ratio of early mitral inflow velocity to septal tissue dopler velocity >8; AND
- one or more of the following: left atrium measurement >34 mL/m2, elevated N-terminal pro-brain natriuretic peptide level within the past 12 months, long term loop diuretic use for control of symptoms or elevated filling pressures on prior cardiac catheterization
- Stable medical therapy, defined as: no change in cardiac medications within 30 days
- Willing to comply with the protocol and provide written informed consent
Who cannot join
- Non-cardiac condition causing limitation of exercise tolerance
- Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60 days
- Clinically significant valvular disease, defined as moderate-severe or severe stenosis or insufficiency
- Significant ischemia seen on stress testing within the past 12 months that was not revascularized
- Subject has taken and investigational medication within the past 30 days
- History of allergy to beets
- Systolic blood pressure of <100 at screening
- Significant medical condition that would interfere with treatment, safety or compliance with the protocol
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation
The objective of this project is to determine if Neo40, a nitric oxide generating lozenge, when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease symptoms and improve quality of life for patients.
Read the detailed description
Heart failure (HF) is the most common principal diagnosis for hospital admission in patients over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Approximately half of patients with the clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent with aging of the population and obesity. There are only two class I recommendations for the treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve symptoms. Exercise training is another approach to improving symptoms, however it may be poorly tolerated.
Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is further reduced to nitric oxide (NO) resulting in intense vasodilation.
Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and increases left sided filling pressure. Borloug, et al demonstrated this with right heart catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2 resulted in decreased filling pressures and increased cardiac output. (2)
Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting of hypoxia and acidosis resulting in targeted vasodilatation.
- Being tested
- Active lozenge, Placebo
- Keywords
- Heart failure, HFpEF, Nitrate supplement
- Medical subject headings
- Heart Failure
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Active lozengeDietary supplement
nitric oxide generating lozenge
PlaceboDrug
placebo tablet
| Study group | Role | What they receive |
|---|---|---|
| Active lozenge first | Active comparator | Subject will take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing. Receives: Dietary Supplement: Active lozenge; Drug: Placebo |
| Placebo lozenge first | Active comparator | Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week and perform cardiac testing. Receives: Dietary Supplement: Active lozenge; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time on Treadmill
change in total time traveled on treadmill
Measured: after one week of active lozenges compared to one week of placebo lozenges
Metabolic Equivalents
change in metabolic equivalents on treadmill
Measured: after one week of active lozenges compared to one week of placebo lozenges
E/E Prime
change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)
Measured: after one week of active lozenges compared to one week of placebo lozenges
Estimated Right Ventricular Systolic Pressure
change in estimated right ventricular systolic pressure on echo
Measured: after one week of active lozenges compared to one week of placebo lozenges
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2017
- Study start29 Jun 2017
- Primary completion22 Aug 2018
- Study completion22 Aug 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)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
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Double-blind, placebo controlled crossover study
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 13 participants (actual)
Sponsor and investigators
- Lead sponsor
- MaineHealth
- Sponsor type
- University, hospital or other
- Collaborators
- HumanN
- Responsible party
- Principal investigator, Ralph Hamill, MaineHealth
- Investigators
- Ralph Hamill, MD, Principal investigator, MaineHealth
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03289481
- Sponsor's protocol ID
- Neo40 Study
- Status last verified
- Sep 2021
- First submitted
- 18 Sep 2017
- Last updated
- 6 Oct 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.
PubMed 26874390Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.
PubMed 26449137
Study at a glance
From the registry record, last updated by the sponsor on 6 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation
- ClinicalTrials.gov ID
- NCT03289481
- Acronym / sponsor ID
- Neo40 Study
- Keywords
- Heart failure, HFpEF, Nitrate supplement
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 13 participants (actual)
- Lead sponsor
- MaineHealthUniversity, hospital or other
- Collaborators
- HumanN
- Study start
- 29 Jun 2017 (actual)
- Primary completion
- 22 Aug 2018 (actual)
- Study completion
- 22 Aug 2018 (actual)
- First posted
- 21 Sep 2017 (actual)
- Results
- Posted 26 Aug 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The objective of this project is to determine if Neo40, a nitric oxide generating lozenge, when consumed twice daily by subjects with HFpEF, will increase exercise tolerance, decrease symptoms and improve quality of life for patients.
Detailed description
Heart failure (HF) is the most common principal diagnosis for hospital admission in patients over 65 years old. There are two types of HF, those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Approximately half of patients with the clinical syndrome of HF have preserved systolic function. HEpEF is becoming more prevalent with aging of the population and obesity. There are only two class I recommendations for the treatment of HFpEF, which are controlling blood pressure and the use of diuretics to relieve symptoms. Exercise training is another approach to improving symptoms, however it may be poorly tolerated.
Nitrate supplement in the form of concentrated beetroot juice was recently shown to improve exercise tolerance in patients with HFpEF. (1) Beetroot juice contains high concentration of nitrate (NO3). This is metabolized to nitrite (NO2). It enters the blood stream, where it is further reduced to nitric oxide (NO) resulting in intense vasodilation.
Patients with diastolic dysfunction are often asymptomatic at rest but complain of dyspnea with exertion. Increase in heart rate with exercise causes reduced diastolic filling time and increases left sided filling pressure. Borloug, et al demonstrated this with right heart catheterization and supine exercise in patients with diastolic dysfunction. Infusion of NO2 resulted in decreased filling pressures and increased cardiac output. (2)
Neo40 is a new product made from concentrated beetroot juice in the form of a lozenge designed to dissolve on the tongue. NO3 supplement causes vasodilatation only in the setting of hypoxia and acidosis resulting in targeted vasodilatation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Double-blind, placebo controlled crossover study
| Arm | Type | Receives |
|---|---|---|
| Active lozenge first | Active comparator | Dietary Supplement: Active lozenge, Drug: PlaceboSubject will take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing. |
| Placebo lozenge first | Active comparator | Dietary Supplement: Active lozenge, Drug: PlaceboSubject will take placebo lozenge for one week, perform cardiac testing then take active lozenge (Vitamin C, Vitamin B12, Nitric Oxide Blend, L-citrulline, Sodium Nitrite) for one week and perform cardiac testing. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Diagnosis of HFpEF, defined as:
- Stable medical therapy, defined as: no change in cardiac medications within 30 days
- Willing to comply with the protocol and provide written informed consent
Key exclusion criteria (8 listed)
- Non-cardiac condition causing limitation of exercise tolerance
- Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60 days
- Clinically significant valvular disease, defined as moderate-severe or severe stenosis or insufficiency
- Significant ischemia seen on stress testing within the past 12 months that was not revascularized
- Subject has taken and investigational medication within the past 30 days
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 |
|---|---|---|
| Active lozengenitric oxide generating lozenge | Dietary supplement | Active lozenge first, Placebo lozenge first |
| Placeboplacebo tablet | Drug | Active lozenge first, Placebo lozenge first |
Primary outcome
Time on Treadmill
Time frame: after one week of active lozenges compared to one week of placebo lozenges
change in total time traveled on treadmill
Metabolic Equivalents
Time frame: after one week of active lozenges compared to one week of placebo lozenges
change in metabolic equivalents on treadmill
E/E Prime
Time frame: after one week of active lozenges compared to one week of placebo lozenges
change in E/E prime on exercise echo (E/E prime is a ratio between early mitral inflow velocity and mitral annular early diastolic velocity in order to measure diastolic dysfunction)
Estimated Right Ventricular Systolic Pressure
Time frame: after one week of active lozenges compared to one week of placebo lozenges
change in estimated right ventricular systolic pressure on echo
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 6 Oct 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 26874390Eggebeen J, Kim-Shapiro DB, Haykowsky M, Morgan TM, Basu S, Brubaker P, Rejeski J, Kitzman DW. One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail. 2016 Jun;4(6):428-37. doi: 10.1016/j.jchf.2015.12.013. Epub 2016 Feb 10.
- Background: PubMed 26449137Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol. 2015 Oct 13;66(15):1672-82. doi: 10.1016/j.jacc.2015.07.067.
- Individual participant dataSharing planned: No
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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.
Ralph Hamill, MD principal investigator
MaineHealth
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Active lozenge in people with Heart Failure With Normal Ejection Fraction, run by MaineHealth 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 7 inclusion and 8 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 6 Oct 2021. 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. 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?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 26 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Time on Treadmill (time frame: after one week of active lozenges compared to one week of placebo lozenges). The study lists 4 primary outcomes in all. 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 NCT03289481, which also lists 2 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 6 Oct 2021; AzTrials last refreshed its copy on 6 Nov 2026.