Treatment of HFpEF With Nitrate Supplement

• Sponsor: MaineHealth (Other)
• Overall Status: Completed
• CT.gov ID: NCT03289481
• Collaborator: HumanN (Industry)
• Enrollment: 13
• Location: 1
• Arms: 2
• Actual Duration (Months): 13.8
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Normal Ejection Fraction	Dietary Supplement: Active lozenge; Drug: Placebo	Early Phase 1

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

• Study Type: Interventional
• Actual Enrollment: 13 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: Double-blind, placebo controlled crossover studyDouble-blind, placebo controlled crossover study
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Masking will be done by the pharmacy. Active and placebo lozenges will look identical.
• Primary Purpose: Treatment
• Official Title: Treatment of HFpEF With Nitrate Supplement: A Double-blind, Placebo Controlled Trial Including Patients With Atrial Fibrillation
• Actual Study Start Date: Jun 29, 2017
• Actual Primary Completion Date: Aug 22, 2018
• Actual Study Completion Date: Aug 22, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active lozenge first 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.	Dietary Supplement: Active lozenge; nitric oxide generating lozenge; Drug: Placebo; placebo tablet
Active Comparator: Placebo lozenge first 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.	Dietary Supplement: Active lozenge; nitric oxide generating lozenge; Drug: Placebo; placebo tablet

Outcome Measures

Primary Outcome Measures

1. Time on Treadmill [after one week of active lozenges compared to one week of placebo lozenges]

   change in total time traveled on treadmill

2. Metabolic Equivalents [after one week of active lozenges compared to one week of placebo lozenges]

   change in metabolic equivalents on treadmill

3. E/E Prime [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)

4. Estimated Right Ventricular Systolic Pressure [after one week of active lozenges compared to one week of placebo lozenges]

   change in estimated right ventricular systolic pressure on echo

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 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

1. Stable medical therapy, defined as: no change in cardiac medications within 30 days

2. Willing to comply with the protocol and provide written informed consent

Exclusion Criteria:

1. Non-cardiac condition causing limitation of exercise tolerance

2. Acute coronary syndrome, myocardial infarction or cardiac revascularization within 60 days

3. Clinically significant valvular disease, defined as moderate-severe or severe stenosis or insufficiency

4. Significant ischemia seen on stress testing within the past 12 months that was not revascularized

5. Subject has taken and investigational medication within the past 30 days

6. History of allergy to beets

7. Systolic blood pressure of <100 at screening

8. Significant medical condition that would interfere with treatment, safety or compliance with the protocol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penobscot Bay Medical Center	Rockport	Maine	United States	04856

Sponsors and Collaborators

• MaineHealth
• HumanN

Investigators

• Principal Investigator: Ralph Hamill, MD, MaineHealth

Study Documents (Full-Text)

• Study Protocol - Mar 20, 2017
• Statistical Analysis Plan - Mar 20, 2019

More Information

Publications

• Borlaug 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.
• 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.

• Responsible Party: Ralph Hamill, Cardiologist, MaineHealth
• ClinicalTrials.gov Identifier: NCT03289481
• Other Study ID Numbers: Neo40 Study
• First Posted: Sep 21, 2017
• Last Update Posted: Oct 6, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ralph Hamill, Cardiologist, MaineHealth: Heart failure; HFpEF; Nitrate supplement
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details	This study was a cross over case-control study (each subject was a control for themselves).

Arm/Group Title	Active Lozenge First	Placebo Lozenge First
Arm/Group Description	Subject will take active lozenge for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing. Active lozenge: nitric oxide generating lozenge	Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge for one week and perform cardiac testing. Active lozenge: nitric oxide generating lozenge
Period Title: Overall Study
STARTED	6	7
COMPLETED	4	5
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Active Lozenge First	Placebo Lozenge First	Total
Arm/Group Description	Subject will take active lozenge for one week, perform cardiac testing then take placebo lozenge for one week and perform cardiac testing. Active lozenge: nitric oxide generating lozenge	Subject will take placebo lozenge for one week, perform cardiac testing then take active lozenge for one week and perform cardiac testing. Active lozenge: nitric oxide generating lozenge	Total of all reporting groups
Overall Participants	4	5	9
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	2 40%	2 22.2%
>=65 years	4 100%	3 60%	7 77.8%
Sex: Female, Male (Count of Participants)
Female	2 50%	1 20%	3 33.3%
Male	2 50%	4 80%	6 66.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 100%	5 100%	9 100%
Region of Enrollment (participants) [Number]
United States	4 100%	5 100%	9 100%
Diagnosis of HFpEF (Count of Participants)
Count of Participants [Participants]	4 100%	5 100%	9 100%

Outcome Measures

1. Primary Outcome

Title	Time on Treadmill
Description	change in total time traveled on treadmill
Time Frame	after one week of active lozenges compared to one week of placebo lozenges

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Lozenge	Placebo
Arm/Group Description	Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.	Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.
Measure Participants	9	9
Mean (Full Range) [seconds]	402.8	181.2

2. Primary Outcome

Title	Metabolic Equivalents
Description	change in metabolic equivalents on treadmill
Time Frame	after one week of active lozenges compared to one week of placebo lozenges

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Lozenge	Placebo
Arm/Group Description	Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.	Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.
Measure Participants	9	9
Mean (Full Range) [cal/min]	7.99	8.46

3. Primary Outcome

Title	E/E Prime
Description	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)
Time Frame	after one week of active lozenges compared to one week of placebo lozenges

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Lozenge	Placebo Lozenge
Arm/Group Description	Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.	Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.
Measure Participants	9	9
Mean (Full Range) [ratio]	1.93	-.05

4. Primary Outcome

Title	Estimated Right Ventricular Systolic Pressure
Description	change in estimated right ventricular systolic pressure on echo
Time Frame	after one week of active lozenges compared to one week of placebo lozenges

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Active Lozenge	Placebo
Arm/Group Description	Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.	Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.
Measure Participants	9	9
Mean (Full Range) [mmHg]	11.79	8.6

Adverse Events

Time Frame	1 year
Arm/Group Title	Active Lozenge		Placebo Lozenge
Arm/Group Description	Participants who received Neo40 (active lozenge) in either the first week or the last week of the study.		Participants who received the placebo (matching Neo40) in either the first week or the last week of the study.
All Cause Mortality
	Active Lozenge		Placebo Lozenge
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)
Serious Adverse Events
	Active Lozenge		Placebo Lozenge
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Active Lozenge		Placebo Lozenge
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/9 (0%)		0/9 (0%)

Limitations/Caveats

Low enrollment number

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.