Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction (NEAT-HFpeF)

A randomized, double-blinded, placebo-controlled crossover study to assess effect of isosorbide mononitrate with dose up-titration on activity tolerance as assessed by (hip-worn, tri-axial) accelerometry.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Drug: Isosorbide Mononitrate; Drug: Placebo

Detailed Description

To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo.

• Study Type: Interventional
• Enrollment (Actual): 110
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Delaware
    • Newark, Delaware, United States, 19718
      • Christiana Care Health Services
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School Of Medicine
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • West Roxbury, Massachusetts, United States, 02132
      • Boston V.A. Healthcare System
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Cleveland, Ohio, United States, 44109
      • Metro Health System
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Lancaster General Hospital
    • Philadelphia, Pennsylvania, United States, 19107
      • Jefferson Medical College
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania Health System
  • Texas
    • Houston, Texas, United States, 77030
      • Michael E DeBakey VA Medical Center
  • Utah
    • Salt Lake CIty, Utah, United States, 84148
      • V.A. Medical Center
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospitals and Clinics
  • Vermont
    • Burlington, Vermont, United States, 05401
      • The University of Vermont - Fletcher Allen Health Care

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥ 50 years
2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
3. Ejection fraction (EF) ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function

4. Stable medical therapy for 30 days as defined by:

   • No addition or removal of ACE, Angiotensin receptor blockers (ARBs), beta-blockers, calcium channel blockers (CCBs) or aldosterone antagonists
   • No change in dosage of ACE, ARBs, beta-blockers,CCBs or aldosterone antagonists of more than 100%

5. One of the following within the last 12 months

   • Previous hospitalization for heart failure (HF) with radiographic evidence of pulmonary congestion (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) or
   • Catheterization documented elevated filling pressures at rest (LVEDP≥15 or PCWP≥20) or with exercise (PCWP≥25) or
   • Elevated NT-proBNP (> 400 pg/ml) or BNP (> 200 pg/ml) or
   • Echo evidence of diastolic dysfunction / elevated filling pressures (at least two) E/A > 1.5 + decrease in E/A of > 0.5 with valsalva Deceleration time ≤ 140 ms Pulmonary vein velocity in systole < diastole (PVs<PVd)sinus rhythm) E/e'≥15 Left atrial enlargement (≥ moderate) Pulmonary artery systolic pressure > 40 mmHg Evidence of left ventricular hypertrophy
   • LV mass/BSA ≥ 96 (♀) or ≥ 116 (♂) g/m2
   • Relative wall thickness ≥ 0.43 (♂ or ♀) [(IVS+PW)/LVEDD]
   • Posterior wall thickness ≥ 0.9 (♀) or 1.0 (♂) cm
6. No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months
7. Ambulatory (not wheelchair / scooter / walker / cane dependent)
8. HF is the primary factor limiting activity as indicated by answering # 2 to the following question:

My ability to be active is most limited by:

1. Joint, foot, leg, hip or back pain
2. Shortness of breath and/or fatigue and/or chest pain
3. Unsteadiness or dizziness
4. Lifestyle, weather, or I just don't like to be active

9. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 Kg/m2 but belt may fit some persons outside this range)

10. Willingness to wear the accelerometer belt for the duration of the trial 11. Willingness to provide informed consent

Exclusion Criteria:

1. Recent (< 3 months) hospitalization for HF
2. Hemoglobin < 8.0 g/dl
3. Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories
4. SBP < 110 mmHg or > 180 mmHg at consent
5. Diastolic blood pressure < 40 mmHg or > 100 mmHg at consent
6. Resting HR > 110 bpm at consent
7. Previous adverse reaction to nitrates necessitating withdrawal of therapy
8. Chronic therapy with phosphodiesterase type-5 inhibitors (intermittent use of phosphodiesterase type-5 inhibitors for erectile dysfunction is allowable if the patient is willing to hold for the duration of the trial)
9. Regularly (> 1x per week) swims or does water aerobics
10. Significant COPD thought to contribute to dyspnea
11. Ischemia thought to contribute to dyspnea
12. Documentation of previous EF < 50%
13. Acute coronary syndrome within 3 months defined by electrocardiographic changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
14. Percutaneous coronary intervention, coronary artery bypass grafting or new biventricular pacing within past 3 months
15. Primary hypertrophic cardiomyopathy
16. Infiltrative cardiomyopathy (amyloid)
17. Constrictive pericarditis or tamponade
18. Active myocarditis
19. Complex congenital heart disease
20. Active collagen vascular disease
21. More than mild aortic or mitral stenosis
22. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation
23. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR > 1.7 in the absence of anticoagulation treatment
24. Terminal illness (other than HF) with expected survival of less than 1 year
25. Enrollment or planned enrollment in another therapeutic clinical trial in the next 3 months
26. Inability to comply with planned study procedures
27. Pregnant women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Isosorbide Mononitrate; Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)	Drug: Isosorbide Mononitrate; Dispense phase 1 study drug: Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg ISMN Week 4: 60 mg ISMN Weeks 5 and 6: 120 mg ISMN Dispense phase-2 study drug: Weeks 7 and 8: No study drug (washout) Week 9: 30 mg ISMN Week 10: 60 mg ISMN Weeks 11 and 12: 120 mg ISMN; Other Names: Imdur, ISMO, Monoket
Placebo Comparator: Isosorbide Mononitate Placebo; Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)	Drug: Placebo; Dispense phase 1 study drug: Weeks 1 and 2: No study drug (baseline) Week 3: 30 mg Placebo Week 4: 60 mg Placebo Weeks 5 and 6: 120 mg Placebo Dispense phase-2 study drug: Weeks 7 and 8: No study drug (washout) Week 9: 30 mg Placebo Week 10: 60 mg Placebo Weeks 11 and 12: 120 mg Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Arbitrary Accelerometry Units (AAU) (Phase I)	To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.	5-6 weeks
Arbitrary Accelerometry Units (AAU) (Phase II)	To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.	11-12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Six Minute Walk Distance (Phase I)	To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.	Week 7
Six Minute Walk Distance (Phase II)	To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.	Week 13
Patient Preference for Isosorbide Mononitrate Treatment at the End of Study.	Self reported participant preference for study period 1 vs. study period 2.	Week 13
Borg Score During 6 Minute Walk Test (Phase I)	To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.	Week 7
Borg Score During 6 Minute Walk Test (Phase II)	To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Borg Scale consists of scale range of 0 to 10 (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). Lower values are considered to be better than higher values.	Week 13
Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I)	To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).	Week 7
Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II)	To evaluate whether isosorbide mononitrate improves quality of life in comparison to placebo. • The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life).Higher values of the overall KCCQ score are considered to be better than lower values.	Week 13
N-terminal Pro-B-type Natriuretic Peptide Level (Phase I)	To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo	Week 7
N-terminal Pro-B-type Natriuretic Peptide Level (Phase II)	To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo	Week 13
Improvement in Daily Activity - Hours Active Per Day (Phase I)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug	5-6 weeks
Improvement in Daily Activity - Hours Active Per Day (Phase II)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Hours active per day during maximal dose of study drug	11-12 weeks
Improvement in Daily Activity - Slope of Daily Average (Phase I)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.	3-6 weeks
Improvement in Daily Activity - Slope of Daily Average (Phase II)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Slope of daily averaged arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement.	9-12 weeks
Improvement in Daily Activity - Area Under the Curve (Phase I)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7*average acceleromtery units/day during 30 mg) + (7*average acceleromtery units/day during 60 mg) + (14*average acceleromtery units/day during 120 mg))/28	3-6 weeks
Improvement in Daily Activity - Area Under the Curve (Phase II)	To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by Area under the curve (AUC) of arbitrary accelerometry units during study drug administration. An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based on patient movement. Higher values indicate more movement. 0 indicates no movement. Area under the curve is defined as ((7*average acceleromtery units/day during 30 mg) + (7*average acceleromtery units/day during 60 mg) + (14*average acceleromtery units/day during 120 mg))/28	9-12 weeks

Collaborators and Investigators

• Sponsor: Adrian Hernandez
• Collaborators: Mayo Clinic; National Heart, Lung, and Blood Institute (NHLBI); University of Vermont
• Investigators: Principal Investigator: Kevin Anstrom, PhD, Duke Clinical Research Institute

Publications and helpful links

General Publications

• Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.
• Snipelisky D, Kelly J, Levine JA, Koepp GA, Anstrom KJ, McNulty SE, Zakeri R, Felker GM, Hernandez AF, Braunwald E, Redfield MM. Accelerometer-Measured Daily Activity in Heart Failure With Preserved Ejection Fraction: Clinical Correlates and Association With Standard Heart Failure Severity Indices. Circ Heart Fail. 2017 Jun;10(6):e003878. doi: 10.1161/CIRCHEARTFAILURE.117.003878.
• Redfield MM, Anstrom KJ, Levine JA, Koepp GA, Borlaug BA, Chen HH, LeWinter MM, Joseph SM, Shah SJ, Semigran MJ, Felker GM, Cole RT, Reeves GR, Tedford RJ, Tang WH, McNulty SE, Velazquez EJ, Shah MR, Braunwald E; NHLBI Heart Failure Clinical Research Network. Isosorbide Mononitrate in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2015 Dec 10;373(24):2314-24. doi: 10.1056/NEJMoa1510774. Epub 2015 Nov 8.

Study record dates

Study Major Dates

• Study Start: April 1, 2014
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: January 3, 2014
• First Submitted That Met QC Criteria: January 31, 2014
• First Posted (Estimate): February 3, 2014

Study Record Updates

• Last Update Posted (Estimate): November 28, 2016
• Last Update Submitted That Met QC Criteria: October 7, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: Heart Failure; Preserved Ejection Fraction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Natriuretic Agents; Diuretics, Osmotic; Diuretics; Nitric Oxide Donors; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate
• Other Study ID Numbers: Pro00050042; 4U10HL084904-10 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: After the study results have been published, site-specific participant data will be shared with sites upon request. Sites are expected to follow their specific institutional policies regarding sharing results with their participants.