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

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ClinicalTrials.gov Identifier: NCT02053493
Recruitment Status : Completed
First Posted : February 3, 2014
Results First Posted : November 28, 2016
Last Update Posted : November 28, 2016
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
University of Vermont
Information provided by (Responsible Party):
Adrian Hernandez, Duke University

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Isosorbide Mononitrate Drug: Placebo Phase 2

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
Study Start Date : April 2014
Actual Primary Completion Date : February 2015
Actual Study Completion Date : March 2015

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

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 Name: 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





Primary Outcome Measures :
  1. Arbitrary Accelerometry Units (AAU) (Phase I) [ Time Frame: 5-6 weeks ]
    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.

  2. Arbitrary Accelerometry Units (AAU) (Phase II) [ Time Frame: 11-12 weeks ]
    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.


Secondary Outcome Measures :
  1. Six Minute Walk Distance (Phase I) [ Time Frame: Week 7 ]
    To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.

  2. Six Minute Walk Distance (Phase II) [ Time Frame: Week 13 ]
    To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.

  3. Patient Preference for Isosorbide Mononitrate Treatment at the End of Study. [ Time Frame: Week 13 ]
    Self reported participant preference for study period 1 vs. study period 2.

  4. Borg Score During 6 Minute Walk Test (Phase I) [ Time Frame: Week 7 ]
    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.

  5. Borg Score During 6 Minute Walk Test (Phase II) [ Time Frame: Week 13 ]
    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.

  6. Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I) [ Time Frame: Week 7 ]
    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).

  7. Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II) [ Time Frame: Week 13 ]
    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.

  8. N-terminal Pro-B-type Natriuretic Peptide Level (Phase I) [ Time Frame: Week 7 ]
    To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo

  9. N-terminal Pro-B-type Natriuretic Peptide Level (Phase II) [ Time Frame: Week 13 ]
    To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo

  10. Improvement in Daily Activity - Hours Active Per Day (Phase I) [ Time Frame: 5-6 weeks ]
    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. Improvement in Daily Activity - Hours Active Per Day (Phase II) [ Time Frame: 11-12 weeks ]
    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

  12. Improvement in Daily Activity - Slope of Daily Average (Phase I) [ Time Frame: 3-6 weeks ]
    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.

  13. Improvement in Daily Activity - Slope of Daily Average (Phase II) [ Time Frame: 9-12 weeks ]
    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.

  14. Improvement in Daily Activity - Area Under the Curve (Phase I) [ Time Frame: 3-6 weeks ]
    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

  15. Improvement in Daily Activity - Area Under the Curve (Phase II) [ Time Frame: 9-12 weeks ]
    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



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Ages Eligible for Study:   50 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02053493


Locations
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United States, Delaware
Christiana Care Health Services
Newark, Delaware, United States, 19718
United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Maryland
Johns Hopkins Hospital
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Brigham and Women's Hospital
Boston, Massachusetts, United States, 02115
Boston V.A. Healthcare System
West Roxbury, Massachusetts, United States, 02132
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, Missouri
Washington University School of Medicine
St Louis, Missouri, United States, 63110
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27705
United States, Ohio
University Hospitals Case Medical Center
Cleveland, Ohio, United States, 44106
Metro Health System
Cleveland, Ohio, United States, 44109
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
Lancaster General Hospital
Lancaster, Pennsylvania, United States, 17604
University of Pennsylvania Health System
Philadelphia, Pennsylvania, United States, 19104
Jefferson Medical College
Philadelphia, Pennsylvania, United States, 19107
Temple University Hospital
Philadelphia, Pennsylvania, United States, 19140
United States, Texas
Michael E Debakey VA Medical Center
Houston, Texas, United States, 77030
United States, Utah
University of Utah Hospitals and Clinics
Salt Lake City, Utah, United States, 84132
V.A. Medical Center
Salt Lake CIty, Utah, United States, 84148
United States, Vermont
The University of Vermont - Fletcher Allen Health Care
Burlington, Vermont, United States, 05401
Sponsors and Collaborators
Adrian Hernandez
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
University of Vermont
Investigators
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Principal Investigator: Kevin Anstrom, PhD Duke Clinical Research Institute
Study Chair: Eugene Braunwald, MD Harvard University

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Adrian Hernandez, Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI, Duke University
ClinicalTrials.gov Identifier: NCT02053493     History of Changes
Other Study ID Numbers: Pro00050042
4U10HL084904-10 ( U.S. NIH Grant/Contract )
First Posted: February 3, 2014    Key Record Dates
Results First Posted: November 28, 2016
Last Update Posted: November 28, 2016
Last Verified: October 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Keywords provided by Adrian Hernandez, Duke University:
Heart Failure
Preserved Ejection Fraction
Additional relevant MeSH terms:
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Heart Failure
Heart Diseases
Cardiovascular Diseases
Isosorbide
Isosorbide Dinitrate
Isosorbide-5-mononitrate
Diuretics, Osmotic
Diuretics
Natriuretic Agents
Physiological Effects of Drugs
Vasodilator Agents
Nitric Oxide Donors
Molecular Mechanisms of Pharmacological Action