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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE January 3, 2014
First Posted Date  ICMJE February 3, 2014
Results First Submitted Date  ICMJE February 4, 2016
Results First Posted Date  ICMJE November 28, 2016
Last Update Posted Date November 28, 2016
Study Start Date  ICMJE April 2014
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 31, 2014)
Change in arbitrary accelerometry units [ Time Frame: 12 weeks ]
To evaluate whether isosorbide mononitrate increases daily activity as assessed by 14-day averaged arbitrary accelerometry units in comparison to placebo. Participants will be assessed at weeks 5-6 and weeks 11-12 Comparison of weeks 5/6 and weeks 11/12
Change History Complete list of historical versions of study NCT02053493 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2016)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: January 31, 2014)
  • Change in 6 minute walk distance [ Time Frame: Baseline, week 7 , week 13 ]
    To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity and quality of life by 6 minute walk distance in comparison to placebo.
  • Improvement in daily activity [ Time Frame: 12 weeks ]
    To evaluate whether isosorbide mononitrate in comparison to placebo improves daily activity as measured by additional accelerometry endpoints:
    • Hours active per day during maximal dose of study drug
    • Slope of daily averaged arbitrary accelerometry units during study drug administration
    • Area under the curve of daily averaged arbitrary accelerometry units during study drug administration
    Participants will be assessed: Hours of activity at weeks 5-6 and 11-12; Slope comparison at weeks 3-6 and 9-12; AUC comparison of weeks 3-6 and 9-12
  • Patient Preference for Isosorbide Mononitrate Treatment at the End of Study. [ Time Frame: 30 weeks ]
    Self reported participant preference for study period 1 vs. study period 2.
  • Change in Borg Score during 6 minute walk test [ Time Frame: Baseline, week 7 and week 14 ]
    To evaluate whether isosorbide mononitrate improves functional capacity and quality of life in comparison to placebo.
  • Quality of Life score(Kansas City Cardiomyopathy Questionnaire) [ Time Frame: Baseline, week 7 and week 14 ]
    To evaluate whether isosorbide mononitrate improves functional capacity and quality of life in comparison to placebo.
  • Change in N-terminal pro-B-type natriuretic peptide level [ Time Frame: Baseline, week 7 and week 14 ]
    To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
Official Title  ICMJE Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction
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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Heart Failure
Intervention  ICMJE
  • 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
  • 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

Study Arms  ICMJE
  • Active Comparator: Isosorbide Mononitrate
    Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks)
    Intervention: Drug: Isosorbide Mononitrate
  • Placebo Comparator: Isosorbide Mononitate Placebo
    Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks)
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 22, 2015)
110
Original Estimated Enrollment  ICMJE
 (submitted: January 31, 2014)
100
Actual Study Completion Date  ICMJE March 2015
Actual Primary Completion Date February 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 50 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02053493
Other Study ID Numbers  ICMJE Pro00050042
4U10HL084904-10 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
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.
Responsible Party Adrian Hernandez, Duke University
Study Sponsor  ICMJE Adrian Hernandez
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Mayo Clinic
  • University of Vermont
Investigators  ICMJE
Principal Investigator: Kevin Anstrom, PhD Duke Clinical Research Institute
Study Chair: Eugene Braunwald, MD Harvard University
PRS Account Duke University
Verification Date October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP