Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction

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

Official Title
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Nitrate's Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Isosorbide Mononitrate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 50 years Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea 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 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% 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 No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months Ambulatory (not wheelchair / scooter / walker / cane dependent) 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: Joint, foot, leg, hip or back pain Shortness of breath and/or fatigue and/or chest pain Unsteadiness or dizziness 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: Recent (< 3 months) hospitalization for HF Hemoglobin < 8.0 g/dl Glomerular filtration rate < 20 ml/min/1.73 m2 on most recent clinical laboratories SBP < 110 mmHg or > 180 mmHg at consent Diastolic blood pressure < 40 mmHg or > 100 mmHg at consent Resting HR > 110 bpm at consent Previous adverse reaction to nitrates necessitating withdrawal of therapy 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) Regularly (> 1x per week) swims or does water aerobics Significant COPD thought to contribute to dyspnea Ischemia thought to contribute to dyspnea Documentation of previous EF < 50% 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) Percutaneous coronary intervention, coronary artery bypass grafting or new biventricular pacing within past 3 months Primary hypertrophic cardiomyopathy Infiltrative cardiomyopathy (amyloid) Constrictive pericarditis or tamponade Active myocarditis Complex congenital heart disease Active collagen vascular disease More than mild aortic or mitral stenosis Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation 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 Terminal illness (other than HF) with expected survival of less than 1 year Enrollment or planned enrollment in another therapeutic clinical trial in the next 3 months Inability to comply with planned study procedures Pregnant women

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Isosorbide Mononitrate<br>Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) | Drug: Isosorbide Mononitrate<br>* 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<br>* Other names: Imdur, ISMO, Monoket;|
| Placebo Comparator: Isosorbide Mononitate Placebo<br>Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) | Drug: Placebo<br>* 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<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure, Preserved Ejection Fraction