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

• Sponsor: Adrian Hernandez (Other)
• Overall Status: Completed
• CT.gov ID: NCT02053493
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Mayo Clinic (Other), University of Vermont (Other)
• Enrollment: 110
• Locations: 22
• Arms: 2
• Duration (Months): 11
• Patients Per Site: 5
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Apr 1, 2014
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: Mar 1, 2015

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Arbitrary Accelerometry Units (AAU) (Phase I) [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) [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) [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) [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. [Week 13]

   Self reported participant preference for study period 1 vs. study period 2.

4. Borg Score During 6 Minute Walk Test (Phase I) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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) [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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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%

1. 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

1. No chronic nitrate therapy or infrequent (≤ 1x week) use of intermittent sublingual nitroglycerin within last 3 months

2. Ambulatory (not wheelchair / scooter / walker / cane dependent)

3. 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

5. 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)

6. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Christiana Care Health Services	Newark	Delaware	United States	19718
2	Emory University School of Medicine	Atlanta	Georgia	United States	30322
3	Northwestern University	Chicago	Illinois	United States	60611
4	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
5	Tufts Medical Center	Boston	Massachusetts	United States	02111
6	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
7	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
8	Boston V.A. Healthcare System	West Roxbury	Massachusetts	United States	02132
9	Mayo Clinic	Rochester	Minnesota	United States	55905
10	Washington University School of Medicine	St Louis	Missouri	United States	63110
11	Duke University Medical Center	Durham	North Carolina	United States	27705
12	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
13	Metro Health System	Cleveland	Ohio	United States	44109
14	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
15	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17604
16	University of Pennsylvania Health System	Philadelphia	Pennsylvania	United States	19104
17	Jefferson Medical College	Philadelphia	Pennsylvania	United States	19107
18	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
19	Michael E Debakey VA Medical Center	Houston	Texas	United States	77030
20	University of Utah Hospitals and Clinics	Salt Lake City	Utah	United States	84132
21	V.A. Medical Center	Salt Lake CIty	Utah	United States	84148
22	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

• Principal Investigator: Kevin Anstrom, PhD, Duke Clinical Research Institute
• Study Chair: Eugene Braunwald, MD, Harvard University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Adrian Hernandez, Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI, Duke University
• ClinicalTrials.gov Identifier: NCT02053493
• Other Study ID Numbers: Pro00050042; 4U10HL084904-10
• First Posted: Feb 3, 2014
• Last Update Posted: Nov 28, 2016
• Last Verified: Oct 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Adrian Hernandez, Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI, Duke University: Heart Failure; Preserved Ejection Fraction
• Additional relevant MeSH terms: Heart Failure; Isosorbide; Isosorbide Dinitrate; Isosorbide-5-mononitrate

Study Results

Participant Flow

Recruitment Details	All patients admitted to the participating HFN centers with signs and symptoms suggestive of HFpEF will be screened including their ability to wear the accelerometer belt. Patients meeting eligibility criteria will be approached regarding participation in this study.
Pre-assignment Detail	All subjects who fulfill all the inclusion criteria and none of the exclusion criteria will undergo the baseline studies and then be randomized.

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Period Title: Overall Study
STARTED	51	59
COMPLETED	50	58
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate	Total
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Total of all reporting groups
Overall Participants	51	59	110
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.8 (8.7)	68.8 (9.7)	69.3 (9.3)
Sex: Female, Male (Count of Participants)
Female	25 49%	38 64.4%	63 57.3%
Male	26 51%	21 35.6%	47 42.7%
Region of Enrollment (participants) [Number]
United States	51 100%	59 100%	110 100%

Outcome Measures

1. Primary Outcome

Title	Arbitrary Accelerometry Units (AAU) (Phase I)
Description	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.
Time Frame	5-6 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	45	56
Mean (Standard Deviation) [accelerometry units]	9370 (4601)	9538 (6286)

2. Secondary Outcome

Title	Six Minute Walk Distance (Phase I)
Description	To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity by 6 minute walk distance in comparison to placebo.
Time Frame	Week 7

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	49	57
Mean (Standard Deviation) [meters]	307.8 (125.5)	327.1 (126.0)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	47	57
Mean (Standard Deviation) [meters]	321.3 (132.4)	329.7 (132.1)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	48	57
Phase1	14 27.5%	14 23.7%
Phase2	18 35.3%	24 40.7%
No Preference	16 31.4%	19 32.2%

5. Secondary Outcome

Title	Borg Score During 6 Minute Walk Test (Phase I)
Description	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.
Time Frame	Week 7

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	44	52
Mean (Standard Deviation) [units on a scale]	4.1 (2.6)	4.0 (2.2)

6. Secondary Outcome

Title	Borg Score During 6 Minute Walk Test (Phase II)
Description	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.
Time Frame	Week 13

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	40	49
Mean (Standard Deviation) [units on a scale]	3.8 (2.3)	3.8 (2.0)

7. Secondary Outcome

Title	Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase I)
Description	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).
Time Frame	Week 7

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	50	58
Mean (Standard Deviation) [units on a scale]	57.3 (23.4)	64.2 (24.2)

8. Secondary Outcome

Title	Kansas City Cardiomyopathy Questionnaire Overall Summary Score (Phase II)
Description	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.
Time Frame	Week 13

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	49	58
Mean (Standard Deviation) [units on a scale]	59.1 (23.6)	61.6 (23.5)

9. Primary Outcome

Title	Arbitrary Accelerometry Units (AAU) (Phase II)
Description	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.
Time Frame	11-12 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	42	49
Mean (Standard Deviation) [accelerometry units]	8824 (3877)	8900 (5457)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	49	57
Mean (Standard Deviation) [pg/mL]	513.0 (803.2)	542.4 (710.9)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	47	54
Mean (Standard Deviation) [pg/mL]	466.1 (677.4)	573.3 (756.1)

12. Secondary Outcome

Title	Improvement in Daily Activity - Hours Active Per Day (Phase I)
Description	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
Time Frame	5-6 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	45	56
Mean (Standard Deviation) [Hours/day]	9.4 (2.4)	9.1 (2.4)

13. Secondary Outcome

Title	Improvement in Daily Activity - Hours Active Per Day (Phase II)
Description	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
Time Frame	11-12 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	42	49
Mean (Standard Deviation) [Hours/day]	9.4 (2.4)	8.8 (2.5)

14. Secondary Outcome

Title	Improvement in Daily Activity - Slope of Daily Average (Phase I)
Description	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.
Time Frame	3-6 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	47	58
Mean (Standard Deviation) [accelerometry units/day]	-3.4 (23.1)	-1.3 (26.9)

15. Secondary Outcome

Title	Improvement in Daily Activity - Slope of Daily Average (Phase II)
Description	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.
Time Frame	9-12 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	42	53
Mean (Standard Deviation) [accelerometry units/day]	2.6 (20.1)	-3.9 (16.4)

16. Secondary Outcome

Title	Improvement in Daily Activity - Area Under the Curve (Phase I)
Description	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
Time Frame	3-6 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	39	54
Mean (Standard Deviation) [accelerometry units]	9621.4 (4367.8)	9714.0 (6273.6)

17. Secondary Outcome

Title	Improvement in Daily Activity - Area Under the Curve (Phase II)
Description	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
Time Frame	9-12 weeks

Outcome Measure Data

Analysis Population Description

Participants with usable data included in the results

Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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	Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
Measure Participants	38	44
Mean (Standard Deviation) [accelerometry units]	9146.5 (3695.3)	9325.9 (5668.2)

Adverse Events

Time Frame	Informed Consent through Week 15 phone visit
Adverse Event Reporting Description	Per protocol, non-serious AEs were not collected; all SAEs were collected except for anticipated, disease-related events in patients with HF with preserved EF. 3 time points summarized: Informed Consent to start of Phase 1 study drug, Phase 1 study drug start to start of Phase 2 study drug, Phase 2 study drug start to Week 15 phone call.
Arm/Group Title	Isosorbide Mononitrate Crossover to Placebo		Placebo Crossover to Isosorbide Mononitrate
Arm/Group Description	Isosorbide Mononitrate with dose up-titration (30 to 120 mg/day over 4 weeks) 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		Isosorbide Mononitrate placebo with dose up-titration (30 to 120 mg/day over 4 weeks) 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
All Cause Mortality
	Isosorbide Mononitrate Crossover to Placebo		Placebo Crossover to Isosorbide Mononitrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Isosorbide Mononitrate Crossover to Placebo		Placebo Crossover to Isosorbide Mononitrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/51 (3.9%)		1/59 (1.7%)
Gastrointestinal disorders
Faecaloma	1/51 (2%)	1	0/59 (0%)	0
Infections and infestations
Cellulitis	1/51 (2%)	1	0/59 (0%)	0
Herpes Zoster	0/51 (0%)	0	1/59 (1.7%)	1
Renal and urinary disorders
Urinary retention	1/51 (2%)	1	0/59 (0%)	0
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	1/51 (2%)	1	0/59 (0%)	0
Other (Not Including Serious) Adverse Events
	Isosorbide Mononitrate Crossover to Placebo		Placebo Crossover to Isosorbide Mononitrate
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.