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

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02053493

Acronym

NEAT-HFpeF

Enrollment

110

Registered

2014-02-03

Start date

2014-04-30

Completion date

2015-03-31

Last updated

2016-11-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Heart Failure

Keywords

Heart Failure, 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.

Interventions

DRUGIsosorbide 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

DRUGPlacebo

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 design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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.
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

Measure	Time frame	Description
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.
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.
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.
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).
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.
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
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.
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
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
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.
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.
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
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
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
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.

Countries

United States

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 details

All subjects who fulfill all the inclusion criteria and none of the exclusion criteria will undergo the baseline studies and then be randomized.

Participants by arm

Arm	Count
Isosorbide Mononitrate Crossover to Placebo 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	51
Placebo Crossover to Isosorbide Mononitrate 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	59
Total	110

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	1	1

Baseline characteristics

Characteristic	Isosorbide Mononitrate Crossover to Placebo	Placebo Crossover to Isosorbide Mononitrate	Total
Age, Continuous	69.8 years STANDARD_DEVIATION 8.7	68.8 years STANDARD_DEVIATION 9.7	69.3 years STANDARD_DEVIATION 9.3
Region of Enrollment United States	51 participants	59 participants	110 participants
Sex: Female, Male Female	25 Participants	38 Participants	63 Participants
Sex: Female, Male Male	26 Participants	21 Participants	47 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	0 / 0	0 / 0
serious Total, serious adverse events	2 / 51	1 / 59

Outcome results

Primary

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.

Time frame: 5-6 weeks