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

Heart Failure Clinical Trial

— NEAT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02053493
• Other study ID #: Pro00050042
• Status: Completed
• Phase: Phase 2
• First received: January 3, 2014
• Last updated: April 22, 2015
• Start date: April 2014
• Est. completion date: March 2015

Study information

• Verified date: April 2015
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: NIH Data and Safety Monitoring BoardUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 110
• Est. completion date: March 2015
• Est. primary completion date: February 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Failure
• Preserved Ejection Fraction

Intervention

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
• 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

Locations

Country	Name	City	State
United States	Emory University School of Medicine	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	The University of Vermont - Fletcher Allen Health Care	Burlington	Vermont
United States	Northwestern University	Chicago	Illinois
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Metro Health System	Cleveland	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Durham V.A. Medical Center	Durham	North Carolina
United States	Michael E Debakey VA Medical Center	Houston	Texas
United States	Lancaster General Hospital	Lancaster	Pennsylvania
United States	Christiana Care Health Services	Newark	Delaware
United States	Jefferson Medical College	Philadelphia	Pennsylvania
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	University of Pennsylvania Health System	Philadelphia	Pennsylvania
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Utah Hospitals and Clinics	Salt Lake City	Utah
United States	V.A. Medical Center	Salt Lake CIty	Utah
United States	Washington University School of Medicine	St Louis	Missouri
United States	Boston V.A. Healthcare System	West Roxbury	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Duke University

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in arbitrary accelerometry units	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	12 weeks	No
Secondary	Change in 6 minute walk distance	To evaluate whether isosorbide mononitrate (ISMN) improves functional capacity and quality of life by 6 minute walk distance in comparison to placebo.	Baseline, week 7 , week 13	No
Secondary	Improvement in daily activity	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	12 weeks	No
Secondary	Patient preference for isosorbide mononitrate treatment at the end of study.	Self reported participant preference for study period 1 vs. study period 2.	30 weeks	No
Secondary	Change in Borg Score during 6 minute walk test	To evaluate whether isosorbide mononitrate improves functional capacity and quality of life in comparison to placebo.	Baseline, week 7 and week 14	No
Secondary	Quality of Life score(Kansas City Cardiomyopathy Questionnaire)	To evaluate whether isosorbide mononitrate improves functional capacity and quality of life in comparison to placebo.	Baseline, week 7 and week 14	No
Secondary	Change in N-terminal pro-B-type natriuretic peptide level	To evaluate whether isosorbide mononitrate improves natriuretic peptide levels in comparison to placebo	Baseline, week 7 and week 14	No