Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
Condition: Heart Failure
MeSH terms: Heart Failure
Intervention: Nebulized Sodium Nitrite; Placebo
Intervention description: Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.; Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 105.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      A randomized, double-blind, placebo-controlled crossover study to assess the effect of
      inorganic nitrite (NO2) on aerobic capacity (peak VO2) after four weeks of dosing.
      Approximately 100 participants will be enrolled in this 2*2 crossover study.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 40 years

          2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic
             explanation for dyspnea

          3. 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. One of the following :

               -  Previous hospitalization for HF with radiographic evidence (pulmonary venous
                  hypertension, vascular congestion, interstitial edema, pleural effusion) of
                  pulmonary congestion or

               -  Catheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP
                  ≥18) 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 manifest by
                  medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a
                  loop diuretic for signs or symptoms of heart failure

          5. Heart failure is 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

        6. Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for
        Peak VO2* Criteria (ml/kg/min) 7. No chronic nitrate therapy or not using intermittent
        sublingual nitroglycerin (requirement for >1 SL nitroglycerin per week) within last 7 days
        8. No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators
        and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study 9.
        Ambulatory (not wheelchair / scooter dependent) 10. 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) 11. Willingness to wear the accelerometer belt for the
        duration of the trial 12. Willingness to provide informed consent

        Exclusion Criteria:

          1. Recent (< 1 month) hospitalization for heart failure

          2. Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase
             activators

          3. Hemoglobin (Hgb) < 8.0 g/dl within 90 days prior to randomization

          4. GFR < 20 ml/min/1.73 m2 within 90 days prior to randomization

          5. Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test
             dose

          6. Resting HR > 110 just prior to test dose

          7. Previous adverse reaction to the study drug which necessitated withdrawal of therapy

          8. Significant chronic obstructive pulmonary disease thought to contribute to dyspnea

          9. Ischemia thought to contribute to dyspnea

         10. Documentation of previous EF < 45%

         11. Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes
             and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical
             setting (chest discomfort or anginal equivalent)

         12. PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months

         13. Primary hypertrophic cardiomyopathy

         14. Infiltrative cardiomyopathy (amyloid)

         15. Constrictive pericarditis or tamponade

         16. Active myocarditis

         17. Complex congenital heart disease

         18. Active collagen vascular disease

         19. More than mild aortic or mitral stenosis

         20. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe
             mitral, tricuspid or aortic regurgitation

         21. 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

         22. Terminal illness (other than HF) with expected survival of less than 1 year

         23. Regularly (> 1x per week) swims or does water aerobics

         24. Enrollment or planned enrollment in another therapeutic clinical trial in next 3
             months.

         25. Inability to comply with planned study procedures

         26. Pregnancy or breastfeeding mothers