Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Screen potential HFpEF patients for eligibility criteria and interest

Study Visit 1

• Initiate consent process and obtain written informed consent.

• Confirm with the participant that HF symptoms are the primary limitation to activity. If so, they proceed to CPET screening. If not, they are considered a screen fail.
• Obtain baseline bloods *- CBC, complete chemistry panel, biomarkers, biorepository and genetics (if agreed to participate) .
• Obtain CPET to verify patient eligibility peak VO2 ≤ 75% predicted and RER ≥ 1.0 (within 3 days prior to randomization) and establish baseline value.
• Qualifying patients perform additional baseline studies: history, assess NYHA class, physical exam, ECG, and KCCQ.
• Open label, single-dose run-in where patient receives maximal dose (80 mg) inhaled inorganic nitrite. Patients who do not tolerate the run-in are considered screen failures.
• Randomize qualifying patients.
• Dispense phase-1 study drug, nebulizers and accelerometers
• Participants take no study drug for two weeks (baseline).
• Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days.
• Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 2 (at least 42 days but up to 49 days post-baseline visit).
• If side effects develop, participants can down-titrate to the previous dose.
• Participants are called frequently to reinforce study procedures and assess compliance.

Study Visit 2 (42-49 Days Post Study Visit 1)

• Participant holds study drug on day of visit.

• Review history, assess NYHA class, perform physical exam and KCCQ.
• Obtain blood draws ** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
• Obtain limited echocardiogram **.
• Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
• Change out accelerometer and dispense phase-2 study drug.
• Participants take no study drug for two weeks (washout).
• Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days.
• Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 3 (at least 42 but up to 49 days after study visit 2).
• If side effects develop Participants can down-titrate to the previously tolerated dose.
• Participants are called frequently to reinforce study procedures and assess compliance.

Study Visit 3 (42-49 Days Post Study Visit 2) • Participant holds study drug on day of visit.

• Review history, assess NYHA class, perform physical exam and KCCQ

• Obtain blood draws** - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate).
• Obtain limited echocardiogram**.
• Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint).
• Return accelerometer and phase-2 study drug.
• End of study drug (phase out).

Phone Visit and End of Study (14 Days Post Study Visit 3)

• A final phone visit is conducted to assess for adverse events.

*Visit 1: baseline blood draw needs to be completed prior to the CPET (if this is not feasible, then they cannot be obtained for at least 3 hours post the CPET and prior to the run-in test dose).

**Visit 2 and Visit 3: blood draws and limited echo need to be obtained prior to study drug administration (if this is not feasible, then it cannot be obtained for at least 3 hours post study drug administration)

Inclusion criteria

• Age ≥ 40 years
• Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea
• 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
• 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
• 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:

• 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

• 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

• Recent (< 1 month) hospitalization for heart failure
• Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators
• Hemoglobin (Hgb) < 8.0 g/dl within 90 days prior to randomization
• GFR < 20 ml/min/1.73 m2 within 90 days prior to randomization
• Systolic blood pressure < 115 mmHg seated or < 90 mmHg standing just prior to test dose
• Resting HR > 110 just prior to test dose
• Previous adverse reaction to the study drug which necessitated withdrawal of therapy
• Significant chronic obstructive pulmonary disease thought to contribute to dyspnea
• Ischemia thought to contribute to dyspnea
• Documentation of previous EF < 45%
• 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)
• PCI, 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
• Regularly (> 1x per week) swims or does water aerobics
• Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months.
• Inability to comply with planned study procedures
• Pregnancy or breastfeeding mothers