Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Nebulized Sodium Nitrite
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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 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: 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

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AIR001 Crossover to Placebo<br>Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug Nebulized Sodium Nitrite (AIR001) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Placebo instead of AIR001. | Drug: Nebulized Sodium Nitrite<br>* 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.<br>* Other names: AIR001;Drug: Placebo<br>* 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.<br>|
| Placebo Comparator: Placebo crossover to AIR001<br>Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug (Placebo) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Nebulized Sodium Nitrite (AIR001) instead of Placebo. | Drug: Nebulized Sodium Nitrite<br>* 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.<br>* Other names: AIR001;Drug: Placebo<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak VO2 | The primary endpoint will be the peak VO2 after 4 weeks treatment with inorganic nitrite as compared to the peak VO2 after 4 weeks treatment with placebo as assessed by cardiopulmonary exercise testing (CPET) performed at peak drug levels. | End of Phase 1 & End of Phase 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Arbitrary Accelerometer Units (AAU) | Average arbitrary accelerometer units (AAU) during at least 14 days and up to 21 days of the maximally tolerated dose of study drug (from 28 days post Study Visit 1 until Study Visit 2 and from 28 days post Study Visit 2 until Study Visit 3). An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based upon patient movement. Higher values indicate more movement. Zero indicates no movement. | End of Phase 1 & End of Phase 2 | 
| Medial E/e' Ratio as Measured by Echocardiography Core Lab | To evaluate whether AIR001 improves Medial E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity for diastolic evaluation) in comparison to placebo. | End of Phase 1 & End of Phase 2 | 
| Left Atrial Volume Index as Measured by Echocardiography | To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo. | End of Phase 1 & End of Phase 2 | 
| Pulmonary Artery Systolic Pressure as Measured by Echocardiography | To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo. | End of Phase 1 & End of Phase 2 | 
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | To evaluate whether AR001 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. | End of Phase 1 & End of Phase 2 | 
| N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo | End of Phase 1 & End of Phase 2 | 
| NYHA (New York Heart Association) Class | To evaluate whether AR001 improves NYHA Class in comparison to placebo. NYHA class was measured at the end of each phase. The site physician evaluated the patient based upon the criteria for NYHA class I-IV used by the American Heart Association. NYHA functional classification provides a way of classifying the extent of heart failure. Class I (least severe): No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV (most severe): Unable to carry on any physical activity without discomfort. | End of Phase 1 & End of Phase 2 | 
| Patient Preference for AIR001 Treatment at the End of Study | Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2) | End of Phase 2 | 
| VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of Ve/VCO2 during study drug administration. The Ve/VCO2 slope is defined as the slope of the linear relationship between ventilation and carbon dioxide output and is a measure of the velocity. | End of Phase 1 & End of Phase 2 | 
| VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 (rate of oxygen consumption measured during incremental exercise) at ventilatory threshold during study drug administration. | End of Phase 1 & End of Phase 2 |