Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

Phase 2

Completed

Conditions: Heart Failure

Interventions: Drug: Nebulized Sodium Nitrite
Drug: Placebo

Registration Number: NCT02742129

Lead Sponsor: Adrian Hernandez

Brief 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.

Detailed Description: 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)

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 105

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
AIR001 Crossover to Placebo	Nebulized Sodium Nitrite	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.
Placebo crossover to AIR001	Nebulized Sodium Nitrite	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.
AIR001 Crossover to Placebo	Placebo	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.
Placebo crossover to AIR001	Placebo	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.

Primary Outcome Measures

Name	Time	Method
Peak VO2	End of Phase 1 & End of Phase 2	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.

Secondary Outcome Measures

Name	Time	Method
Average Arbitrary Accelerometer Units (AAU)	End of Phase 1 & End of Phase 2	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.
Medial E/e' Ratio as Measured by Echocardiography Core Lab	End of Phase 1 & End of Phase 2	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.
Left Atrial Volume Index as Measured by Echocardiography	End of Phase 1 & End of Phase 2	To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
Pulmonary Artery Systolic Pressure as Measured by Echocardiography	End of Phase 1 & End of Phase 2	To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score	End of Phase 1 & End of Phase 2	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.
N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)	End of Phase 1 & End of Phase 2	Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
NYHA (New York Heart Association) Class	End of Phase 1 & End of Phase 2	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.
Patient Preference for AIR001 Treatment at the End of Study	End of Phase 2	Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab	End of Phase 1 & End of Phase 2	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.
VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab	End of Phase 1 & End of Phase 2	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.

Trial Locations

Locations (20): Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
Jefferson Medical College
🇺🇸
Philadelphia, Pennsylvania, United States
The University of Vermont - Fletcher Allen Health Care
🇺🇸
Burlington, Vermont, United States
University Hospitals Cleveland Medical Center
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Cleveland, Ohio, United States
Cleveland Clinic Foundation
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Cleveland, Ohio, United States
University of Pennsylvania Health System
🇺🇸
Philadelphia, Pennsylvania, United States
Duke University Medical Center
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Durham, North Carolina, United States
Emory University School of Medicine
🇺🇸
Atlanta, Georgia, United States
Northwestern University
🇺🇸
Chicago, Illinois, United States
Johns Hopkins Hospital
🇺🇸
Baltimore, Maryland, United States
Tufts Medical Center
🇺🇸
Boston, Massachusetts, United States
Brigham and Women's Hospital
🇺🇸
Boston, Massachusetts, United States
Boston V.A. Healthcare System
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West Roxbury, Massachusetts, United States
Abington Memorial Hospital
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Abington, Pennsylvania, United States
Stony Brook University Medical Center
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Stony Brook, New York, United States
University of Missouri Health System
🇺🇸
Columbia, Missouri, United States
Mayo Clinic
🇺🇸
Rochester, Minnesota, United States
Metro Health System
🇺🇸
Cleveland, Ohio, United States
V.A St. Louis Health Care System
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Saint Louis, Missouri, United States
Washington University School of Medicine
🇺🇸
Saint Louis, Missouri, United States