Inorganic Nitrite Delivery to Improve Exercise Capacity i... | NCT02742129

ID	Type	Description	Link
5U10HL084904	U.S. NIH Grant/Contract		View source

Status Module

Name	Class
National Heart, Lung, and Blood Institute (NHLBI)	NIH
Aires Pharmaceuticals, Inc.	INDUSTRY
University of Vermont	OTHER
Université de Montréal

Description Module

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)

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
AIR001 Crossover to Placebo	Experimental	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 Drug: Placebo
Placebo crossover to AIR001	Placebo Comparator	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 Drug: Placebo

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Nebulized Sodium Nitrite	Drug	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.

Outcomes Module

Primary Outcomes

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 Outcomes

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.

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Kevin Hernandez, MD	Duke Clinical Research Institute	Principal Investigator
Eugene Braunwald, MD	Harvard University	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Emory University School of Medicine		Atlanta	Georgia	30322	United States
Northwestern University

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
32150314	Derived	Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF, Dunlay S, McNulty S, Chakraborty H, Stevenson LW, Redfield MM, Borlaug BA. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020 Jun;22(6):1009-1018. doi: 10.1002/ejhf.1788. Epub 2020 Mar 9.
30398602	Derived	Borlaug BA, Anstrom KJ, Lewis GD, Shah SJ, Levine JA, Koepp GA, Givertz MM, Felker GM, LeWinter MM, Mann DL, Margulies KB, Smith AL, Tang WHW, Whellan DJ, Chen HH, Davila-Roman VG, McNulty S, Desvigne-Nickens P, Hernandez AF, Braunwald E, Redfield MM; National Heart, Lung, and Blood Institute Heart Failure Clinical Research Network. Effect of Inorganic Nitrite vs Placebo on Exercise Capacity Among Patients With Heart Failure With Preserved Ejection Fraction: The INDIE-HFpEF Randomized Clinical Trial. JAMA. 2018 Nov 6;320(17):1764-1773. doi: 10.1001/jama.2018.14852.

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	AIR001 Crossover to 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
SAP	No	Yes	No	Statistical Analysis Plan	Apr 11, 2017	Dec 6, 2018

Arm/Group Information

ID	Title	Description
BG000	AIR001 Crossover to 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. Nebulized Sodium Nitrite: 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. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally to
BG001	Placebo Crossover to AIR001	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. Nebulized Sodium Nitrite: 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. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally
BG002	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

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.

All patients randomized.

Posted

Mean

Standard Deviation

ml/kg/min

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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. Nebulized Sodium Nitrite: 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. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally to
OG001	Placebo Crossover to AIR001	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. Nebulized Sodium Nitrite: 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. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally

Units	Counts
Participants	OG00053 OG00152

Title

Denominators

Categories

Phase 1

- ParticipantsOG00049
- ParticipantsOG00148

Title	Measurements
	OG00013.4± 3.2

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	The mixed models used to generate the p-values included all patients, including those with incomplete data.	Mixed Models Analysis		0.2650		Mean Difference (Final Values)	-0.20			2-Sided	95	-0.56	0.16					Superiority	The statistical analysis compared the patient level data collected during the AIR001 period to the data collected during the placebo period. The Outcome Measure data is displaying the data as collected during each study phase and is combined together based upon expected treatment assignment for analysis.

Secondary

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.

All patients randomized.

Posted

Mean

Standard Deviation

accelerometry units

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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 (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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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.

All patients randomized.

Posted

Mean

Standard Deviation

ratio

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

Left Atrial Volume Index as Measured by Echocardiography

To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.

All patients randomized.

Posted

Mean

Standard Deviation

ml/m^2

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

Pulmonary Artery Systolic Pressure as Measured by Echocardiography

To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.

All patients randomized.

Posted

Mean

Standard Deviation

mmHg

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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.

All patients randomized.

Posted

Mean

Standard Deviation

units on a scale

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001

Secondary

N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)

Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo

All patients randomized.

Posted

Mean

Standard Deviation

pg/mL

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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.

All patients randomized.

Posted

Count of Participants

Participants

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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)

All randomized patients with available data.

Posted

Count of Participants

Participants

End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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.

All patients randomized.

Posted

Mean

Standard Deviation

unitless

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Secondary

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.

All patients randomized.

Posted

Mean

Standard Deviation

ml/min

End of Phase 1 & End of Phase 2

ID	Title	Description
OG000	AIR001 Crossover to 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.
OG001	Placebo Crossover to AIR001	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.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Crohn's Disease	Gastrointestinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Chest Pain	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Sudden Death	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Foreign body in gastrointestinal tract	Injury, poisoning and procedural complications	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Diabetic ketoacidosis	Metabolism and nutrition disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0001 affected103 at risk EG0010 affected102 at risk
Pneumonia	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG0000 affected103 at risk EG0012 affected102 at risk
Sepsis	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG0000 affected103 at risk EG0011 affected102 at risk
Staphylococcal bacteraemia	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG0000 affected103 at risk EG0011 affected102 at risk
Fall	Injury, poisoning and procedural complications	MedDRA (Unspecified)	Non-systematic Assessment	EG0000 affected103 at risk EG0011 affected102 at risk
Syncope	Nervous system disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0000 affected103 at risk EG0011 affected102 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0006 affected103 at risk EG0011 affected102 at risk
Fatigue	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0006 affected103 at risk EG0013 affected102 at risk
Dizziness	Nervous system disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00017 affected103 at risk EG00119 affected102 at risk
Headache	Nervous system disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0007 affected103 at risk EG0019 affected102 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00030 affected103 at risk EG00110 affected102 at risk
dsypnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00011 affected103 at risk EG0014 affected102 at risk
Productive Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0009 affected103 at risk EG0010 affected102 at risk
Throat irritation	Respiratory, thoracic and mediastinal disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG00010 affected103 at risk EG0011 affected102 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA (Unspecified)	Non-systematic Assessment	EG0005 affected103 at risk EG0013 affected102 at risk
Chest discomfort	General disorders	MedDRA (Unspecified)	Non-systematic Assessment	EG0003 affected103 at risk EG0014 affected102 at risk

ID	Term
D006331	Heart Diseases
D002318	Cardiovascular Diseases

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	AIR001	Time period in which patient received AIR001 plus 2 weeks regardless of study phase.	1	103	5	103	79	103
EG001	Placebo	Time period in which patient received placebo plus 2 weeks regardless of study phase.	0	102	4	102	51	102