INDIE-HFpEF: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF

• Sponsor: Adrian Hernandez (Other)
• Overall Status: Completed
• CT.gov ID: NCT02742129
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH), Aires Pharmaceuticals, Inc. (Industry), University of Vermont (Other), Université de Montréal (Other), Mayo Clinic (Other), Massachusetts General Hospital (Other)
• Enrollment: 105
• Locations: 20
• Arms: 2
• Actual Duration (Months): 16.6
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure	Drug: Nebulized Sodium Nitrite; Drug: Placebo	Phase 2

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)

Study Design

• Study Type: Interventional
• Actual Enrollment: 105 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF
• Actual Study Start Date: Aug 10, 2016
• Actual Primary Completion Date: Dec 13, 2017
• Actual Study Completion Date: Dec 27, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: 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.; Other Names: AIR001 ; Drug: Placebo; 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.
Placebo Comparator: 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.	Drug: 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.; Other Names: AIR001 ; Drug: Placebo; 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.

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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

7. 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.

8. 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)

9. 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.

10. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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

5. 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

6. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University School of Medicine	Atlanta	Georgia	United States	30322
2	Northwestern University	Chicago	Illinois	United States	60611
3	Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
4	Tufts Medical Center	Boston	Massachusetts	United States	02111
5	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
6	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
7	Boston V.A. Healthcare System	West Roxbury	Massachusetts	United States	02132
8	Mayo Clinic	Rochester	Minnesota	United States	55905
9	University of Missouri Health System	Columbia	Missouri	United States	65212
10	V.A St. Louis Health Care System	Saint Louis	Missouri	United States	63106
11	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
12	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
13	Duke University Medical Center	Durham	North Carolina	United States	27705
14	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
15	Metro Health System	Cleveland	Ohio	United States	44109
16	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
17	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
18	University of Pennsylvania Health System	Philadelphia	Pennsylvania	United States	19104
19	Jefferson Medical College	Philadelphia	Pennsylvania	United States	19107
20	The University of Vermont - Fletcher Allen Health Care	Burlington	Vermont	United States	05401

Sponsors and Collaborators

• Adrian Hernandez
• National Heart, Lung, and Blood Institute (NHLBI)
• Aires Pharmaceuticals, Inc.
• University of Vermont
• Université de Montréal
• Mayo Clinic
• Massachusetts General Hospital

Investigators

• Principal Investigator: Kevin Hernandez, MD, Duke Clinical Research Institute
• Study Chair: Eugene Braunwald, MD, Harvard University

Study Documents (Full-Text)

• Statistical Analysis Plan - Apr 11, 2017
• Study Protocol - Apr 22, 2016

More Information

Publications

None provided.

• Responsible Party: Adrian Hernandez, Professor of Medicine, DUMC; Director, Health Services and Outcomes Research, DCRI, Duke University
• ClinicalTrials.gov Identifier: NCT02742129
• Other Study ID Numbers: Pro00071526; 5U10HL084904
• First Posted: Apr 18, 2016
• Last Update Posted: Mar 13, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Heart Failure

Study Results

Participant Flow

Recruitment Details	Patients with a diagnosis of HFpEF are screened for entry criteria. Willing participants meeting entry criteria will be consented and questioned to confirm that HF symptoms are the primary limitation to activity.
Pre-assignment Detail	All consented participants continuing to meet the screening criteria will undergo a baseline HFN study-specific CPET to confirm Peak VO2 ≤75% with peak respiratory exchange ratio ≥ 1.0. All subjects that fulfill the CPET and other inclusion criteria and none of the exclusion criteria will be randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Period Title: Phase 1
STARTED	53	52
COMPLETED	51	50
NOT COMPLETED	2	2
Period Title: Phase 1
STARTED	51	50
COMPLETED	50	48
NOT COMPLETED	1	2

Baseline Characteristics

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001	Total
Arm/Group Description	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	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	Total of all reporting groups
Overall Participants	53	52	105
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.8 (8.5)	67.5 (11.6)	67.7 (10.1)
Sex: Female, Male (Count of Participants)
Female	36 67.9%	23 44.2%	59 56.2%
Male	17 32.1%	29 55.8%	46 43.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 1.9%	1 1%
Not Hispanic or Latino	53 100%	51 98.1%	104 99%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	6 11.3%	7 13.5%	13 12.4%
White	47 88.7%	45 86.5%	92 87.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Peak VO2
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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	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
Measure Participants	53	52
Phase 1	13.4 (3.2)	13.8 (3.8)
Phase 2	13.7 (3.0)	13.6 (3.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.2650
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Average Arbitrary Accelerometer Units (AAU)
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	5692 (2886)	5341 (3115)
Phase 2	5688 (2950)	5289 (2976)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data
	Type of Statistical Test	Superiority
	Comments	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
Statistical Test of Hypothesis	p-Value	0.9069
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.68
	Confidence Interval	(2-Sided) 95%; -263.65 to 234.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Medial E/e' Ratio as Measured by Echocardiography Core Lab
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	15.4 (8.3)	18.3 (11.8)
Phase 2	15.0 (7.3)	17.4 (11.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.9338
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -1.16 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Left Atrial Volume Index as Measured by Echocardiography
Description	To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	36.3 (16.5)	40.1 (20.6)
Phase 2	37.2 (13.9)	39.1 (20.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.8151
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -2.79 to 2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Pulmonary Artery Systolic Pressure as Measured by Echocardiography
Description	To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	38.2 (9.7)	39.6 (13.5)
Phase 2	35.0 (7.3)	37.3 (9.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.4658
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -1.41 to 3.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	65.6 (18.8)	59.8 (18.4)
Phase 2	64.1 (18.4)	59.4 (21.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.3902
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; -1.37 to 3.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)
Description	Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	494.8 (542.3)	550.4 (746.5)
Phase 2	513.9 (606.0)	545.2 (784.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.7404
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.69
	Confidence Interval	(2-Sided) 95%; -53.21 to 74.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	NYHA (New York Heart Association) Class
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
I	1 1.9%	0 0%
II	21 39.6%	29 55.8%
III	26 49.1%	20 38.5%
IV	1 1.9%	0 0%
I	0 0%	1 1.9%
II	24 45.3%	22 42.3%
III	24 45.3%	25 48.1%
IV	1 1.9%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.4282
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Patient Preference for AIR001 Treatment at the End of Study
Description	Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
Time Frame	End of Phase 2

Outcome Measure Data

Analysis Population Description

All randomized patients with available data.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	48	47
Phase 1 Patient Felt Better	23 43.4%	15 28.8%
Phase 2 Patient Felt Better	17 32.1%	20 38.5%
No Preference	8 15.1%	12 23.1%

10. Secondary Outcome

Title	VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	31.8 (5.7)	33.9 (6.9)
Phase 2	32.1 (6.0)	33.6 (7.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.1067
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -1.08 to 0.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab
Description	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.
Time Frame	End of Phase 1 & End of Phase 2

Outcome Measure Data

Analysis Population Description

All patients randomized.

Arm/Group Title	AIR001 Crossover to Placebo	Placebo Crossover to AIR001
Arm/Group Description	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.	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.
Measure Participants	53	52
Phase 1	7.8 (1.6)	8.0 (1.9)
Phase 2	7.9 (1.6)	7.8 (1.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	AIR001 Crossover to Placebo, Placebo Crossover to AIR001
	Comments	The mixed models used to generate the p-values included all patients, including those with incomplete data.
	Type of Statistical Test	Superiority
	Comments	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.
Statistical Test of Hypothesis	p-Value	0.4411
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Consent to 2 weeks post end of Phase 2
Adverse Event Reporting Description	Per protocol, all AEs/SAEs were collected except for anticipated, disease-related events in patients with HF with preserved EF. If a patient stopped participation in the study for any reason prior to the beginning of a study phase, that patient would not be included in the denominator for the treatment received in the period that was missed.
Arm/Group Title	AIR001		Placebo
Arm/Group Description	Time period in which patient received AIR001 plus 2 weeks regardless of study phase.		Time period in which patient received placebo plus 2 weeks regardless of study phase.
All Cause Mortality
	AIR001		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/103 (1%)		0/102 (0%)
Serious Adverse Events
	AIR001		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/103 (4.9%)		4/102 (3.9%)
Gastrointestinal disorders
Crohn's Disease	1/103 (1%)		0/102 (0%)
General disorders
Chest Pain	1/103 (1%)		0/102 (0%)
Sudden Death	1/103 (1%)		0/102 (0%)
Infections and infestations
Pneumonia	0/103 (0%)		2/102 (2%)
Sepsis	0/103 (0%)		1/102 (1%)
Staphylococcal bacteraemia	0/103 (0%)		1/102 (1%)
Injury, poisoning and procedural complications
Foreign body in gastrointestinal tract	1/103 (1%)		0/102 (0%)
Fall	0/103 (0%)		1/102 (1%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/103 (1%)		0/102 (0%)
Hypoglycaemia	1/103 (1%)		0/102 (0%)
Nervous system disorders
Syncope	0/103 (0%)		1/102 (1%)
Other (Not Including Serious) Adverse Events
	AIR001		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/103 (76.7%)		51/102 (50%)
Gastrointestinal disorders
Nausea	6/103 (5.8%)		1/102 (1%)
General disorders
Fatigue	6/103 (5.8%)		3/102 (2.9%)
Chest discomfort	3/103 (2.9%)		4/102 (3.9%)
Infections and infestations
Upper respiratory tract infection	5/103 (4.9%)		3/102 (2.9%)
Nervous system disorders
Dizziness	17/103 (16.5%)		19/102 (18.6%)
Headache	7/103 (6.8%)		9/102 (8.8%)
Respiratory, thoracic and mediastinal disorders
Cough	30/103 (29.1%)		10/102 (9.8%)
dsypnoea	11/103 (10.7%)		4/102 (3.9%)
Productive Cough	9/103 (8.7%)		0/102 (0%)
Throat irritation	10/103 (9.7%)		1/102 (1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.