Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF (INDIE-HFpEF)

• ClinicalTrials.gov Identifier: NCT02742129
• Recruitment Status: Completed
• First Posted: April 18, 2016
• Results First Posted: March 13, 2019
• Last Update Posted: March 13, 2019
• Sponsor: Adrian Hernandez
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Aires Pharmaceuticals, Inc.; University of Vermont; Université de Montréal; Mayo Clinic; Massachusetts General Hospital
• Information provided by (Responsible Party): Adrian Hernandez, Duke University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Heart Failure
• Interventions: Drug: Nebulized Sodium Nitrite; Drug: Placebo
• Enrollment: 105

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 Details	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 2
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 Number of Baseline Participants		53	52	105
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	53 participants	52 participants	105 participants
		67.8 (8.5)	67.5 (11.6)	67.7 (10.1)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	52 participants	105 participants
	Female	36 67.9%	23 44.2%	59 56.2%
	Male	17 32.1%	29 55.8%	46 43.8%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	52 participants	105 participants
	Hispanic or Latino	0 0.0%	1 1.9%	1 1.0%
	Not Hispanic or Latino	53 100.0%	51 98.1%	104 99.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	53 participants	52 participants	105 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	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%	0 0.0%
	Unknown or Not Reported	0 0.0%	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
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: ml/kg/min
Phase 1	Number Analyzed	49 participants	48 participants
		13.4 (3.2)	13.8 (3.8)
Phase 2	Number Analyzed	49 participants	45 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.16
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: accelerometry units
Phase 1	Number Analyzed	49 participants	47 participants
		5692 (2886)	5341 (3115)
Phase 2	Number Analyzed	41 participants	46 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.68
	Confidence Interval	(2-Sided) 95%; -263.65 to 234.29
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: ratio
Phase 1	Number Analyzed	46 participants	44 participants
		15.4 (8.3)	18.3 (11.8)
Phase 2	Number Analyzed	47 participants	46 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -1.16 to 1.27
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: ml/m^2
Phase 1	Number Analyzed	44 participants	37 participants
		36.3 (16.5)	40.1 (20.6)
Phase 2	Number Analyzed	40 participants	40 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -2.79 to 2.20
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: mmHg
Phase 1	Number Analyzed	38 participants	36 participants
		38.2 (9.7)	39.6 (13.5)
Phase 2	Number Analyzed	32 participants	38 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -1.41 to 3.05
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: units on a scale
Phase 1	Number Analyzed	50 participants	49 participants
		65.6 (18.8)	59.8 (18.4)
Phase 2	Number Analyzed	49 participants	48 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; -1.37 to 3.49
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: pg/mL
Phase 1	Number Analyzed	48 participants	49 participants
		494.8 (542.3)	550.4 (746.5)
Phase 2	Number Analyzed	47 participants	48 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.69
	Confidence Interval	(2-Sided) 95%; -53.21 to 74.6
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Measure Type: Count of Participants; Unit of Measure: Participants
Phase 1	Number Analyzed	49 participants	49 participants
	I	1 2.0%	0 0.0%
	II	21 42.9%	29 59.2%
	III	26 53.1%	20 40.8%
	IV	1 2.0%	0 0.0%
Phase 2	Number Analyzed	49 participants	48 participants
	I	0 0.0%	1 2.1%
	II	24 49.0%	22 45.8%
	III	24 49.0%	25 52.1%
	IV	1 2.0%	0 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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.18
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed	48	47
Measure Type: Count of Participants; Unit of Measure: Participants
Phase 1 Patient Felt Better	23 47.9%	15 31.9%
Phase 2 Patient Felt Better	17 35.4%	20 42.6%
No Preference	8 16.7%	12 25.5%

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: unitless
Phase 1	Number Analyzed	49 participants	49 participants
		31.8 (5.7)	33.9 (6.9)
Phase 2	Number Analyzed	48 participants	45 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -1.08 to 0.11
	Estimation Comments	[Not Specified]

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.
Overall Number of Participants Analyzed		53	52
Mean (Standard Deviation); Unit of Measure: ml/min
Phase 1	Number Analyzed	47 participants	45 participants
		7.8 (1.6)	8.0 (1.9)
Phase 2	Number Analyzed	47 participants	43 participants
		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	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.16
	Estimation Comments	[Not Specified]

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 (%)	Affected / at Risk (%)
Total	1/103 (0.97%)	0/102 (0.00%)
Serious Adverse Events
	AIR001	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	5/103 (4.85%)	4/102 (3.92%)
Gastrointestinal disorders
Crohn's Disease * 1	1/103 (0.97%)	0/102 (0.00%)
General disorders
Chest Pain * 1	1/103 (0.97%)	0/102 (0.00%)
Sudden Death * 1	1/103 (0.97%)	0/102 (0.00%)
Infections and infestations
Pneumonia * 1	0/103 (0.00%)	2/102 (1.96%)
Sepsis * 1	0/103 (0.00%)	1/102 (0.98%)
Staphylococcal bacteraemia * 1	0/103 (0.00%)	1/102 (0.98%)
Injury, poisoning and procedural complications
Foreign body in gastrointestinal tract * 1	1/103 (0.97%)	0/102 (0.00%)
Fall * 1	0/103 (0.00%)	1/102 (0.98%)
Metabolism and nutrition disorders
Diabetic ketoacidosis * 1	1/103 (0.97%)	0/102 (0.00%)
Hypoglycaemia * 1	1/103 (0.97%)	0/102 (0.00%)
Nervous system disorders
Syncope * 1	0/103 (0.00%)	1/102 (0.98%)
1 Term from vocabulary, MedDRA (Unspecified); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	4%
	AIR001	Placebo
	Affected / at Risk (%)	Affected / at Risk (%)
Total	79/103 (76.70%)	51/102 (50.00%)
Gastrointestinal disorders
Nausea * 1	6/103 (5.83%)	1/102 (0.98%)
General disorders
Fatigue * 1	6/103 (5.83%)	3/102 (2.94%)
Chest discomfort * 1	3/103 (2.91%)	4/102 (3.92%)
Infections and infestations
Upper respiratory tract infection * 1	5/103 (4.85%)	3/102 (2.94%)
Nervous system disorders
Dizziness * 1	17/103 (16.50%)	19/102 (18.63%)
Headache * 1	7/103 (6.80%)	9/102 (8.82%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	30/103 (29.13%)	10/102 (9.80%)
dsypnoea * 1	11/103 (10.68%)	4/102 (3.92%)
Productive Cough * 1	9/103 (8.74%)	0/102 (0.00%)
Throat irritation * 1	10/103 (9.71%)	1/102 (0.98%)
1 Term from vocabulary, MedDRA (Unspecified); * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Adrian Hernandez
• Organization: Duke Clinical Research Institute
• Phone: 919-668-7515
• EMail: Adrian.Hernandez@duke.edu

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

Reddy YNV, Lewis GD, Shah SJ, LeWinter M, Semigran M, Davila-Roman VG, Anstrom K, Hernandez A, Braunwald E, Redfield MM, Borlaug BA. INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in Heart Failure With Preserved Ejection Fraction): Rationale and Design. Circ Heart Fail. 2017 May;10(5). pii: e003862. doi: 10.1161/CIRCHEARTFAILURE.117.003862. Review.

• Responsible Party: Adrian Hernandez, Duke University
• ClinicalTrials.gov Identifier: NCT02742129
• Other Study ID Numbers: Pro00071526; 5U10HL084904 ( U.S. NIH Grant/Contract )
• First Submitted: April 8, 2016
• First Posted: April 18, 2016
• Results First Submitted: December 6, 2018
• Results First Posted: March 13, 2019
• Last Update Posted: March 13, 2019