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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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:
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
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
Hide 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
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001 Total
Hide 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
Hide 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%
1.Primary Outcome
Title Peak VO2
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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)
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide Description To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
Time Frame End of Phase 1 & End of Phase 2
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide Description To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
Time Frame End of Phase 1 & End of Phase 2
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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)
Hide Description Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
Time Frame End of Phase 1 & End of Phase 2
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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%
Hide 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
Hide Description Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
Time Frame End of Phase 2
Hide Outcome Measure Data
Hide Analysis Population Description
All randomized patients with available data.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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
Hide 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
Hide Outcome Measure Data
Hide Analysis Population Description
All patients randomized.
Arm/Group Title AIR001 Crossover to Placebo Placebo Crossover to AIR001
Hide 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)
Hide 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]
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
Hide 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%) 
Hide 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
Hide 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
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
Layout table for Results Point of Contact information
Name/Title: Adrian Hernandez
Organization: Duke Clinical Research Institute
Phone: 919-668-7515
EMail: Adrian.Hernandez@duke.edu
Layout table for additonal information
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