Trial Outcomes & Findings for Inhaled Nitrite in Subjects With Pulmonary Hypertension (NCT NCT01431313)

Results Overview

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

48 participants

Primary outcome timeframe

Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Results posted on

2019-03-28

Participant Flow

Subjects were enrolled in the trial between June 2012 and October 2017.

Participant milestones

Participant milestones
Measure	WHO Group I PAH Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) MPAP ≥ 25 mm Hg, PWCP \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, LVEF ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III PH MPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg, and PVR ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Overall Study STARTED	20	20	8
Overall Study COMPLETED	20	20	8
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Inhaled Nitrite in Subjects With Pulmonary Hypertension

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	WHO Group I PAH n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II PH n=20 Participants MPAP ≥ 25 mm Hg, PWCP \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, LVEF ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III PH n=8 Participants MPAP ≥ 25 mm Hg, PCWP ≤ 15 mm Hg, and PVR ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	Total n=48 Participants Total of all reporting groups
Age, Continuous	56 years STANDARD_DEVIATION 13 • n=5 Participants	70 years STANDARD_DEVIATION 7 • n=7 Participants	68 years STANDARD_DEVIATION 6 • n=5 Participants	64 years STANDARD_DEVIATION 12 • n=4 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	9 Participants n=7 Participants	3 Participants n=5 Participants	25 Participants n=4 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	11 Participants n=7 Participants	5 Participants n=5 Participants	23 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=5 Participants	20 Participants n=7 Participants	7 Participants n=5 Participants	47 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	19 Participants n=5 Participants	20 Participants n=7 Participants	6 Participants n=5 Participants	45 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since pulmonary vascular resistance (PVR) was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of PVR over all subsequent times and doses (beta from the mixed effects model, converted back from natural log to Woods units), and is reported as the mean and 95% confidence interval.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=8 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Pulmonary Vascular Resistance (PVR)	0.77 Woods units Interval 0.28 to 1.26	0.40 Woods units Interval 0.07 to 0.74	-0.39 Woods units Interval -0.93 to 0.16

SECONDARY outcome

Timeframe: 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose

Time in minutes to maximum PVR decrease. During study procedure, hemodynamics were measured at 0, 15, 30, 45, and 60 minutes after 45 mg followed by same times after 90 mg dose. The time point at which each patient's maximal decrease in PVR occurred was recorded and reported as the mean and standard deviation in each cohort.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=8 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Time to Maximum Pulmonary Vascular Resistance (PVR) Decrease	42.0 minutes Standard Deviation 19.2	33.0 minutes Standard Deviation 17.9	42.5 minutes Standard Deviation 14.1

SECONDARY outcome

Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of MAP over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=8 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Systemic Blood Pressure (Mean Arterial Pressure, MAP)	-5.1 mmHg Interval -7.6 to -2.6	-3.4 mmHg Interval -6.6 to -0.3	-9.5 mmHg Interval -13.1 to -6.0

SECONDARY outcome

Timeframe: Time zero, 15, 30, 45 and 60 minutes after nebulization of 45mg followed by 90 mg dose

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. Since systemic vascular resistance was not normally distributed, it was transformed to natural log prior to analysis. The reported mean is the change from baseline of SVR over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=8 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Systemic Vascular Resistance (SVR)	-0.43 mmHg⋅min/L Interval -1.42 to 0.55	1.19 mmHg⋅min/L Interval 0.21 to 2.15	-2.04 mmHg⋅min/L Interval -3.4 to -0.67

SECONDARY outcome

Timeframe: Pre dose and 60 minutes post last dosage inhaled

Population: Data are reported in each group for the subset in whom this data was collected.

Characteristic impedance (Zc) which may be related to compliance effects in the large, conduit arteries.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=14 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=6 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Pulmonary Vascular Impedance / Wave Intensity	-0.004 dyne*sec/cm5 Interval -1.02 to 0.33	-0.34 dyne*sec/cm5 Interval -0.83 to -0.02	-0.20 dyne*sec/cm5 Interval -0.69 to 0.29

SECONDARY outcome

Timeframe: Pre-dose, 15 minutes post 45mg and 90mg inhalation

Population: Data are reported in each group for the subset in whom this data was collected.

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of plasma nitrite concentrations in mixed venous blood over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=18 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=6 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Plasma Nitrite Concentrations in Mixed Venous Blood	9.9 micromolar Interval 7.4 to 12.5	7.0 micromolar Interval 4.7 to 9.2	7.4 micromolar Interval 2.7 to 12.1

SECONDARY outcome

Timeframe: Pre-dose, 15 minutes post 45mg and 90mg inhalation

Population: Data are reported only for WHO Group I PAH and WHO Group III Pulmonary Hypertension (PH), as there was insufficient data for this analysis for WHO Group II PH. Data are reported in each group for the subset in whom this data was collected.

Linear mixed effects model across all time points and doses relative to baseline. The mixed effects model takes into account all time points combined (repeated measures) and has been extensively described for clinical trials (please see references). In this model, the effect of treatment on hemodynamics (measured at 0, 15, 30, 45, and 60 minutes after 45mg followed by same times after 90 mg dose) was compared with baseline values. We assessed the overall linear trend of treatment. The effect of treatment on hemodynamics in each patient group was assessed separately in mixed-effects models. The reported mean is the change from baseline of pulmonary artery occlusion (capillary) pullback nitrite concentration over all subsequent times and doses (beta from the mixed effects model), and is reported as the mean and 95% confidence interval.

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=9 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=3 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Pulmonary Artery Occlusion (Capillary) Pullback Nitrite	9.2 micromolar Interval 6.2 to 12.1	—	2.4 micromolar Interval 0.04 to 4.7

SECONDARY outcome

Timeframe: Maximal effect at 15 minutes post 45mg or 90mg inhalation vs Pre dose

Population: Data are reported in each group for the subset in whom this data was collected.

Basal platelet oxygen consumption measured in isolated platelets by extracellular flux analysis (XF24, Seahorse Biosciences, Billerica, MA).

Outcome measures

Outcome measures
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=6 Participants Idiopathic, primary or familial pulmonary arterial hypertension (PAH) associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=16 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=1 Participants mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Change in Mitochondrial Oxygen Consumption Compared to Baseline After Each Dose of Nitrite	-17.58 picomoles O2/min Interval -29.66 to -5.5	8.62 picomoles O2/min Interval -4.97 to 22.21	-11.64 picomoles O2/min Interval -54.12 to 30.83

Adverse Events

WHO Group I Pulmonary Arterial Hypertension (PAH)

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

WHO Group II Pulmonary Hypertension (PH)

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

WHO Group III Pulmonary Hypertension (PH)

Serious events: 0 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	WHO Group I Pulmonary Arterial Hypertension (PAH) n=20 participants at risk Idiopathic, primary or familial pulmonary arterial hypertension PAH associated with one of the following connective tissue diseases: PAH associated with exposure to drugs and toxins eg, anorexigens, L-tryptophan, toxic rapeseed oil. Stable PAH for at least 3 months if on therapy. Additionally, the mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group II Pulmonary Hypertension (PH) n=20 participants at risk mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) \> 15, and Transpulmonary Gradient (TPG) \> 12. Additionally, left ventricular ejection fraction (LVEF) ≥ 40% and dyspnea resulting at least a mild limitation to physical activity (functional class II or greater). Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.	WHO Group III Pulmonary Hypertension (PH) n=8 participants at risk mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤ 15 mm Hg, and pulmonary vascular resistance (PVR) ≥ 3 Woods units. Sodium Nitrite Inhalation Solution (AIR001) 45mg dosage with one subsequent escalation dosage of 90mg based on tolerability.
Infections and infestations Upper respiratory infection	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	12.5% 1/8 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization
Gastrointestinal disorders Diarrhea	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	12.5% 1/8 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization
Respiratory, thoracic and mediastinal disorders shortness of breath	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
Cardiac disorders Lightheaded/Dizziness	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
General disorders Headache	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
Gastrointestinal disorders Nausea	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
Musculoskeletal and connective tissue disorders Back/neck pain	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
Cardiac disorders palpitations	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization
Renal and urinary disorders increase in serum creatinine from baseline	0.00% 0/20 • 30 days +/- 5 days from Right Heart Catheterization	5.0% 1/20 • Number of events 1 • 30 days +/- 5 days from Right Heart Catheterization	0.00% 0/8 • 30 days +/- 5 days from Right Heart Catheterization

Additional Information

Marc A. Simon, MD

University of Pittsburgh

Phone: 4128023131

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place