Heart Failure
Conditions
Brief summary
A randomized, double-blind, placebo-controlled crossover study to assess the effect of inorganic nitrite (NO2) on aerobic capacity (peak VO2) after four weeks of dosing. Approximately 100 participants will be enrolled in this 2\*2 crossover study.
Detailed description
Screen potential HFpEF patients for eligibility criteria and interest Study Visit 1 • Initiate consent process and obtain written informed consent. * Confirm with the participant that HF symptoms are the primary limitation to activity. If so, they proceed to CPET screening. If not, they are considered a screen fail. * Obtain baseline bloods \*- CBC, complete chemistry panel, biomarkers, biorepository and genetics (if agreed to participate) . * Obtain CPET to verify patient eligibility peak VO2 ≤ 75% predicted and RER ≥ 1.0 (within 3 days prior to randomization) and establish baseline value. * Qualifying patients perform additional baseline studies: history, assess NYHA class, physical exam, ECG, and KCCQ. * Open label, single-dose run-in where patient receives maximal dose (80 mg) inhaled inorganic nitrite. Patients who do not tolerate the run-in are considered screen failures. * Randomize qualifying patients. * Dispense phase-1 study drug, nebulizers and accelerometers * Participants take no study drug for two weeks (baseline). * Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days. * Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 2 (at least 42 days but up to 49 days post-baseline visit). * If side effects develop, participants can down-titrate to the previous dose. * Participants are called frequently to reinforce study procedures and assess compliance. Study Visit 2 (42-49 Days Post Study Visit 1) • Participant holds study drug on day of visit. * Review history, assess NYHA class, perform physical exam and KCCQ. * Obtain blood draws \*\* - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate). * Obtain limited echocardiogram \*\*. * Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint). * Change out accelerometer and dispense phase-2 study drug. * Participants take no study drug for two weeks (washout). * Participants take 46 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day for 7 days. * Participants take 80 mg study drug at a minimum of 4 hours apart, 3 times a day, during active part of the day until returning for study visit 3 (at least 42 but up to 49 days after study visit 2). * If side effects develop Participants can down-titrate to the previously tolerated dose. * Participants are called frequently to reinforce study procedures and assess compliance. Study Visit 3 (42-49 Days Post Study Visit 2) • Participant holds study drug on day of visit. • Review history, assess NYHA class, perform physical exam and KCCQ * Obtain blood draws\*\* - CBC, complete chemistry panel, biomarkers, biorepository (if agreed to participate). * Obtain limited echocardiogram\*\*. * Perform CPET with Study Drug administered immediately before starting the CPET (primary endpoint). * Return accelerometer and phase-2 study drug. * End of study drug (phase out). Phone Visit and End of Study (14 Days Post Study Visit 3) • A final phone visit is conducted to assess for adverse events. \*Visit 1: baseline blood draw needs to be completed prior to the CPET (if this is not feasible, then they cannot be obtained for at least 3 hours post the CPET and prior to the run-in test dose). \*\*Visit 2 and Visit 3: blood draws and limited echo need to be obtained prior to study drug administration (if this is not feasible, then it cannot be obtained for at least 3 hours post study drug administration)
Interventions
DRUGNebulized 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.
DRUGPlacebo
Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Aires Pharmaceuticals, Inc.
University of Vermont
Université de Montréal
Mayo Clinic
Massachusetts General Hospital
Adrian Hernandez
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 40 years 2. Symptoms of dyspnea (NYHA class II-IV) without evidence of a non-cardiac or ischemic explanation for dyspnea 3. EF ≥ 50% as determined on imaging study within 12 months of enrollment with no change in clinical status suggesting potential for deterioration in systolic function 4. One of the following : * Previous hospitalization for HF with radiographic evidence (pulmonary venous hypertension, vascular congestion, interstitial edema, pleural effusion) of pulmonary congestion or * Catheterization documented elevated filling pressures at rest (PCWP ≥15 or LVEDP ≥18) or with exercise (PCWP ≥25) or * Elevated NT-proBNP (\>400 pg/ml) or BNP(\>200 pg/ml) or * Echo evidence of diastolic dysfunction/elevated filling pressures manifest by medial E/e' ratio≥15 and/or left atrial enlargement and chronic treatment with a loop diuretic for signs or symptoms of heart failure 5. Heart failure is primary factor limiting activity as indicated by answering # 2 to the following question: My ability to be active is most limited by: 1. Joint, foot, leg, hip or back pain 2. Shortness of breath and/or fatigue and/or chest pain 3. Unsteadiness or dizziness 4. Lifestyle, weather, or I just don't like to be active 6\. Peak VO2 ≤75% predicted with peak respiratory exchange ratio≥1.0 CPET Normal Values for Peak VO2\* Criteria (ml/kg/min) 7. No chronic nitrate therapy or not using intermittent sublingual nitroglycerin (requirement for \>1 SL nitroglycerin per week) within last 7 days 8. No daily use of phosphodiesterase 5 inhibitors or soluble guanylyl cyclase activators and willing to withhold prn use of phosphodiesterase 5 inhibitors for duration of study 9. Ambulatory (not wheelchair / scooter dependent) 10. Body size allows wearing of the accelerometer belt as confirmed by ability to comfortably fasten the test belt provided for the screening process (belt designed to fit persons with BMI 20-40 kg/m2 but belt may fit some persons outside this range) 11. Willingness to wear the accelerometer belt for the duration of the trial 12. Willingness to provide informed consent
Exclusion criteria
1. Recent (\< 1 month) hospitalization for heart failure 2. Ongoing requirement for PDE5 inhibitor, organic nitrate or soluble guanylyl cyclase activators 3. Hemoglobin (Hgb) \< 8.0 g/dl within 90 days prior to randomization 4. GFR \< 20 ml/min/1.73 m2 within 90 days prior to randomization 5. Systolic blood pressure \< 115 mmHg seated or \< 90 mmHg standing just prior to test dose 6. Resting HR \> 110 just prior to test dose 7. Previous adverse reaction to the study drug which necessitated withdrawal of therapy 8. Significant chronic obstructive pulmonary disease thought to contribute to dyspnea 9. Ischemia thought to contribute to dyspnea 10. Documentation of previous EF \< 45% 11. Acute coronary syndrome within 3 months defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g., troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent) 12. PCI, coronary artery bypass grafting, or new biventricular pacing within past 3 months 13. Primary hypertrophic cardiomyopathy 14. Infiltrative cardiomyopathy (amyloid) 15. Constrictive pericarditis or tamponade 16. Active myocarditis 17. Complex congenital heart disease 18. Active collagen vascular disease 19. More than mild aortic or mitral stenosis 20. Intrinsic (prolapse, rheumatic) valve disease with moderate to severe or severe mitral, tricuspid or aortic regurgitation 21. Acute or chronic severe liver disease as evidenced by any of the following: encephalopathy, variceal bleeding, INR \> 1.7 in the absence of anticoagulation treatment 22. Terminal illness (other than HF) with expected survival of less than 1 year 23. Regularly (\> 1x per week) swims or does water aerobics 24. Enrollment or planned enrollment in another therapeutic clinical trial in next 3 months. 25. Inability to comply with planned study procedures 26. Pregnancy or breastfeeding mothers
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peak VO2 | End of Phase 1 & End of Phase 2 | The primary endpoint will be the peak VO2 after 4 weeks treatment with inorganic nitrite as compared to the peak VO2 after 4 weeks treatment with placebo as assessed by cardiopulmonary exercise testing (CPET) performed at peak drug levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Medial E/e' Ratio as Measured by Echocardiography Core Lab | End of Phase 1 & End of Phase 2 | To evaluate whether AIR001 improves Medial E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity for diastolic evaluation) in comparison to placebo. |
| Left Atrial Volume Index as Measured by Echocardiography | End of Phase 1 & End of Phase 2 | To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo. |
| Pulmonary Artery Systolic Pressure as Measured by Echocardiography | End of Phase 1 & End of Phase 2 | To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo. |
| Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | End of Phase 1 & End of Phase 2 | To evaluate whether AR001 improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Higher values of the overall KCCQ score are considered to be better than lower values. |
| Average Arbitrary Accelerometer Units (AAU) | End of Phase 1 & End of Phase 2 | Average arbitrary accelerometer units (AAU) during at least 14 days and up to 21 days of the maximally tolerated dose of study drug (from 28 days post Study Visit 1 until Study Visit 2 and from 28 days post Study Visit 2 until Study Visit 3). An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based upon patient movement. Higher values indicate more movement. Zero indicates no movement. |
| NYHA (New York Heart Association) Class | End of Phase 1 & End of Phase 2 | To evaluate whether AR001 improves NYHA Class in comparison to placebo. NYHA class was measured at the end of each phase. The site physician evaluated the patient based upon the criteria for NYHA class I-IV used by the American Heart Association. NYHA functional classification provides a way of classifying the extent of heart failure. Class I (least severe): No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV (most severe): Unable to carry on any physical activity without discomfort. |
| Patient Preference for AIR001 Treatment at the End of Study | End of Phase 2 | Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2) |
| VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | End of Phase 1 & End of Phase 2 | To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of Ve/VCO2 during study drug administration. The Ve/VCO2 slope is defined as the slope of the linear relationship between ventilation and carbon dioxide output and is a measure of the velocity. |
| VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | End of Phase 1 & End of Phase 2 | To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 (rate of oxygen consumption measured during incremental exercise) at ventilatory threshold during study drug administration. |
| N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | End of Phase 1 & End of Phase 2 | Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| AIR001 Crossover to Placebo Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug Nebulized Sodium Nitrite (AIR001) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Placebo instead of AIR001.
Nebulized Sodium Nitrite: Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally to | 53 |
| Placebo Crossover to AIR001 Phase 1: Participants will wear an accelerometer device daily but take no study drug for 14 days (washout period). On day 15, participants begin phase I study drug (Placebo) at 46 mg, at minimum of 4 hours apart, for 3 doses per day during the active portion of the participant's day. On day 22 participants increase study drug dose to 80 mg at the same frequency. Regardless of participant's ability to tolerate study drug or if the participant requires down-titration, participants will begin Phase 2. Phase 2: Is identical to Phase 1 except subject will be taking Nebulized Sodium Nitrite (AIR001) instead of Placebo.
Nebulized Sodium Nitrite: Inhaled, nebulized inorganic sodium nitrite vs. inhaled, nebulized placebo at a dose of 80 mg (or maximally tolerated dose) administered at a minimum of 4 hours apart, three times per day, during the active part of the day. Placebo: Inhaled, nebulized placebo vs. inhaled, nebulized inorganic sodium nitrite at a dose of 80 mg (or maximally | 52 |
| Total | 105 |
Baseline characteristics
| Characteristic | Placebo Crossover to AIR001 | Total | AIR001 Crossover to Placebo |
|---|---|---|---|
| Age, Continuous | 67.5 years STANDARD_DEVIATION 11.6 | 67.7 years STANDARD_DEVIATION 10.1 | 67.8 years STANDARD_DEVIATION 8.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 104 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 13 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 45 Participants | 92 Participants | 47 Participants |
| Sex: Female, Male Female | 23 Participants | 59 Participants | 36 Participants |
| Sex: Female, Male Male | 29 Participants | 46 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 103 | 0 / 102 |
| other Total, other adverse events | 79 / 103 | 51 / 102 |
| serious Total, serious adverse events | 5 / 103 | 4 / 102 |
Outcome results
Primary
Peak VO2
The primary endpoint will be the peak VO2 after 4 weeks treatment with inorganic nitrite as compared to the peak VO2 after 4 weeks treatment with placebo as assessed by cardiopulmonary exercise testing (CPET) performed at peak drug levels.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Peak VO2 | Phase 1 | 13.4 ml/kg/min | Standard Deviation 3.2 |
| AIR001 Crossover to Placebo | Peak VO2 | Phase 2 | 13.7 ml/kg/min | Standard Deviation 3 |
| Placebo Crossover to AIR001 | Peak VO2 | Phase 2 | 13.6 ml/kg/min | Standard Deviation 3.6 |
| Placebo Crossover to AIR001 | Peak VO2 | Phase 1 | 13.8 ml/kg/min | Standard Deviation 3.8 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.26595% CI: [-0.56, 0.16]Mixed Models Analysis
Secondary
Average Arbitrary Accelerometer Units (AAU)
Average arbitrary accelerometer units (AAU) during at least 14 days and up to 21 days of the maximally tolerated dose of study drug (from 28 days post Study Visit 1 until Study Visit 2 and from 28 days post Study Visit 2 until Study Visit 3). An arbitrary accelerometer unit is calculated within the accelerometer device that is worn by the patient and represents level of activity based upon patient movement. Higher values indicate more movement. Zero indicates no movement.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Average Arbitrary Accelerometer Units (AAU) | Phase 1 | 5692 accelerometry units | Standard Deviation 2886 |
| AIR001 Crossover to Placebo | Average Arbitrary Accelerometer Units (AAU) | Phase 2 | 5688 accelerometry units | Standard Deviation 2950 |
| Placebo Crossover to AIR001 | Average Arbitrary Accelerometer Units (AAU) | Phase 1 | 5341 accelerometry units | Standard Deviation 3115 |
| Placebo Crossover to AIR001 | Average Arbitrary Accelerometer Units (AAU) | Phase 2 | 5289 accelerometry units | Standard Deviation 2976 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete datap-value: 0.906995% CI: [-263.65, 234.29]Mixed Models Analysis
Secondary
Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score
To evaluate whether AR001 improves quality of life in comparison to placebo. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a disease-specific patient-reported outcomes measure for patients with heart failure. It consists of 23 items, is comprised of 7 clinically relevant scales (Symptom Frequency, Symptom Burden, Symptom Stability, Physical Limitation, Social Limitation, Quality of Life, and Self-Efficacy), and yields 3 summary scores (Clinical Summary, Total Symptom, and Overall Summary Scores). Scale and summary scores range between 0 and 100, with higher scores indicating better health status (eg, better functioning, fewer symptoms, better quality of life). Higher values of the overall KCCQ score are considered to be better than lower values.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | Phase 2 | 64.1 units on a scale | Standard Deviation 18.4 |
| AIR001 Crossover to Placebo | Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | Phase 1 | 65.6 units on a scale | Standard Deviation 18.8 |
| Placebo Crossover to AIR001 | Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | Phase 1 | 59.8 units on a scale | Standard Deviation 18.4 |
| Placebo Crossover to AIR001 | Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Score | Phase 2 | 59.4 units on a scale | Standard Deviation 21.1 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.390295% CI: [-1.37, 3.49]Mixed Models Analysis
Secondary
Left Atrial Volume Index as Measured by Echocardiography
To evaluate whether AIR001 improves Left atrial volume index in comparison to placebo.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Left Atrial Volume Index as Measured by Echocardiography | Phase 1 | 36.3 ml/m^2 | Standard Deviation 16.5 |
| AIR001 Crossover to Placebo | Left Atrial Volume Index as Measured by Echocardiography | Phase 2 | 37.2 ml/m^2 | Standard Deviation 13.9 |
| Placebo Crossover to AIR001 | Left Atrial Volume Index as Measured by Echocardiography | Phase 2 | 39.1 ml/m^2 | Standard Deviation 20.4 |
| Placebo Crossover to AIR001 | Left Atrial Volume Index as Measured by Echocardiography | Phase 1 | 40.1 ml/m^2 | Standard Deviation 20.6 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.815195% CI: [-2.79, 2.2]Mixed Models Analysis
Secondary
Medial E/e' Ratio as Measured by Echocardiography Core Lab
To evaluate whether AIR001 improves Medial E/e' ratio (the ratio between early mitral inflow velocity and mitral annular early diastolic velocity for diastolic evaluation) in comparison to placebo.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Medial E/e' Ratio as Measured by Echocardiography Core Lab | Phase 1 | 15.4 ratio | Standard Deviation 8.3 |
| AIR001 Crossover to Placebo | Medial E/e' Ratio as Measured by Echocardiography Core Lab | Phase 2 | 15.0 ratio | Standard Deviation 7.3 |
| Placebo Crossover to AIR001 | Medial E/e' Ratio as Measured by Echocardiography Core Lab | Phase 1 | 18.3 ratio | Standard Deviation 11.8 |
| Placebo Crossover to AIR001 | Medial E/e' Ratio as Measured by Echocardiography Core Lab | Phase 2 | 17.4 ratio | Standard Deviation 11.1 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.933895% CI: [-1.16, 1.27]Mixed Models Analysis
Secondary
N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP)
Evaluate whether AIR001 improves natriuretic peptide levels in comparison to placebo
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | Phase 1 | 494.8 pg/mL | Standard Deviation 542.3 |
| AIR001 Crossover to Placebo | N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | Phase 2 | 513.9 pg/mL | Standard Deviation 606 |
| Placebo Crossover to AIR001 | N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | Phase 1 | 550.4 pg/mL | Standard Deviation 746.5 |
| Placebo Crossover to AIR001 | N-terminal Pro-B-type Natriuretic Peptide Level (NT-proBNP) | Phase 2 | 545.2 pg/mL | Standard Deviation 784.5 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.740495% CI: [-53.21, 74.6]Mixed Models Analysis
Secondary
NYHA (New York Heart Association) Class
To evaluate whether AR001 improves NYHA Class in comparison to placebo. NYHA class was measured at the end of each phase. The site physician evaluated the patient based upon the criteria for NYHA class I-IV used by the American Heart Association. NYHA functional classification provides a way of classifying the extent of heart failure. Class I (least severe): No limitation of physical activity; Class II: Slight limitation of physical activity; Class III: Marked limitation of physical activity; Class IV (most severe): Unable to carry on any physical activity without discomfort.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 1 | I | 1 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 1 | II | 21 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 1 | III | 26 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 1 | IV | 1 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 2 | I | 0 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 2 | II | 24 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 2 | III | 24 Participants |
| AIR001 Crossover to Placebo | NYHA (New York Heart Association) Class | Phase 2 | IV | 1 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 2 | IV | 0 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 1 | I | 0 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 2 | I | 1 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 1 | II | 29 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 2 | III | 25 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 1 | III | 20 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 2 | II | 22 Participants |
| Placebo Crossover to AIR001 | NYHA (New York Heart Association) Class | Phase 1 | IV | 0 Participants |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.428295% CI: [-0.08, 0.18]Mixed Models Analysis
Secondary
Patient Preference for AIR001 Treatment at the End of Study
Self-reported participant preference for study period 1 (Phase 1) vs. study period 2 (Phase 2)
Time frame: End of Phase 2
Population: All randomized patients with available data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| AIR001 Crossover to Placebo | Patient Preference for AIR001 Treatment at the End of Study | Phase 1 Patient Felt Better | 23 Participants |
| AIR001 Crossover to Placebo | Patient Preference for AIR001 Treatment at the End of Study | Phase 2 Patient Felt Better | 17 Participants |
| AIR001 Crossover to Placebo | Patient Preference for AIR001 Treatment at the End of Study | No Preference | 8 Participants |
| Placebo Crossover to AIR001 | Patient Preference for AIR001 Treatment at the End of Study | Phase 1 Patient Felt Better | 15 Participants |
| Placebo Crossover to AIR001 | Patient Preference for AIR001 Treatment at the End of Study | Phase 2 Patient Felt Better | 20 Participants |
| Placebo Crossover to AIR001 | Patient Preference for AIR001 Treatment at the End of Study | No Preference | 12 Participants |
Secondary
Pulmonary Artery Systolic Pressure as Measured by Echocardiography
To evaluate whether AIR001 improves pulmonary artery systolic pressure in comparison to placebo.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | Pulmonary Artery Systolic Pressure as Measured by Echocardiography | Phase 1 | 38.2 mmHg | Standard Deviation 9.7 |
| AIR001 Crossover to Placebo | Pulmonary Artery Systolic Pressure as Measured by Echocardiography | Phase 2 | 35.0 mmHg | Standard Deviation 7.3 |
| Placebo Crossover to AIR001 | Pulmonary Artery Systolic Pressure as Measured by Echocardiography | Phase 1 | 39.6 mmHg | Standard Deviation 13.5 |
| Placebo Crossover to AIR001 | Pulmonary Artery Systolic Pressure as Measured by Echocardiography | Phase 2 | 37.3 mmHg | Standard Deviation 9.2 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.465895% CI: [-1.41, 3.05]Mixed Models Analysis
Secondary
VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab
To evaluate whether ARI001 in comparison to placebo improves ventilator efficiency as measured by Slope of Ve/VCO2 during study drug administration. The Ve/VCO2 slope is defined as the slope of the linear relationship between ventilation and carbon dioxide output and is a measure of the velocity.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 1 | 31.8 unitless | Standard Deviation 5.7 |
| AIR001 Crossover to Placebo | VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 2 | 32.1 unitless | Standard Deviation 6 |
| Placebo Crossover to AIR001 | VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 1 | 33.9 unitless | Standard Deviation 6.9 |
| Placebo Crossover to AIR001 | VE/VCO2 Slope (Ventilatory Efficiency) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 2 | 33.6 unitless | Standard Deviation 7.3 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.106795% CI: [-1.08, 0.11]Mixed Models Analysis
Secondary
VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab
To evaluate whether ARI001 in comparison to placebo improves submaximal exercise capacity as measured by VO2 (rate of oxygen consumption measured during incremental exercise) at ventilatory threshold during study drug administration.
Time frame: End of Phase 1 & End of Phase 2
Population: All patients randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AIR001 Crossover to Placebo | VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 1 | 7.8 ml/min | Standard Deviation 1.6 |
| AIR001 Crossover to Placebo | VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 2 | 7.9 ml/min | Standard Deviation 1.6 |
| Placebo Crossover to AIR001 | VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 1 | 8.0 ml/min | Standard Deviation 1.9 |
| Placebo Crossover to AIR001 | VO2 at Ventilatory Threshold (Submaximal Exercise Capacity) as Provided by Cardiopulmonary Exercise Testing Core Lab | Phase 2 | 7.8 ml/min | Standard Deviation 1.7 |
Comparison: The mixed models used to generate the p-values included all patients, including those with incomplete data.p-value: 0.441195% CI: [-0.37, 0.16]Mixed Models Analysis