Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension, PAH, Inhaled Nitric Oxide, iNO, long term oxygen therapy, oxygen therapy
Brief summary
Phase 3, placebo controlled, double-blind, randomized clinical study to determine safety, tolerability, and efficacy of pulsed, inhaled nitric oxide (iNO) versus placebo in symptomatic subjects with pulmonary arterial hypertension (PAH). Part 1 and Part 2
Detailed description
Phase 3, placebo controlled, double-blind, randomized, clinical study to determine safety, tolerability and efficacy of pulsed inhaled nitric oxide (iNO) versus placebo as add-on therapy in subjects with pulmonary arterial hypertension (PAH) who remain symptomatic on approved PAH monotherapy or combination approved PAH therapy and long term oxygen therapy (LTOT). (Part 1 and Part 2)
Interventions
Inhaled Nitric Oxide 15mcg/Kg IBW/hr for two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period (Week 3 to Week 18)
DRUGPlacebo
Part 1 Placebo arm: Inhaled Nitric Oxide 15mcg/Kg IBW/hrfor two week run in period dose titrated to Inhaled Nitric Oxide 75 mcg/kg IBW/hr at randomizationTreatment Period
Sponsors
Worldwide Clinical Trials
Bellerophon Pulse Technologies
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Signed Informed Consent Form (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments 2. A confirmed diagnosis of PAH Group 1 who have either idiopathic PAH (IPAH), heritable PAH, drug and toxin-induced PAH, associated PAH (APAH) with connective tissue disease (CTD), APAH with repaired simple congenital systemic to pulmonary shunt (i.e., atrial septal defect, ventricular septal defect and/or patent ductus arteriosus; complete repair at least 1 year prior to Screening), APAH with human immunodeficiency virus (HIV), or APAH with portal hypertension 3. Subjects receiving at least one PAH specific therapy (ERA or PDE-5 inhibitor, or inhaled, subcutaneous, or intravenous prostacyclin or a prostacyclin analog) with the same type of therapy for at least 3 months with stable dosing 4 weeks prior to Screening. (Subjects should be receiving optimal therapy according to the disease severity) 4. Subjects using oxygen therapy by nasal cannula for at least 4 weeks prior to Screening 5. PAH diagnosis confirmed by RHC within the previous 5 years, according to the following definitions: * PVR ≥ 400 dynes.sec.cm-5 (5 Wood units) * mPAP ≥ 25 mmHg * PCWP or LVEDP ≤ 15 mmHg * Subjects who otherwise meet all the inclusion criteria and none of the
Exclusion criteria
but have not undergone a RHC within the previous 5 years may be considered eligible for the study if they undergo a RHC and then meet the pulmonary hemodynamics criterion 6. 6MWD ≥ 100 meters and ≤ 450 meters prior to randomization 7. WHO Functional Class II-IV. Subjects with WHO Functional Class IV should be treated with prostacyclin or a prostacyclin analog (subcutaneous or intravenous), plus at least one additional PAH specific therapy (ERA or PDE-5), if available to the subject and reimbursed by health insurance 8. Age between 18 and 85 years (inclusive) 9. Willingness to use INOpulse delivery device for at least 12 hours per day 10. Willingness to continue on study drug until the subject has completed Week 18 assessments 11. Female subjects of childbearing potential must have a negative pre-treatment pregnancy test (serum or urine). All female subjects should take adequate precaution to avoid pregnancy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18) | Change in 6MWD from Week 2 (2 weeks after randomization and run-in period) to Week 18 (end of blinded treatment period) | The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. All patients were required to complete two walks while on chronic oxygen therapy given at a standard rate during the test and throughout the study while using the investigational product (INOpulse device with nitric oxide or matching placebo). The average of two walks at Week 2 visit (2 weeks after Run-In) was used as the Baseline 6MWD. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time (in Days) to First Clinical Worsening Event (TTCW) | From Randomization to Week 18 (End of blinded treatment period) | Clinical worsening was assessed continuously from Randomization to Week 18 (End of blinded treatment period). Clinical worsening events were defined as death (all causes), atrial septostomy, hospitalization due to worsening of pulmonary arterial hypertension (PAH), initiation of new pulmonary arterial hypertension treatment including endothelin receptor antagonists \[ERAs\], phosphodiesterase type-5 \[PDE-5\] inhibitors or prostanoids, an increase in existing treatment of ERA or PDE-5, increase in the dose or frequency of an inhaled prostanoids, or an increase in the dose of an intravenous or subcutaneous prostanoids by \>10%, a decrease of \>15% from baseline or \>30% compared with the last study related measurement in 6MWD or worsening of WHO Functional Class (e.g., from Class II to Class III or IV, OR Class III to Class IV). All worsening events were entered by the study sites into the eCRF. |
| Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18) | From Randomization to Week 18 (End of blinded treatment period) | WHO FC (where Class I is defined as No limitations in daily physical activities. No symptoms of dyspnea and with routine exertion and Class IV is defined as Inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest) for PAH was taken at randomization (Week 0) for all participants and was assessed after blinded treatment (Week 18). The number of participants that had an improvement (lower functional class) as compared to baseline were measured. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18) | From Screening (28 days prior to baseline/randomization) to end of Blinded Treatment Period (Week 18) | Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Screening visit (prior to starting study drug at Randomization) and after 16 weeks of blinded treatment therapy (Week 18). The change in NT-proBNP between Screening (28 days prior to baseline/randomization) and the end of blinded treatment period (Week 18) is reported. |
| Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18) | From Randomization to Week 18 (End of blinded treatment period) | The Borg dyspneas score is a self-rating scale to evaluate the severity of dyspnea (from 0 no shortness of breath at all to 10 very, very severe / maximal) shortness of breath, where high score on the scale signifies a worse score. The self assessment was collected from each participant immediately after each 6-minute walk test throughout the blinded treatment period. The change in Borg dyspnea Score at the end of the blinded treatment period (Week 18) compared to baseline (randomization) (Week 0) is reported. |
| Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18) | From Randomization to Week 18 (End of blinded treatment period) | Unsatisfactory Clinical Response was defined as the number of participants with WHO Functional Class III (defined as moderate dyspnea with routine activities and activities of daily living. No symptoms at rest.) or Class IV (defined as inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest) with no improvement in 6-minute walk distance (6MWD) from baseline to end of blinded treatment period (Week 18). |
Countries
Australia, Austria, Belgium, Canada, Colombia, Croatia, Czechia, France, Germany, Israel, Italy, Netherlands, Portugal, Serbia, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
50 participants did not meet the inclusion and/or exclusion criteria and were not randomized
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Nitric Oxide Includes all randomized subjects that completed 2 week run in period and opted to continue with 16 week treatment period. Treated with Inhaled Nitric Oxide at dose of 75 mcg/Kg IBW/hr | 52 |
| Placebo Includes all randomized subjects that completed 2 week run in period and opted to continue with 16 week treatment period. Treated with Placebo at dose of 75 mcg/Kg IBW/hr | 58 |
| Total | 110 |
Baseline characteristics
| Characteristic | Total | Placebo | Inhaled Nitric Oxide |
|---|---|---|---|
| 6 Minute Walk Distance (6MWD) | 312 meters | 323 meters | 286 meters |
| Age, Continuous | 64 Years | 63 Years | 65 Years |
| Cardiac Index | 2.18 L/minute/m^2 | 2.30 L/minute/m^2 | 2.05 L/minute/m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 107 Participants | 56 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Oxygen Use (Hours/Day) at Baseline <8 hours per day | 95 Participants | 49 Participants | 46 Participants |
| Oxygen Use (Hours/Day) at Baseline >8 hours per day | 15 Participants | 9 Participants | 6 Participants |
| Pulmonary Vascular Resistance (PVR) via RHC | 839 dynes.second/cm^5 | 940 dynes.second/cm^5 | 726 dynes.second/cm^5 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 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 | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 107 Participants | 55 Participants | 52 Participants |
| Sex: Female, Male Female | 76 Participants | 36 Participants | 40 Participants |
| Sex: Female, Male Male | 34 Participants | 22 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 74 | 3 / 78 |
| other Total, other adverse events | 22 / 74 | 25 / 78 |
| serious Total, serious adverse events | 13 / 74 | 10 / 78 |
Outcome results
Primary
Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18)
The 6-minute walk distance test (6MWD) is a non-encouraged test performed in a 30 m long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed. All patients were required to complete two walks while on chronic oxygen therapy given at a standard rate during the test and throughout the study while using the investigational product (INOpulse device with nitric oxide or matching placebo). The average of two walks at Week 2 visit (2 weeks after Run-In) was used as the Baseline 6MWD.
Time frame: Change in 6MWD from Week 2 (2 weeks after randomization and run-in period) to Week 18 (end of blinded treatment period)
Population: 6MWD Change from Week 2 (2 weeks after randomization and run-in period) to Week 18 (end of blinded treatment period) (Week 18). MMRM model includes Baseline 6MWD as covariate, Treatment Group, Visit, Prostanoids usage status and Treatment by Visit Interaction as fixed effects. No imputation performed for primary analysis. ITT analysis set only includes study participants that completed 16 weeks of Part 1 blinded treatment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18) | 4.88 meters | Standard Error 6.9 |
| Placebo | Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18) | 2.89 meters | Standard Error 10.13 |
p-value: 0.8795% CI: [-22.47, 26.45]Mixed Models Analysis
Secondary
Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18)
WHO FC (where Class I is defined as No limitations in daily physical activities. No symptoms of dyspnea and with routine exertion and Class IV is defined as Inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest) for PAH was taken at randomization (Week 0) for all participants and was assessed after blinded treatment (Week 18). The number of participants that had an improvement (lower functional class) as compared to baseline were measured.
Time frame: From Randomization to Week 18 (End of blinded treatment period)
Population: ITT analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18) | 2 Participants |
| Placebo | Number of Participants With an Improvement in World Health Organization Functional Class (WHO FC) Baseline (Randomization) to End of Treatment Period (Week 18) | 1 Participants |
Secondary
Time (in Days) to First Clinical Worsening Event (TTCW)
Clinical worsening was assessed continuously from Randomization to Week 18 (End of blinded treatment period). Clinical worsening events were defined as death (all causes), atrial septostomy, hospitalization due to worsening of pulmonary arterial hypertension (PAH), initiation of new pulmonary arterial hypertension treatment including endothelin receptor antagonists \[ERAs\], phosphodiesterase type-5 \[PDE-5\] inhibitors or prostanoids, an increase in existing treatment of ERA or PDE-5, increase in the dose or frequency of an inhaled prostanoids, or an increase in the dose of an intravenous or subcutaneous prostanoids by \>10%, a decrease of \>15% from baseline or \>30% compared with the last study related measurement in 6MWD or worsening of WHO Functional Class (e.g., from Class II to Class III or IV, OR Class III to Class IV). All worsening events were entered by the study sites into the eCRF.
Time frame: From Randomization to Week 18 (End of blinded treatment period)
Population: ITT analysis population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Time (in Days) to First Clinical Worsening Event (TTCW) | 22 Days | Standard Deviation 42.3 |
| Placebo | Time (in Days) to First Clinical Worsening Event (TTCW) | 19 Days | Standard Deviation 32.8 |
p-value: 0.55Log Rank
Other Pre-specified
Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18)
The Borg dyspneas score is a self-rating scale to evaluate the severity of dyspnea (from 0 no shortness of breath at all to 10 very, very severe / maximal) shortness of breath, where high score on the scale signifies a worse score. The self assessment was collected from each participant immediately after each 6-minute walk test throughout the blinded treatment period. The change in Borg dyspnea Score at the end of the blinded treatment period (Week 18) compared to baseline (randomization) (Week 0) is reported.
Time frame: From Randomization to Week 18 (End of blinded treatment period)
Population: ITT analysis population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18) | -0.47 Scores on a Scale | Standard Error 0.23 |
| Placebo | Change in Borg Dyspnea Scale Immediately Following 6-minute Walk Test (6MWT) From Baseline (Randomization) to End of Treatment Period (Week 18) | -0.23 Scores on a Scale | Standard Error 0.23 |
p-value: 0.4795% CI: [-0.89, 0.41]ANCOVA
Other Pre-specified
Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18)
Plasma NT-proBNP concentration is a useful biomarker for the severity of PAH as it is associated with changes in right heart morphology and function. NT-proBNP sample collection occurred at Screening visit (prior to starting study drug at Randomization) and after 16 weeks of blinded treatment therapy (Week 18). The change in NT-proBNP between Screening (28 days prior to baseline/randomization) and the end of blinded treatment period (Week 18) is reported.
Time frame: From Screening (28 days prior to baseline/randomization) to end of Blinded Treatment Period (Week 18)
Population: ITT analysis population who had NT Pro BNP levels at Screening and at the end of blinded treatment period (Week 18)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18) | 117.8 pg/mL | Standard Error 22.8 |
| Placebo | Change in Plasma N-Terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Screening to End of Treatment Period (Week 18) | 207.9 pg/mL | Standard Error 24.8 |
p-value: 0.0195% CI: [-156, -22.1]ANCOVA
Other Pre-specified
Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18)
Unsatisfactory Clinical Response was defined as the number of participants with WHO Functional Class III (defined as moderate dyspnea with routine activities and activities of daily living. No symptoms at rest.) or Class IV (defined as inability to perform even minimal activities. Signs and symptoms of right heart failure may be present. Dyspnea present at rest) with no improvement in 6-minute walk distance (6MWD) from baseline to end of blinded treatment period (Week 18).
Time frame: From Randomization to Week 18 (End of blinded treatment period)
Population: ITT analysis population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Nitric Oxide 75mcg/KgIBW/Hr | Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18) | 32 Participants |
| Placebo | Number of Participants With an Unsatisfactory Clinical Response From Baseline (Randomization) to End of Treatment Period (Week 18) | 35 Participants |
p-value: 0.2695% CI: [0.48, 2.29]Cochran-Mantel-Haenszel