A Phase 3, Placebo Controlled, Double-Blind, Randomized, Clinical Study to Determine Efficacy, Safety, and Tolerability of Pulsed, Inhaled Nitric Oxide (iNO) Versus Placebo in Symptomatic Subjects With PAH (Part 1 and Part 2)
Overview
- Phase
- Phase 3
- Intervention
- Inhaled Nitric Oxide 75 mcg/kg IBW/hr
- Conditions
- Pulmonary Arterial Hypertension
- Sponsor
- Bellerophon Pulse Technologies
- Enrollment
- 207
- Locations
- 109
- Primary Endpoint
- Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18)
- Status
- Terminated
- Last Updated
- 3 years ago
Overview
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)
Investigators
Eligibility Criteria
Inclusion Criteria
- •Signed Informed Consent Form (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments
- •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
- •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)
- •Subjects using oxygen therapy by nasal cannula for at least 4 weeks prior to Screening
- •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
- •6MWD ≥ 100 meters and ≤ 450 meters prior to randomization
Exclusion Criteria
- •Subjects with known HIV infection who have a history within the past 3 months of any opportunistic pulmonary disease (e.g., tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of Screening
- •PAH associated with untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy
- •Subjects with pulmonary conditions that may contribute to PAH including, but not limited to, chronic bronchiectasis, cystic fibrosis, or other pulmonary condition that the Investigator may deem to contribute to the severity of the disease or impair the delivery of iNO due to airway disease
- •Subjects receiving riociguat
- •Subjects receiving oral prostanoids as monotherapy
- •PAH associated with significant venous or capillary involvement, known or suspected pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
- •Any subject with WHO PH Groups 2, 3, 4 or 5
- •Subjects with any of the following cardiac abnormalities:
- •a. Underlying cardiomyopathy or clinically significant aortic or mitral valve disease in the opinion of the investigator b. Left ventricular systolic dysfunction (LVSD), i.e., left ventricular ejection fraction (LVEF) \< 40% or left ventricular shortening fraction (LVSF) \< 22%, as determined by local reading c. Current symptomatic coronary artery disease, myocardial infarction within 1 year, or any coronary artery interventions within 6 months
- •Systemic hypertension defined as systolic blood pressure (SBP) \> 160 mmHg and/or diastolic blood pressure (DBP) \> 100 mmHg persistent at Screening after a period of rest (treated or untreated)
Arms & Interventions
Inhaled Nitric Oxide 75mcg/KgIBW/Hr
Part 1: 15Mcg/kg IBW/hr during Run-in Period dose titrated to Inhaled Nitric Oxide / 75mcg/KgIBW/Hr upon randomization to treatment arm. Part 2: iNO 75 mcg/kg IBW/hr Open Label Treatment (Open Label Treatment - All Subjects)
Intervention: Inhaled Nitric Oxide 75 mcg/kg IBW/hr
Placebo
Part 1: Placebo dose setting 15mcg/kg IBW/hr Run In Period / Placebo dose setting 75 mcg/kg IBW/hr treatment period
Intervention: Placebo
Outcomes
Primary Outcomes
Change in 6-minute Walk Distance (6MWD) From Baseline (Randomization) to End of Treatment Period (Week 18)
Time Frame: 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 Outcomes
- Time (in Days) to First Clinical Worsening Event (TTCW)(From Randomization to Week 18 (End of blinded treatment period))
- 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))