Inhaled Nitric Oxide/INOpulse DS for Pulmonary Arterial Hypertension (PAH)

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bellerophon ( Bellerophon Pulse Technologies )
ClinicalTrials.gov Identifier:
NCT01457781
First received: October 12, 2011
Last updated: May 22, 2014
Last verified: May 2014
  Purpose

This is a Phase 2, 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 Symptomatic Subjects with Pulmonary Arterial Hypertension (PAH).


Condition Intervention Phase
Pulmonary Arterial Hypertension
Pulmonary Hypertension
Drug: Nitric Oxide
Other: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase 2, 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 Symptomatic Subjects With Pulmonary Arterial Hypertension (PAH)

Resource links provided by NLM:


Further study details as provided by Bellerophon:

Primary Outcome Measures:
  • The primary endpoint is change in pulmonary vascular resistance (PVR) (dynes. sec/cm-5) from baseline to EOS Part 1. [ Time Frame: baseline to Week 16 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in 6 minute walk distance (6MWD) from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ] [ Designated as safety issue: No ]
  • Time (in days) to first clinical worsening event (TTCW) from randomization to EOS Part 1 [ Time Frame: randomization to Week 16 ] [ Designated as safety issue: No ]
  • Change in World Health Organization (WHO) Functional Class from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ] [ Designated as safety issue: No ]
  • Change in Borg Dyspnea Score (BDS) from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ] [ Designated as safety issue: No ]
  • Change in patient reported outcome (PRO) scores by the SF-36 short form version 2 and the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) from baseline to EOS Part 1 [ Time Frame: baseline to Week 16 ] [ Designated as safety issue: No ]

Estimated Enrollment: 78
Study Start Date: April 2012
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 0.025 mg inhaled nitric oxide
Inhaled nitric oxide (iNO) 0.025 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (3.0 mg/L [2440 ppm] NO mini-cylinder; change q 24 hours)
Drug: Nitric Oxide
0.025 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (3.0 mg/L [2440 ppm] NO mini-cylinder; change q 24 hours)
Active Comparator: 0.075 mg inhaled nitric oxide
Inhaled nitric oxide (iNO) 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (6.0 mg/L [4880 ppm] NO mini-cylinder; change q 24 hours)
Drug: Nitric Oxide
Cohort 2: 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (3.0 mg/L [2440 ppm] NO mini-cylinder; change q 24 hours)
Placebo Comparator: placebo
Placebo 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks* (99.999% Nitrogen [N2] mini-cylinder; change q 24 hours)
Other: Placebo
Placebo 0.075 mg/kg IBW/hr for up to 24 hours/day x 16 weeks (Nitrogen N2, 99.999%)

Detailed Description:

Study to determine if inhaled nitric oxide (iNO) given through a special delivery device (INOpulse® DS) is safe and efficacious in treating Pulmonary Arterial Hypertension (PAH). Medical literature and clinical experience suggests that iNO at pulsed doses of 0.013 to 0.1 mg/kg per hour for 1 month to 2+ years appears safe and suggests efficacy for the treatment of pulmonary hypertension.

There are two parts to this study. In Part 1 (week 0 to week 16), the objectives are to determine the safety, tolerability, efficacy, and exploratory objectives of two different doses of iNO delivered by a pulsed delivery device in symptomatic subjects with PAH who remain symptomatic due to PAH on approved PAH monotherapy or combination approved PAH therapy. In Part 2 (week 17 to end of study Part 2 [EOS Part 2]), the objective is to compile data on the long-term effects of iNO on safety, tolerability, clinical and hemodynamic measures.

  Eligibility

Ages Eligible for Study:   16 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Signed informed consent form (ICF) (and assent as appropriate) prior to the initiation of any study mandated procedures or assessments
  2. A confirmed diagnosis of Pulmonary Hypertension Group 1 (PAH) who have either idiopathic PAH (IPAH), heritable PAH, anorexigen-induced PAH, associated PAH (APAH) with connective tissue disease (CTD), APAH with repaired simple congenital systemic to pulmonary shunt (i.e., atrial septal defect [ASD], ventricular septal defect [VSD] and/or patent ductus arteriosus [PDA]; complete repair at least 1 year prior to Screening) or APAH with human immunodeficiency virus (HIV)
  3. Confirmation of PAH diagnosis at the time of Baseline RHC according to the following definition: mPAP ≥ 25 mmHg at rest, with a concomitant mean pulmonary capillary wedge pressure (mPCWP), mean left atrial pressure (mLAP), or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg and a PVR ≥ 240 dynes.sec/cm-5
  4. 6MWD at least 100 meters and no greater than 450 meters
  5. The subject is receiving at least one approved PAH therapy and is clinically symptomatic from PAH (e.g., onset or increased dyspnea on exertion, dizziness, near-syncope, syncope, chest pain or peripheral edema)
  6. Background PAH medication doses (including calcium channel blockade if being used to treat PAH) must be stable for at least 12 weeks prior to Screening
  7. If on background conventional therapy (e.g., digoxin, diuretics, supplemental oxygen, anticoagulation), it must have been started at least 30 days prior to Screening and be on a stable dose for at least 30 days except for anticoagulation dose
  8. If previously treated with an endothelin receptor antagonist (ERA), phosphodiesterase-5 (PDE-5) inhibitor, prostacyclin or a prostacyclin analog and is no longer on said treatment at Screening (per inclusion criteria as above), subject must have been off said treatment for > 90 days at Screening
  9. If previously treated with a calcium channel blocker as treatment for PAH and is no longer on the calcium channel blocker treatment at Screening (per inclusion criteria as above), subject must have been off the calcium channel blocker treatment for > 90 days at Screening
  10. Age between 16 and 80 years (inclusive)
  11. Male height ≤ 200 cm (6'7") or Female height ≤ 210 cm (6'11")
  12. Subjects are willing and considered in the judgment of the Investigator able to use the INOpulse DS device continuously for up to 24 hours per day
  13. Females of childbearing potential must have a negative pre-treatment serum pregnancy test and must be on a reliable method of contraception (including double protection if appropriate, e.g., for subjects concurrently treated with bosentan therapy)

Exclusion Criteria:

  1. Subjects with known HIV infection within the past 2 years who have a history of or show any clinical or laboratory evidence of any opportunistic pulmonary disease (e.g., tuberculosis, Pneumocystis carinii pneumonia, or other pneumonias) at the time of Screening
  2. PAH associated with portal hypertension, untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy
  3. Any subject with unrepaired congenital heart disease or repaired congenital heart disease other than the simple congenital to systemic shunts specified in the inclusion criteria, i.e., PAH associated with non-corrected simple congenital systemic-to-pulmonary shunts, corrected simple congenital systemic-to-pulmonary shunt with residual shunt post repair, or complex systemic-to- pulmonary shunts, corrected or non-corrected, or any other complex congenital heart disease, corrected or non-corrected
  4. PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), known pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
  5. Any subject with WHO PH Groups 2, 3, 4 or 5
  6. Left ventricular systolic dysfunction, i.e., left ventricular ejection fraction (LVEF) < 40% or left ventricular shortening fraction (LVSF) < 22%
  7. Left ventricular diastolic dysfunction, i.e., PCWP > 15 mmHg at rest or with exercise, acute volume loading or pharmacologic testing
  8. History of clinically significant cardiomyopathy or valvular heart disease (i.e., moderate or greater aortic insufficiency; moderate or greater aortic stenosis; or moderate or greater mitral valve disease)
  9. Clinically significant cardiac ischemic disease requiring use of nitrates, or hospital admission for acute coronary syndrome or intervention (percutaneous coronary intervention, coronary artery stent, coronary artery bypass surgery) within the past 90 days
  10. Down syndrome
  11. Any subject who develops a PCWP > 20 mmHg during AVT with iNO
  12. 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)
  13. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest
  14. Moderate to severe obstructive lung disease defined as both a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 65% of predicted value (bronchodilator administration prior to testing is optional; the test should be done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)
  15. Moderate to severe restrictive lung disease: total lung capacity (TLC) < 60% of predicted; if TLC 60% to 70% predicted, a high resolution CT scan showing diffuse disease or more than mild patchy disease (done within 3 years for all subjects with the exception of APAH/CTD which needs to be done within 6 months prior to Screening)
  16. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
  17. Estimated creatinine clearance < 30 mL/min (Cockcroft-Gault formula)
  18. Hemoglobin < 10 gm/dL at Screening or Baseline
  19. Acute or chronic physical impairment (other than dyspnea due to PAH) that would limit the ability to comply with study procedures or adherence to therapy, including carrying and wearing the INOpulse device per study protocol
  20. Pregnant or breast-feeding at Screening
  21. Administered L-arginine within 30 days prior to Screening
  22. Known concomitant life-threatening disease with a life expectancy less than 1 year
  23. Recently started (< 12 weeks prior to randomization) or planned cardiopulmonary rehabilitation program to start within the 16 week controlled study
  24. Atrial septostomy within 3 months of randomization
  25. Any subject with PAH who is treatment naïve or receiving any unapproved therapy as their only PAH treatment (including calcium channel blockade if the calcium channel blockade is the only treatment for the PAH)
  26. Any subject who requires the use of a continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), or other positive pressure devices to treat obstructive sleep apnea
  27. Medical problem(s) likely to preclude completion of Part 1
  28. Use of investigational drugs or devices within 30 days prior to enrollment into the study (other than acute vasodilator testing with iNO or IV epoprostenol)
  29. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study
  30. Any condition other than the subject's PAH that, in that opinion of the investigator, affects their ability to perform the 6MWT
  31. Refusal to follow the protocol, including the two RHCs in Part 1 and one RHC in Part 2
  32. Unable to travel to the investigational site for all required study visits and for all additional visits per the judgment of the Investigator or Sponsor
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01457781

  Show 51 Study Locations
Sponsors and Collaborators
Bellerophon Pulse Technologies
Investigators
Study Director: Brahm Goldstein, MD Bellerophon Therapeutics
  More Information

No publications provided

Responsible Party: Bellerophon ( Bellerophon Pulse Technologies )
ClinicalTrials.gov Identifier: NCT01457781     History of Changes
Other Study ID Numbers: IK-7001-PAH-201
Study First Received: October 12, 2011
Last Updated: May 22, 2014
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Bellerophon:
Inhaled nitric oxide
pulmonary arterial hypertension
pulmonary hypertension
PAH

Additional relevant MeSH terms:
Hypertension, Pulmonary
Hypertension
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Cardiovascular Diseases
Nitric Oxide
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Free Radical Scavengers
Antioxidants
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Endothelium-Dependent Relaxing Factors
Vasodilator Agents
Cardiovascular Agents
Gasotransmitters
Protective Agents

ClinicalTrials.gov processed this record on August 01, 2014