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Clinical Study of Pulsed, Inhaled Nitric Oxide Versus Placebo in Symptomatic Subjects With PAH (INOvation-1)

This study is currently recruiting participants.
Verified August 2017 by Bellerophon ( Bellerophon Pulse Technologies )
Sponsor:
ClinicalTrials.gov Identifier:
NCT02725372
First Posted: April 1, 2016
Last Update Posted: August 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
Bellerophon ( Bellerophon Pulse Technologies )
January 19, 2016
April 1, 2016
August 17, 2017
April 2016
July 2018   (Final data collection date for primary outcome measure)
Six Minute Walk Distance (6MWD) - Change from baseline 6MWD at 18 Weeks [ Time Frame: Change from baseline to 18 weeks ]
Change in 6MWD from baseline to 18 weeks
Six Minute Walk Distance (6MWD) - Change from baseline 6MWD at 18 Weeks [ Time Frame: Baseline, 18 Weeks ]
Complete list of historical versions of study NCT02725372 on ClinicalTrials.gov Archive Site
  • Time to Clinical Worsening (TTCW) [ Time Frame: baseline to 18 weeks ]

    1. TTCW, the time (in days) from start of treatment to first event (first day the event is noted), with iNO as compared to placebo, measured from baseline to 18 weeks . TTCW event is defined as any of the following:

    1. Death (all-cause mortality)
    2. Atrial septostomy
    3. Hospitalization due to worsening of PAH (adjudicated)
    4. Start of new specific PAH TX (endothelin receptor antagonists [ERAs], phosphodiesterase type-5 [PDE-5] inhibitors or prostanoids), an increase in the dose of an 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%.
    5. Decrease of >15% from baseline or >30% compared with the last study related measurement in 6MWD should be confirmed by a repeat measurement performed at least 14 days later
    6. Worsening of WHO Functional Class (e.g., from Class II to Class III or IV, OR Class III to Class IV); and confirmed by a repeat assessment at least 14 days later
  • Change in World Health Organization (WHO) Functional Class [ Time Frame: from baseline to 18 weeks ]
    Change in World Health Organization (WHO) Functional Class from baseline to 18 weeks
  • Time to Clinical Worsening (TTCW) [ Time Frame: Through study completion, up to 2 years ]

    The time (in days) from start of treatment to first event (first day the event is noted), measured from baseline to end of study. TTCW event is defined as any of the following:

    1. Death (all-cause mortality)
    2. Atrial septostomy
    3. Hospitalization due to worsening of PAH (adjudicated)
    4. Start of new specific PAH treatment (endothelin receptor antagonists [ERAs], phosphodiesterase type-5 [PDE-5] inhibitors or prostanoids), an increase in the dose of an 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%.
    5. Decrease of >15% from baseline or >30% compared with the last study related measurement in 6MWD should be confirmed by a repeat measurement performed at least 14 days later
    6. Worsening of WHO Functional Class (e.g., from Class II to Class III or IV, OR Class III to Class IV); and should be confirmed by a repeat assessment at least 14 days later
  • Change in World Health Organization (WHO) Functional Class [ Time Frame: Through study completion, up to 2 years ]
  • Change in health-related quality of life using Short Form-36 (SF-36) version 2 health survey [ Time Frame: from baseline to 18 weeks ]
    Change in QOL SF36 from Baseline to 18 weeks
  • Change in Pulmonary Hemodynamics [ Time Frame: from baseline to 18 weeks ]
    Change in pulmonary hemodynamics (i.e., cardiac output [CO], cardiac index [CI], mean pulmonary artery pressure [mPAP], mean pulmonary capillary wedge pressure [mPCWP], systolic pulmonary artery pressure [sPAP], diastolic pulmonary artery pressure [dPAP], pulmonary vascular resistance [PVR], and oxygen saturation by pulse oximeter [SpO2], mixed venous O2, and right atrial pressure [RAP]), measured by right heart catheterization (RHC), with iNO as compared to placebo, from baseline to 18 weeks, in a subset of subjects (approximately 50), at selected sites
  • Change in Echocardiogram measurements [ Time Frame: from baseline to 18 weeks ]
    Change in echocardiogram measurements right ventricular function (including right ventricular fractional area change, systolic pulmonary artery pressure [sPAP], tricuspid annular motion/tricuspid annular plane systolic excursion, tricuspid annular systolic velocity, and Tei index) and left ventricular function (including left ventricular ejection fraction [LVEF], LV size, and improvement in LV early diastolic relaxation velocity), with iNO as compared to placebo, from baseline to 18 weeks, in a subset of subjects (approximately 50), at selected sites
  • Change in Prop BNP [ Time Frame: from screening to 18 weeks ]
    as compared to placebo from screening to 18 weeks
  • Change in Borg Dyspnea Scale [ Time Frame: from baseline to 18 weeks ]
    immediately following 6MWT with iNO as compared to Placebo from baseline, to 18weeks
  • Change in 6MWD [ Time Frame: from baseline to 18weeks ]
    as related to degree of drug adherence, with iNO as compared to placebo,
  • Unsatisfactory Clinical Response [ Time Frame: from baseline to 18weeks ]
    Number of subjects with unsatisfactory clinical response, with iNO as compared to placebo, from baseline to 18 weeks. Defined as WHO Functional Class III or IV symptoms with no improvement
  • Subjects undergoing heart-lung or lung transplant [ Time Frame: from baseline to 18weeks ]
    Number of subjects undergoing heart-lung or lung transplantation, number of subjects listed for transplantation, deaths while awaiting transplant, from baseline to 18 week
  • Medical Resource Utilization [ Time Frame: from baseline to 18 weeks ]
    Economic evaluation of the use as compared to placebo from baseline to 18weeks and baseline to EOS. Number of hospitalizations, Er visits and outpatient visits in the previous year as compared to study duration. Frequency duration and diagnosis will be recorded.
  • Change in health-related quality of life using Short Form-36 (SF-36) version 2 health survey [ Time Frame: Through study completion, up to 2 years ]
  • Change in cardiac output (CO) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in cardiac index (CI) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in mean pulmonary artery pressure (mPAP) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in mean pulmonary capillary wedge pressure (mPCWP) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in systolic pulmonary artery pressure (sPAP) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in diastolic pulmonary artery pressure (dPAP) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in pulmonary vascular resistance (PVR) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in oxygen saturation by pulse oximeter (SpO2) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in mixed venous O2 measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in right atrial pressure (RAP) measured by Right Heart Catheterization (RHC) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of right ventricular fractional area in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of right ventricular systolic pulmonary artery pressure (sPAP) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of right ventricular tricuspid annular motion/tricuspid annular plane systolic excursion in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of right ventricular tricuspid annular systolic velocity in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of right ventricular Tei index in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of left ventricular ejection fraction (LVEF) in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of left ventricular size in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in echocardiogram measurements of improvement in LV early diastolic relaxation velocity in a subset of subjects at selected sites [ Time Frame: Through study completion, up to 2 years ]
  • Change in NT-proBNP [ Time Frame: Screening, Week 18 ]
  • Change in Borg dyspnea score immediately following Six Minute Walk Test (6MWT) [ Time Frame: Through study completion, up to 2 years ]
  • Change in Six Minute Walk Distance (6MWD) as related to degree of drug adherence [ Time Frame: Through study completion, up to 2 years ]
  • Number of subjects with unsatisfactory clinical response [ Time Frame: Baseline, Week 2, Week 6, Week 10, Week 14, Week 18 ]
    Defined as WHO Functional Class III or IV symptoms with no improvement in 6MWD
  • Number of subjects undergoing heart-lung or lung transplantation, number of subjects listed for transplantation, and deaths while waiting transplantation [ Time Frame: Through study completion, up to 2 years ]
  • Medical healthcare resource utilization questionnaire [ Time Frame: Through study completion, up to 2 years ]
    At screening, subjects will be asked about the number of hospitalizations, ER visits, and outpatient visits in the previous year. At each visit thereafter, the subject's medical healthcare resource utilization in terms of number of hospitalizations and outpatient medical care, including ER visits, since the previous visit.
  • Incidence and severity of Adverse Events [ Time Frame: Through study completion, up to 2 years ]
  • Incidence of device malfunction and/or device failure leading to an Adverse Event [ Time Frame: Through study completion, up to 2 years ]
  • Incidence of rebound pulmonary hypertension [ Time Frame: Baseline, Week 2 ]
  • Clinically significant changes in clinical laboratory tests, pulmonary function tests, vital signs [ Time Frame: Through study completion, up to 2 years ]
 
Clinical Study of Pulsed, Inhaled Nitric Oxide Versus Placebo in Symptomatic Subjects With PAH
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)
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
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)
Interventional
Phase 3
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Pulmonary Arterial Hypertension
  • Drug: Inhaled Nitric Oxide 75 mcg/kg IBW/hr
    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)
    Other Names:
    • Inhaled Nitric Oxide
    • iNO
  • Drug: Placebo
    Placebo arm: Inhaled Nitric Oxide 15mcg/Kg IBW/hr
    Other Names:
    • Inhaled Nitric Oxide
    • iNO
  • Experimental: 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

    Intervention: Drug: Inhaled Nitric Oxide 75 mcg/kg IBW/hr
  • Placebo Comparator: Placebo

    Part 1:

    Placebo dose setting 15mcg/kg IBW/hr Run In Period / Placebo dose setting 75 mcg/kg IBW/hr treatment period

    Part 2: iNO 75 mcg/kg IBW/hr Open Label Treatment

    Intervention: Drug: Placebo
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
188
December 2018
July 2018   (Final data collection date for primary outcome measure)

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 (EOS)
  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.

Exclusion Criteria:

  1. 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
  2. PAH associated with untreated thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders or splenectomy
  3. 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
  4. Subjects receiving riociguat
  5. Subjects receiving oral prostanoids as monotherapy
  6. PAH associated with significant venous or capillary involvement, known or suspected pulmonary veno-occlusive disease, or pulmonary capillary hemangiomatosis
  7. Any subject with WHO PH Groups 2, 3, 4 or 5
  8. Subjects with any of the following cardiac abnormalities:

    1. Underlying cardiomyopathy or clinically significant aortic or mitral valve disease in the opinion of the investigator
    2. 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
    3. Current symptomatic coronary artery disease, myocardial infarction within 1 year, or any coronary artery interventions within 6 months
  9. 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)
  10. Subjects with a history of deep vein thrombosis, pulmonary embolism/infarction or prothrombotic disorder must have had chronic thromboembolic pulmonary hypertension (CTEPH) excluded by ventilation/perfusion lung (V/Q) scan
  11. Severe obstructive lung disease defined as both a forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) < 70% and FEV1 < 55% of predicted value
  12. 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
  13. Any subject who develops or has developed a PCWP > 20 mmHg during acute vasodilator testing (AVT)
  14. Systemic hypotension defined as SBP < 90 mmHg persistent at Screening after a period of rest
  15. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
  16. On dialysis
  17. 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 (i.e., 6MWT), including carrying and wearing the pulsed delivery device per study protocol, or medical problem(s) likely to preclude completion of the study
  18. Pregnant or breastfeeding females at Screening
  19. Administered L-arginine within 1 month prior to Screening
  20. Known concomitant life-threatening disease with a life expectancy less than 1 year
  21. Atrial septostomy within 3 months preceding randomization
  22. The concurrent use of the INOpulse device with a continuous positive airway pressure (CPAP), Bilevel positive airway presure BiPAP, or any other positive pressure device.
  23. Use of investigational drugs or devices within 1 month prior to Screening (other than acute vasodilator testing with iNO)
  24. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study
  25. Any subject who has been enrolled in any previous clinical study with inhaled NO administered through pulse delivery.
Sexes Eligible for Study: All
18 Years to 85 Years   (Adult, Senior)
No
Contact: Deena Peace deena.peace@bellerophon.com
Contact: Deborah Quinn, MD deborah.quinn@bellerophon.com
Australia,   Austria,   Belgium,   Canada,   Czechia,   France,   Germany,   Israel,   Italy,   Netherlands,   Portugal,   Serbia,   Spain,   Ukraine,   United Kingdom,   United States
 
 
NCT02725372
PULSE-PAH-004
Yes
Not Provided
Plan to Share IPD: No
Bellerophon ( Bellerophon Pulse Technologies )
Bellerophon Pulse Technologies
Worldwide Clinical Trials
Study Director: Deborah Quinn, MD Bellerophon Therapuetics
Bellerophon
August 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP