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    Summary
    EudraCT Number:2015-005223-90
    Sponsor's Protocol Code Number:PULSE-PAH-004
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-05-24
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-005223-90
    A.3Full title of the trial
    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 PULMONARY ARTERIAL HYPERTENSION (PAH): INOvation-1 (Part 1 and Part 2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy, tolerability and safety of pulsed inhaled nitric oxide 75mcg/kg IBW/hr, 12 hours per day or longer for 18 weeks in symptomatic subjects with pulmonary arterial hypertension. (Part 1), followed by an open-label extension (Part 2) which
    provides active therapy to all subjects completing the first 18 weeks.
    A.4.1Sponsor's protocol code numberPULSE-PAH-004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBellerophon Pulse Technologies LLC
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBellerophon Pulse Technologies LLC
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationWorldwide Clinical Trials Ltd
    B.5.2Functional name of contact pointClinical Study Start Up
    B.5.3 Address:
    B.5.3.1Street Address1st Floor Waterfront House, Beeston Business Park, Beeston
    B.5.3.2Town/ cityNottingham
    B.5.3.3Post codeNG9 1LA
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number44207121 6161
    B.5.6E-mailsarah.bly@worldwide.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameinhaled nitric oxide & INOpulse delivery
    D.3.2Product code iNO
    D.3.4Pharmaceutical form Medicinal gas, compressed
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPInhalation use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNITRIC OXIDE
    D.3.9.1CAS number 10102-43-9
    D.3.9.3Other descriptive nameinhaled NO with pulsed delivery
    D.3.9.4EV Substance CodeSUB12540MIG
    D.3.10 Strength
    D.3.10.1Concentration unit PPM part per million
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4880
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Yes
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboMedicinal gas, compressed
    D.8.4Route of administration of the placeboInhalation use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary Arterial Hypertension
    E.1.1.1Medical condition in easily understood language
    An increased blood pressure in the pulmonary artery leading to shortness of breath, dizziness, fainting, leg swelling and/or other symptoms.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part 1 - Blinded Treatment Period:
    To evaluate the efficacy of inhaled nitric oxide (iNO) on exercise using 6-minute walk distance (6MWD) in subjects with pulmonary arterial hypertension (PAH) currently receiving background PAH medication and LTOT.

    Part 2 Open Label Period:
    To Evaluate the long term safety and tolerability of iNO
    E.2.2Secondary objectives of the trial
    Part 1 -Blinded Treatment Period:
    To evaluate the safety and tolerability of iNO

    Part 2 Open Label Period:
    To Evaluate the change in exercise tolerance in subjects who switch from placebo to active therapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Part 1 Blinded Treatment Period

    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 congenital heart disease (unrepaired or repaired 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 last subject completes 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.

    Part 2 Open Label Period
    Inclusion Criteria Part 2:
    1. Informed Consent Form prior to the initiation of any study mandated procedures or assessments
    2. Subject must have completed 18 weeks of blinded therapy and all assessments at week 18
    3. In the opinion of the Investigator, open label treatment is in the best interest of the subject after 18 weeks of blinded treatment is completed
    E.4Principal exclusion criteria
    Part 1 Blinded Treatment Period
    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:
    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
    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 pressure 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.

    Part 2 Open Label Period:
    1. Subject has initiated therapy with Riociguat
    E.5 End points
    E.5.1Primary end point(s)
    Part 1 Blinded Treatment Period
    Primary Endpoint: The efficacy of iNO as measured by the placebo-adjusted change in 6MWD from baseline to 18 weeks.

    Part 2 Open Label Period:
    Primary Endpoint: The incidence of AEs and SAEs with long term therapy
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part 1 Blinded Treatment Period:
    18 weeks

    Part 2 Open Label Period:
    until the investigational drug device is approved and available as a marketed product or the Sponsor decides to terminate the study
    E.5.2Secondary end point(s)
    Part 1 Blinded Treatment Period:
    Secondary Endpoints:
    1. TTCW (for the combined studies PULSE-PAH-003 and PULSE-PAH-004). 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:
    a. Death (all-cause mortality)
    b. Atrial septostomy
    c. Hospitalization due to worsening of PAH (adjudicated)
    d. 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%.
    e. Decrease of >15% from baseline or > 30% compared with the last study related measurement in 6MWD and should be confirmed by a repeat measurement performed at least 14 days later
    f. 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
    2. Change in WHO Functional Class, with iNO as compared to placebo, from baseline to 18 weeks.

    Part 2 Open Label Period:
    To evaluate the change in 6MWD in subjects who switch from placebo to active therapy at 4 months and 8 months and 12 months of therapy
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part 1 Blinded Treatment Phase:
    18 weeks

    Part 2 Open Label Period:
    until the investigational drug device is approved and available as a marketed product or the Sponsor decides to terminate the study
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Part 2 of the trial consist of an Open label Period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    Colombia
    Croatia
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    Portugal
    Serbia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 28
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 188
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    If the subject discontinues participation, they would continue to receive the standard of care.
    For subjects who complete the trial, they’ll be given the opportunity to stay on the medication in a long term extension.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-05-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-08-16
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-08-07
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