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.

• Register: EUCTR
• Last refreshed on: 3 August 2020
• Main ID: EUCTR2015-005223-90-GB
• Date of registration: 11/04/2016
• Prospective Registration: Yes
• Primary sponsor: Bellerophon Pulse Technologies LLC
• Public title: 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.
• Scientific title: 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)
• Date of first enrolment: 12/07/2016
• Target sample size: 188
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-005223-90
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: yes; Other trial design description: Part 2 of the trial consist of an Open label Period; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Canada, Colombia, Croatia, Czech Republic, France, Germany, Hungary, Israel, Italy, Korea, Republic of, Netherlands, Portugal, Serbia, Spain, Ukraine, United Kingdom, United States

Contacts

• Name: Clinical Study Start Up
• Affiliation: Worldwide Clinical Trials Ltd

• Name: Clinical Study Start Up
• Affiliation: Worldwide Clinical Trials Ltd

Key inclusion & exclusion criteria

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 with congenital heart disease (unrepaired or 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 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 160
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 28

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 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 Screen

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension
MedDRA version: 20.0 Level: PT Classification code 10064911 Term: Pulmonary arterial hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

Therapeutic area: Diseases [C] - Respiratory Tract Diseases [C08]

Intervention(s)

Product Name: inhaled nitric oxide & INOpulse delivery
Product Code: iNO
Pharmaceutical Form: Medicinal gas, compressed
INN or Proposed INN: NITRIC OXIDE
CAS Number: 10102-43-9
Other descriptive name: inhaled NO with pulsed delivery
Concentration unit: PPM part per million
Concentration type: equal
Concentration number: 4880-
Pharmaceutical form of the placebo: Medicinal gas, compressed
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Main Objective: 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

Primary 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

Secondary Objective: 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

Timepoint(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

Secondary Outcome(s)

Secondary 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

Timepoint(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

Secondary ID(s)

NCT02725372

PULSE-PAH-004

Source(s) of Monetary Support

Bellerophon Pulse Technologies LLC

Ethics review

Status: Approved
Approval date: 06/06/2016
Contact: