Evaluation of impact of inhaled nitric oxide on pulmonary vessel blood volume measured by high resolution computed tomography (HRCT) in subjects with World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD) on Long-Term Oxygen Therapy (LTOT) (Part 1) and in subjects with WHO Group 3 Pulmonary Hypertension (PH) Associated with Idiopathic pulmonary fibrosis (IPF) on Long-Term Oxygen Therapy (LTOT) (Part 2).

• Register: EUCTR
• Last refreshed on: 10 July 2017
• Main ID: EUCTR2014-003423-21-BE
• Date of registration: 29/08/2014
• Prospective Registration: Yes
• Primary sponsor: Bellerophon Pulse Technologies LLC
• Public title: Evaluation of impact of inhaled nitric oxide on pulmonary vessel blood volume measured by high resolution computed tomography (HRCT) in subjects with World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD) on Long-Term Oxygen Therapy (LTOT) (Part 1) and in subjects with WHO Group 3 Pulmonary Hypertension (PH) Associated with Idiopathic pulmonary fibrosis (IPF) on Long-Term Oxygen Therapy (LTOT) (Part 2).
• Scientific title: An Exploratory, Two-Part, Clinical Study to Assess the Effect of Pulsed, Inhaled Nitric Oxide (iNO) on Functional Pulmonary Imaging Parameters in Subjects with World Health Organization (WHO) Group 3 Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD) on Long-Term Oxygen Therapy (LTOT) (Part 1) and in Subjects with WHO Group 3 PH associated with Idiopathic pulmonary fibrosis (IPF) on LTOT (Part 2).
• Date of first enrolment: 29/09/2014
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003423-21
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: yes Other: yes Other trial design description: An Exploratory, Two-Part, Clinical Study. Part 2b is a chronic open label design. If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 3
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Belgium

Contacts

• Name: Jan De Backer
• Affiliation: Fluidda nv

• Name: Jan De Backer
• Affiliation: Fluidda nv

Key inclusion & exclusion criteria

Inclusion criteria:
Part 1
1. A confirmed diagnosis of COPD by the Global initiative for chronic Obstructive Lung Disease (GOLD) criteria
2. Pulmonary hypertension determined by 1 of the following within the past 12 months
a. A right heart catherization (not obtained within ± 7 days of an exacerbation) with an mPAP = 25 mmHg, or
b. An echocardiogram (not obtained within ± 7 days of an exacerbation) with a TRV = 2.9 meters per second (m/s), or a systolic PAP = 38 mmHg by 2-D echocardiogram.
(Note: a subject with a TRV < 2.9 m/s will meet this inclusion criteria if there is an acceptable mPAP = 25 mmHg determined by right heart catherization)
3. Current or former smokers with at least 10 pack-years of tobacco cigarette smoking history before study entry
4. Age = 40 years, = 80 years
5. A post-bronchodilatory FEV1/FVC < 0.7 and a FEV1 < 60% predicted (values obtained within 6 months prior to screening can be used unless obtained within ± 7 days of an exacerbation; otherwise, the test must be performed during screening)
6. Receiving LTOT for = 3 months and = 10 hours per day as determined by history
7. Females of childbearing potential must have a negative pre-treatment urine pregnancy test
8. Signed informed consent prior to the initiation of any study mandated procedures or assessments
Part 2:
1. Patients will have a diagnosis of IPF as determined by a responsible and experienced Respiratory physician and based on;
• HCRT: usual interstitial pneumonia
• FVC: 50-90% of predicted FVC
2. PH defined as sPAP = 50 mm Hg by echocardiogram
3. Age = 40 years
4. Receiving LTOT for = 3 months
5. Females of childbearing potential must have a negative pre-treatment urine pregnancy test
6. Signed informed consent prior to the initiation of any study mandated procedures or assessments

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 5
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 5

Exclusion criteria:
Part 1:
1. A diagnosis of asthma or other non-COPD respiratory disease, in the opinion of the Investigator
2. Lack of patency of nares upon physical examination
3. Experienced during the last month an exacerbation requiring:
a) start of or increase in systemic oral corticosteroid therapy, and/or
b) hospitalization
4. Left ventricular dysfunction as measured by:
Screening echocardiographic evidence of left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] < 40%), or
Screening echocardiographic evidence of left ventricular diastolic dysfunction greater than moderate (i.e., > Grade 2), or
Any history of pulmonary capillary wedge pressure (PCWP), left atrial pressure (LAP) or left ventricular end diastolic pressure (LVEDP) > 18 mm Hg as measured during cardiac catheterization within the past 6 months unless documented to have resolved by a subsequent cardiac catheterization
5. Renal impairment (i.e., an estimated GFRMDRD < 30 ml/min/1.73 m2) or history of renal failure using the equation (Levey et al., 2007):
estimated GFRMDRD = 175×Scr-1.154×Age-0.203 ×1.212 (if black) ×0.742 (if female)
where Scr = Standardized serum creatinine
Subjects with possible compromised kidney function (eGFRMDRD between 30 and 60 ml/min/1.73 m2) may be enrolled provided the Radiology Department and Principal Investigator review the medical records of subjects with an eGFRMDRD between 30 and 60 ml/min/1.73 m2 in order to confirm the contrast agent can be safely administered to these subjects and approval by both the Radiology Department and Principal Investigator must be obtained before enrolling these subjects.
6. Known allergy to contrast media.
7. Clinically significant valvular heart disease that may contribute to PH, including mild or greater aortic valvular disease (aortic stenosis or regurgitation) and/or moderate or greater mitral valve disease (mitral stenosis or regurgitation), or status post mitral valve replacement
8. Use within 30 days of screening or current use of approved PH medications such as sildenafil or bosentan (use of Cialis® or Viagra® for erectile dysfunction is permitted)
9. Use of investigational drugs or devices within 30 days prior to enrollment into the study
10. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study
Part 2:
1. Patients with a current IPF exacerbation or exacerbation within the past 30 days.
2. Lack of patency of nares upon physical examination
3. Left ventricular dysfunction as measured by:
a) Screening echocardiographic evidence of left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] < 40%), or
b) Screening echocardiographic evidence of left ventricular diastolic dysfunction > moderate (i.e., > Grade 3), or
c) Any history of pulmonary capillary wedge pressure (PCWP), left atrial pressure (LAP) or left ventricular end diastolic pressure (LVEDP) > 18 mmHg as measured during cardiac catheterization within the past 6 months unless documented to have resolved by a subsequent cardiac catheterization
4. Renal impairment (i.e., an estimated GFRMDRD < 30 ml/min/1.73 m2) or history of renal failure using the equation (Levey et al., 2007): estimated GFRMDRD = 175 × Scr -1.154 × Age-0.203 × 1.212 (if black) × 0.742 (if female) where Scr = Standardized serum creatinine
Subjects with possible compromised kidney function (eGFRMD

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

Health Condition(s) or Problem(s) studied

Part 1: Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD) Part 2: Pulmonary Hypertension (PH) Associated with Idiopathic pulmonary fibrosis (IPF)
MedDRA version: 18.1 Level: PT Classification code 10021240 Term: Idiopathic pulmonary fibrosis System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 18.1 Level: LLT Classification code 10010952 Term: COPD System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 18.1 Level: PT Classification code 10009033 Term: Chronic obstructive pulmonary disease System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 18.1 Level: PT Classification code 10037400 Term: Pulmonary hypertension System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
MedDRA version: 18.1 Level: HLT Classification code 10037401 Term: Pulmonary hypertensions System Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders

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

Intervention(s)

Trade Name: INOmax 400ppm mol/mol inhalation gas
Product Name: INO
Pharmaceutical Form: Pressurised inhalation
INN or Proposed INN: NITRIC OXIDE
CAS Number: 10102-43-9
Current Sponsor code: IK-7002
Concentration unit: mg/kg/h milligram(s)/kilogram/hour
Concentration type: up to
Concentration number: 0.075-
Pharmaceutical form of the placebo: Pressurised inhalation
Route of administration of the placebo: Inhalation use

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Part 1: Treatment Visit: at Baseline and after administration of iNO
Part 2a: Treatment Visit A: at Baseline and after administration of iNO/Placebo and Treatment Visit B (at least 5 Days after Treatment Visit A): at Baseline and after administration of iNO/Placebo

Main Objective: The objective of this exploratory study is to examine the utility of high resolution computed tomography (HRCT) to measure changes in functional pulmonary imaging parameters as a function of short term iNO administration using the medical device INOpulse® in subjects with WHO Group 3 PH associated with COPD (Part 1) and in subjects with WHO Group 3 PH associated with IPF (Part 2) on LTOT. In Part 1 iNO was administered by the investigational INOpulse® DS-C device. In Part 2 the INOpulse® device will be used.

Secondary Objective: Not applicable

Primary end point(s): The primary endpoint in this exploratory study is the change from baseline in lobar blood volume at total lung capacity (TLC) after dosing with pulsed iNO (Part 1) and iNO or Placebo (Part 2a) as measured by HRCT.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: Part 1: Treatment Visit: at Baseline and after administration of iNO
Part 2a only:
- HRCT: Treatment Visit A and B: at Baseline and after administration of iNO/Placebo
- Borg Dyspnea Score: at Treatment Visit A, B and follow-up: LTOT, iNO/Placebo + LTOT, LTOT post iNO/Placebo exposure, and 24 hrs post iNO/Placebo exposure
- breathing questionnaire: at Treatment Visit A, B and follow-up: LTOT, LTOT post iNO/Placebo exposure, and 24 hrs post iNO/Placebo exposure
- echocardiogram: at screening, Treatment Visit A and B
Part 2b only:
- Change in 6MWT with Borg Dyspnea Score and SpO2, at the beginning and end of 6MWT: Visit 1, 2, 3, and 4
- Borg Dyspnea Score: Visit 1, 2, 3, and 4
- breathing questionnaire: Visit 1, 2, 3, and 4

Secondary end point(s): Secondary endpoints in this exploratory study are the changes from baseline measured by HRCT after dosing with pulsed iNO (Part 1) and iNO or Placebo (Part 2a) in:
• Blood vessel % and density on lobar level
• Total lung volume at TLC
• Lobar volumes at TLC
• Internal airflow distribution based on lobar expansion
• Airway volume down to generation 8-10 at TLC
• Computational Fluid Dynamics (CFD)-based resistance on lobar level
• Ventilation/perfusion (V/Q) matching
Part 2a only (Acute; Placebo vs. iNO 75 mcg/kg IBW/hr)
• Change in Borg Dyspnea Score (LTOT, iNO/Placebo + LTOT, LTOT post iNO/Placebo exposure, and 24 hrs post iNO/Placebo exposure)
• Changes in breathing questionnaire (LTOT, LTOT post iNO/Placebo exposure, and 24 hrs post iNO/Placebo exposure)
• Changes in RV and LV function (LTOT, iNO/Placebo + LTOT, post iNO/Placebo LTOT alone) by echocardiogram
Part 2b Only (Chronic dosing)
• Change in 6MWT with Borg Dyspnea Score and SpO2, at the beginning and end of the 6MWT and symptoms evaluated using a questionnaire after 4 weeks use of iNO 75 mcg/kg IBW/hr and 2 weeks post discontinuation of iNO

Secondary ID(s)

IK-7002-COPD-006

FLUI-2014-117

Source(s) of Monetary Support

Bellerophon Pulse Technologies LLC