E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Part 1: Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD)
Part 2: Pulmonary Hypertension (PH) Associated with Idiopathic pulmonary fibrosis (IPF) |
Deel 1: Pulmonale hypertensie (PH) geassocieerd met chronische obstructieve longziekte (COPD)
Deel 2: Pulmonale hypertensie (PH) geassocieerd met Idiopathische longfibrose (IPF) |
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E.1.1.1 | Medical condition in easily understood language |
Part 1: Pulmonary Hypertension (PH) Associated with Chronic Obstructive Pulmonary Disease (COPD)
Part 2: Pulmonary Hypertension (PH) Associated with Idiopathic pulmonary fibrosis (IPF) |
Deel 1: Pulmonale hypertensie (PH) geassocieerd met chronische obstructieve longziekte (COPD)
Deel 2: Pulmonale hypertensie (PH) geassocieerd met Idiopathische longfibrose (IPF) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10021240 |
E.1.2 | Term | Idiopathic pulmonary fibrosis |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10010952 |
E.1.2 | Term | COPD |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10009033 |
E.1.2 | Term | Chronic obstructive pulmonary disease |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037400 |
E.1.2 | Term | Pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037401 |
E.1.2 | Term | Pulmonary hypertensions |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
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. |
Het primaire doel van deze verkennende studie is het nut te onderzoeken van hoge resolutie computertomografie (HRCT) om veranderingen in de functionele pulmonale beeldvorming parameters te meten in functie van de op korte termijn iNO administratie met behulp van het medisch INOpulse® device bij patiënten met WHO groep 3 PH geassocieerd met COPD (Deel 2) en bij patiënten met WHO groep 3 PH geassocieerd met IPF (Deel 2) die LTOT krijgen. In deel 1 werd iNO toegediend door het te onderzoeken INOpulse® DS-C device. In deel 2 zal het INOpulse® device worden gebruikt. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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Deel 1:
1. Een bevestigde diagnose van COPD door de Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria
2. Pulmonale hypertensie bepaald in de afgelopen 12 maanden door 1 van de volgende :
a. Een rechter hart catheterisatie (niet binnen ± 7 dagen van een exacerbatie) met een mPAP ≥ 25 mmHg of
b. Een echocardiogram (niet binnen ± 7 dagen van een exacerbatie) met een TRV ≥ 2,9 meter per seconde (m /s), of een systolische PAP ≥ 38 mmHg door een 2-D echocardiogram.
(Opmerking: een patiënt met een TRV <2,9 m / s zal voldoen aan deze criteria als er een aanvaardbaar mPAP ≥ 25 mmHg bepaald wordt door een rechter hart catheterisatie)
3. Huidige of ex-rokers met minstens 10 pack-jaren rookgeschiedenis vóór de studie
4. Leeftijd ≥ 40 jaar, ≤ 80 jaar
5. Een post-bronchusdilatoire FEV1 / FVC <0,7 en een FEV1 <60% predicted (waarden verkregen binnen de 6 maanden vóór de screening kunnen worden gebruikt, tenzij verkregen binnen ± 7 dagen van een exacerbatie, anders moet de test bij screening worden uitgevoerd)
6. Het ontvangen van LTOT gedurende ≥ 3 maanden en ≥ 10 uur per dag, zoals bepaald door de geschiedenis
7. Vruchtbare vrouwen moeten een negatieve urine zwangerschapstest hebben vóór de behandeling
8. Ondertekend geïnformeerde toestemming voorafgaand aan alle procedures of beoordelingen in opdracht van de studie
Deel 2:
1. Een bevestigde diagnose van IPF door een verantwoordelijke en ervaren longarts en op basis van;
• HCRT: gebruikelijke interstitiële pneumonie
• FVC: 50-90% van de voorspelde FVC
2. PH bepaald als SPAP ≥ 50 mm Hg door een echocardiogram
3. Leeftijd ≥ 40 jaar
4. Het ontvangen van LTOT gedurende ≥ 3 maanden
5. Vruchtbare vrouwen moeten een negatieve urine zwangerschapstest hebben vóór de behandeling
6. Ondertekend geïnformeerde toestemming voorafgaand aan alle procedures of beoordelingen in opdracht van de studie
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E.4 | Principal 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 (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.
5. Known allergy to contrast media.
6. 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
7. Use within 30 days of screening or current use of approved specific PH medications (ERA or PDE-5 inhibitor, or oral, inhaled, subcutaneous, or intravenous prostacyclin or a prostacyclin analog)
8. Use of investigational drugs or devices within 30 days prior to enrollment into the study
9. Any underlying medical or psychiatric condition that, in the opinion of the Investigator, makes the subject an unsuitable candidate for the study
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E.5 End points |
E.5.1 | 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. |
Het primaire eindpunt in deze verkennende studie is de verandering ten opzichte van baseline in lobaire bloedvolume op de totale longcapaciteit (TLC) na toediening van gepulste iNO (Deel 1) en iNO of Placebo (Deel 2) gemeten door HRCT. |
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E.5.1.1 | 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 |
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E.5.2 | 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
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E.5.2.1 | 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 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Exploratory human pharmacol. study with the intent of determining the utility of proposed biomarker |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
An Exploratory, Two-Part, Clinical Study. Part 2b is a chronic open label design. |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |