Comparative PK PD Study in PAH Patients (Fox vs. I-Neb)

Study Overview
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Brief Summary
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Administration of iloprost aerosol comparing two nebulizers: FOX and I-Neb

Official Title
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A Multi-center, Open-label, Randomized Cross-over Study to Compare the Acute Tolerability and Pharmacokinetics of BAYQ6256 (Iloprost; Ventavis) Inhalation Using the I-Neb Nebulizer and the FOX Nebulizer in Patients With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: lloprost(Ventavis,BAYQ6252, 20 µg/mL)
* Drug: lloprost(Ventavis,BAYQ6252, 10 µg/mL)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged ≥ 18 years Current diagnosis of pulmonary hypertension (updated Dana Point Classification 1). Current inhalative therapy with 5 µg iloprost using the I-Neb nebulizer WHO functional class III at the time of the patient's commencement of inhalative therapy with iloprost Hemodynamic diagnosis of Pulmonary arterial hypertension(PAH) showing mean pulmonary arterial pressure (mPAP) > 25 mmHg, pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) < 15 mmHg and pulmonary vascular resistance (PVR) > 320 dyn•s•cm-5 If non-specific types of chronic treatment for PAH are being administered: Stable dosage of these for at least the 4 weeks up to screening If PAH-specific drug treatments (such as endothelin receptor antagonist (ERA) or phosphodiesterase-5 (PDE5) inhibitors) are being administered: Stable dosage of these for at least the 3 months up to screening. Exclusion Criteria: PAH related to any other etiology, especially to pulmonary veno-occlusive disease (PVOD) Clinically relevant obstructive lung disease Evidence of thromboembolic disease (probable pulmonary embolism) within 3 years before screening Cerebrovascular events within 3 months before screening Atrial septostomy within the 6 months before screening Severe arrhythmia, or severe coronary heart disease or unstable angina, or myocardial infarction within 6 months before screening, or congenital or acquired valvular defects with clinically relevant myocardial function disorders unrelated to PAH Systolic blood pressure < 85 mm Hg, or uncontrolled systemic hypertension (systolic BP > 160 mmHg or diastolic BP > 100 mmHg) Hepatic impairment (Child Pugh B, C) or chronic renal insufficiency (creatinine > 2.5 mg/dl) and /or requirement of dialysis Clinically relevant bleedings disorders or conditions with increased risk for hemorrhages (active ulcers, trauma etc.) Addition or dose change of PAH specific drug treatments such as ERA or PDE5 inhibitors within 3 months before screening, or addition or dose change of non-specific treatments for PAH such as calcium channel blockers, nitrates, digitalis, diuretics within 4 weeks before Screening, or any kind of prostanoid other than those mentioned in inclusion criteria within less than 5 half-lives before treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: I-Neb - FOX<br>Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer; followed by single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer in a cross-over fashion. A washout period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks in a cross-over fashion. | Drug: lloprost(Ventavis,BAYQ6252, 20 µg/mL)<br>* 20 µg/mL iloprost nebulizer solution, inhaled with FOX nebulizer<br>Drug: lloprost(Ventavis,BAYQ6252, 10 µg/mL)<br>* 10 µg/mL iloprost nebulizer solution, inhaled with I-Neb nebulizer<br>|
| Experimental: FOX - I-Neb<br>Part 1: Subjects received single inhalation of 1.25 mcg iloprost using 10 mcg/ml iloprost solution (Ventavis 10) and then 2.5 mcg iloprost using Ventavis 10, both using the FOX nebulizer on Day 1. Part 2: On Day 2, subjects received single inhalation of 5 mcg iloprost using 20 mcg/ml iloprost solution (Ventavis 20) with the FOX nebulizer; followed by single inhalation of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer in a cross-over fashion. A wash-out period of at least 2 hours was maintained between treatments in Part 1 and Part 2. Part 3: Continued on Day 2, and through until Day 30, subjects received multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 20 with the FOX nebulizer for 2 weeks; followed by multiple inhalations (approximately 6 to 9 inhalations per day) of 5 mcg iloprost using Ventavis 10 with the I-Neb nebulizer for 2 weeks in a cross-over fashion. | Drug: lloprost(Ventavis,BAYQ6252, 20 µg/mL)<br>* 20 µg/mL iloprost nebulizer solution, inhaled with FOX nebulizer<br>Drug: lloprost(Ventavis,BAYQ6252, 10 µg/mL)<br>* 10 µg/mL iloprost nebulizer solution, inhaled with I-Neb nebulizer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients with a meaningful maximum increase (i.e. >=25%) in heart rate AND/OR a meaningful maximum decrease (i.e. >=20%) in systolic blood pressure within the 30 minutes after the start of inhalation |  | multiple measurements within 30 minutes after iloprost inhalation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum change in systolic, diastolic and mean arterial blood pressure |  | From baseline to multiple BP measurements within 2 hours after iloprost inhalation | 
| Maximum change in heart rate within the 30 minutes following inhalation |  | From baseline to multiple HR measurements within 30 minutes after iloprost inhalation | 
| Maximum change in oxygen saturation within the 30 minutes following inhalation using finger pulse oxymetry |  | From baseline to multiple measurements within 30 minutes after iloprost inhalation | 
| AUC (area under the plasma concentration curve of BAYQ6256 from zero to infinity) |  | Multiple timepoints up to 1 hour | 
| Maximum observed drug concentration in plasma after single dose administration |  | Multiple blood sampling within 60 minutes after Ventavis inhalation and subsequent iloprost bioanalytics | 
| Time to reach maximum drug observed concentration in plasma after single dose |  | Multiple blood sampling within 60 minutes after Ventavis inhalation and subsequent iloprost bioanalytics | 
| half-life (associated with terminal slope) |  | Multiple blood sampling within 60 minutes after Ventavis inhalation and subsequent iloprost bioanalytics |