Iloprost Power Disc-15 in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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A Phase IIIb, Multicenter, Open-Label Study of Patients With Pulmonary Arterial Hypertension Treated With Iloprost(Inhalation)Evaluating Safety and Inhalation Times When Converting From Power Disc-6 to Power Disc-15 With the I-neb® Adaptive Aerosol Delivery® System (I-neb® AAD®)

Official Title
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A Phase IIIb, Multicenter, Open-label Study of Patients With Pulmonary Arterial Hypertension Treated With Iloprost(Inhalation)Evaluating Safety and Inhalation Times When Converting From Power Disc-6 (PD-6) to Power Disc-15 (PD-15) With the I-neb® AAD®

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Iloprost PD-6
* Drug: Iloprost PD-15


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent prior to initiation of any study-mandated procedure. Male or female patients aged 18-85 years. Patients with symptomatic pulmonary arterial hypertension in New York Heart Association (NYHA) functional class III or IV at the time of initiation of iloprost inhalation (Ventavis®) therapy using the Power Disc-6 (PD-6). Patients with the following types of pulmonary arterial hypertension (PAH) belonging to World Health Organization (WHO) Group I: 1.1: Idiopathic (IPAH) 1.2: Familial (FPAH) 1.3: Associated with (APAH) 1.3.1: Collagen vascular disease 1.3.2: Congenital systemic-to-pulmonary shunts at least 2 years post surgical repair 1.3.4: Human immunodeficiency virus (HIV) infection 1.3.5: Drugs and toxins PAH confirmed by the most recent right heart catheterization showing: Mean pulmonary arterial pressure (mPAP)≥ 25 mmHg at rest Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg. If both PCWP and LVEDP are available then the LVEDP value is retained for inclusion. Pulmonary vascular resistance (PVR) > 240 dyn-sec/cm^5 Compliant with a treatment regimen of commercial iloprost inhalation (Ventavis® 5 μg) using the I-neb® AAD® equipped with the PD-6 for at least 4 weeks prior to screening. Pulmonary function tests (PFTs) including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), and total lung capacity (TLC), performed within 6 months of screening. If taking other medications for PAH, these must have been stable for 60 days prior to baseline. If taking corticosteroids, these must have been stable for 60 days prior to baseline. Women of childbearing potential with a negative urine pre-treatment pregnancy test at baseline and who: consistently and correctly use (from screening and up to 28 days after discontinuation of study drug) a reliable method of contraception with a Pearl index of < 1%, are sexually abstinent, or have a vasectomized partner. A woman is considered to have childbearing potential unless she meets at least one of the following criteria: Previous bilateral salpingo-oophorectomy or hysterectomy Premature ovarian failure confirmed by a specialist gynecologist XY genotype, Turner syndrome, uterine agenesis Is aged > 50 years and not treated with any kind of hormone replacement therapy (HRT) for at least 2 years prior to screening, with amenorrhea for at least 24 consecutive months Exclusion Criteria: PAH belonging to WHO group II-V. PAH belonging to WHO group I other than that listed in the inclusion criteria, i.e., PAH associated with: 1.3.3: Portal hypertension 1.3.6: Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders, splenectomy) 1.4: Associated with significant venous or capillary involvement: 1.4.1: Pulmonary veno-occlusive disease (PVOD) 1.4.2: Pulmonary capillary hemangiomatosis (PCH). Receipt of any prostacyclin or prostacyclin analog other than iloprost within 12 weeks before screening. Anticipation of the need for intravenous prostacyclin use within 28 days of starting the Power Disc-15 (PD-15). HIV-seropositive with any of the following: Concomitant active opportunistic infections within 6 months prior to screening Detectable viral load within 6 months of screening CD4+ T-cell count < 200 mm^3 within 3 months of screening Changes in antiretroviral regimen within 3 months of screening Anticipated changes in antiretroviral regimen during study periods 1 or 2 Using inhaled pentamidine Systemic hypotension with systolic blood pressure < 95 mmHg. Uncontrolled systemic hypertension (systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg on repeated measurement). History of left-sided heart disease, including any of the following: hemodynamically significant aortic or mitral valve disease restrictive or congestive cardiomyopathy left ventricular ejection fraction < 40% by multigated radionucleotide angiogram (MUGA), angiography, or echocardiography coronary artery disease with continuing symptoms of angina pectoris life-threatening cardiac arrhythmias Atrial septostomy within 1 year. History of pulmonary embolism prior to diagnosis of PAH unless it can be documented that chronic thromboembolic pulmonary hypertension (CTEPH) has been specifically excluded (e.g., ventilation/perfusion (VQ) scan, pulmonary angiogram). Restrictive lung disease: TLC < 60% of normal predicted value. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5 or clinically relevant chronic obstructive lung disease or asthma (including any patient requiring concomitant medication to control symptoms of bronchospasm including as needed (p.r.n.) use). Clinically relevant bleeding disorder or active bleeding. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C or hepatic cirrhosis. Pregnant or breast-feeding. Chronic renal insufficiency, as defined by a creatinine of > 2.5 mg/dL or the requirement for dialysis. Hemoglobin < 75% of the lower limit of normal range. Any condition that prevents compliance with the protocol or adherence to therapy or ability to provide informed consent. Participation in any other clinical trial, except observational, or receipt of an investigational product within 30 days prior to enrollment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Iloprost<br>The study enrolled patients who were already using iloprost with PD-6 without any safety or tolerability concerns, thereby facilitating a direct comparison of the PD-15 to the PD-6. The single-arm design allowed each patient to serve as his/her own control | Drug: Iloprost PD-6<br>* Period 1 (PD-6): study period defined as the 14 days prior to the first dose of study iloprost inhalation with PD-15. Commercial iloprost inhalation solution delivered using the Power Disc-6 with the I-neb® Adaptive Aerosol Delivery (AAD®) system administered 6 to 9 times per day<br>* Other names: Ventavis;Drug: Iloprost PD-15<br>* Period 2 (PD-15): study period between the administration of the first dose with PD-15 on Day 1 until Day 28 inclusive. Period 3 (PD-15): study period from Day 29 until discontinuation of the PD-15. Commercial iloprost inhalation solution delivered using the Power Disc-15 with the I-neb® Adaptive Aerosol Delivery (AAD®) system administered 6 to 9 times per day<br>* Other names: Ventavis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Reporting Treatment-emergent Adverse Events (AEs) | Number of patients reporting at least one treatment-emergent AE/Serious AE | From the first dose to last dose of investigational product, an average of approximately 268 days, plus 48 hours | 
| Number of Patients Who Discontinued Iloprost PD-15 Treatment Due to an AE | Number of patients reporting at least one treatment-emergent AE/Serious AE leading to discontinuation of study investigational treatment | From the first dose of investigational product to study discontinuation, an average of approximately 268 days | 
| Number of Patients Reporting Treatment-emergent Serious AEs | Number of patients reporting at least one treatment-emergent serious AEs | From the first to last dose of investigational product, an average of approximately 268 days, plus 48 hours | 
| Systolic Blood Pressure - Iloprost PD-6 (Period 1) | Systolic blood pressure was measured immediately prior to first dosing with Iloprost PD-15 | Day 1 | 
| Systolic Blood Pressure - Iloprost PD-15 (Period 2) | Systolic blood pressure was measured on Day 28 of treatment with Iloprost PD-15 | Day 28 | 
| Systolic Blood Pressure - Iloprost PD-15 (Period 3) | Systolic blood pressure was measured at the end of study visit | an average of approximately 268 days | 
| Change in Systolic Blood Pressure - (Period 1 to Period 2) | Systolic blood pressure was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and Day 28 of treatment with Iloprost PD-15 (Period 2) | Day 1 and Day 28 | 
| Change in Systolic Blood Pressure - (Period 1 to Period 3) | Systolic blood pressure was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and at the end of treatment with Iloprost PD-15 (Period 3) | Day 1 and End of study visit, an average of approximately 268 days | 
| Diastolic Blood Pressure - Iloprost PD-6 (Period 1) | Diastolic blood pressure was measured immediately prior to first dosing with Iloprost PD-15 | Day 1 | 
| Diastolic Blood Pressure - Iloprost PD-15 (Period 2) | Diastolic blood pressure was measured on Day 28 of treatment with Iloprost PD-15 | Day 28 | 
| Diastolic Blood Pressure - Iloprost PD-15 (Period 3) | Diastolic blood pressure was measured at the end of study visit | an average of approximately 268 days | 
| Change in Diastolic Blood Pressure - (Period 1 to Period 2) | Diastolic blood pressure was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and Day 28 of treatment with Iloprost PD-15 (Period 2) | Day 1 and Day 28 | 
| Change in Diastolic Blood Pressure - (Period 1 to Period 3) | Diastolic blood pressure was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and at the end of treatment with Iloprost PD-15 (Period 3) | Day 1 and End of study visit, an average of approximately 268 days | 
| Heart Rate - Iloprost PD-6 (Period 1) | Heart rate was measured immediately prior to first dosing with Iloprost PD-15 | Day 1 | 
| Heart Rate - Iloprost PD-15 (Period 2) | Heart rate was measured on Day 28 of treatment with Iloprost PD-15 | Day 28 | 
| Heart Rate - Iloprost PD-15 (Period 3) | Heart rate was measured at the end of study visit | an average of approximately 268 days | 
| Change in Heart Rate - (Period 1 to Period 2) | Heart rate was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and Day 28 of treatment with Iloprost PD-15 (Period 2) | Day 1 and Day 28 | 
| Change in Heart Rate - (Period 1 to Period 3) | Heart rate was measured on Day 1 prior to treatment with Iloprost PD-15 (Period 1) and at the end of treatment with Iloprost PD-15 (Period 3) | Day 1 and End of study visit, an average of approximately 268 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Inhalation Time - Iloprost PD-6 (Period 1) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Inhalation Time - Iloprost PD-15 (Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Inhalation Time - Iloprost PD-15 (Period 3) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 240 days | 
| Change in Average Inhalation Time - (Period 1 to Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average approximately 56 days | 
| Average Number of Days of Dosing - Iloprost PD-6 (Period 1) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Number of Days of Dosing - Iloprost PD-15 (Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Number of Days of Dosing - Iloprost PD-15 (Period 3) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 240 days | 
| Change in Average Number of Days of Dosing - (Period 1 to Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average approximately 56 days | 
| Average Number of Daily Doses - Iloprost PD-6 (Period 1) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Number of Daily Doses - Iloprost PD-15 (Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Average Number of Daily Doses - Iloprost PD-15 (Period 3) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 240 days | 
| Change in Average Number of Daily Doses - (Period 1 to Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average approximately 56 days | 
| Percentage of Complete Doses Delivered - Iloprost PD-6 (Period 1) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Percentage of Complete Doses Delivered - Iloprost PD-15 (Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 28 days | 
| Percentage of Complete Doses Delivered - Iloprost PD-15 (Period 3) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average of approximately 240 days | 
| Change in Percentage of Complete Doses Delivered - (Period 1 to Period 2) | The time and date of inhalation, inhalation time (minutes), and dose completion status (<12.5%, ≥12.5 to <100%, full) were recorded in the memory chip of the I-neb® AAD® each time it was used. | average approximately 56 days | 
| New York Health Association (NYHA) Functional Class - Iloprost PD-6 (Period 1, Prior to First Dose With Iloprost PD-15) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | average of approximately 28 days | 
| NYHA Functional Class - Iloprost PD-15 (Period 2, Day 28) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | average of approximately 28 days | 
| NYHA Functional Class - Iloprost PD-15 (Period 3, End of Study Visit)) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | average of approximately 268 days | 
| Number of Patients With Improved, no Change, or Worsening of NYHA Functional Class - (Period 1, Prior to First Dose With Iloprost PD-15 to Period 2, Day 28) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | average approximately 28 days | 
| Number of Patients With Improved, no Change, or Worsening of NYHA Functional Class - (Period 1, Prior to First Dose With Iloprost PD-15 to Period 3, End of Study Visit) | Disease severity was assessed by NYHA classification of PAH criteria: Class I: no limitation of physical activity (PA). Ordinary PA: no undue dyspnea/fatigue, chest pain, near syncope. Class II: slight limitation of PA. Comfortable at rest. Ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class III: marked limitation of PA. Comfortable at rest. Less than ordinary PA: undue dyspnea/fatigue, chest pain, near syncope. Class IV: inability to carry out PA without symptoms. Right heart failure. Dyspnea/fatigue may even have been present at rest. Discomfort increased by any PA. | average approximately 268 days | 
| Patient Global Self Assessment - Iloprost PD-6 (Period 1, Prior to First Dose With Iloprost PD-15) | The Patient Global Self Assessment is a 7-point scale that was presented to patients prior to conducting visit-specific study procedures. Patients were asked to compare their current PAH status to their status in the past by selecting one of the following options: markedly better; moderately better; mildly better; no change; mildly worse; moderately worse; or markedly worse. On Day 1 prior to their first dose of iloprost with PD-15 (Baseline), patients were asked to compare their PAH status to that during Screening (if the Screening and Baseline visits were conducted on the same day, then patients were asked to compare their PAH status to that in the past 2 weeks). On Day 28 and at the end of study (EOS) visit, patients were asked to compare their PAH status to that of the previous visit. | average of approximately 28 days | 
| Patient Global Self Assessment - Iloprost PD-15 (Period 2, Day 28) | The Patient Global Self Assessment is a 7-point scale that was presented to patients prior to conducting visit-specific study procedures. Patients were asked to compare their current PAH status to their status in the past by selecting one of the following options: markedly better; moderately better; mildly better; no change; mildly worse; moderately worse; or markedly worse. On Day 1 prior to their first dose of iloprost with PD-15 (Baseline), patients were asked to compare their PAH status to that during Screening (if the Screening and Baseline visits were conducted on the same day, then patients were asked to compare their PAH status to that in the past 2 weeks). On Day 28 and at the EOS visit, patients were asked to compare their PAH status to that of the previous visit. | average of approximately 28 days | 
| Patient Global Self Assessment - Iloprost PD-15 (Period 3, End of Study Visit)) | The Patient Global Self Assessment is a 7-point scale that was presented to patients prior to conducting visit-specific study procedures. Patients were asked to compare their current PAH status to their status in the past by selecting one of the following options: markedly better; moderately better; mildly better; no change; mildly worse; moderately worse; or markedly worse. On Day 1 prior to their first dose of iloprost with PD-15 (Baseline), patients were asked to compare their PAH status to that during Screening (if the Screening and Baseline visits were conducted on the same day, then patients were asked to compare their PAH status to that in the past 2 weeks). On Day 28 and at the EOS visit, patients were asked to compare their PAH status to that of the previous visit. | average of approximately 268 days | 
| Number of Patients With Improved, no Change, or Worse Patient Global Self Assessment - Change From Previous Visit to Period 2, Day 28 | The Patient Global Self Assessment is a 7-point scale that was presented to patients prior to conducting visit-specific study procedures. Patients were asked to compare their current PAH status to their status in the past by selecting one of the following options: markedly better; moderately better; mildly better; no change; mildly worse; moderately worse; or markedly worse. On Day 1 prior to their first dose of iloprost with PD-15 (Baseline), patients were asked to compare their PAH status to that during Screening (if the Screening and Baseline visits were conducted on the same day, then patients were asked to compare their PAH status to that in the past 2 weeks). On Day 28 and at the EOS visit, patients were asked to compare their PAH status to that of the previous visit. | average of approximately 28 days | 
| Number of Patients With Improved, no Change, or Worse Patient Global Self Assessment - Change From Previous Visit to Period 3, End of Study Visit | The Patient Global Self Assessment is a 7-point scale that was presented to patients prior to conducting visit-specific study procedures. Patients were asked to compare their current PAH status to their status in the past by selecting one of the following options: markedly better; moderately better; mildly better; no change; mildly worse; moderately worse; or markedly worse. On Day 1 prior to their first dose of iloprost with PD-15 (Baseline), patients were asked to compare their PAH status to that during Screening (if the Screening and Baseline visits were conducted on the same day, then patients were asked to compare their PAH status to that in the past 2 weeks). On Day 28 and at the EOS visit, patients were asked to compare their PAH status to that of the previous visit. | average of approximately 268 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pulmonary arterial hypertension, inhaled therapy, power disc-15