Upfront Combination Pulmonary Arterial Hypertension Therapy

Study Overview
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Brief Summary
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To evaluate the safety and efficacy of first-line combination therapy using riociguat with ambrisentan in patients with Pulmonary Arterial Hypertension (PAH).

Detailed Description
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This is a prospective, multi-center, open-label, exploratory study with patients followed for a period of one year. The treatment duration period in this study begins at the initiation of ambrisentan plus riociguat and will continue for 12 months. Patients will come to clinic for a visit at month 4 and 12. Assessments will include Right Heart Catheterization, 6 Minute walk test, cardiac MRI, questionnaires and nt-Pro-BNP.

Official Title
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Upfront Riociguat and Ambrisentan Combination Therapy for Pulmonary Arterial Hypertension: A Safety and Efficacy Pilot Study

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Riociguat Oral Product


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; Males or females ≥ 18 years of age i. Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception. ii. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile. Patients with symptomatic Functional Class III PAH in the following categories: i. Idiopathic (IPAH) ii. Familial (FPAH) iii. Associated with connective tissue disease iv. Associated with drugs or toxins; PAH diagnosed by right heart catheterization, defined as: i. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg ii. PVR > 3 mmHg/l/min (Wood units) or > 240 dyn sec cm-5 iii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg; 150 m ≤ 6 Minute Walk Test (6MWT) distance ≤ 480 m Exclusion Criteria: PAH associated with any other condition than those described in the inclusion criteria (patients with PAH associated with portal hypertension, HIV and CHD should not be included); PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy; Valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included); Restrictive lung disease: total lung capacity (TLC) < 60% of normal predicted value; Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) < 0.5; Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C; Pregnancy or breast-feeding; Systolic blood pressure < 95 mmHg; Body weight < 40 kg; Hemoglobin > 25% below the lower limit of the normal range; Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal ranges; Renal insufficiency as defined by creatinine clearance < 30 mL/min or on dialysis Treatment with phosphodiesterase type 5 inhibitors, any prostanoid (excluding acute administration during a catheterization procedure to test vascular reactivity) or with any other PH specific medication; Treatment or planned treatment with calcineurin-inhibitors (i.e., cyclosporine A and tacrolimus), CYP2C9 and CYP3A4 inhibitors (i.e., ketoconazole, fluconazole) within 1 week of study start; Treatment or planned treatment with nitrate drugs, short acting nitrate-containing medications, alpha blockers or protease inhibitors (i.e., ritonavir); Known hypersensitivity to ambrisentan, riociguat or any of their excipients; Patients with any contraindication to riociguat treatment or ERA treatment Patients with syncope, a rapid rate of symptom progression or with high or rising nt-BNP levels in the judgment of the investigators Any contraindications specified in the product monographs of either ambrisentan or riociguat, including: 1. Patients at increased risk of hypotension with concomitant or underlying conditions such as coronary artery disease, hypovolemia, severe left ventricular outflow obstruction or autonomic dysfunction; patients with resting hypotension 2. Patients with history of serious hemoptysis or patients who have previously undergone bronchial arterial embolization 20. Patients with pulmonary veno-occlusive disease 21. Ongoing participation in any interventional clinical studies.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combo Riociguat and Ambrisentan Therapy<br>Riociguat Oral Product and Ambrisentan Oral Product to be given in combination to de novo (untreated) patients. | Drug: Riociguat Oral Product<br>* Dual therapy of Riociguat and Ambrisentan at initiation of treatment.<br>* Other names: Ambrisentan Oral Product;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary Vascular resistance | Change from baseline to month 4 and month 12 in pulmonary vascular resistance (PVR) as assessed by Right Heart Catheterization. | 4 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemodynamic Variables | Change in hemodynamic variables (mPAP, RAP, CI) from baseline to month 4 and month 12 as assessed by Right Heart Catheterization. | 4 and 12 months | 
| Echocardiographic parameters | Change in echocardiographic parameters (TAPSE, RV strain, Tei index, Left ventricular Eccentricity index, RV:LV area ratio) as assessed by Echocardiogram. | 4 and 12 months | 
| RV function | Change from baseline to month 4 in RV function as assessed by cardiac MRI. | 4 and 12 months | 
| NT-PRo-BNP | Change from baseline NT-PRo-BNP value from baseline to month 4 and month 12 | 4 and 12 Months | 
| Exercise capacity | Change from baseline to month 4 and month 12 in exercise capacity assessed by the 6 minute walk test | 4 and 12 months | 
| Dyspnea | Change from baseline to month 4 and month 12 in dyspnea as assessed by study questionnaire. | 4 and 12 months | 
| Quality of Life Assessment | Change from baseline to month 4 and month 12 in quality of life as assessed by study questionnaire. | 4 and 12 months | 
| Functional Class | Change from baseline to month 4 and month 12 in functional class as assessed by study questionnaire. | 4 and 12 months | 
| Survival | Survival at 12 months | 12 months | 
| Clinical worsening | Time to clinical worsening over 12 months | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Hypertension