A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil).

Study Overview
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Brief Summary
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The Study Hypothesis: Aggressive, upfront, dual therapy for treatment-naïve NYHA I/II/III PAH is superior to a traditional step-up approach. The study will evaluate: Impact of dual, upfront, therapy on cardiovascular parameters in PAH as gauged by cardiac magnetic resonance imaging (cMRI) at 24 weeks and event free survival at outcome at 48 weeks. Value of novel biomarkers (NT-pro BNP, Mts1/S100A4, and insulin resistance) and cutting-edge imaging technologies (cardiac MRI) as newer endpoints for clinical trials in PAH. Utility of longer clinical trial design with the use of combined clinical events as time to clinical worsening surrogate

Detailed Description
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This is a 48 week interventional study evaluating the effect of Dual therapy ( Treprostinil inhalations and Tadalafil) versus Mono therapy (Tadalafil). The impact of the therapy on cardiovascular parameters in PAH measured at 24 weeks and event free survival outcome at 48 weeks.

Official Title
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CombinatiON Up-FRON t Therapy for PAH - A Phase 4, Randomized, Multicenter Study of Inhaled Treprostinil in Treatment naïve Pulmonary Arterial Hypertension Patients Starting on Tadalafil

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: treprostinil inhalations
* Drug: tadalafil


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18 and < 75 years at baseline visit. Diagnosis of Idiopathic PAH, Heritable PAH (including Hereditary Hemorrhagic Telangiectasia), Associated PAH (including collagen vascular disorders, drug+toxin exposure, repaired congenital heart disease repaired > 5 years, portopulmonary disease, and human immunodeficiency virus (HIV) infection not on protease inhibitor). PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or phosphodiesterase inhibitors within 12 months prior to enrollment. Previous Right Heart Catheterization that documented: Mean PAP; 25 mmHg. Pulmonary capillary wedge pressure < 15 mmHg. Pulmonary Vascular Resistance; 3.0 Wood units or 240 dynes/sec/cm5 5.6MW distances; 150 m and < 450 meters. 6. WHO functional class II or III as judged by principal investigators. Exclusion Criteria: Exclusion criteria: Group II - V pulmonary hypertension. PAH with unrepaired congenital heart defect. Current or prior PAH treatments within the last 6-12 months including experimental PAH therapies (including but not limited to tyrosine kinase inhibitors, rho-kinase inhibitors, phosphodiesterase inhibitors, prostacycline, or cGMP modulators). TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed tomography must be available to exclude significant interstitial lung disease. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted Significant left-sided heart disease (based on pre-trial Echocardiogram): Significant aortic or mitral valve disease Diastolic dysfunction ; Grade II C.LV systolic function < 45% d. Pericardial constriction e. Restrictive cardiomyopathy f. Significant coronary disease with demonstrable ischemia Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min (by MDRD equation) Current atrial arrhythmias Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm Severe hypotension: SBP < 80 mmHg. Pregnant or breast-feeding Psychiatric, addictive, or other disorder that compromises patient's ability to provide informed consent, follow study protocol, and adhere to treatment instructions Co-morbid conditions that would impair a patient's exercise performance and ability to assess WHO functional class, including but not limited to chronic low-back pain or peripheral musculoskeletal problems. Contraindications for magnetic resonance imaging, including significant claustrophobia, implanted metallic objects, or others as per Appendix X). Known allergy to treprostinil or tadalafil. Active oral nitrate use. Diabetes mellitus. Planned initiation of cardiac or pulmonary rehabilitation during period of study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 69 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: tadalafil alone<br>tadalafil 40mg QD(Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated). | Drug: tadalafil<br>* tadalafil 20mg QD PO increasing to 40mg QD as tolerated<br>* Other names: Adcirca;|
| Active Comparator: tadalafil and treprostinil inhalations<br>Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths.Each breath provides approximately 6 mcg of treprostinil.Tadalafil 20 mg QD PO increasing to 40 mg QD as tolerated. | Drug: treprostinil inhalations<br>* Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.<br>* Other names: Tyvaso;Drug: tadalafil<br>* tadalafil 20mg QD PO increasing to 40mg QD as tolerated<br>* Other names: Adcirca;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Right Ventricular Ejection Fraction | Effect of dual-upfront therapies versus mono-therapy on percent change of right ventricular function assesed by cardiac MRI (cMRI) at 24 weeks compared with the baseline. | Basline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 Minute Walk Distance | Change in 6MWD during 24 week period compared between Tada and Tada+iTre. | Baseline and 24 weeks | 
| N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Change from baseline in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) | Baseline and 24 weeks | 
| Change in NYHA/WHO Class | At 48 week,WHO/NYHA functional class was assessed for change in WHO/NYHA functional class.Change NYHA is measured as decrease or increase in NYHA class in the subjects compared with baseline. NYHA /WHO functional class is described below: NYHA functional class I:no symptoms and no limitation in ordinary physical activity NYHA functional class II:Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity NYHA functional class III:Marked limitation in activity due to symptoms, even during less-than-ordinary activity NYHA functional class IV:Severe limitations. Experiences symptoms even while at rest A higher functional class represent worse symptoms. | Baseline and 48 week | 
| B-type Natriuretic Peptide (BNP) | B-type Natriuretic peptide measures the percent change from baseline. | Baseline and 24 weeks |