A 48-week Study of the Effect of Dual Therapy (Inhaled Treprostinil and Tadafafil) Versus Monotherapy (Tadalafil).
Condition: Hypertension, Pulmonary
MeSH terms: Hypertension, Pulmonary; Hypertension
Intervention: treprostinil inhalations; tadalafil
Intervention description: Treprostinil inhalation QID starting at 3 breaths per inhalation & gradually increasing to 9 breaths. Each breath provides approximately 6mcg of treprostinil.; tadalafil 20mg QD PO increasing to 40mg QD as tolerated
Intervention MeSH terms: Treprostinil; Tadalafil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Maximum age: 69 Years
Healthy volunteers: No

Summary:

      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:

        1. 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.

        2. 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.

        3. Utility of longer clinical trial design with the use of combined clinical events as time
           to clinical worsening surrogate
    

Eligibility criteria:

        Inclusion criteria:

          1. Age 18 and < 75 years at baseline visit.

          2. 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).

          3. PAH treatment naïve including any prostacycline, endothelin receptor antagonist, or
             phosphodiesterase inhibitors within 12 months prior to enrollment.

          4. Previous Right Heart Catheterization that documented:

               1. Mean PAP; 25 mmHg.

               2. Pulmonary capillary wedge pressure < 15 mmHg.

               3. 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:

          1. Group II - V pulmonary hypertension.

          2. PAH with unrepaired congenital heart defect.

          3. 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).

          4. TLC < 60% predicted; if TLC b/w 60 and 70% predicted, high resolution computed
             tomography must be available to exclude significant interstitial lung disease.

          5. FEV1 / FVC < 70% predicted and FEV1 < 60% predicted

          6. Significant left-sided heart disease (based on pre-trial Echocardiogram):

               1. Significant aortic or mitral valve disease

               2. Diastolic dysfunction ; Grade II C.LV systolic function < 45%

             d. Pericardial constriction e. Restrictive cardiomyopathy f. Significant coronary
             disease with demonstrable ischemia

          7. Chronic renal insufficiency defined as an estimated creatinine clearance < 30 ml/min
             (by MDRD equation)

          8. Current atrial arrhythmias

          9. Uncontrolled systemic hypertension: SBP > 160 mm or DBP > 100mm

         10. Severe hypotension: SBP < 80 mmHg.

         11. Pregnant or breast-feeding

         12. Psychiatric, addictive, or other disorder that compromises patient's ability to
             provide informed consent, follow study protocol, and adhere to treatment instructions

         13. 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.

         14. Contraindications for magnetic resonance imaging, including significant
             claustrophobia, implanted metallic objects, or others as per Appendix X).

         15. Known allergy to treprostinil or tadalafil.

         16. Active oral nitrate use.

         17. Diabetes mellitus.

         18. Planned initiation of cardiac or pulmonary rehabilitation during period of study.