Treprostinil Combined With Tadalafil for Pulmonary Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Tadalafil; Placebo
Intervention description: Tadalafil 40mg for 12 weeks; Placebo for 12 weeks
Intervention MeSH terms: Tadalafil
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: treprostinil; pulmonary hypertension, tadalafil

Summary:

      Objectives: To test whether the combined administration of the medications treprostinil(a
      prostacycline therapy), and tadalafil(a PDE-5 [ phosphodiesterase type 5]Inhibitor therapy)
      is better than the administration of treprostinil alone. This treatment would be offered to
      newly diagnosed patients with pulmonary arterial hypertension who are on no treatment for
      this disease and are deemed candidates for the medication treprostinil by their physician.
      The combination therapy will be compared to single therapy with only treprostinil in a
      double-blind manner.

      Current therapy is to begin one treatment, either a PDE5 inhibitor or a prostacycline,
      depending on the severity of the patient's PAH (pulmonary arterial hypertension) disease and
      add additional therapies as deterioration occurs. This treatment could add two agents
      initially.

      Secondary objectives are: To improve pulmonary arterial pressures as measured through a
      cardiac echocardiogram, improve the subject's 6minute walk distance, delaying the time to
      clinical worsening, and lowering plasma BNP levels.

      Research Procedures: To begin the administration of both treatments at the same time.

      Time period is 16 weeks with a one- year follow-up. Cardiac Echocardiograms, clinic physician
      exams, and lab work will be followed. Subjects will be between the ages of 18 - 75.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Adult patients 18-80 years of age

          2. World Health Organization Group 1 PAH

               1. Idiopathic PAH

               2. Heritable PAH

               3. PAH associated with connective tissue disease

               4. PAH associated with surgical repair of congenital left to right shunt

               5. PAH associated with anorectic drug use

          3. WHO functional Class III-IV

          4. 6 minute walking distance > 150-meters and < 450 meters

          5. Right heart catheterization showing mean PAP (pulmonary arterial pressure)> 25 mmHg
             and PCWP (pulmonary capillary wedge pressure) < 15 mmHg within 6 months of study
             entry.

        Exclusion Criteria:

          1. Pulmonary hypertension associated with

             a. Portal hypertension b. HIV infection c. Pulmonary venous hypertension defined as
             PCWP > 15 mmHg d. Chronic lung disease defined as i. FEV1(forced expiratory volume at
             one second

             )/FVC (forced vital capacity) less than 0.65 ii. TLC < 0.70 iii. Untreated Sleep Apnea
             with AHI (apnea-hypopnea index )> 20 or hemoglobin oxygen saturation nadir < 87% e.
             Chronic Thromboembolic Disease f. Sarcoidosis g. Pulmonary veno occlusive disease
             (PVOD)

          2. Concomitant use of nitrates (any form) either regularly or intermittently.

          3. Concomitant use of potent CYP3A inhibitors (e.g., ritonavir, ketoconazole,
             itraconazole)

          4. Vascular disease of the retina including retinitis pigmentosa, any sudden vision loss,
             including any damage to the optic nerve or NAION

          5. low blood pressure or high blood pressure that is not controlled

          6. Postural hypotension

          7. Inability to manage home infusion therapy

          8. Pulmonary vasodilator therapy with any phosphodiesterase inhibitor or endothelin
             receptor antagonist within 30 days of study entry

          9. Participation in a clinical investigational study within previous 30 days

         10. Renal failure defined as:

               1. estimated creatinine clearance < 30 ml/min

               2. serum creatinine > 2.5 mg/dl

         11. Subjects with liver function abnormalities (ALT [Alanine Aminotransferase or AST
             (Alanine Aminotransferase ) > 3 times the upper limit of normal at screening or at
             baseline) or chronic liver disease

         12. History of hypersensitivity reaction or adverse effect related to tadalafil

         13. Life expectancy < 12 months

         14. History of deformed penis shape, an erection that lasted more than 4 hours, or
             Peyronie's disease.

         15. Blood cell problems such as sickle cell anemia, multiple myeloma, or leukemia

         16. Pregnant or planning to become pregnant or breast feed.