Treprostinil Combined With Tadalafil for Pulmonary Hypertension

Randomized Placebo Controlled Trial of Treprostinil Infusion Combined With Oral Tadalafil or Placebo in Pulmonary Arterial Hypertension

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.

Background: Many cardiovascular diseases such as essential hypertension, coronary artery disease and congestive heart failure respond better to combinations of vasoactive drugs, than to therapy with a single agent. Three categories of pulmonary anti-hypertensive medications have been developed over the last 20 years, but their effect on management of PAH when used in combination are mostly unknown. Two of the pulmonary arterial hypertension (PAH) drug groups are prostacyclines, and PDE5 inhibitors. Although the effects of prostacyclins are mediated via cAMP (cyclic guanosine monophosphate) and the effects of PDE5 inhibitors are mediated via cGMP, there is considerable cross talk between these nucleotides suggesting that adequate levels of both may be needed to maintain normal pulmonary vascular tone and cellular growth responses.

Objective/Hypothesis: This proposal hypothesizes that increasing the levels of both nucleotides (prostacyclines and PDE5 inhibitors), may be more efficacious in the treatment of PAH than increasing either one alone.

Specific Aims: The primary objective of this study is to determine if the combination of treprostinil infusion combined with tadalafil is more efficacious than treprostinil alone in improving the change from baseline in the 6 minute walking distance after 16 weeks of therapy.

Study Design: The proposed study is a multi-center, randomized, double blind, two cohort, parallel group, and 16-week study with 1-year long-term follow-up. The study aims to compare the efficacy of combination therapy with treprostinil infusion and tadalafil to treprostinil infusion alone.

Study Population: All patients who have been newly diagnosed with PAH and who, after consultation with their physician, have elected to be treated with treprostinil infusion will be invited to participate. A total of 66 subjects will be sort to enroll.

Treprostinil dosing will follow a 4 week up-titration schedule with a target 4week dose of 8ng/kg/min minimum, followed by a 12 week randomized tadalafil period.

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.