Pulmonary Rehab in COPD: Response to Tyvaso

Study Hypothesis:

Our hypothesis is that pre-treating patients with COPD with inhaled treprostinil prior to
pulmonary rehabilitation sessions will result in improved exercise tolerance during
sessions. This in turn will lead to an increased response to pulmonary rehabilitation,
resulting in improved exercise tolerance and quality of life.

Study Background:

Pulmonary rehabilitation (PR) is a widely accepted intervention in patients with advanced
COPD. This has consistently been shown to improve patients' quality of life and functional
ability. Indeed, enrollment and completion of a course of PR is a prerequisite prior to
major interventions such as lung volume reduction surgery or transplantation. A typical
course of PR includes 20 sessions of supervised exercise and educational activity over an 8
week period. Sessions are usually held three times per week and last between 2-3 hours each.
Most patients with COPD will have a ventilatory limitation to exercise and while many are
oxygen dependent, a minority of patients will have a true hypoxic limitation to exercise.
Nonetheless, when patients with COPD are ambulated on oxygen they feel better and walk
further. Indeed, supplemental oxygen remains one of the few interventions that have been
demonstrated to be associated with improved survival in patients with COPD.

There have been a few studies and case reports utilizing inhaled pulmonary vasodilators in
patients with COPD, although none to date have used treprostinil. One study of 10 patients
with COPD and pulmonary hypertension found improved gas exchange and exercise tolerance
following using of inhaled iloprost an alternative inhaled pulmonary vasodilator. No adverse
effects were observed. [Dernaika TA, Beavin M, Kinasewitz GT. Iloprost improves gas exchange
and exercise tolerance in patients with pulmonary hypertension and chronic obstructive
pulmonary disease. Respiration; 2010: 79(5): 377-382.)] A case report of a patient with
pulmonary hypertension and COPD found sustained improvements in exercise tolerance with
regular use of inhaled iloprost. [Hegewald MJ, Elliott CG. Sustained improvement with
iloprost in a COPD patient with severe pulmonary hypertension. Chest 2009; 135(2): 536-537.]
While these limited trials support the concept of physiologic improvement with use of
inhaled pulmonary vasodilators in COPD, our study differs from these in several important
ways. This study is unique in that there has never been a prior similar study of medication
pretreatment prior to PR to enhance exercise performance in any patient subgroup.
Furthermore, treprostinil has not yet been evaluated for use on an as needed basis.

Indication Studied:

COPD/Pulmonary rehabilitation

Study Objectives:

- Primary Objective: To determine the effect of inhaled treprostinil, administered prior
to pulmonary rehabilitation sessions, on the six minute walk test distance (6MWT) in
COPD patients after completing an 8 week course of pulmonary rehabilitation

- Secondary Objectives: To assess the effect inhaled treprostinil, administered prior to
pulmonary rehabilitation in COPD patients, on secondary outcomes including quality of
life (as measured by the St. George's respiratory questionnaire, Clinical COPD
Questionaire), BODE index, lowest nadir of oxygen saturation on 6 minute walk test,
number of exacerbations, ER visits, hospitalizations, and change in measures of
strength training.

Trial Design:

An adaptive, prospective, randomized, double-blind, placebo-controlled study of 34 patients
with advanced COPD who have been referred for pulmonary rehabilitation. All patients will be
screened at baseline with an arterial blood gas. A test dose of inhaled nitric oxide (NO)
will be administered to all subjects for 2-5 minutes. An ABG will then be repeated. Patients
who have a worsened A-a gradient will be screened out. Patients will be randomized to
receive one dose of inhaled treprostinil or placebo prior to each of their exercise
sessions. All patients will be pretreated with albuterol prior to the dose of inhaled
treprostinil (or placebo).

Patient Population:

We plan to screen 50 patients with a goal of enrolling 34 patients. Patients referred for
pulmonary rehabilitation at Inova Fairfax Hospital with moderate to severe COPD as a primary
diagnosis will be screened for inclusion in the trial. Inclusion and exclusion criteria are
listed below.

Inclusion Criteria:

1. Willing to sign informed consent prior to initiation of any study mandated procedure

2. Male or female ≥ 40 years of age

3. Women of childbearing potential must use a reliable method of contraception from
screening until 1 month after end of study medication

4. Clinical diagnosis of moderate to severe COPD, with an obstructive pattern on
pulmonary function tests showing both:

- FEV1/FVC < 0.7 and

- FEV1 ≤ 60% of predicted value, on standard COPD therapy

5. Current or past smokers of ≥ 10 pack years

6. If taking oral (< 20 mg/day of prednisone equivalent) or inhaled corticosteroids,
inhaled beta-agonists (short and long acting), or inhaled muscarinic antagonists
(short and long acting), or statins the dose must be stable for at least 30 days
prior to initial PR visit.

7. Ability to adequately participate in exercise testing/pulmonary rehabilitation
program with supplemental oxygen use over the period of the study (in the best
opinion of the investigator)

Exclusion Criteria:

1. Patients fulfilling one or more of the following criteria of documented COPD
exacerbation within 1 months prior to screening:

- Use of antibiotics for COPD exacerbation

- Initiation or dose increase of steroids (inhaled, oral or intravenous) for COPD
exacerbation

- Hospitalization for COPD exacerbation

2. BMI > 40 kg/m2

3. Unstable coronary artery disease, unstable angina, or myocardial infarction within 3
months prior to screening

4. History of pulmonary edema, or uncontrolled heart failure

5. Uncontrolled systemic hypertension with a blood pressure >180/105 mmHg at rest

6. Systemic hypotension with systolic blood pressure < 85 mmHg

7. Uncontrolled arrhythmias

8. History of syncope

9. Planned surgical intervention during the study period

10. Any known factor or disease that might interfere with treatment compliance, study
conduct or interpretation of the results including musculo-skeletal limitations,
peripheral arterial disease, drug or alcohol dependence or psychiatric disease

11. Severe hepatic impairment (Child-Pugh Class C)

12. Chronic renal insufficiency, as defined by serum creatinine of > 2.5 mg/dL or
estimated creatinine clearance < 30 mL/min or the requirement for dialysis

13. Pregnant or nursing

14. Currently (within 30 days prior to enrollment) taking specific pulmonary arterial
hypertension therapy (e.g., bosentan, ambrisentan, tadalafil, sildenafil,
epoprostenol, treprostinil, iloprost, beraprost), sildenafil and tadalafil for
erectile dysfunction is permitted

15. Initiation of a pulmonary rehabilitation program within 3 months prior to screening
or initiation or changes during the study

16. Participation in any other clinical trial, except observational, or receipt of an
investigational medicinal product within 30 days prior to RHC visit

17. Known concomitant life-threatening disease with a life expectancy < 6 months

18. Known hypersensitivity to treprostinil or any of the excipients of the drug
formulations.

19. Known hypersensitivity to inhaled nitric oxide