Rehabilitation of Idiopathic Pulmonary Fibrosis (IPF) Patients

Chronic lung disease is common in the veteran population. While chronic obstructive
pulmonary disease (COPD) is most prominent, fibrotic lung diseases, typified by idiopathic
pulmonary fibrosis (IPF), are clearly increasing. We have developed extensive experience
with a VA idiopathic pulmonary fibrosis (IPF) population in the context of a randomized,
controlled clinical trial of vasodilator therapy.

Based on the current literature and our preliminary experience with exercise testing in IPF
patients, we hypothesize that:

1. Formal pulmonary rehabilitation (i.e., an aerobic exercise program) will result in
improved outcomes for IPF patients, demonstrable as an:

1. Increase in exercise tolerance as quantified by 6-minute walk test (MWT) distance;

2. Decrease in post-exercise dyspnea as quantified by the Borg dyspnea scale; and an

3. Overall subjective improvement in quality of life as quantified by Saint George's
Respiratory Questionnaire.

2. Metabolic and physiologic mechanisms of improved exercise tolerance and decreased
dyspnea will include:

1. More efficient oxygen metabolism demonstrated by maximum O2 uptake (VO2max);

2. Decreased post-exercise oxidant stress demonstrated by post-exercise isoprostanes
and plasma total antioxidant capacity (TAC); and,

3. Maintenance of maximum inspiratory and expiratory pressures (PInmax and PExmax).

Our Specific Objectives are:

1. To investigate formal pulmonary rehabilitation and exercise tolerance in IPF patients

The following important endpoints will be assessed to test the working hypothesis that
pulmonary rehabilitation improves exercise capacity and lessens dyspnea:

1. 6-MWT distance;

2. Dyspnea index; and,

3. Quality of life (Saint George's Respiratory Questionnaire [SGRQ]).

2. To assess changes in oxygen uptake, markers of oxidant stress and pulmonary function
resulting from pulmonary rehabilitation

To test the working hypothesis that improved outcomes are associated with more efficient O2
utilization, decreased markers of oxidant stress and maintained effort dependent pulmonary
function, the following variables will be measured:

1. Maximum oxygen uptake (VO2max);

2. Markers of oxidant stress, including plasma and urine isoprostanes and plasma total
antioxidant capacity; and,

3. Maximum inspiratory and expiratory pressures (PInmax and PExmax). Completion of these
Specific Objectives will position our research group to conduct future studies of 1)
mechanisms of exercise limitation and 2) antioxidant therapies, both in this defined
population and those who are at risk of developing pulmonary fibrosis. The long term
impact of this application is thus to develop effective pulmonary rehabilitation
strategies for IPF patients, based on knowledge of underlying changes in oxygen
metabolism and oxidant stress.

Inclusion Criteria:

- Clinical presentation consistent with IPF with onset between three months and 48
months prior to screening.

- Diagnosis made by high-resolution computed tomographic scan showing highly probable
IPF.

- Absence of severe pulmonary hypertension (i.e., PAsys must be 50 mm Hg, based on
echocardiography) and absence of decompensated right heart failure (NYHA class I or
II acceptable).

- Age 40 through 80, inclusive.

- Abnormal pulmonary function tests (FVC 40-90% predicted or DLCO 30-90% predicted or
impaired gas exchange with rest or exercise).

- Six-minute walk distance 150 m and 500 m.

- Worsening as demonstrated by any one of the following within the past year: > 10%
decrease in percent predicted forced vital capacity or worsening dyspnea at rest or
upon exertion, based on history.

- Ability to understand and sign a written informed consent form and comply with the
requirements of the study.

- Absence of clinical features suggesting infection, neoplasm, sarcoidosis or
collagen-vascular disease.

Exclusion Criteria:

- Echocardiographic evidence of severe pulmonary hypertension (PAsys>50 mm Hg, based on
echocardiography or TR velocity 3.2 m/sec).

- Severe heart failure (NYHA class III or IV or LVEF < 45%).

- Six-minute walk distance < 150 m or > 500 m.

- FEV1/FVC ratio < 0.7 at screening (post-bronchodilator).

- Residual volume > 100% predicted.

- Any condition other than IPF likely to result in the death of the participant within
the next two years.

- History of unstable or deteriorating cardiac or neurologic disease.

- Pregnancy or lactation. Patients who are: (a) pregnant or (b) breast feeding are
excluded from the study.

- Current treatment with N-acetylcysteine or other antioxidant, corticosteroids (either
oral or inhaled), Cytoxan, azathioprine, colchicine, pirfenidone, anti-tumor necrosis
factor therapy or endothelin receptor blockers. Prior treatment is permitted, but at
least four weeks of treatment washout prior to inclusion in this study are required.

- Investigational therapy for any indication within 28 days prior to enrollment.

- Degenerative arthritis, cerebrovascular accident or other limitation to mobility
preventing completion of the 6-minute walk test.

- Oxygen saturation on room air <80% at rest.