Effect of Roflumilast on Airway Blood Flow as an Expression of Airway Inflammation in COPD

Participants will be enrolled in the study for three months There will be 6 study days
(visits). The patients will be asked to come to the research laboratory in the morning of the
study day. They will be instructed to abstain from ingesting alcoholic beverages or using
PDE5 inhibitors the night before the study, and from consuming coffee or caffeinated drinks
in the morning of the study day because of their potential acute cardiovascular actions. The
patients will also be asked not to have a fatty breakfast on the study day to avoid potential
effects of fat on the absorption of roflumilast.

The visits will be separated by at least 48 hours. Study period 1: The patients will be
randomized into two arms: roflumilast or placebo. Qaw will be measured before and at 15, 30,
60, 120 and 240min in each arm (parallel design) Study period 2: Patients will be randomized
to either roflumilast for 4 weeks or placebo for 4 weeks and airway blood flow reactivity
will be measured at the end of the treatment period. The patients will then be taken off
medication or placebo for 4 weeks and reassigned to the alternate treatment (roflumilast or
placebo) for 4 weeks and airway blood flow reactivity will be measured after the this
treatment period (cross-over design).

The treatments will be administered in a double-blind randomized design, using active
roflumilast and identically appearing roflumilast placebo provided by Forest.

Visit 1

On this visit, a medical history will be obtained from the patients and they will undergo a
physical examination and complete pulmonary function testing. If they meet entry criteria,
Qaw will be measured before and 15 min after the inhalation of 180 µg albuterol using a
spacer (ΔQaw). We have previously shown that vasodilation peaks between 5 and 30 min after
inhaling this dose of albuterol in healthy non-smokers; in patients with COPD, who exhibit a
vasodilatory response to inhaled albuterol, the peak effects also occur at the same time as
in healthy subjects. Since all patients enrolled in the present study will be regular ICS
users, we expect that all of them will have a vasodilator response to albuterol as previously
shown.

Visit 2

On this day, Qaw will be measured before and at 15, 30, 60,120 and 240 min after the oral
administration of either 500µg roflumilast or placebo, blinded to patient and investigator
(acute roflumilast effects).

Visit 3

The patients will be given either 500µg roflumilast or placebo (alternate to treatment at
visit 2) blinded to patient and investigator. One hour later, Qaw will be measured before and
15 min after the inhalation of 180µg albuterol using a spacer (ΔQaw). Pharmacokinetic studies
have shown that the geometric mean plasma concentration of roflumilast after a 500µg dose
peaks at one hour after oral drug administration.

The patients will then be randomized in a double blind fashion to either roflumilast 500 µg
or placebo every morning before breakfast. They will be asked to return for a follow up visit
4 weeks later (visit 4).

Visit 4

The patients will not take their morning dose (roflumilast or placebo) on this day. Qaw will
be measured before and 15 min after the inhalation of 180 µg albuterol using a spacer (ΔQaw).
The treatment will be discontinued and the patients will be asked to return for visit 5 after
a 4-week washout period.

Visit 5

The protocol of visit 4 will be repeated. The patients will then be started on the alternate
treatment for 4 weeks: Those on roflumilast between visits 3 and 4 will now be placed on
placebo, and those on placebo between visits 3 and 4 will be placed on roflumilast. The
patients will be asked to return for a final visit (visit 6) 4 weeks later.

Visit 6

The protocol of visit 4 will be repeated. The patients will then undergo an exit exam and be
discharged from the study

Inclusion Criteria:

- Twenty-four patients with physician-diagnosed COPD (female and male, current smokers
or ex-smokers) over the age of 45 years will be recruited for this study.

- The patients will have to have a smoking history of at least 10 pack-years, and they
must have been using an ICS regularly for at least 4 weeks at the time of screening.

- Confirmation of the diagnosis of COPD will require the presence of persistent
exertional dyspnea and a post-bronchodilator FEV1 of less than 80% of predicted and
FEV1/FVC ratio less than 0.7 (GOLD stage ≥2). At entry into the study, the patients
will have to be clinically stable; they will be allowed to remain on their regular
COPD treatment regimen and use a LABA and/or LAMA until 24 hours before, and a SABA
and/or short-acting muscarinic antagonist (SAMA) until 6 hours before coming to the
laboratory. If using roflumilast, the subjects will have to discontinue it 4 weeks
before entering into the study.-

Exclusion Criteria:

- Women of childbearing potential who do not use accepted birth control measures

- Pregnant and breast-feeding women.

- Use of cardiovascular medications that cannot be held on the study days

- Use of oral airway medications or anti-inflammatory agents

- Use of supplemental oxygen that cannot be discontinued during the laboratory visit

- Subjects with known SABA or roflumilast intolerance

- An acute COPD exacerbation within four weeks prior to the study