A Pilot Study to Determine the Feasibility and Utility of Implementing of the Full Scale TOM Trial

The protocol is a small scale pilot of the full-scale TOM trial, and it will utilize a
placebo design and incorporates 4 treatment arms. In the Vanguard Protocol all participants
are to complete a 4 week run-in with Advair 100/50, followed by randomization to 1 of 4 arms
of study treatment. The 4 drug treatment combinations are (2 inhalers, 2 pills):

- Advair 250/50, Placebo, Placebo, Placebo

- Advair 100/50 and montelukast, Placebo, Placebo

- Advair 100/50 and theophylline, Placebo, Placebo

- Advair 100/50 and ipratropium, Placebo, Placebo The 24 week treatment phase will be
followed by a 4 week washout period on Advair 100/50. There is no crossover.

Inclusion Criteria:

- Gender and Age:

- Males and females, ages 18- 50

Current Smoker:

- Smoke at least 5 cigarettes per day for at least 5 years

- Positive urine cotinine test

Asthma:

- Physician diagnosed asthma

- Symptomatic, as evidenced by

- Use of SABA two or more times per week for relief of asthma symptoms, or

- One or more nocturnal awakenings per week for asthma symptoms ACRC - SC MEETING -
19 MAY 2012 SAPS │ 25 Confidential, not for attribution or citation.

- Pre-BD FEV1 greater than or equal to 40% predicted

- Asthma diagnosis confirmed by either

- albuterol reversibility of FEV1 by 12% or more, or

- 20% fall in FEV1 at 8mg or less of methacholine

- If over age 45, a DLco greater than 80% predicted

- Females of childbearing potential: not pregnant, not lactating and agree to practice
an adequate birth control method (abstinence, combination barrier and spermicide, or
hormonal) for the duration of the study.

Exclusion Criteria:

- Diagnosis of COPD or emphysema

- Other major chronic illnesses in the opinion of the investigator that might interfere
with the study:

− e.g. including but not limited to uncontrolled diabetes, uncontrolled HIV infection
or other immune system disorder, hyperthyroidism, seizure disorders, renal failure,
liver disease, non-skin cancer, unstable psychiatric illness.

- Recent active substance abuse (in past 6 months)

- Lung disease other than asthma including COPD, bronchiectasis, sarcoidosis, or other
significant lung disease

- Unstable cardiac disease (decompensated CHF, unstable angina, recent MI, atrial
fibrillation, supraventricular or ventricular tachycardia, congenital heart disease,
or severe uncontrolled hypertension).

- High risk of near fatal or fatal asthma as defined by the following 1-3

- ICU admission of asthma in the past year

- more than 2 hospitalizations for asthma in the previous year

- more than 3 ED visits for asthma in the previous year

- intubation or ICU admission for asthma in the past 2 years

- use of more than 2 canisters of inhaled short-acting beta2-agonist in past month

- Acute asthma exacerbation in the past 4 weeks (treatment with systemic
corticosteroids)