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)