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

Phase 4

Completed

Conditions: Asthma

Interventions: Drug: Fluticasone 250 mg/salmeterol 50 mg
Drug: Theophylline 400 mg
Drug: Montelukast 10mg
Drug: ipratropium

Registration Number: NCT01696214

Lead Sponsor: University of California, San Diego

Brief Summary: The primary aim of the pilot (SAPS) protocol is to determine the feasibility and utility of implementing the provisional design of the full scale TOM trial (e.g., the six month treatment period, the impact of the smoking cessation intervention).

There is no active hypothesis for the Vanguard Protocol.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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)

Study & Design

Study Type: INTERVENTIONAL

Study Design: FACTORIAL

Arm && Interventions

Group	Intervention	Description
fluticasone 250 mg/salmeterol 50mg	Fluticasone 250 mg/salmeterol 50 mg	Participants will be assigned to inhaled fluticasone 250/salmeterol 50 twice a day for 24 weeks with placebo theophylline, placebo ipratropium, and placebo montelukast.
Theophylline	Theophylline 400 mg	Participants will continue fluticasone 100 mg/salmeterol 50 mg once a day and will be assigned to theophylline 400 mg once a day for 24 weeks with placebo ipratropium and placebo montelukast.
Montelukast	Montelukast 10mg	Participants will continue fluticasone 100 mg/salmeterol 50 mg once a day and will be assigned to montelukast 10 mg once a day for 24 weeks with placebo theophylline and placebo ipratropium.
Ipratropium	ipratropium	Participants will continue fluticasone 100 mg/salmeterol 50 mg once a day and be assigned to a 24 week treatment of ipratropium 2.5 mL, 0.02% 3 times daily via mini nebulizer with placebo theophylline and placebo montelukast.

Primary Outcome Measures

Name	Time	Method
Asthma Control Test	Outcome measure was assessed at the initial visit, at randomization following a wash-in period of 1 month, monthly for 24 weeks and at follow-up visit 1 month off study drug. Median scores over the 24 weeks of treatment were compared.	The primary symptomatic measure, the Asthma Control Test (ACT), has been shown to be valid for measuring poor asthma control in asthmatic children and non-smoking adults. The ACT is a tool developed by Nathan and collaborators a decade ago for evaluating asthma control. It consists of five questions with five possible answers each. A maximum score of 25 points indicates complete asthma control. A score between 20 and 24 represents partially controlled asthma, while a score 19 or below indicates poorly controlled asthma and a score \<16 indicates uncontrolled asthma. The minimally important clinical difference has been determined to be 3.

Secondary Outcome Measures

Name	Time	Method
The Asthma Symptom Utility Index (ASUI)	Outcome measure was assessed at the initial visit, at randomization following a wash-in period of 1 month, monthly for 24 weeks and a follow-up visit 1 month off study drug. Median scores, change from initial visit and end of treatment, were compared	The Asthma Symptom Utility Index (ASUI), an important secondary outcome in the proposed full-scale TOM Trial, has also been shown to be useful in tracking the frequency and severity of asthma-related symptoms in non-smoking asthmatics. ASUI is a brief, interviewer-administered, patient preference-based scale assessing frequency and severity of selected asthma-related symptoms and treatment side effects. 11 items are reviewed, with 2-week recall to assess four symptoms (cough, wheeze, shortness of breath, and awakening at night) and medication side-effects each on two dimensions (frequency and severity). 4-point Likert scale is used to assess frequency (not at all, 1 to 3 days, 4 to 7 days, and 8 to 14 days) and severity (not applicable, mild, moderate and severe). Scores range from 0 (worst possible symptoms) to 1 (no symptoms). The change between two time points, initial visit and after 24 weeks of treatment, is reported. The median value is reported with the standard deviation.
Percent (%) Perdicted FEV1 Changes	Outcome measure was assessed at the initial visit, at randomization following a wash-in period of 1 month, monthly for 24 weeks. Median scores over the 24 weeks of treatment were compared	Physiologic measures of % predicted FEV1