Asthma
Conditions
Keywords
asthma,smokers
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.
Interventions
DRUGFluticasone 250 mg/salmeterol 50 mg
Drug: Fluticasone 250 mg/salmeterol 50 mg Participants will be assigned to a 24 week treatment with inhaled fluticasone/salmeterol or matching placebo
DRUGMontelukast 10mg
Participants will be assigned to montelukast once a day for 24 weeks.
DRUGTheophylline 400 mg
Participants will be assigned to theophylline once a day for 24 weeks
DRUGipratropium
Participants will be assigned to ipratropium 2.5 mL of 0.02% solution via mini nebulizer 3 times a day day for 24 weeks.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ipratropium Participants will continue fluticasone 100 mg/salmeterol 50 mg once a day and be assigned to a 24 week treatment of ipratropium 0.02% solution, 2.5 ml via mini nebulizer for 24 weeks with placebo theophylline and montelukast.
Ipratropium: Participants will be assigned to ipratropium 0.02% solution, 2.5 ml via mini nebulizer 3 times | 4 |
| Theophylline Participants will continue fluticasone 100 mg/salmeterol 50 mg once a day and will be assigned to theophylline 300 mg once a day for 24 weeks with placebo tiotroprium and montelukast.
Theophylline: Participants will be assigned to theophylline 300 mg once a day for 24 weeks | 5 |
| Montelukast 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 tiotroprium.
Montelukast 10mg: Participants will be assigned to montelukast 10 mg once a day for 24 weeks. | 5 |
| Fluticasone 250 mg/Salmeterol 50mg Participants will be assigned to inhaled fluticasone 250 mg/salmeterol 50 mg twice a day for 24 weeks with placebo theophylline, tiotroprium, and montelukast.
Fluticasone 250 mg/salmeterol 50 mg:
Participants will be assigned to a 24 week treatment with inhaled fluticasone 250 mg /salmeterol 50 | 5 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Theophylline | Montelukast | Ipratropium | Fluticasone 250 mg/Salmeterol 50mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants | 5 Participants | 4 Participants | 5 Participants | 19 Participants |
| Age, Continuous | 48 years | 39 years | 49 years | 28 years | 41 years |
| Region of Enrollment United States | 5 participants | 5 participants | 4 participants | 5 participants | 19 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 4 Participants | 1 Participants | 10 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 0 Participants | 4 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 5 | 5 / 5 | 5 / 5 | 5 / 5 |
| serious Total, serious adverse events | 0 / 4 | 0 / 5 | 1 / 5 | 0 / 5 |
Outcome results
Primary
Asthma Control Test
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ipratropium | Asthma Control Test | 17.5 units on a scale |
| Theophylline | Asthma Control Test | 13 units on a scale |
| Montelukast | Asthma Control Test | 12 units on a scale |
| Fluticasone 250 mg/Salmeterol 50mg | Asthma Control Test | 10 units on a scale |
Secondary
Percent (%) Perdicted FEV1 Changes
Physiologic measures of % predicted FEV1
Time frame: 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
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Ipratropium | Percent (%) Perdicted FEV1 Changes | -1.62 percent predicted FEV1 | Standard Deviation 7.89 |
| Theophylline | Percent (%) Perdicted FEV1 Changes | 4.73 percent predicted FEV1 | Standard Deviation 7.72 |
| Montelukast | Percent (%) Perdicted FEV1 Changes | 0.87 percent predicted FEV1 | Standard Deviation 10.57 |
| Fluticasone 250 mg/Salmeterol 50mg | Percent (%) Perdicted FEV1 Changes | -5.71 percent predicted FEV1 | Standard Deviation 5.24 |
Secondary
The Asthma Symptom Utility Index (ASUI)
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Ipratropium | The Asthma Symptom Utility Index (ASUI) | 0.16 units on a scale | Standard Deviation 0.07 |
| Theophylline | The Asthma Symptom Utility Index (ASUI) | 0.24 units on a scale | Standard Deviation 0.2 |
| Montelukast | The Asthma Symptom Utility Index (ASUI) | 0.14 units on a scale | Standard Deviation 0.15 |
| Fluticasone 250 mg/Salmeterol 50mg | The Asthma Symptom Utility Index (ASUI) | 0.13 units on a scale | Standard Deviation 0.18 |