Should Non-eosinophilic Asthmatic Subjects be Treated With Inhaled Corticosteroids?

Study Overview
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Brief Summary
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The efficacy of inhaled corticosteroids (ICS) in asthmatic subjects showing no sputum eosinophils is controversial. The broad aim of this study is to assess whether ICS alone or in combination with long-acting beta-2 agonists are an effective treatment in non-eosinophilic asthmatic subjects. Methods: The investigators will perform a randomized double-blind, placebo-controlled, multicenter study comparing the efficacy of ICS and placebo for 4 weeks followed by a 4-week open treatment period with ICS/salmeterol in steroid-naïve asthmatic subjects without sputum eosinophilia. The primary outcome will be the the Asthma Control Questionnaire (ACQ) score after four weeks of treatment by ICS or placebo. This study will determine whether or not non-eosinophilic asthmatic subjects respond to ICS and if they further benefit from the addition of a long-acting beta-2 agonists. This study will also determine whether or not the assessment of airway inflammation should be performed in every asthmatic patient in order to give the most appropriate treatment.

Detailed Description
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General objective: To assess whether inhaled corticosteroids alone or in combination with long-acting beta-2 agonists are an effective treatment in non-eosinophilic asthmatic subjects. Specific objective 1. To compare the change in clinical and functional outcomes after treatment with fluticasone or placebo in non-eosinophilic asthmatic subjects. Specific objective 2. To assess whether the combination of inhaled corticosteroids (ICS) and with long-acting beta-2 agonists provides an improvement of asthma control compared to the treatment with ICS or placebo in non-eosinophilic asthmatics. Hypothesis: Treatment with ICS induces a significant clinical and physiologic improvement of non-eosinophilic asthmatic subjects. ICS/Salmeterol also provides a clinical and physiologic benefit compared to placebo. Primary end point: Asthma Control Questionnaire (ACQ) score after 4 weeks of treatment with ICS or placebo. The Asthma Control Questionnaire has been chosen as a primary outcome since it is the most relevant clinical measure to assess asthma control over a short period of time. In patients whose asthma is stable between clinic visits, reliability of the ACQ is high (intraclass correlation coefficient (ICC)=0.90). Furthermore, the questionnaire is also very responsive to changes in asthma control(7). Therefore, this is the ideal tool to assess and compare the changes in asthma control over a short period of time. This instrument has the advantage of including both asthma symptoms as well as forced expiratory flow in one second (FEV1). A change of ACQ of 0.5 has been shown to be clinically significant. Therefore, we will be able to assess whether or not a treatment with ICS has the ability to significantly improve asthma control in non-eosinophilic asthmatic subjects. The questionnaire is provided in appendix III. Other functional and clinical outcomes such as quality of life, FEV1, provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20), number of rescue medication and number of asthma exacerbations will also be assessed as secondary outcomes. The study has two steps: The first step will be a randomized double-blind, placebo-controlled, multicenter study comparing the efficacy of ICS and placebo for 4 weeks in asthmatic subjects without sputum eosinophilia followed by an open ICS/salmeterol 4-week treatment for all subjects. (See study design in appendix III). Inclusion criteria One hundred subjects will be enrolled.

Official Title
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Should Non-eosinophilic Asthmatic Subjects be Treated With Inhaled Corticosteroids?

Conditions
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Asthma

Intervention / Treatment
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* Drug: Placebo (sham inhaler)
* Drug: Fluticasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Are between 18 and 70 years of age at the time of signing the informed consent. Have a diagnosis of asthma according to the Guidelines for the Diagnosis and Management of Asthma and have not been treated with ICS in the previous two months. Have a PC20 methacholine less than 8 mg/ml. Have a baseline FEV1 greater or equal to 65% of predicted value (at least 6 hours after bronchodilator). Are not optimally controlled with short-acting 2 agonists as shown by awakenings due to asthmatic symptoms at least once a week, or regular use of salbutamol on 4 or more occasions per week (excluding exercise prophylaxis) due to asthma symptoms. ACQ score equal or greater than 2 Have sputum eosinophils less than 2% Are non smokers or ex-smokers who smoked a maximum of 10 pack/year. Exclusion Criteria: Hospitalized patients within the last 3 months Current or recent (within the last month) symptoms of a cold or flu Patients with a history of near fatal asthma Subjects on inhaled corticosteroids, prednisone, long-acting beta 2 agonists, montelukast or theophylline, within 2 months prior to entry into the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active treatment group (A)<br>Intervention : treatment with inhaled corticosteroids (Fluticasone) will be administered to this group | Drug: Fluticasone<br>* Fluticasone 250mcg bid for one month<br>* Other names: Flovent;|
| Placebo Comparator: Control group treated with placebo (B)<br>treatment with placebo | Drug: Placebo (sham inhaler)<br> <br> * Other names: Sham inhaler;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Control Questionnaire (ACQ) Score After 4 Weeks of Treatment With Inhaled Corticosteroids (ICS) or Placebo | Validated questionnaire assessing asthma control after 4 weeks of treatment with ICS or placebo. The ACQ has 7 questions (the top scoring 5 symptoms, FEV1% pred. and daily rescue bronchodilator use). Patients are asked to recall how their asthma has been during the previous week and to respond to the symptom and bronchodilator use questions on a 7-point scale (0=no impairment, 6= maximum impairment). The ACQ score is the mean of 7 items and thus ranges between 0 (well controlled) and 6 (extremely poorly controlled) to yield a mean score out of 6. The higher the score, the worst asthma control is. | Four weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Asthma Quality of Life Questionnaire (AQLQ) Score After 4 Weeks of Treatment | Validated questionnaire assessing quality of life related to asthma after 4 weeks of treatment. The AQLQ is composed of 32 questions in 4 domains (symptoms, activity limitation, emotional function and environmental stimuli). The activity domain contains 5 'patient-specific' questions. This allows patients to select 5 activities in which they are most limited and these activities will be assessed at each follow-up. Patients are asked to think about how they have been during the previous two weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all - 1 = severely impaired). The AQLQ score is rated on a 7-point scale (1=maximal impairment, 7=no impairment) to yield a mean score out of 7. The worse the quality of life is , the lower the score is. | Four weeks | 
| Change in Forced Expiratory Volume in One Second (FEV1) | Change in forced expiratory volume in one second (FEV1) after fluticasone or placebo treatment. | Four weeks | 
| Change in Provocative Concentration of Methacholine Inducing a 20% Fall in FEV1 (PC20) | Change in provocative concentration of methacholine inducing a 20% fall in FEV1 (PC20) after fluticasone or placebo treatment | Four weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Non-eosinophilic Asthma, sputum eosinophils, Inhaled Corticosteroids