Steroids In Eosinophil Negative Asthma

Study Overview
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Brief Summary
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Because approximately half of all mild-moderately-severe asthma is persistently non-eosinophilic, it is important to determine prospectively if patients who are persistently non-eosinophilic differ in their benefit from inhaled corticosteroid treatment compared to patients who are not persistently non-eosinophilic.

Detailed Description
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SIENA is a 42-week randomized, stratified, 3-period double-blind placebo-controlled crossover study of patients with symptomatic mild-to-moderate asthma, not already taking an inhaled corticosteroid, in whom the effect of medium-dose inhaled corticosteroid (ICS) will be compared with the effect of placebo and with a long-acting muscarinic antagonist (LMA).

Official Title
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Steroids In Eosinophil Negative Asthma

Conditions
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Asthma

Intervention / Treatment
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* Drug: Mometasone 220mcg BID
* Drug: Tiotropium Respimat 5mcg QD
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Physician-diagnosed asthma for at least previous 12 months. Able to perform reproducible spirometry. Baseline FEV1≥70% of predicted. Asthma confirmed either by: Beta-agonist reversibility to 4 puffs albuterol ≥ 12% OR Methacholine PC20 ≤ 16 mg/ml At least 1 of the following indications for chronic controller therapy: Asthma Symptoms > 2 days/week OR Nocturnal Asthma Symptoms > 2 nights/month OR Short-acting beta-agonist use for symptom control > 2 days/week For participants ≥18 years of age: Ability to provide informed consent. For participants under 18 years of age: Ability to provide verbal or written assent and ability of parent to provide informed consent. Willingness, if female and able to conceive, to utilize one medically-acceptable form of contraception. Exclusion Criteria: Chronic inhaled or oral corticosteroid therapy. Use of inhaled or oral corticosteroid therapy within 6 weeks. New allergen immunotherapy within the past 3 months or anticipated changes to an ongoing immunotherapy regimen. Use of omalizumab within 3 months. History of: bladder-neck obstruction, urinary retention or benign prostatic hyperplasia narrow angle glaucoma significant cardiovascular disorders and arrhythmias life-threatening asthma requiring treatment with intubation or mechanical ventilation within the past 5 years Respiratory tract infection within past 6 weeks. History of smoking within the past 1 year, or > 10 pack-years total if ≥ 18 years of age, or > 5 pack-years total if < 18 years of age. Chronic diseases or medical conditions (other than asthma) that could put the participant at risk by participation, e.g. chronic diseases of the lung (other than asthma), heart, liver, kidney, endocrine or nervous system, or immunodeficiency.

Ages Eligible for Study
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Minimum Age: 12 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mometasone then Tiotropium then Placebo<br>Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD, followed by Placebo | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |
| Experimental: Mometasone then Placebo then Tiotropium<br>Mometasone 220mcg BID, followed by Placebo, followed by Tiotropium Respimat 5mcg QD | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |
| Experimental: Placebo then Mometasone then Tiotropium<br>Placebo, followed by Mometasone 220mcg BID, followed by Tiotropium Respimat 5mcg QD | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |
| Experimental: Placebo then Tiotropium then Mometasone<br>Placebo, followed by Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |
| Experimental: Tiotropium then Placebo then Mometasone<br>Tiotropium Respimat 5mcg QD, followed by Placebo, followed by Mometasone 220mcg BID | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |
| Experimental: Tiotropium then Mometasone then Placebo<br>Tiotropium Respimat 5mcg QD, followed by Mometasone 220mcg BID, followed by Placebo | Drug: Mometasone 220mcg BID<br>* Mometasone is an ICS<br>* Other names: Asmanex;Drug: Tiotropium Respimat 5mcg QD<br>* Tiotropium is a LMA<br>Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pairwise Comparison of Treatments Based on Composite Measure Using Treatment Failures, Asthma Control Days, and Percent Predicted FEV1. | This composite outcome uses a hierarchical method to ascertain differences in asthma control. For each participant, treatments are first compared to see if they differ in terms of treatment failures. If one treatment results in no treatment failures and another treatment does, it is deemed the superior treatment and no further comparisons are made. If treatment superiority cannot be assigned by treatment failures, then they are compared by asthma control days (ACDs). If one treatment yields at least 31 annualized ACDs more than another, it is deemed the superior treatment. If treatment superiority still cannot be assigned by ACDs, then they are compared by percent predicted FEV1 at the end of a treatment period. If one treatment yields at least 5% greater FEV1 than another, it is deemed the superior treatment. If treatment superiority cannot be assigned by exacerbations, ACDs or FEV1, then that participant is classified as having no differential response. | End of 12-week treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Failure | Treatment Failure includes: Awakening from asthma three or more times in a two-week period or on two consecutive nights, or Using albuterol for relief of symptoms four or more times/day for two or more consecutive days, or Albuterol has been relieving symptoms for less than four hours after each treatment over a 12-hour period, or Using albuterol for relief of symptoms daily for seven days, and this use exceeds two times the weekly use of albuterol in the baseline period, or exercise induces unusual breathlessness | End of 12-week treatment period | 
| Annualized Asthma Control Days | Asthma Control Days (ACD) are based on patient completed electronic daily diaries, and are defined as: A day with no rescue albuterol use (pre-exercise albuterol will not be counted), no non-study asthma medications, no daytime asthma symptoms (shortness of breath, wheezing, chest tightness, phlegm/mucus rated as mild, moderate or severe, or cough rated as moderate or severe), no nighttime asthma symptoms, no unscheduled healthcare visits for asthma, and no PEF < 80% of predetermined baseline. Annualized ACD are calculated as the proportion of ACD during the treatment period multiplied by 365. | End of 12-week treatment period | 
| Forced Expiratory Volume at One Second (FEV1) Percent of Predicted | FEV1, expressed as percent of predicted FEV1 based on age, sex, race, and height. | End of 12-week treatment period | 
| Peak Expiratory Flow Rate | Peak expiratory flow rate is a person's maximum speed of expiration. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. | End of 12-week treatment period | 
| Asthma Exacerbations | Asthma exacerbations are more severe episodes of acute worsening, defined by meeting one or more of the following: FEV1 <50% of baseline on 2 consecutive measurements FEV1 <40% of predicted on 2 consecutive measurements Use of ≥ 16 puffs of as needed β-agonist per 24 hours for a period of 48 hours Use of oral/parenteral corticosteroid due to asthma | End of 12-week treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Mometasone, Tiotropium