Study of Safety of Foradil in Patients With Persistent Asthma

Study Overview
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Brief Summary
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The purpose of this study was to assess whether the risk of serious asthma-related events (asthma-related hospitalizations, asthma related intubations, and asthma related deaths) in adolescents and adults (12 years of age and older) taking inhaled formoterol fumarate/fluticasone propionate combination was the same as those taking inhaled fluticasone propionate alone.

Detailed Description
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This was a 26 week, double blind, randomized, active-controlled safety study of Foradil in free combination with inhaled corticosteroid versus an inhaled corticosteroid alone in adults and adolescent patients with persistent asthma. The primary objective of the study was to demonstrate that the addition of formoterol fumarate to fluticasone propionate is non-inferior to fluticasone propionate alone in terms of the risk of composite serious asthma related events (asthma-related hospitalization, asthma-related intubation, and asthma-related death). The individual components of the composite primary endpoint (i.e., asthma-related hospitalization, asthma-related intubation and asthma-related death) will be assessed as a secondary safety endpoints. The efficacy assessment is the secondary objective.

Official Title
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A 26 Week, Randomized, Active-controlled Safety Study of Double-blind Formoterol Fumarate in Free Combination With an Inhaled Corticosteroid Versus an Inhaled Corticosteroid in Adolescent and Adult Patients With Persistent Asthma.

Conditions
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Persistent Asthma

Intervention / Treatment
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* Drug: Formoterol 12 mcg
* Drug: Fluticasone propionate 100 mcg
* Drug: Fluticasone propionate 250 mcg
* Drug: Fluticasone propionate 500 mcg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Written informed consent, and assent if applicable, must be obtained before any assessment is performed. Male or female patients 12 years of age and older Confirmed diagnosis of persistent asthma, as defined by national and international asthma guidelines (e.g., GINA; NIH; etc.) for at least 1 year prior to study enrollment. PEF≥50% of predicted normal value. Current and appropriate use of one of the treatments listed in the protocol for asthma. Recent asthma exacerbation between 30 days and 12 months prior to randomization that either: required treatment with systemic corticosteroids (tablets, suspension, or injection) or required hospitalization (defined as an inpatient stay or >24-hour stay in an observation area in an emergency room or other equivalent facility) Key Exclusion Criteria: History of life-threatening asthma episode that required intubation and/or was associated with hypercapnia requiring non-invasive ventilatory support. Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other than asthma. Current evidence of, or past physician assessment of, chronic bronchitis, emphysema, or chronic obstructive pulmonary disease. History of smoking ≥ 10 pack years. Exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine. Suspected or documented bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved at randomization. Worsening/Unstable asthma within 7 days prior to randomization. Any asthma exacerbation requiring systemic corticosteroids within 30 days of randomization or more than 4 separate exacerbations in the 12 months preceding randomization. Two or more hospitalizations for greater than 24 hours duration for treatment of asthma in the 12 months preceding randomization. History of hypersensitivity to any beta2-agonist, sympathomimetic drug, inhaled corticosteroids, or systemic corticosteroid therapy or any component of the possible study treatments in this trial, including severe milk protein hypersensitivity. Use of anti-IgE (e.g., omalizumab) or any other monoclonal antibody, in the 6 months prior to randomization. Use of (Beta) β-blockers within 1 day prior to first dose of study medication. Use of ICS, LABA, ICS+LABA, LTRAs, leukotriene modifiers, anticholinergics, or theophylline must be discontinued prior to the first dose of investigational treatment. Use of a potent CYP3A4 inhibitor within 4 weeks of randomization (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin).

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOM 12 mcg + FP<br>Formoterol 12 mcg + fluticasone propionate 100 mcg, 250 mcg or 500 mcg for inhalation | Drug: Formoterol 12 mcg<br>* Formoterol 12 mcg one inhalation twice daily, via dry powder inhaler<br>* Other names: FOR258;Drug: Fluticasone propionate 100 mcg<br>* Fluticasone propionate 100 mcg one inhalation twice daily via dry powder inhaler<br>Drug: Fluticasone propionate 250 mcg<br>* Fluticasone propionate 250 mcg one inhalation twice daily via dry powder inhaler<br>Drug: Fluticasone propionate 500 mcg<br>* Fluticasone propionate 500 mcg, one inhalation twice daily via dry powder inhaler<br>|
| Active Comparator: fluticasone propionate (FP)<br>fluticasone propionate 100 mcg, 250 mcg or 500 mcg + Placebo to Match Formoterol 12 mcg for inhalation | Drug: Fluticasone propionate 100 mcg<br>* Fluticasone propionate 100 mcg one inhalation twice daily via dry powder inhaler<br>Drug: Fluticasone propionate 250 mcg<br>* Fluticasone propionate 250 mcg one inhalation twice daily via dry powder inhaler<br>Drug: Fluticasone propionate 500 mcg<br>* Fluticasone propionate 500 mcg, one inhalation twice daily via dry powder inhaler<br>Drug: Placebo<br>* Placebo to match formoterol one inhalation twice daily via dry powder inhaler<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of First Occurrence(s) of Any Composite Endpoint Including Asthma-related Hospitalizations, Intubations and Deaths During the Study at 26 Weeks | The primary safety endpoint was the number of first occurrence(s) of any composite endpoint. The composite events include asthma-related deaths, asthma-related intubations and asthma-related hospitalizations. The number of events includes all adjudication confirmed events, one patient could experience multiple events during the course of study; Event rate = 100 * n patients with any events / total N patients in treatment group. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Asthma Exacerbations at 26 Weeks | Number of asthma exacerbations events | 26 weeks | 
| Percentage of Days of School/Work Missed at 26 Weeks | The percentage of days of school/work missed during the treatment period (26 weeks). Overall percentage of school days missed for each student patient or of work days missed is calculated by total number of days missed divided by total days of treatment. | 26 weeks | 
| Percentage of Days With Limited Ability to Perform Normal Daily Activities at 26 Weeks | The percentage of days with limited ability to perform normal daily activities during the treatment period (26 weeks). Percentage is calculated as total number of days when the patient had limited ability to perform normal daily activities divided by total days of treatment. | 26 weeks | 
| Percentage of Days With Nighttime Awakenings at 26 Weeks | Percentage of days with nighttime awakenings during the treatment period (26 weeks) | 26 weeks | 
| Percentage of Days With no Rescue Medication Use at 26 Weeks | Percentage of rescue free days is calculated as total number of days with no rescue medication was taken divided by total days of treatment. | 26 weeks | 
| Percentage of Days With no Symptoms at 26 Weeks | Percentage of days with no symptoms during the treatment period (26 weeks). Percentage is calculated as total number of days with no symptoms divided by total days of treatment. | 26 weeks | 
| Change From Baseline in Asthma Control Questionnaire (ACQ - 6) Total Score at Week 26 | Change from baseline in Asthma control Questionnaire (ACQ - 6) total score at week 26. Results of the Asthma control questionnaire (ACQ-6); The average score of the six questions is calculated as the sum of scores divided by the number of questions that were answered at the time point, as long as there were at least 4 questions answered. The ACQ6 score is calculated as the mean of the responses to the first 6 questions of the ACQ. The ACQ is a scale containing 7 questions, each question has a 7-point scale which ranges from 0 to 6; a total score of 0 corresponds to no impairment and a total score of 6 corresponds to maximum impairment. | baseline and 26 weeks | 
| Unplanned Healthcare Utilization at Visit 3 (Week 4), Visit 4 (Week 12) and Visit 5 (Week 26) | Unplanned healthcare utilization by visit (Telephone contact with study doctor (MD); Telephone contact with other physician (MD) or healthcare provider (HCP); Unscheduled or unplanned visit to study doctor (including home visits); Unscheduled or unplanned visit to other physician or healthcare provider (including home visits); Emergency department or hospital visit (< 24 hours); Hospital admission or Emergency department visit (> 24 hours). | Week 4, Week 12, and Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, formoterol fumarate, Foradil, inhaled corticosteroid, fluticasone propionate, safety