Crossover Study Comparing Fluticasone Furoate (FF)/Vilanterol (VI) Once Daily Versus Fluticasone Propionate (FP) Twice Daily in Subjects With Asthma and Exercise-Induced Bronchoconstriction (EIB)

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, double-dummy, crossover study with two 2-week treatment periods separated by a 2-week wash-out period. Subjects will participate in up to eight study visits and have a follow up phone call approximately a week after the last clinic visit. Visits 1, 2, 3, 5 and 6 are evening visits that will be conducted between 5PM and 11PM. Visit 4 and Visit 7 are also evening visits that will begin between 5PM and 11PM and continue over a period of approximately 24 hours. Subjects will be required to attend three clinic visits during this 24-hour period. An exercise challenge (using a treadmill) will be conducted at Visit 2, Visit 3 and Visit 6 (after 23 hours of the first treatment dose in each Treatment Period); and at 12 and 23 hours post evening dose at Visits 4 and 7. Spirometry will be conducted at specified visits and prior to and after each exercise challenge. Subjects with symptomatic allergic rhinitis at Visit 1 (screening) may be treated for up to four weeks with intranasal corticosteroids followed by a repeat screening visit to determine eligibility prior to entry into the study. Eligible subjects at visit 1 will complete a 4-week single blind run-in on FP 250 microgram (mcg) twice daily (BID), followed by 2-week double-blind Treatment Period 1 on randomized treatment, a 2-week single blind washout period on FP 250 mcg BID, 2-week double-blind Treatment Period 2 receiving the alternative treatment, and follow-up contact approximately 7-days after completing Treatment Period 2. The total duration of study participation is approximately 11 weeks; and up to 15 weeks for subjects with Symptomatic Allergic Rhinitis. The primary objective of the study is to evaluate the protective effect of fluticasone furoate/vilanterol (FF/VI) 100/25 mcg once-daily compared with fluticasone propionate (FP) 250 mcg twice-daily against exercise-induced bronchoconstriction in adolescent and adult subjects aged 12 to 50 with persistent asthma. ELLIPTA, ACCUHALER, and DISKUS are registered trademarks of the GlaxoSmithKline group of companies.

Official Title
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201832: A Randomised, Double-Blind, Double-Dummy, Crossover Comparison of Fluticasone Furoate/Vilanterol 100/25 mcg Once Daily Versus Fluticasone Propionate 250 mcg Twice Daily in Adolescent and Adult Subjects With Asthma and Exercise-Induced Bronchoconstriction

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone furoate/ Vilanterol 100 mcg/25 mcg
* Drug: Fluticasone propionate 250 mcg
* Drug: Placebo via ELLIPTA inhaler
* Drug: Placebo via DISKUS / ACCUHALER


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent: Subjects must give their signed and dated written informed consent to participate prior to commencing any study related activities. Age Range: 12 to 50 years of age, inclusive, at Visit 1 (Screening). Diagnosis: A diagnosis of asthma, as defined by the National Institutes of Health for at least 12 weeks prior to Visit 1. Asthma Severity: Subjects must have a pre-bronchodilator FEV1 of >=70 percent of the predicted normal value. Predicted values will be based upon Global Lung Function Initiative equations for spirometry reference values. Evidence of EIB: Subjects must answer Yes to at least 2 of the following 3 questions reflecting on the previous 12 months: Are you short of breath during exercise or other physical exertion? Do you wheeze after exercise or other physical exertion? Do you cough after exercise or other physical exertion? Concurrent Anti-Asthma Therapy: Subjects must be taking low- to moderate dose inhaled steroids for 12 weeks prior to Visit 1 in order to participate with no change in dose for the 4 weeks prior to Visit 1. Gender: Subjects may be male or an eligible female. A female is eligible to enter and participate in the study if she is of: Non-child bearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile).Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence of hormone replacement therapy. OR Child bearing potential, has a negative pregnancy test at screening, and agrees to acceptable contraceptive methods approved in their local country, when used consistently and correctly (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study - screening to follow-up contact). Albuterol/salbutamol Use: All subjects must be able to replace their current short-acting beta2-agonist with albuterol/salbutamol, to be used only on an as-needed basis for the duration of the study. Each subject must be judged capable of withholding albuterol/salbutamol for at least 6 hours prior to performing spirometric evaluations. Physical Capacity: Each subject must be physically able to perform the exercise challenges on a treadmill when bronchodilators have been withheld. Exclusion Criteria: Intermittent Asthma, Seasonal Asthma, or Exercise-Induced Bronchoconstriction Only: Subjects with only intermittent or seasonal asthma or only exercise-induced asthma are excluded from participation in this study. History of Life-threatening Asthma: Defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 10 years. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12 weeks of Visit 1 or that resulted in an overnight hospitalization requiring additional treatment for asthma within 6 months prior to Visit 1. Symptomatic Allergic Rhinitis: Subjects with symptomatic allergic rhinitis at Visit 1 may be treated for up to four weeks with intranasal corticosteroids followed by a repeat screening visit to determine eligibility prior to entry into the study. Subjects that continue to be symptomatic after up to four weeks of treatment will be excluded. 12-Lead Electrocardiogram (ECG): A subject is not eligible if he/she has an abnormal, clinically significant ECG as determined by the investigator at the Screening Visit. Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant during the study. Respiratory Infection: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in asthma management or, in the opinion of the investigator, is expected to affect the subject's asthma status or the subject's ability to participate in the study. Concurrent Respiratory Disease: A subject must not have current evidence of: 1. Atelectasis 2. Bronchopulmonary dysplasia 3. Chronic bronchitis 4. Chronic obstructive pulmonary disease (COPD) (current or past diagnosis including asthma/COPD overlap) 5. Pneumonia 6. Pneumothorax 7. Interstitial lung disease 8. Or any evidence of concurrent respiratory disease other than asthma. Other Concurrent Diseases/Abnormalities: A subject must not have any clinically significant, uncontrolled condition, or disease state that, in the opinion of the investigator, would put the safety of the subject at risk through study participation or would confound the interpretation of the efficacy results if the condition/disease exacerbated during the study. Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1 or within five half-lives (t1/2) of the prior investigational study, whichever is longer of the two periods. Allergies: 1) Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or excipients used with FF/VI 100/25 or FP 250 (i.e., drug, lactose or magnesium stearate). 2) Milk Protein Allergy: History of severe milk protein allergy. 3) Latex Allergy: History of allergy or sensitivity to latex that in the opinion of the investigator contraindicates the subject's participation in the study. Concomitant Medication: Administration of prescription or non-prescription medication that would significantly affect the course of asthma, or interact with study drug. Immunosuppressive Medications: A subject must not be using or require the use of immunosuppressive medications during the study. Compliance: A subject will not be eligible if he/she or his/her parent or legal guardian has any infirmity, disability, disease, or geographical location which seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol. Tobacco/Marijuana Use: Current tobacco smoker or has a smoking history of >=10 pack-years (20 cigarettes/day for 10 years). A subject may not have used inhaled tobacco products or inhaled marijuana within the past 3 months (e.g. cigarettes, cigars, electronic cigarettes, or pipe tobacco). Affiliation with Investigator's Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, sub-investigator, study-coordinator or an employee of the participating investigator.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 50 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FF/VI 100/25 mcg + Placebo DISKUS®/ ACCUHALER®<br>Randomised subjects will receive FF/VI 100/25 mcg once daily via ELLIPTA inhaler and placebo twice daily via DISKUS / ACCUHALER for 2 weeks in Period 1. There will be a washout period of 2 weeks between treatment periods in which subjects will receive FP 250 mcg twice daily. Subjects will receive FP 250 mcg twice daily via DISKUS inhaler and placebo once daily via ELLIPTA inhaler for 2 weeks in Period 2. | Drug: Fluticasone furoate/ Vilanterol 100 mcg/25 mcg<br>* FF/VI 100/25 mcg will be administered via ELLIPTA inhaler once daily in the evening<br>Drug: Placebo via DISKUS / ACCUHALER<br>* Placebo will be administered via DISKUS / ACCUHALER, twice daily, once in the morning and once in the evening<br>|
| Experimental: FP 250 mcg + Placebo ELLIPTA®<br>Randomised subjects will receive FP 250 mcg twice daily via DISKUS inhaler and placebo once daily via ELLIPTA inhaler for 2 weeks in Period 1. There will be a washout period of 2 weeks between treatment periods in which subjects will receive FP 250 mcg twice daily. Subjects will receive FF/VI 100/25 mcg once daily via ELLIPTA inhaler and placebo twice daily via DISKUS inhaler for 2 weeks in Period 2. | Drug: Fluticasone propionate 250 mcg<br>* FP 250mcg will be administered via DISKUS inhaler, twice daily, once in the morning and once in the evening<br>Drug: Placebo via ELLIPTA inhaler<br>* Placebo will be administered via ELLIPTA inhaler once daily in the evening<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Percent Decrease in Forced Expiratory Volume in One Second (FEV1) Following Exercise Challenge at 12 Hours (Hrs) Post Evening Dose From Pre-exercise FEV1. | The exercise challenge test is a stepped challenge on a treadmill. It was performed at 12 hrs post evening dose at the end of the 2-week treatment period, wherein the participants exercised sufficiently to reach a heart rate between 80 to 95 percent of their predicted maximum within 4 minutes (min) and maintained the heart rate with exercise for an additional 6 min followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Maximal percent decrease was calculated as pre-exercise FEV1 minus minimum post exercise FEV1 (smallest FEV1 value collected within one hr following exercise challenge) divided by pre-exercise FEV1 multiplied by 100. Pre-exercise FEV1 was defined as the FEV1 collected prior to the exercise challenge test at 12 hr post dose. ITT Population comprised of all participants randomized to treatment and who received at least one dose of study medication. | At Week 2 of treatment period 1 and 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal Percent Decrease in FEV1 Following Exercise Challenge at 23 Hrs Post Evening Dose From Pre-exercise FEV1. | The exercise challenge test is a stepped challenge on a treadmill. It was performed at 23 hrs post evening dose at the end of the 2-week treatment period, wherein the participants exercised sufficiently to reach a heart rate between 80 to 95 percent of their predicted maximum within 4 min and maintained the heart rate with exercise for an additional 6 min followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Maximal percent decrease was calculated as pre-exercise FEV1 minus minimum post exercise FEV1 (smallest FEV1 value collected within one hr following exercise challenge) divided by pre-exercise FEV1 multiplied by 100. Pre-exercise FEV1 was defined as the FEV1 collected prior to the exercise challenge test at 23 hr post dose. | At Week 2 of treatment period 1 and 2 | 
| Proportion of Participants With a 30 Min Post-challenge FEV1 no More Than 5 Percent Lower Than Pre-exercise FEV1 Following the Exercise Challenge at 12 Hrs and 23 Hrs Post Evening Dose. | The blinded treatment exercise challenge test was performed at the end of 2-weeks of treatment period 1 and treatment period 2 on a treadmill at 12 hrs and 23 hrs after administration of the evening dose of study treatment. The challenge was followed immediately by serial assessments of FEV1 at 5, 10, 15, 30, 45 and 60 min post-exercise. Pre-exercise FEV1 was defined as the FEV1 value collected prior to the exercise challenge test at 23 hrs post-dose. Number of participants listed is the number in the ITT population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | At Week 2 of treatment period 1 and 2 | 
| Weighted Mean 0-60 Min for Percentage Decrease From Pre-exercise FEV1 Following Exercise Challenge at 12 Hrs and 23 Hrs Post Evening Dose. | The exercise challenge testing at the end of 2 week treatment period was performed on a treadmill at 12 hrs and 23 hrs after administration of the evening dose of double-blind treatment. Following exercise challenge testing, post-exercise FEV1 values were assessed serially at 5, 10, 15, 30, 45 and 60 min. Pre-exercise FEV1 was defined as the FEV1 value collected prior to the exercise challenge test at 23 hrs post-dose. Number of participants listed is the number in the ITT population. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | At Week 2 of treatment period 1 and 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluticasone furoate, activity monitoring, Vilanterol, Cross-over, exercise-induced bronchoconstriction, exercise challenge, double-dummy, asthma, spirometry, fluticasone propionate