A Phase IIA FF/VI Study to Measure FeNO in Asthmatic Patients.

Study Overview
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Brief Summary
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For asthmatic subjects, a combination of inhaled corticosteroid (FF) and long-acting beta2 receptor agonist (VI) is recommended for use (once daily) and fraction of exhaled nitric oxide (FeNO) is a non-invasive airway inflammation marker. In this randomised, double blind, placebo-controlled, two-period, crossover repeat dose study, the duration of action of fluticasone furoate (FF) will be determined by monitoring the return of FeNO levels to baseline, following the treatment with FF/vilanetrol (VI) in asthmatic subjects. Subjects who meet the eligibility criteria will participate in the following two treatment periods: FF/VI 100/25 mcg once-daily and placebo once-daily. Approximately 28 subjects will be enrolled in order to achieve 24 evaluable subjects. A 2-week treatment period will be followed by a 21-day monitoring/washout period before crossing over to the next treatment period. Total duration of each subject will be a maximum of 21 weeks. FeNO will be monitored up to 21 days after treatment with FF/VI together with FEV1 (up to 7 days).

Official Title
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A Randomised, Placebo-controlled, Double-blind, Two Period Crossover Study to Characterise the Exhaled Nitric Oxide Time Profile as a Biomarker of Airway Inflammation in Adult Asthma Patients Following Repeat Administration of Inhaled Fluticasone Furoate (FF)/ Vilanterol (VI) 100/25 mcg.

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone furoate (FF) (100 mcg)
* Drug: Vilanterol (VI) (25 mcg)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age of subject: Between 18 and 65 years of age inclusive, at the time of signing the informed consent. A doctor diagnosis of asthma for at least 6 months prior to the start of the study. Severity of disease: A screening pre-bronchodilator forced expiratory volume in one second (FEV1) >=60% of predicted values, which will be based upon NHANES III Reversibility of disease: Demonstrated presence of reversible airway disease at screening (repeat testing of eligibility can be undertaken following the screening visit up to Day -7) OR The presence of reversible airways disease can have been demonstrated historically within 6 months of the screening visit. Reversible airway disease is defined as increase in FEV1 of >=12% over baseline and an absolute change of >=200 mL within 30 minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol/spacer (or equivalent nebulised treatment with albuterol/salbutamol solution). Current Therapy: Short-acting beta2-agonists (SABA) prescribed for at least 12 weeks prior to screening. No inhaled corticosteroids (ICS), long-actint beta2-receptor agonist (LABA), long acting muscarinic anatagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy for three months prior to the start of the study. Non-smoker or ex-smoker (no smoking in previous 12 weeks, ≤10 pack years). Screening and Day -7 AM fraction of inhaled nitric oxide (FeNO) values > 40ppb. Both screening and Day -7 AM FeNO values for treatment Period 1 need to be > 40ppb for the subject to be eligible. Bodyweight and BMI: Bodyweight >=50 kg and body mass index (BMI) within the range 18.0 40.0 kg/m2 (inclusive) Male OR Female: Females: A female subject is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG[ test), not lactating, and at least one of the following conditions applies: Non-reproductive potential defined as: Pre-menopausal females reporting one of the following: Tubal ligation Hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion Hysterectomy Bilateral Oophorectomy Postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone [FSH] and estradiol levels consistent with menopause [refer to laboratory reference ranges for confirmatory levels]). Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. Reproductive potential and agrees to follow one of the options listed in the Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) from 30 days prior to the first dose of study medication and until after the last dose of study medication and completion of the follow-up visit The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion Criteria: A history of life-threatening asthma, which is defined as an asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 5 years Other significant pulmonary diseases to include (but not limited to): pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma. 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 screening that 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. However, subjects can be rescreened to allow for an adequate time period (of at least 4 weeks) between resolution of the infection and the date of randomisation. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12 weeks of screening or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to screening. Pre-defined concomitant medications and restrictions of nitrate-rich foods Tobacco Use: Current smokers or a smoking history of >=10 pack years. A subject may not have used any inhaled tobacco products in 12 weeks preceding the screening visit. Previous Participation: Exposure to more than four new chemical entities within 12 months prior to the first dosing day. Other concurrent Diseases/Abnormalities: A subject has 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 study results if the condition/disease exacerbated during the study. The list of additional excluded conditions/diseases includes, but is not limited to the following: Congestive heart failure-Known aortic aneurysm Clinically significant coronary heart disease-Clinically significant cardiac arrhythmia Stroke within 3 months of Visit 1-Uncontrolled hypertension Recent or poorly controlled peptic ulcer-Haematologic, hepatic, or renal disease Immunologic compromise-Current malignancy Tuberculosis (current or untreated)-Cushing's disease Addison's disease-Uncontrolled diabetes mellitus Liver cirrhosis-Systemic Lupus Erythematosus Uncontrolled thyroid disorder-Recent history of drug or alcohol abuse Oropharyngeal examination: A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening. Pregnancy and Lactating Females: Pregnant females as determined by positive serum hCG test at screening or by positive urine hCG test prior to dosing. Lactating females Allergies: Milk Protein Allergy: History of severe milk protein allergy. Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of the Dry Powder Inhaler (DPI) (i.e., lactose or magnesium stearate). Historical Allergy: History of drug or other allergy that, in the opinion of investigator or GSK Medical Monitor, contraindicates their participation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Fluticasone furoate/vilanterol (FF/VI) 100/25 mcg<br>Subjects will receive FF/VI 100/25 mcg each morning (once daily) from Day 1 to Day 14, followed by a 21-day monitoring/washout period | Drug: Fluticasone furoate (FF) (100 mcg)<br>* First blister strip contains FF blended with lactose, 100 mcg per blister<br>Drug: Vilanterol (VI) (25 mcg)<br>* Second blister strip contains vilanterol blended with lactose and magnesium stearate, 25 mcg per blister<br>|
| Placebo Comparator: Placebo<br>Subjects will receive placebo each morning (once daily) from Day 1 to Day 14, followed by a 21-day monitoring/washout period | Drug: Placebo<br>* Matching placebo will have two blister strips, identical in appearance to the inhaler containing active study medication; one containing lactose and the second strip containing lactose and magnesium stearate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Fraction of Exhaled Nitric Oxide (FeNO) Over Time Following the Cessation of Repeat Dose Treatment With FF/VI | FeNO is non-invasive marker of airway inflammation in asthma participants. It was measured by the participants, using Niox Vero device at AM (pre-dose) and PM on Day -7 and all way through Day 29 of each TP. The FeNO measurements were done over time following stop of repeat dose treatment with FF/VI. Change from Baseline was measured as ratio of post-dose visit value to Baseline value. Baseline was defined as Day 1(Pre-dose). Subject level Baseline defined as the mean of Baseline across periods for each participant. Period level Baseline defined as the difference between the Baseline and subject level Baseline for each period and each participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). Summary of ratio from Baseline for exhaled nitric oxide reported as Geometric mean and Geometric coefficient of Variation. NA indicates data was not available. | Baseline and up to Day 29 in each treatment period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in FeNO Over the FF/VI Treatment Period | In participants with asthma the FeNO is a non-invasive marker of airway inflammation. The FeNO was measured by the participants AM (pre-dose) and PM on Day -7 and all the way through Day 29 of each treatment period. The measurements were recorded using Niox Vero device provided at the site. These FeNO measurements were done throughout the treatment period. Change from Baseline was measured by the value at post-dose visit minus the Baseline value. Baseline was defined as Day 1(Pre-dose). Subject level Baseline is defined as the mean of Baseline across periods for each participant. Period level Baseline is defined as the difference between the Baseline and subject level Baseline for each period and each participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Baseline and up to Day 29 in each treatment period | 
| Change From Baseline in Peak Expiratory Flow (PEF) During Treatment and Following Cessation of Repeat Dose Treatment With FF/VI | The PEF is a lung function evaluation assessed using a PEF meter. It was defined as the maximum amount of air exhaled during forced exhalation with lungs fully inflated. For PEF measurements the best of the 3 recordings were recorded AM and PM (i.e every 12 hours), from Day-7 through to Day 29 of TP1, and then from Day 1 of TP2 through to the (29). Change from Baseline was measured by the value at post-dose visit minus the Baseline value. Baseline was defined as Day 1(Pre-dose). Subject level Baseline is defined as the mean of Baseline across periods for each participant. Period level Baseline is defined as the difference between the Baseline and subject level Baseline for each period and each participant. Only those participants available at the specified time points were analyzed (represented by n=X in the category titles). NA indicates data was not available. | Baseline and up to Day 29 in TP1; Baseline and up to follow up (Day 29) in TP2 | 
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) Pre-treatment and for up to 7 Days After Cessation of Repeat Dose Treatment With FF/VI | FEV1 is defined as the maximal amount of air which can be exhaled forcefully in one second. Three technically acceptable FEV1 measurements were made using a spirometer, and were measured on pre-dose on Day 1, taken pre-dose on Day 14 and every morning and evening until Day 19, and in the morning on Day 21. Change from Baseline was measured by the value at post-dose visit minus the Baseline value. Baseline was defined as Day 1(Pre-dose). Subject level Baseline is defined as the mean of Baseline across periods for each participant. Period level Baseline is defined as the difference between the Baseline and subject level Baseline for each period and each participant. | Baseline every morning and evening until Day 21 of each treatment period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fluticasone furoate/vilanterol, Asthma, fraction of exhaled nitric oxide, cross-over