Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects

Study Overview
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Brief Summary
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This is a randomized, placebo-controlled, 2-period crossover, escalating repeat dose study, aiming to investigate whether higher potency of different inhaled corticosteroid confers an improvement in the topical efficacy to systemic activity ratio in asthmatic subjects. It will compare the dose response for topical efficacy via airway responsiveness (to adenosine-5'-monophosphate [AMP] challenge), and the dose response for systemic activity via 24 hour plasma cortisol suppression, and thereby compare the relative therapeutic index, for the following inhaled corticosteroids: fluticasone furoate (FF), fluticasone propionate (FP) and budesonide (BUD). There will be a screening visit 4 - 42 days before the first dose of study treatment, and AMP challenge Provocative concentration 20 (PC20) of <=80 milligrams per milliliter (mg/mL) at screening visit 2 i.e. at 4 - 14 days before the first dose of study treatment. Subjects will be randomized to one of 5 or 12 treatment sequences, and will have one or two treatment periods, each comprising 5 consecutive 7-day phases of escalating doses of either FF, FP, BUD or placebo. There will be a 25- to 42-day washout period between treatment periods. The study duration for each subject will be approximately 13 or 24 weeks including the follow-up period.

Official Title
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An Escalating Dose, Randomized, Placebo-controlled, Incomplete-block, 2-period Cross-over Study to Assess the Dose Response for Topical Efficacy Via Airway Responsiveness to Adenosine-5'-Monophosphate (AMP) Challenge and the Dose Response for Systemic Activity Via 24h Plasma Cortisol Suppression and Thereby the Relative Therapeutic Index for Fluticasone Furoate (FF), Fluticasone Propionate (FP) and Budesonide (BUD) in Asthmatic Subjects

Conditions
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Asthma

Intervention / Treatment
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* Drug: Fluticasone furoate (FF) Dry Powder Inhaler
* Drug: Fluticasone propionate (FP) Dry Powder Inhaler
* Drug: Budesonide (BUD) Turbuhaler
* Drug: Placebo (ELLIPTA or DISKUS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria - Subjects must be 18 to 65 years of age inclusive, at the time of signing the informed Consent. - Documented history of bronchial asthma, first diagnosed at least 6 months prior to the screening visit - Pre-bronchodilator FEV1 >=65% of predicted at screening; the pre-dose baseline FEV1 should not have changed significantly in the opinion of the investigator from the screening baseline value and should be >=65% predicted for the subject to continue - Documented sensitivity to AMP with a provocative concentration of AMP resulting in a fall of >=20% FEV1 with a PC20 AMP <=80 mg/mL at the screening visit - Current therapy could include short-acting Beta2-agonists (SABA) prescribed SABA for at least 12 weeks prior to screening, if needed; subjects receiving low-dose ICS may take part after a 4-week ICS washout prior to AMP challenge. The subject's asthma symptoms must remain stable during this 4-week period as assessed at screening visit 2. Stable asthma is defined as no more than 2 consecutive days where >=12 inhalations/day of salbutamol were used; or no severe asthma exacerbations requiring use of systemic corticosteroids (tablets, suspension, or injection) or an in-patient hospitalization or emergency department visit due to asthma that required systemic corticosteroids; or no clinical asthma worsening which in the opinion of the investigator requires additional asthma treatment other than study medication or salbutamol; subjects taking Long-acting beta2-agonist (LABA), long-acting muscarinic antagonist (LAMA), leukotriene receptor antagonist (LTRA) therapy within three months prior to the start of the study are not eligible; subjects taking biological therapies within 6 months prior to start of the study are not eligible. - Bodyweight >=50 Kilogram (kg) and BMI within the range 18.0-35.0 kg/meter (m)^2 (inclusive) - Male and 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 prior to randomization: • Non-reproductive potential defined as pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented 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. 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 highly effective methods for avoiding pregnancy in females of reproductive potential from 30 days prior to the first dose of study medication and until at least five terminal half-lives after the last dose of study medication. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. - Aspartate aminotransferase and Alanine transaminase <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin ≤1.5 x ULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%) - Light smokers, who smoke <=20 cigarettes per week or equivalent unit dose of other tobacco products or e-cigarettes, are eligible for the study. Smokers who intend to stop, reduce or increase their smoking habit during the study period are not eligible. - Having provided written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Exclusion Criteria: - A history of life-threatening asthma, 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) severe pneumonia within 6 months of the screening visit, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, tuberculosis or other respiratory abnormalities other than asthma. - Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear within 4 weeks of screening that: 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. - A subject will not be eligible if he/she has clinical visual evidence of oral candidiasis at screening. - 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 randomization. - Use of prohibited medications including, anti-depressant drugs, and anti-asthma drugs (other than short acting inhaled beta-agonists supplied as rescue medication, oral contraceptives, non-steroidal anti-inflammatory drugs, stable doses of antihistamines, and paracetamol) for 1 week prior to screening and throughout the course of the study. Anti-histamines should be withheld 4 days prior to AMP challenge; subjects must also be able to abstain from short acting inhaled beta-agonists, for 8 hours prior to spirometry. - Subjects undergoing de-sensitization therapy - Current smokers who smoke > 20 cigarettes per week or the equivalent unit dose of other tobacco products or e-cigarettes, or smokers with a smoking history of >=10 pack years. - History of regular alcohol consumption exceeding 21 units per week for men and 14 units per week for females (1 unit =5 ounces [150 mL] of wine or 12 ounces [360 mL] of beer or 1.5 ounces [45 mL] of spirits) within 6 months of screening. - All subjects who are currently or in the last month have worked night-shifts are excluded from the study - Exposure to more than four new chemical entities within 12 months prior to the first dosing day or received an investigational product within 30 days of study start, or 5 half-lives of study drug if that is longer. - 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. (e.g. stroke or myocardial infarction within 3 months, uncontrolled hypertension, congestive heart failure, uncontrolled diabetes mellitus.) - Evidence of cancer or history of cancer in the past 5 years other than adequately treated basal or squamous cell carcinoma of the skin or adequately treated in situ carcinoma of the cervix. - Pregnant females as determined by positive urine HCG test at screening or by positive urine HCG test prior to dosing and lactating females. - Subjects with active or chronic infections including hepatitis B or C, human immunodeficiency virus. A positive serology at screening. - Allergies: History of severe milk protein allergy Drug Allergy defined as any adverse reaction including immediate or delayed hypersensitivity to intranasal, inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to the constituents of FF, FP or BUD (i.e., lactose or magnesium stearate etc.) Historical Allergy defined as history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation. - Significant abnormality in the 12-lead electrocardiogram (ECG) performed at screening. The mean of the three individual ECGs will be taken. Mean QT interval corrected for heart rate (QTc) >450 millisecond (msec) for males or QTc>470 msec for female subjects and >480 in subjects with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF).

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm AB - FF followed by FP<br>Each treatment period (TP) comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or FP. In TP 1, subjects will receive evening (PM) dose of 1 puff of FF 25 microgram (mcg) (Total daily dose [TDD] = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puff of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puff of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by morning (AM) and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>|
| Experimental: Arm AC - FF followed by BUD<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or BUD. In TP 1, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD = 100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD = 400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD = 1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>|
| Experimental: Arm AD - FF followed by ELLIPTA Placebo<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FF or ELLIPTA Placebo. In TP 1, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phases followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|
| Experimental: Arm BA - FP followed by FF<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or FF. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>|
| Experimental: Arm BC - FP followed by BUD<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or BUD. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD = 400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>|
| Experimental: Arm BE - FP followed by DISKUS Placebo<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either FP or DISKUS Placebo. In TP 1, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. Each TP will be followed by a washout period of 25-42 days. | Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|
| Experimental: Arm CA - BUD followed by FF<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or FF. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>|
| Experimental: Arm CB - BUD followed by FP<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or FP. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD =500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>|
| Experimental: Arm CE - BUD followed by DISKUS Placebo<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either BUD or DISKUS Placebo. In TP 1, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each DISKUS Placebo in second, third and fourth phase; and AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. Washout period will be of 25-42 days. | Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|
| Experimental: Arm DA - ELLIPTA Placebo followed by FF<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either ELLIPTA Placebo or FF. In TP 1, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FF 25 mcg (TDD = 25 mcg) in first phase followed by PM dose of 1 puff of FF 100 mcg (TDD = 100 mcg) in second phase; PM dose of 1 puff of FF 200 mcg (TDD = 200 mcg) in third phase; PM dose of 2 puffs of FF 200 mcg (TDD = 400 mcg) in fourth phase and PM dose of 4 puffs of FF 200 mcg (TDD = 800 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone furoate (FF) Dry Powder Inhaler<br>* Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|
| Experimental: Arm EB - DISKUS Placebo followed by FP<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either DISKUS Placebo or FP. TP 1, subjects will receive PM dose of 1 puff of DISKUS Placebo in first phase followed by AM and PM doses of 1 puff each of DISKUS Placebo in second, third and fourth phase; AM and PM doses of 2 puffs each of DISKUS Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of FP 50 mcg (TDD = 50 mcg) in first phase followed by AM and PM doses of 1 puff each of FP 100 mcg (TDD = 200 mcg) in second phase; AM and PM doses of 1 puff each of FP 250 mcg (TDD = 500 mcg) in third phase; AM and PM doses of 1 puff each of FP 500 mcg (TDD = 1000 mcg) in fourth phase and AM and PM doses of 2 puffs each of FP 500 mcg (TDD = 2000 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Fluticasone propionate (FP) Dry Powder Inhaler<br>* Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|
| Experimental: Arm DC - ELLIPTA Placebo followed by BUD<br>Each TP comprises of 5 consecutive 7-day dosing phases with escalating doses of either ELLIPTA Placebo or BUD. In TP 1, subjects will receive PM dose of 1 puff of ELLIPTA Placebo in first, second and third phase followed by PM dose of 2 puffs of ELLIPTA Placebo in fourth phase and PM dose of 4 puffs of ELLIPTA Placebo in fifth phase. In TP 2, subjects will receive PM dose of 1 puff of BUD 100 mcg (TDD =100 mcg) in first phase followed by AM and PM doses of 1 puff each of BUD 200 mcg (TDD =400 mcg) in second phase; AM and PM doses of 1 puff each of BUD 400 mcg (TDD = 800 mcg) in third phase; AM and PM doses of 2 puffs each of BUD 400 mcg (TDD =1600 mcg) in fourth phase and AM and PM doses of 4 puffs each of BUD 400 mcg (TDD = 3200 mcg) in fifth phase. Washout period will be of 25-42 days. | Drug: Budesonide (BUD) Turbuhaler<br>* Budesonide comprises white to off-white rounded granules, which disintegrate to a fine powder upon slight pressure, will be administered using Turbuhaler for both treatment periods.<br>Drug: Placebo (ELLIPTA or DISKUS)<br>* Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Provocative Concentration (PC) of Adenosine 5' Monophosphate (AMP) Causing a 20 Percent (%) Reduction in Forced Expiratory Volume in 1 Second (FEV1) (AMP PC20)- Dose Response Analysis | The percentage fall in FEV1 was calculated using highest FEV1 (post saline) minus highest FEV1 (post AMP) divided by highest FEV1 (post saline)*100 where highest FEV1 (post saline) is the highest value of two FEV1 measurements at 60 and 180 seconds after the saline control, highest FEV1 (post AMP) is the highest value of the two FEV1 measurements at 60 and 180 seconds after the dose of AMP. Results are presented treatment wise. The analysis method was a 3 parameter Emax model with log 2 transformed AMP PC20 as the outcome variable, assuming common Emax across FF, FP and BUD, and with an unstructured variance-covariance matrix. Mean and 95% Confidence Interval (CI) presented are predicted estimate. | 12 hours post last dose on Day 7 | 
| Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis | Blood samples for measurement of plasma cortisol were collected at given time point. The weighted means were derived by calculating the area under the curve (AUC) over the 0-24-hour period using the trapezoidal rule, and then dividing it by the actual time interval. Results are presented treatment wise. Mean and 95% CI presented are predicted estimate. The analysis method was an inhibitory exponential power-law model with log e transformed cortisol as the outcome variable, assuming 100% inhibition at highest doses. | Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7 | 
| Theraputic Index of FF | Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter[nmol/L]) divided by Dose at which 80% of the maximum effect is reached (ED80) for AMP PC20 for FF 25 mcg, FF 100 mcg, FF 200 mcg, FF 400 mcg, FF 800 mcg. Theraputic index has been presented. Only those participants with data available at the specified time points were analyzed. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively. | 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7 | 
| Theraputic Index of FP | Therapeutic Index was calculated by Dose at which 20% of the maximum effect is reached (ED20) for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter[nmol/L]) divided by ED80 for AMP PC20 for FP 50 mcg, FP 200 mcg, FP 500 mcg, FP 1000 mcg, FP 2000 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively. | 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7 | 
| Theraputic Index of BUD | Therapeutic Index was calculated by ED20 for Cortisol Suppression 0-24 Hours Weighted Mean (nanomoles per liter[nmol/L]) divided by ED80 for AMP PC20 for BUD 100 mcg, BUD 400 mcg, BUD 800 mcg, BUD 1600 mcg, BUD 3200 mcg. Theraputic index has been presented. The timeframe mentioned is for AMP PC20 and Cortisol suppression respectively. | 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward medical occurrence that at any dose results in death, Is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect. Results are presented treatment wise. | Up to Week 18 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles). | Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability of Placebo in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise. | Day 2 to 8 PM, Day 9 to 14 AM and PM, Day 15 PM, Day 16 to 21 AM and PM, Day 22 PM,Day 23 to 28 AM and PM, Day 29 PM,Day 30 to 35 AM and PM in Period 2 | 
| PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2,3,4,5,6,7 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2,3,4,5,6,7 PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 8,9,10,11,12,13,14 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 8,9,10,11,12,13,14 PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 15,16,17,18,19,20,21 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 15,16,17,18,19,20 PM, Day 21 AM and PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Days 22,23,24,25,26,27,28 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Days 22,23,24,25,26,27,28 PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Days 29,30,31,32,33,34,35 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 29,30,31,32,33,34,35 PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2,3,4,5,6,7 PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2,3,4,5,6,7 AM and PM in period 2 | 
| PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Days 8,9,1,0,11,12,13,14 AM and PM in period 1 | 
| PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 8,9,1,0,11,12,13,14 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. One participant who was supposed to receive FP 1000 mg during day 22-28 and FP 2000 mg during day 28-35 but this participant continued the 3rd escalation phase dose (FP 500 mg) in fourth escalation phase and took FP 1000 mg (4th phase dose) in the fifth escalation phase (days 28-35). | Day 15 PM, Day 16,17,18,19,20,21,22,23,24,25,26,27,28 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 15 PM, Day 16,17,18,19,20,21 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. One participant who was supposed to receive FP 1000 mg during day 22-28 and FP 2000 mg during day 28-35 but this participant continued the 3rd escalation phase dose (FP 500 mg) in fourth escalation phase and took FP 1000 mg (4th phase dose) in the fifth escalation phase (days 28-35). | Day 22 PM, Day 23,24,25,26,27,28,29,30,31,32,33,34,35 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2 to 6 AM and PM, Day 7 PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 2,3,4,5,6,7 PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 8 PM, Day 9 to 14 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 8 PM, Day 9 to 14 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 15,16, 17, 18, 19, 20, 21 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 15 PM, Day 16, 17, 18, 19, 20, 21 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 1 | 
| Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2 | PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise. | Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 2 | 
| Number of Participants With Clinically Significant Abnormal Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP were measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate | Pulse rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate | Respiratory rate was measured after participants had rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature | Temperature was measured after participants have been rested in supine position for at least 5 minutes. Results are presented treatment wise. No data collected separately for this outcome measure as any abnormal value would be recorded as an Adverse Event. | Up to Week 18 | 
| Number of Participants With Abnormal Physical Examination | Physical examinations included assessment of the cardiovascular, respiratory, gastrointestinal, skin, abdomen (liver and spleen), and neurological systems. This analysis was planned and data was not collected and captured in the database. Results are presented treatment wise. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Hematology Parameters | Blood samples were collected for assessement of following hematology parameters: basophils, eosinophils, Erythrocyte mean corpuscular volume (MCV), hemoglobin, hematocrit, Erythrocyte mean corpuscular hemoglobin (MCH), leukocytes, lymphocytes, monocytes, platelets. Results are presented treatment wise. Only participants with clinically significant abnormal hematology data was reported. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Chemistry Parameters | Blood samples were collecte for assessment of following chemistry parametres:Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), albumin, alkaline phosphatase, bilirubin, calcium, creatinine, glucose, direct bilirubin, potassium, protein, sodium, urea. Results are presented treatment wise. Only participants with clinically significant abnormal chemistry data was reported. | Up to Week 18 | 
| Number of Participants With Clinically Significant Abnormal Urinalysis Parameters | Urine sample were collected to assess following urine parameters: potential of hydrogen (pH), glucose, protein, blood and ketones by dipstick. Results are presented treatment wise. Only participants with clinically significant abnormal urinalysis data was reported. | Up to Week 18 | 
| Forced Expiratory Volume in 1 Second (FEV 1) in Period 1 | FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with American Thoracic Society (ATS) guidelines using European Respiratory Society (ERS)guidelines for predicted values. Results are presented treatment wise. | Day 1 (pre-dose) in Period 1 | 
| Forced Expiratory Volume in 1 Second (FEV 1) in Period 2 | FEV1 was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise. | Day 1 (pre-dose) in Period 2 | 
| Forced Vital Capacity (FVC) in Period 1 | FVC was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise. | Day 1 (pre-dose) in Period 1 | 
| Forced Vital Capacity (FVC) in Period 2 | FVC was measured with participants in a sitting position using a calibrated spirometer in accordance with ATS guidelines using ERS guidelines for predicted values. Results are presented treatment wise. | Day 1 (pre-dose) in Period 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dose-response, AMP challenge, cortisol suppression, dose escalation, therapeutic index