AsthmaPhase 2NCT02991859

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

A Phase 2 study testing Fluticasone furoate (FF) Dry Powder Inhaler, Fluticasone propionate (FP) Dry Powder Inhaler and Budesonide (BUD) Turbuhaler in people with Asthma, run by GlaxoSmithKline at 3 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Asthma
What is being tested?: Fluticasone furoate (FF) Dry Powder Inhaler, Fluticasone propionate (FP) Dry Powder Inhaler and Budesonide (BUD) Turbuhaler
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 56 participants
Where: 3 sitesin 2 countries
Study dates: 9 Feb 2017to 20 Dec 2018
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

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).

Trial locations and contacts

3 sites in 2 countries.

Country

City, postcode or hospital

3 sites in 2 countries

United Kingdom2 sites

GSK Investigational Site
Harrow, Middlesex, HA1 3UJ
GSK Investigational Site
Manchester, M23 9QZ

Other trials in United Kingdom

Germany1 site

GSK Investigational Site
Berlin, 14050

Other trials in Germany

About this study

Official title: 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

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.

Conditions: Asthma
Being tested: Fluticasone furoate (FF) Dry Powder Inhaler, Fluticasone propionate (FP) Dry Powder Inhaler, Budesonide (BUD) Turbuhaler, Placebo (ELLIPTA or DISKUS)
Keywords: Dose-response, AMP challenge, cortisol suppression, dose escalation, therapeutic index
Medical subject headings: Asthma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Fluticasone furoate (FF) Dry Powder InhalerDrug
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods
Fluticasone propionate (FP) Dry Powder InhalerDrug
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods
Budesonide (BUD) TurbuhalerDrug
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.
Placebo (ELLIPTA or DISKUS)Drug
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Study groups in NCT02991859
Study group	Role	What they receive
Arm AB - FF followed by FP	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Fluticasone propionate (FP) Dry Powder Inhaler
Arm AC - FF followed by BUD	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Budesonide (BUD) Turbuhaler
Arm AD - FF followed by ELLIPTA Placebo	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Placebo (ELLIPTA or DISKUS)
Arm BA - FP followed by FF	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Fluticasone propionate (FP) Dry Powder Inhaler
Arm BC - FP followed by BUD	Experimental	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. Receives: Drug: Fluticasone propionate (FP) Dry Powder Inhaler; Drug: Budesonide (BUD) Turbuhaler
Arm BE - FP followed by DISKUS Placebo	Experimental	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. Receives: Drug: Fluticasone propionate (FP) Dry Powder Inhaler; Drug: Placebo (ELLIPTA or DISKUS)
Arm CA - BUD followed by FF	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Budesonide (BUD) Turbuhaler
Arm CB - BUD followed by FP	Experimental	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. Receives: Drug: Fluticasone propionate (FP) Dry Powder Inhaler; Drug: Budesonide (BUD) Turbuhaler
Arm CE - BUD followed by DISKUS Placebo	Experimental	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. Receives: Drug: Budesonide (BUD) Turbuhaler; Drug: Placebo (ELLIPTA or DISKUS)
Arm DA - ELLIPTA Placebo followed by FF	Experimental	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. Receives: Drug: Fluticasone furoate (FF) Dry Powder Inhaler; Drug: Placebo (ELLIPTA or DISKUS)
Arm EB - DISKUS Placebo followed by FP	Experimental	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. Receives: Drug: Fluticasone propionate (FP) Dry Powder Inhaler; Drug: Placebo (ELLIPTA or DISKUS)
Arm DC - ELLIPTA Placebo followed by BUD	Experimental	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. Receives: Drug: Budesonide (BUD) Turbuhaler; Drug: Placebo (ELLIPTA or DISKUS)

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7

Secondary outcomes (45)

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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Day 1 (pre-dose) in Period 2

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

9 Feb 201720 Dec 2018

First posted14 Dec 2016 (estimated)
Study start9 Feb 2017
Primary completion20 Dec 2018
Study completion20 Dec 2018

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for AsthmaStudies of the same condition, open and under way.
More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 56 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02991859
Sponsor's protocol ID: 203162
Other IDs: 2016-003002-14, 2016
Status last verified: Jul 2020
First submitted: 9 Dec 2016
Last updated: 31 Jul 2020
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Yes: IPD for this study will be made available via the Clinical Study Data Request site.

Publications

Daley-Yates P, Brealey N, Thomas S, Austin D, Shabbir S, Harrison T, Singh D, Barnes N. Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression. Br J Clin Pharmacol. 2021 Feb;87(2):483-493. doi: 10.1111/bcp.14406. Epub 2020 Jun 17.
PubMed 32484940

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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RecruitingPhase 3
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All Asthma trials

Study at a glance

From the registry record, last updated by the sponsor on 31 Jul 2020. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: 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
ClinicalTrials.gov ID: NCT02991859
Acronym / sponsor ID: 203162
Conditions: Asthma
Keywords: Dose-response, AMP challenge, cortisol suppression, dose escalation, therapeutic index
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 56 participants (actual)
Lead sponsor: GlaxoSmithKlineIndustry (pharma, biotech, devices)
Study start: 9 Feb 2017 (actual)
Primary completion: 20 Dec 2018 (actual)
Study completion: 20 Dec 2018 (actual)
First posted: 14 Dec 2016 (estimated)
Results: Posted 30 Mar 2020

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Crossover
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 12

Arm	Type	Receives
Arm AB - FF followed by FP	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Fluticasone propionate (FP) Dry Powder InhalerEach 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.
Arm AC - FF followed by BUD	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Budesonide (BUD) TurbuhalerEach 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.
Arm AD - FF followed by ELLIPTA Placebo	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Placebo (ELLIPTA or DISKUS)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.
Arm BA - FP followed by FF	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Fluticasone propionate (FP) Dry Powder InhalerEach 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.
Arm BC - FP followed by BUD	Experimental	Drug: Fluticasone propionate (FP) Dry Powder Inhaler, Drug: Budesonide (BUD) TurbuhalerEach 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.
Arm BE - FP followed by DISKUS Placebo	Experimental	Drug: Fluticasone propionate (FP) Dry Powder Inhaler, Drug: Placebo (ELLIPTA or DISKUS)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.
Arm CA - BUD followed by FF	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Budesonide (BUD) TurbuhalerEach 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.
Arm CB - BUD followed by FP	Experimental	Drug: Fluticasone propionate (FP) Dry Powder Inhaler, Drug: Budesonide (BUD) TurbuhalerEach 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.
Arm CE - BUD followed by DISKUS Placebo	Experimental	Drug: Budesonide (BUD) Turbuhaler, Drug: Placebo (ELLIPTA or DISKUS)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.
Arm DA - ELLIPTA Placebo followed by FF	Experimental	Drug: Fluticasone furoate (FF) Dry Powder Inhaler, Drug: Placebo (ELLIPTA or DISKUS)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.
Arm EB - DISKUS Placebo followed by FP	Experimental	Drug: Fluticasone propionate (FP) Dry Powder Inhaler, Drug: Placebo (ELLIPTA or DISKUS)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.
Arm DC - ELLIPTA Placebo followed by BUD	Experimental	Drug: Budesonide (BUD) Turbuhaler, Drug: Placebo (ELLIPTA or DISKUS)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.

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Fluticasone furoate (FF) Dry Powder InhalerDry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods	Drug	Arm AB - FF followed by FP, Arm AC - FF followed by BUD, Arm AD - FF followed by ELLIPTA Placebo, Arm BA - FP followed by FF, Arm CA - BUD followed by FF, Arm DA - ELLIPTA Placebo followed by FF
Fluticasone propionate (FP) Dry Powder InhalerDry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods	Drug	Arm AB - FF followed by FP, Arm BA - FP followed by FF, Arm BC - FP followed by BUD, Arm BE - FP followed by DISKUS Placebo, Arm CB - BUD followed by FP, Arm EB - DISKUS Placebo followed by FP
Budesonide (BUD) TurbuhalerBudesonide 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.	Drug	Arm AC - FF followed by BUD, Arm BC - FP followed by BUD, Arm CA - BUD followed by FF, Arm CB - BUD followed by FP, Arm CE - BUD followed by DISKUS Placebo, Arm DC - ELLIPTA Placebo followed by BUD
Placebo (ELLIPTA or DISKUS)Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.	Drug	Arm AD - FF followed by ELLIPTA Placebo, Arm BE - FP followed by DISKUS Placebo, Arm CE - BUD followed by DISKUS Placebo, Arm DA - ELLIPTA Placebo followed by FF, Arm DC - ELLIPTA Placebo followed by BUD, Arm EB - DISKUS Placebo followed by FP

Primary outcome

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
Time frame: 12 hours post last dose on Day 7
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.
Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis
Time frame: Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
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.
Theraputic Index of FF
Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
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.
Theraputic Index of FP
Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
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.
Theraputic Index of BUD
Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
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.

45 secondary outcomes

Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)
Time frame: Up to Week 18
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Up to Week 18
Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate
Time frame: Up to Week 18
Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate
Time frame: Up to Week 18
Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature
Time frame: Up to Week 18
Number of Participants With Abnormal Physical Examination
Time frame: Up to Week 18
Number of Participants With Clinically Significant Abnormal Hematology Parameters
Time frame: Up to Week 18
Number of Participants With Clinically Significant Abnormal Chemistry Parameters
Time frame: Up to Week 18

Results and safety

Results posted to the registry on 30 Mar 2020, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Arm AB - FF Followed by FP	2	2
Arm AC - FF Followed by BUD	3	2
Arm AD - FF Followed by ELLIPTA Placebo	2	2
Arm BA - FP Followed by FF	2	2
Arm BC - FP Followed by BUD	3	2
Arm BE - FP Followed by DISKUS Placebo	3	3
Arm CA - BUD Followed by FF	2	2
Arm CB - BUD Followed by FP	2	2
Arm CE - BUD Followed by DISKUS Placebo	2	2
Arm DA - ELLIPTA Placebo Followed by FF	2	2
EB - DISKUS Placebo Followed by FP	2	2
Arm DC - ELLIPTA Placebo Followed by BUD	2	2
Fluticasone Furoate (FF)	7	7
Fluticasone Propionate (FP)	7	7
Budesonide (BUD)	6	6
ELLIPTA	3	3
DISKUS	3	3

Primary outcome: 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

Time frame: 12 hours post last dose on Day 7. Mean (95% Confidence Interval). Unit: Milligrams per milliliter

Measure	FF 25 mcg n = 19	FF 100 mcg n = 19	FF 200 mcg n = 18	FF 400 mcg n = 18	FF 800 mcg n = 17	FP 50 mcg n = 20	FP 200 mcg n = 20	FP 500 mcg n = 18	FP 1000 mcg n = 16	FP 2000 mcg n = 17	BUD 100 mcg n = 18	BUD 400 mcg n = 18	BUD 800 mcg n = 18	BUD 1600 mcg n = 18	BUD 3200 mcg n = 17
Value	33.45 (19.10 to 58.60)	81.45 (44.65 to 148.58)	115.69 (66.82 to 200.31)	145.97 (85.02 to 250.59)	167.26 (95.36 to 293.37)	15.19 (10.80 to 21.36)	20.47 (13.94 to 30.07)	31.39 (18.88 to 52.19)	48.67 (27.30 to 86.78)	76.35 (43.21 to 134.91)	16.00 (11.41 to 22.44)	23.91 (15.08 to 37.90)	34.62 (19.28 to 62.16)	54.33 (28.40 to 103.93)	84.17 (45.48 to 155.79)

FF 25 mcg vs FF 200 mcg vs FF 400 mcg vs FF 800 mcg: 3 parameter Emax model: 13.50 (95% CI 9.39 to 19.39)
FF 25 mcg vs FF 200 mcg vs FF 400 mcg vs FF 800 mcg: 3 parameter Emax model: 14.44 (95% CI 8.21 to 25.40)
FF 25 mcg vs FF 200 mcg vs FF 400 mcg vs FF 800 mcg: 3 parameter Emax model: 48.52 (95% CI 18.21 to 129.32)

Population analysed: Pharmacodymanic (PD) population. Participants who were randomized and received at least one dose of trial medication and also have at least one post dose PD measurement. Only those participants with data available at the specified time points were analyzed.

Primary outcome: Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis

Time frame: Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7. Mean (95% Confidence Interval). Unit: nanomoles per liter

Measure	FF 25 mcg n = 19	FF 100 mcg n = 19	FF 200 mcg n = 18	FF 400 mcg n = 18	FF 800 mcg n = 18	FP 50 mcg n = 20	FP 200 mcg n = 19	FP 500 mcg n = 18	FP 1000 mcg n = 16	FP 2000 mcg n = 16	BUD 100 mcg n = 16	BUD 400 mcg n = 16	BUD 800 mcg n = 18	BUD 1600 mcg n = 18	BUD 3200 mcg n = 17
Value	172.73 (159.88 to 186.62)	163.03 (151.01 to 176.02)	150.95 (139.48 to 163.37)	129.40 (117.82 to 142.12)	95.09 (82.26 to 109.93)	173.04 (160.15 to 186.97)	164.22 (152.11 to 177.29)	147.89 (136.59 to 160.13)	124.21 (112.88 to 136.68)	87.62 (75.37 to 101.85)	169.87 (157.23 to 183.52)	152.50 (141.26 to 164.63)	132.06 (122.05 to 142.90)	99.05 (90.24 to 108.72)	55.71 (48.26 to 64.31)

FF 25 mcg vs FF 100 mcg vs FF 200 mcg vs FF 400 mcg: Exponential power-law model: 176.09 (95% CI 162.87 to 190.38)
FF 25 mcg vs FF 100 mcg vs FF 200 mcg vs FF 400 mcg vs FF 800 mcg: exponential power-law model: 899.99 (95% CI 698.36 to 1101.62)
FP 50 mcg vs FP 200 mcg vs FP 500 mcg vs FP 1000 mcg vs FP 2000 mcg: exponential power-law model: 176.09 (95% CI 162.87 to 190.38)

Population analysed: PD population. Only those participants with data available for each dose escalation phase were analyzed.

Primary outcome: Theraputic Index of FF

Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7. Number. Unit: Ratio

Measure	Fluticasone Propionate (FP) n = 51
Value	1.49

Fluticasone Propionate (FP): Emax Model: 289.73 (95% CI 224.82 to 354.64)
Fluticasone Propionate (FP): Emax Model: 194.09 (95% CI 72.82 to 517.28)

Population analysed: PD population. Only those participants with data available at the specified time points were analyzed.

Primary outcome: Theraputic Index of FP

Time frame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7. Number. Unit: Ratio

Measure	Fluticasone Propionate (FP) n = 51
Value	0.15

Fluticasone Propionate (FP): Emax Model: 639.36 (95% CI 506.94 to 771.79)
Fluticasone Propionate (FP): Emax Model: 4325.07 (95% CI 1792.02 to 10438.64)

Population analysed: PD population. Only those participants with data available at the specified time points were analyzed.

45 secondary outcomes are reported in the full results.

Adverse events

Time frame: Serious adverse events and non-serious adverse events were collected up to 18 weeks.. Other adverse events reported at 3% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo	0 of 17 (0%)	10 of 17 (58.8%)	0 of 17
FF 25 mcg	0 of 20 (0%)	6 of 20 (30%)	0 of 20
FF 100 mcg	0 of 19 (0%)	8 of 19 (42.1%)	0 of 19
FF 200 mcg	0 of 19 (0%)	7 of 19 (36.8%)	0 of 19
FF 400 mcg	0 of 18 (0%)	6 of 18 (33.3%)	0 of 18
FF 800 mcg	0 of 18 (0%)	7 of 18 (38.9%)	0 of 18
FP 50 mcg	0 of 21 (0%)	10 of 21 (47.6%)	0 of 21
FP 200 mcg	0 of 20 (0%)	4 of 20 (20%)	0 of 20
FP 500 mcg	0 of 20 (0%)	4 of 20 (20%)	0 of 20
FP 1000 mcg	0 of 18 (0%)	8 of 18 (44.4%)	0 of 18
FP 2000 mcg	0 of 17 (0%)	6 of 17 (35.3%)	0 of 17
BUD 100 mcg	0 of 18 (0%)	6 of 18 (33.3%)	0 of 18
BUD 400 mcg	0 of 18 (0%)	8 of 18 (44.4%)	0 of 18
BUD 800 mcg	0 of 18 (0%)	5 of 18 (27.8%)	0 of 18
BUD 1600 mcg	0 of 18 (0%)	6 of 18 (33.3%)	0 of 18
BUD 3200 mcg	0 of 18 (0%)	3 of 18 (16.7%)	0 of 18

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 31 Jul 2020.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 32484940Daley-Yates P, Brealey N, Thomas S, Austin D, Shabbir S, Harrison T, Singh D, Barnes N. Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression. Br J Clin Pharmacol. 2021 Feb;87(2):483-493. doi: 10.1111/bcp.14406. Epub 2020 Jun 17.
Individual participant dataSharing planned: Yes. IPD for this study will be made available via the Clinical Study Data Request site.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

GSK Clinical Trials study director

GlaxoSmithKline

3 sites in 2 countries: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Jul 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United Kingdom, Germany. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Mar 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

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 (time frame: 12 hours post last dose on Day 7). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02991859, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Jul 2020.