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

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ClinicalTrials.gov Identifier: NCT02991859
Recruitment Status : Completed
First Posted : December 14, 2016
Last Update Posted : January 29, 2019
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Asthma Drug: Fluticasone furoate (FF) Dry Powder Inhaler Drug: Fluticasone propionate (FP) Dry Powder Inhaler Drug: Budesonide (BUD) Turbuhaler Drug: Placebo (ELLIPTA or DISKUS) Phase 2

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 56 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : February 9, 2017
Actual Primary Completion Date : December 20, 2018
Actual Study Completion Date : December 20, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Asthma

Arm Intervention/treatment
Experimental: Arm AB - FF followed by FP
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Fluticasone propionate (FP) Dry Powder Inhaler
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Experimental: Arm AC - FF followed by BUD
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Budesonide (BUD) Turbuhaler
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.

Experimental: Arm AD - FF followed by ELLIPTA Placebo
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Experimental: Arm BA - FP followed by FF
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Fluticasone propionate (FP) Dry Powder Inhaler
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Experimental: Arm BC - FP followed by BUD
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
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Drug: Budesonide (BUD) Turbuhaler
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.

Experimental: Arm BE - FP followed by DISKUS Placebo
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
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Experimental: Arm CA - BUD followed by FF
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Budesonide (BUD) Turbuhaler
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.

Experimental: Arm CB - BUD followed by FP
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
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Drug: Budesonide (BUD) Turbuhaler
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.

Experimental: Arm CE - BUD followed by DISKUS Placebo
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
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.

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Experimental: Arm DA - ELLIPTA Placebo followed by FF
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
Dry inhalation powder 25 mcg, 100 mcg, and 200 mcg per blister strip will be administered using ELLIPTA for both treatment periods

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Experimental: Arm EB - DISKUS Placebo followed by FP
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
Dry Inhalation powder 50 mcg, 100 mcg, 250 mcg, and 500 mcg per blister strip will be administered using DISKUS for both treatment periods

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.

Experimental: Arm DC - ELLIPTA Placebo followed by BUD
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
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.

Drug: Placebo (ELLIPTA or DISKUS)
Lactose dry powder inhaler will be administered using ELLIPTA or DISKUS for both treatment periods.




Primary Outcome Measures :
  1. Provocative concentration (PC) of AMP causing a 20% reduction in forced expiratory volume in 1 second (FEV1) (AMP PC20) [ Time Frame: At Day 7 (12 hours post dose) of each escalation phase in both treatment periods ]
    AMP is used as stimulus to cause bronchoconstriction. The AMP challenges will be done 12 hour post-evening dose on Day 7 after each 7-day dose escalation phase of each treatment period (Treatment periods 1 and 2). Subjects will inhale doubling increments of AMP (0.04, 0.08, 0.16, 0.32, 0.63, 1.25, 2.5, 5.0, 10.0, 20.0, 40.0, 80.0, 160.0 and 320.0 milligram [mg]/milliliter [mL]) until a >=20% fall in FEV1 from the post-diluent value is achieved or the highest permitted dose of AMP (320 mg/mL) is achieved.

  2. 24-hour weighted mean plasma cortisol suppression [ Time Frame: Day 6 to Day 7 of each escalation phase in both treatment periods ]
    Blood samples will be collected for a 24 hour period from pre-dose evening dose on Day 6 to pre-dose evening dose on Day 7.

  3. Dose at which 20% cortisol suppression is reached ([ED20] cortisol suppression) [ Time Frame: Day 6 to Day 7 of each escalation phase in both treatment periods ]
    Blood samples will be collected for a 24 hour period from pre-dose evening dose on Day 6 to predose evening dose on Day 7. Maximum effect (Emax) model will be used to obtain the ED20 0-24 hour weighted mean cortisol suppression.

  4. Dose at which 80% of the maximum AMP PC20 is reached ([ED80] for AMP PC20) [ Time Frame: Day 6 to Day 7 of each escalation phase in both treatment periods ]
    The AMP challenges will be done 12 hour post-evening dose on Day 7 after each 7 day dose escalation phase of each treatment period. Maximum effect (Emax) model will be used to obtain the ED80 for AMP PC20.


Secondary Outcome Measures :
  1. Number of subjects with any adverse event (AE) and any serious adverse event (SAE) as a measure of safety and tolerability [ Time Frame: Approximately 24weeks ]
    An AE is any untoward medical occurrence in a clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, other situations judged by physician, is associated with liver injury and impaired liver function

  2. Peak expiratory flow rate (PEFR) as a measure of safety and tolerability [ Time Frame: On Days 1, 8, 15, 22, and 29 in both treatment periods ]
    PEFR is a subject's maximum speed of expiration and will be measured using a peak flow meter. Subjects need to record the highest PEFR measurement in paper diary (before each dose) of three maneuvers attempted twice daily

  3. Systolic and diastolic blood pressure (BP) as a measure of safety [ Time Frame: Days 1 (pre-dose) and 36 in both treatment periods ]
    Vital signs will be measured after subjects have been rested in supine position for at least 5 minutes.

  4. Pulse rate as a measure of safety [ Time Frame: Days 1 (pre-dose) and 36 in both treatment periods ]
    Vital signs will be measured after subjects have been rested in supine position for at least 5 minutes

  5. Body temperature as a measure of safety [ Time Frame: Days 1 (pre-dose) and 36 in both treatment periods ]
    Vital signs will be measured after subjects have been rested in supine position for at least 5 minutes

  6. Respiratory rate as a measure of safety [ Time Frame: Days 1 (pre-dose) and 36 in both treatment periods ]
    Vital signs will be measured after subjects have been rested in supine position for at least 5 minutes

  7. Physical examinations as a measure of safety [ Time Frame: At Screening and Follow-up (at approximately Week 24) ]
    A complete physical examination will include, at a minimum, assessment of the cardiovascular, respiratory, gastrointestinal, skin, abdomen (liver and spleen), and neurological systems.

  8. Number of subjects with abnormal Hematology laboratory tests [ Time Frame: Approximately 24weeks ]
    Hematology values will be assessed.

  9. Number of subjects with abnormal clinical chemistry laboratory tests [ Time Frame: Approximately 24weeks ]
    Clinical chemistry values will be assessed.

  10. Number of subjects with abnormal routine urinalysis laboratory tests [ Time Frame: Approximately 24weeks ]
    Routine urinalysis parameters will be assessed.

  11. Forced expiratory volume in 1 second (FEV1) as a measure of safety and tolerability [ Time Frame: At Day 1 (pre-dose) in both treatment periods and Follow-up (at approximately Week 24) ]
    It will be measured with subjects in a sitting position using a calibrated spirometer

  12. Forced vital capacity (FVC) as a measure of safety and tolerability [ Time Frame: At Day 1 (pre-dose) in both treatment periods and Follow-up (at approximately Week 24) ]
    It will be measured with subjects in a sitting position using a calibrated spirometer



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02991859


Locations
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Germany
GSK Investigational Site
Berlin, Germany, 14050
United Kingdom
GSK Investigational Site
Harrow, Middlesex, United Kingdom, HA1 3UJ
GSK Investigational Site
London, United Kingdom, NW10 7EW
GSK Investigational Site
Manchester, United Kingdom, M23 9QZ
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT02991859     History of Changes
Other Study ID Numbers: 203162
2016-003002-14 ( EudraCT Number )
First Posted: December 14, 2016    Key Record Dates
Last Update Posted: January 29, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GlaxoSmithKline:
Dose-response
AMP challenge
cortisol suppression
dose escalation
therapeutic index

Additional relevant MeSH terms:
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Fluticasone
Budesonide
Anti-Inflammatory Agents
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists