Clinical trial NCT02991859: Phase 2a, AMP Challenge, Dose Escalation Study to Assess the Dose Response for Topical Efficacy and Systemic Activity in Asthmatic Subjects
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Asthma
Keywords: Dose-response
AMP challenge
cortisol suppression
dose escalation
therapeutic index
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-12-14
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


Eligibility 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).

Primary outcomes:
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
timeFrame: 12 hours post last dose on Day 7
measure: Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis
timeFrame: Pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
measure: Theraputic Index of FF
timeFrame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
measure: Theraputic Index of FP
timeFrame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
measure: Theraputic Index of BUD
timeFrame: 12 hours post-dose on Day 7, pre-dose PM dose on Day 6 to pre-dose PM dose Day 7
Secondary outcomes:
measure: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)
timeFrame: Up to Week 18
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1
timeFrame: 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
measure: PEFR as a Measure of Safety and Tolerability of Placebo in Period 2
timeFrame: 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
measure: PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1
timeFrame: Day 2,3,4,5,6,7 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2
timeFrame: Day 2,3,4,5,6,7 PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1
timeFrame: Day 8,9,10,11,12,13,14 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2
timeFrame: Day 8,9,10,11,12,13,14 PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 1
timeFrame: Day 15,16,17,18,19,20,21 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FF 200 mcg in Period 2
timeFrame: Day 15,16,17,18,19,20 PM, Day 21 AM and PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 1
timeFrame: Days 22,23,24,25,26,27,28 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FF 400 mcg in Period 2
timeFrame: Days 22,23,24,25,26,27,28 PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 1
timeFrame: Days 29,30,31,32,33,34,35 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FF 800 mcg in Period 2
timeFrame: Day 29,30,31,32,33,34,35 PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 1
timeFrame: Day 2,3,4,5,6,7 PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FP 50 mcg in Period 2
timeFrame: Day 2,3,4,5,6,7 AM and PM in period 2
measure: PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 1
timeFrame: Days 8,9,1,0,11,12,13,14 AM and PM in period 1
measure: PEFR as a Measure of Safety and Tolerability for FP 200 mcg in Period 2
timeFrame: Day 8,9,1,0,11,12,13,14 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 1
timeFrame: Day 15 PM, Day 16,17,18,19,20,21,22,23,24,25,26,27,28 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 500 mcg in Period 2
timeFrame: Day 15 PM, Day 16,17,18,19,20,21 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 1
timeFrame: Day 22 PM, Day 23,24,25,26,27,28,29,30,31,32,33,34,35 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 1000 mcg in Period 2
timeFrame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 1
timeFrame: Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for FP 2000 mcg in Period 2
timeFrame: Day 29 PM, Day 30,31,32,33,34,35 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 1
timeFrame: Day 2 to 6 AM and PM, Day 7 PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 100 mcg in Period 2
timeFrame: Day 2,3,4,5,6,7 PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 1
timeFrame: Day 8 PM, Day 9 to 14 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 400 mcg in Period 2
timeFrame: Day 8 PM, Day 9 to 14 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 1
timeFrame: Day 15,16, 17, 18, 19, 20, 21 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 800 mcg in Period 2
timeFrame: Day 15 PM, Day 16, 17, 18, 19, 20, 21 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 1
timeFrame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 1600 mcg in Period 2
timeFrame: Day 22 PM, Day 23,24,25,26,27,28 AM and PM in period 2
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 1
timeFrame: Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 1
measure: Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability for BUD 3200 mcg in Period 2
timeFrame: Day 29 PM, Day 30, 31,32,33,34,35 AM and PM in period 2
measure: Number of Participants With Clinically Significant Abnormal Vital Signs: Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Vital Signs: Pulse Rate
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Vital Signs: Respiratory Rate
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Vital Signs: Temperature
timeFrame: Up to Week 18
measure: Number of Participants With Abnormal Physical Examination
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Hematology Parameters
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Chemistry Parameters
timeFrame: Up to Week 18
measure: Number of Participants With Clinically Significant Abnormal Urinalysis Parameters
timeFrame: Up to Week 18
measure: Forced Expiratory Volume in 1 Second (FEV 1) in Period 1
timeFrame: Day 1 (pre-dose) in Period 1
measure: Forced Expiratory Volume in 1 Second (FEV 1) in Period 2
timeFrame: Day 1 (pre-dose) in Period 2
measure: Forced Vital Capacity (FVC) in Period 1
timeFrame: Day 1 (pre-dose) in Period 1
measure: Forced Vital Capacity (FVC) in Period 2
timeFrame: Day 1 (pre-dose) in Period 2
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Harrow
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.