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NCT02991859

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

Completed Phase 2 Results posted Last updated 31 July 2020
What this trial tests

Phase 2 trial testing Fluticasone furoate (FF) Dry Powder Inhaler in Asthma in 56 participants. Completed in 20 December 2018.

Timeline
9 February 2017
Primary endpoint
20 December 2018
20 December 2018

Quick facts

Lead sponsorGlaxoSmithKline
PhasePhase 2
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designcrossover
Maskingquadruple
Primary purposetreatment
Enrollment56
Start date9 February 2017
Primary completion20 December 2018
Estimated completion20 December 2018
Sites3 locations across United Kingdom, Germany

Drugs / interventions tested

Conditions studied

Sponsor

GlaxoSmithKline — full company profile →

Who can join

Adults 18 to 65, any sex, with Asthma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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 Primary · 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 unstr

GroupValue95% CI
FF 25 mcg33.4519.10 – 58.60
FF 100 mcg81.4544.65 – 148.58
FF 200 mcg115.6966.82 – 200.31
FF 400 mcg145.9785.02 – 250.59
FF 800 mcg167.2695.36 – 293.37
FP 50 mcg15.1910.80 – 21.36
FP 200 mcg20.4713.94 – 30.07
FP 500 mcg31.3918.88 – 52.19
FP 1000 mcg48.6727.30 – 86.78
FP 2000 mcg76.3543.21 – 134.91
BUD 100 mcg16.0011.41 – 22.44
BUD 400 mcg23.9115.08 – 37.90
Cortisol Suppression 0-24 Hours Weighted Mean-Dose Response Analysis Primary · 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.

GroupValue95% CI
FF 25 mcg172.73159.88 – 186.62
FF 100 mcg163.03151.01 – 176.02
FF 200 mcg150.95139.48 – 163.37
FF 400 mcg129.40117.82 – 142.12
FF 800 mcg95.0982.26 – 109.93
FP 50 mcg173.04160.15 – 186.97
FP 200 mcg164.22152.11 – 177.29
FP 500 mcg147.89136.59 – 160.13
FP 1000 mcg124.21112.88 – 136.68
FP 2000 mcg87.6275.37 – 101.85
BUD 100 mcg169.87157.23 – 183.52
BUD 400 mcg152.50141.26 – 164.63
Theraputic Index of FF Primary · 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.

GroupValue95% CI
Fluticasone Propionate (FP)1.49
Theraputic Index of FP Primary · 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.

GroupValue95% CI
Fluticasone Propionate (FP)0.15
Theraputic Index of BUD Primary · 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.

GroupValue95% CI
Budesonide (BUD)0.11
Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) Secondary · Up to Week 18

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.

Any AEs
GroupValue95% CI
Placebo10
FF 25 mcg6
FF 100 mcg8
FF 200 mcg7
FF 400 mcg6
FF 800 mcg7
FP 50 mcg10
FP 200 mcg4
FP 500 mcg4
FP 1000 mcg8
FP 2000 mcg6
BUD 100 mcg6
Any SAEs
GroupValue95% CI
Placebo0
FF 25 mcg0
FF 100 mcg0
FF 200 mcg0
FF 400 mcg0
FF 800 mcg0
FP 50 mcg0
FP 200 mcg0
FP 500 mcg0
FP 1000 mcg0
FP 2000 mcg0
BUD 100 mcg0
Peak Expiratory Flow Rate (PEFR) as a Measure of Safety and Tolerability of Placebo in Period 1 Secondary · 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 is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.Only those participants with data available at the indicated time points were analyzed (represented by n=X in the category titles).

Day 2, PM, n=12
GroupValue95% CI
Placebo522.5± 25.4
Day 3, PM, n=12
GroupValue95% CI
Placebo517.5± 27.0
Day 4, PM, n=12
GroupValue95% CI
Placebo514.2± 27.8
Day 5,PM, n=12
GroupValue95% CI
Placebo521.7± 24.2
Day 6, PM, n=12
GroupValue95% CI
Placebo522.5± 29.1
Day 7, PM, n=12
GroupValue95% CI
Placebo539.2± 32.3
Day 8, PM, n=12
GroupValue95% CI
Placebo530.8± 27.8
Day 9, AM, n=5
GroupValue95% CI
Placebo576.0± 37.5
PEFR as a Measure of Safety and Tolerability of Placebo in Period 2 Secondary · 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 is a participant's maximum speed of expiration and was measured using a peak flow meter. Participants recorded their PEFR measurement before each dose in a paper diary. Results are presented treatment wise.

Day 2, PM, n=4
GroupValue95% CI
Placebo422.5± 28.9
Day 3, PM, n=4
GroupValue95% CI
Placebo415.0± 27.2
Day 4, PM, n=4
GroupValue95% CI
Placebo398.8± 26.6
Day 5,PM, n=4
GroupValue95% CI
Placebo407.5± 37.5
Day 6, PM, n=4
GroupValue95% CI
Placebo411.3± 29.0
Day 7, PM, n=4
GroupValue95% CI
Placebo410.0± 36.7
Day 8, PM, n=4
GroupValue95% CI
Placebo415.0± 36.1
Day 9, AM, n=2
GroupValue95% CI
Placebo430.0± 80.0
PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 1 Secondary · Day 2,3,4,5,6,7 PM in period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Day 2, PM, n=14
GroupValue95% CI
FF 25 mcg479.6± 30.9
Day 3, PM, n=14
GroupValue95% CI
FF 25 mcg475.7± 32.9
Day 4, PM, n=14
GroupValue95% CI
FF 25 mcg473.0± 31.1
Day 5,PM, n=14
GroupValue95% CI
FF 25 mcg476.1± 26.6
Day 6, PM, n=13
GroupValue95% CI
FF 25 mcg503.1± 24.6
Day 7, PM, n=13
GroupValue95% CI
FF 25 mcg502.3± 28.1
PEFR as a Measure of Safety and Tolerability for FF 25 mcg in Period 2 Secondary · Day 2,3,4,5,6,7 PM in period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Day 2, PM, n=5
GroupValue95% CI
FF 25 mcg572.0± 48.9
Day 3, PM, n=5
GroupValue95% CI
FF 25 mcg570.0± 54.5
Day 4, PM, n=5
GroupValue95% CI
FF 25 mcg568.0± 55.0
Day 5,PM, n=5
GroupValue95% CI
FF 25 mcg573.0± 54.9
Day 6, PM, n=6
GroupValue95% CI
FF 25 mcg550.8± 52.2
Day 7, PM, n=6
GroupValue95% CI
FF 25 mcg560.0± 45.3
PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 1 Secondary · Day 8,9,10,11,12,13,14 PM in period 1

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Day 8, PM, n=13
GroupValue95% CI
FF 100 mcg497.3± 24.9
Day 9, PM, n=13
GroupValue95% CI
FF 100 mcg500.4± 28.2
Day 10, PM, n=13
GroupValue95% CI
FF 100 mcg491.2± 31.0
Day 11, PM, n=12
GroupValue95% CI
FF 100 mcg507.5± 30.9
Day 12, PM, n=13
GroupValue95% CI
FF 100 mcg500.2± 30.2
Day 13, PM, n=13
GroupValue95% CI
FF 100 mcg515.4± 29.7
Day 14, PM, n=13
GroupValue95% CI
FF 100 mcg505.8± 28.7
PEFR as a Measure of Safety and Tolerability for FF 100 mcg in Period 2 Secondary · Day 8,9,10,11,12,13,14 PM in period 2

PEFR is a participant's maximum speed of expiration and was measured using a peak flow meter. Results are presented treatment wise.

Day 8, PM
GroupValue95% CI
FF 100 mcg540.0± 43.8
Day 9, PM
GroupValue95% CI
FF 100 mcg567.5± 42.6
Day 10, PM
GroupValue95% CI
FF 100 mcg556.7± 43.4
Day 11, PM
GroupValue95% CI
FF 100 mcg561.7± 44.6
Day 12, PM
GroupValue95% CI
FF 100 mcg573.3± 50.0
Day 13, PM
GroupValue95% CI
FF 100 mcg563.3± 53.0
Day 14, PM
GroupValue95% CI
FF 100 mcg555.8± 46.9

Adverse events — posted to ClinicalTrials.gov

Time frame: Serious adverse events and non-serious adverse events were collected up to 18 weeks.. Reporting threshold: 3%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 0/17 (0%)
Deaths: 0/17
FF 25 mcg
Serious: 0/20 (0%)
Deaths: 0/20
FF 100 mcg
Serious: 0/19 (0%)
Deaths: 0/19
FF 200 mcg
Serious: 0/19 (0%)
Deaths: 0/19
FF 400 mcg
Serious: 0/18 (0%)
Deaths: 0/18
FF 800 mcg
Serious: 0/18 (0%)
Deaths: 0/18
FP 50 mcg
Serious: 0/21 (0%)
Deaths: 0/21
FP 200 mcg
Serious: 0/20 (0%)
Deaths: 0/20
FP 500 mcg
Serious: 0/20 (0%)
Deaths: 0/20
FP 1000 mcg
Serious: 0/18 (0%)
Deaths: 0/18
FP 2000 mcg
Serious: 0/17 (0%)
Deaths: 0/17
BUD 100 mcg
Serious: 0/18 (0%)
Deaths: 0/18
BUD 400 mcg
Serious: 0/18 (0%)
Deaths: 0/18
BUD 800 mcg
Serious: 0/18 (0%)
Deaths: 0/18
BUD 1600 mcg
Serious: 0/18 (0%)
Deaths: 0/18
BUD 3200 mcg
Serious: 0/18 (0%)
Deaths: 0/18
Other adverse events (66 terms — click to expand)

ReactionSystemPlaceboFF 25 mcgFF 100 mcgFF 200 mcgFF 400 mcgFF 800 mcgFP 50 mcgFP 200 mcgFP 500 mcgFP 1000 mcgFP 2000 mcgBUD 100 mcgBUD 400 mcgBUD 800 mcgBUD 1600 mcgBUD 3200 mcg
HeadacheNervous system disorders
Seasonal allergyImmune system disorders
Chest discomfortGeneral disorders
Oropharyngeal painRespiratory, thoracic and mediastinal disorders
WheezingRespiratory, thoracic and mediastinal disorders
NauseaGastrointestinal disorders
Catheter site bruiseGeneral disorders
DizzinessNervous system disorders
NasopharyngitisInfections and infestations
Back painMusculoskeletal and connective tissue disorders
RhinorrhoeaRespiratory, thoracic and mediastinal disorders
Catheter site painGeneral disorders
CoughRespiratory, thoracic and mediastinal disorders
AsthmaRespiratory, thoracic and mediastinal disorders
Nasal congestionRespiratory, thoracic and mediastinal disorders
ContusionInjury, poisoning and procedural complications
Dry mouthGastrointestinal disorders
DysgeusiaNervous system disorders
Abdominal painGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
Arthropod biteInjury, poisoning and procedural complications
Catheter site related reactionGeneral disorders
DiarrhoeaGastrointestinal disorders
Pain in extremityMusculoskeletal and connective tissue disorders
RhinitisInfections and infestations
AnxietyPsychiatric disorders
Catheter site swellingGeneral disorders
ConstipationGastrointestinal disorders
Decreased appetiteMetabolism and nutrition disorders
Dry throatRespiratory, thoracic and mediastinal disorders
DysmenorrhoeaReproductive system and breast disorders
DyspepsiaGastrointestinal disorders
DysphagiaGastrointestinal disorders
EczemaSkin and subcutaneous tissue disorders
Eye swellingEye disorders
Eyelid oedemaEye disorders
FatigueGeneral disorders
Feeling jitteryGeneral disorders
Flank painMusculoskeletal and connective tissue disorders
GastroenteritisInfections and infestations

Data from ClinicalTrials.gov NCT02991859 adverse events section.

Sponsor's own description

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.

Publications & conference data

3 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.
    Daley-Yates P, Brealey N, Thomas S, Austin D, et al · · 2021 · cited 40× · PMID 32484940 · DOI 10.1111/bcp.14406
  2. Pharmacology Versus Convenience: A Benefit/Risk Analysis of Regular Maintenance Versus Infrequent or As-Needed Inhaled Corticosteroid Use in Mild Asthma.
    Daley-Yates P, Aggarwal B, Lulic Z, Fulmali S, et al · · 2022 · cited 13× · PMID 34873657 · DOI 10.1007/s12325-021-01976-4
  3. Inhaled glucocorticoid-induced metabolome changes in asthma.
    Daley-Yates P, Keppler B, Brealey N, Shabbir S, et al · · 2022 · cited 10× · PMID 35900313 · DOI 10.1530/eje-21-0912

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