AsthmaPhase 2NCT01400906

Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.

A Phase 2 study testing 100 micrograms Fluticasone propionate, 500 micrograms Fluticasone propionate and lactose powder in people with Asthma, run by GlaxoSmithKline at 2 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

People with asthma suffer from breathlessness because the small tubes (bronchioles) that carry air in and out of the lungs become inflamed and narrow. Steroids reduce the inflammation, and are commonly used to control asthma, but they do not work well in some asthmatics, particularly those who smoke. Read more about this study

Who is it for?: Ages 18 to 55 years
Conditions the study is for: Asthma
What is being tested?: 100 micrograms Fluticasone propionate, 500 micrograms Fluticasone propionate and lactose powder
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 36 participants
Where: 2 sitesin 2 countries
Study dates: 20 Jul 2011to 12 Dec 2012
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 55 years
All sexes
No healthy volunteers
Adult

Who may be able to join

males and females between 18 and 55 years of age inclusive
female subject of child-bearing potential and agrees to use one of the contraception methods; or of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
male subjects with female partners of child-bearing potential must agree to use a contraception method
body weight ≥50 kg and BMI within the range (18.5-35) kg/m2 (inclusive)
documented history of bronchial asthma, first diagnosed at least 6 months prior to the first screening visit (according to the BTS guideline 2009), and currently being treated only with prn short-acting inhaled β2-agonist therapy
current smokers or non-smokers or ex-smokers

Show all 14Show fewer

pre-bronchodilator FEV1 >70% of predicted at screening
sensitivity to methacholine with a provocative concentration of methacholine resulting in a 20 % fall in FEV1 of < 8 mg/ml at screening
able to produce acceptable induced sputum samples
positive wheal and/or flare reaction (≥ 3 mm relative to negative control) to at least one allergen on skin prick testing at screening or within 12 months of the study start
screening allergen challenge must demonstrate that the subject experiences both an early and late asthmatic response.
AST, ALT, alkaline phosphatase and bilirubin <=1.5xULN
written informed consent
able to understand and comply with the study procedures, planned treatment period and other protocol requirements and stated restrictions

Who cannot join

past or present disease (other than asthma)
respiratory tract infection and / or exacerbation of asthma within 4 weeks prior the first dose of study drug
history of life-threatening asthma
symptomatic with hay fever at screening or predicted to have symptomatic hay fever during the time of the study
administration of oral or injectable steroids within 5 weeks of the screening visit or intranasal and / or inhaled steroids within 4 weeks of the screening visit
unable to abstain from other medication, including non-steroidal anti-inflammatory drugs, anti-depressants, anti-histamines, anti-asthma and anti-rhinitis or hay fever medication, other than short acting β2-agonists and paracetamol (up to 4 gram per day) for the treatment of minor ailments (such as headache) from 14 days before screening until the follow-up visit

Show all 26Show fewer

unable to abstain from short acting β2-agonists as described in the restriction section of the protocol
if, after two consecutive administrations of saline, during the allergen challenge at screening, the subject still has a fall of FEV1 of 10%
a positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result
clinical significant abnormalities in safety laboratory analysis at screening
significant abnormality on 12-lead ECG at screening
the subject is undergoing an allergen desensitisation therapy. Subjects with a positive pre-study drug/alcohol screen
a history of regular alcohol consumption within 6 months of the screening visit
a positive test for HIV antibody
the subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer)
history of being unable to tolerate or complete methacholine and / or allergen challenge test
use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication
unable to abstain from medication or supplements that significantly inhibit the cytochrome P450 subfamily enzyme CYP3A4, including but not limited to antiretrovirals (protease inhibitors - e.g. ritonavir indinavir, nelfinavir, ritonavir, saquinavir); imidazole and triazole anti-fungals (e.g. ketoconazole, itraconazole) and macrolide antibiotics (e.g. clarithromycin, telithromycin) from screening and throughout the study
consumption of red wine, seville oranges, grapefruit or grapefruit juice from 7 days prior to the first dose of study medication
history of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that contraindicates their participation
donation of blood or blood products in excess of 500 mL within a 56 day period
pregnant females at screening or prior to dosing
lactating females
unwillingness or inability to follow the procedures outlined in the protocol
subject is mentally or legally incapacitated
urinary cotinine levels indicative of smoking or history or regular use of tobacco- or nicotine-containing products within 6 months prior to screening (for subjects taking part in the non-smokers group of the study)

Trial locations and contacts

2 sites in 2 countries.

Country

City, postcode or hospital

2 sites in 2 countries

Belgium1 site

GSK Investigational Site
Brussels, 1020

Other trials in Belgium

United Kingdom1 site

GSK Investigational Site
London, NW10 7EW

Other trials in United Kingdom

About this study

Official title: A Randomized, Double Blind, Placebo-controlled Three-way Crossover Study in Mild Asthmatics to Evaluate the Effect of Smoking Status on the Attenuation by Inhaled Corticosteroids of the Allergen-induced Asthmatic Response.

This study is done to find out more about why smokers with asthma do not benefit from steroid treatment. In this study, the effect of Flixotide (fluticasone propionate), a steroid widely used to treat asthma, is tested in smokers and non-smokers with mild asthma.

16 smokers and 16 non-smokers, aged 18-55 years will be enrolled in this study.

Subjects will take each of the following treatments:

100 micrograms Flixotide twice daily for 7 days;
500 micrograms Flixotide twice daily for 7 days; and
placebo (dummy medicine) twice daily for 7 days.

Study design: subjects will have a screening visit (over 2 days), and will take part in 3 treatment periods (which are separated by interval of at least 14 days); a follow-up visit is scheduled 7 days after the last intake of study treatment.

The order in which order the subjects will take the treatments is defined at random. Total study duration: about 11 weeks.

To test the effects of Flixotide, the subject's responses to :

an inhaled allergen test
a PC20 methacholine test
blood, urine and sputum PD markers will be analysed.

This study will take place in 2 centres: 1 in the United Kingdom and 1 in Belgium. The units will recruit participants by advertising (newspaper, radio, and websites), word of mouth, from volunteer databases, and via the centres' websites.

Read the detailed description

Most patients with asthma are successfully treated with inhaled corticosteroid (ICS) therapy, either alone or in combination with long-acting beta 2-agonists, with minimal or no side effects. However, a significant proportion of asthmatic patients, including present cigarette smokers and former cigarette smokers, fail to respond well to ICS, alone or in combination with other therapies.

In a randomized, placebo-controlled study, the efficacy of inhaled fluticasone propionate (FP), 1000 μg/day on peak expiratory flow (PEF) and bronchial hyper-reactivity in smokers with mild asthma was assessed compared with non-smoking asthmatics. Asthmatics who smoked showed impaired responses to ICS therapy compared with non-smoking asthmatics [Chalmers, 2002] and this lack of responsiveness appears to be dose-dependent. When the dose of ICS is increased, the disparity between lung function, rescue inhaler usage and asthma control seen in smokers and non-smokers decreases [Tomlinson, 2005].

Interestingly, smoking also affects the ability of ICS to suppress exhaled nitric oxide (eNO) levels in asthmatics [Horváth, 2004]. Smoking cessation improves basal lung function but requires at least a year to demonstrate any improvement in Glucocorticoid (GC) responsiveness with respect to morning peak expiratory flow, but not FEV1, after therapy with high-dose oral prednisolone [Chaudhuri , 2006].

Smoking asthmatics have more severe disease requiring more therapy, have more hospital admissions and are more likely to die from asthma [Thomson, 2005].

Cigarette smoking remains therefore one of the commonest causes of steroid resistance in asthma, however many aspects of the development and restoration of corticosteroid resistance remain unclarified in this population partly due to the paucity of studies performed.

The mechanisms underlying GC resistance in smoking asthmatics are incompletely understood but are thought to include noneosinophilic (often neutrophilic) airway inflammation [Chalmers, 2001], impaired corticosteroid receptor function, and/or reduced histone deacetylase activity [Adcock, 2008]. In support of these effects of smoking on asthma, animal models show that smoking can increase inflammation in allergic models of asthma and can affect steroid responsiveness.

Tobacco smoke exposure (4 cigarettes/day for 3weeks) had a small neutrophilic effect in mice, whereas ovalbumin exposure had no inflammatory effect in the airways, but increased allergen-specific IgE [Moerloose, 2006]. More recently in mouse models, cigarette smoke has been shown to enhance T-helper-(TH)2-driven airway inflammation [Van Hove , 2008].

Inhaled allergens are an important trigger of exacerbations in asthma [Johnston, 2006].

The airway inflammation induced by inhaled allergens, and the effects of drugs on this airway inflammation, can be studied using an experimental allergen challenge model. All the currently approved drugs used to treat asthma modify, in some way, allergen-induced airway responses. Following inhalation of the appropriate allergen extract, sensitive subjects, i.e. atopic-asthmatics, develop an acute bronchoconstriction which peaks at 20 to 30 minutes post-allergen and lasts for approximately two hours before recovery.

This early response (EAR) reflects mast cell activation and subsequent release of mainly spasmogenic mediators and correlates with the extent of airway inflammation and disease activity [Grzelewska-Rsymowska, 1995]. In approximately 50% of patients, the EAR is followed by a late-phase asthmatic response (LAR). This more prolonged airway narrowing is associated with influx of activated inflammatory cells, especially eosinophils, into the airways and represents the more chronic features of asthma, consisting of a prolonged airway narrowing through both bronchospasm and airway inflammation.

The sequelae of the LAR can last several days and up to 3 weeks. Also, the late response has been shown to be associated with an increase in airway hyperresponsiveness (AHR) to stimuli, such as methacholine for several days after allergen challenge [Hansel, 2002].

This clinically relevant model of allergic bronchoconstriction has been useful in humans for exploring the time-course of cellular inflammation and the associated physiological changes, particularly related to eosinophils, basophils and dendritic cells [O'Byrne, 2009].In non smoking asthmatics, regular treatment with inhaled corticosteroids has been shown to attenuate the early allergic response, perhaps by reducing the number of mast cells in airways [Gauvreau, 2000] and to improve the late-phase asthmatic response [Kidney, 1997; Cockcroft, 1987].

As previous allergen challenge studies with therapeutic interventions have been conducted only in the population of non-smokers, this study will be the first to examine the allergen challenge response to FP in smoking asthmatics. The primary endpoint of this study will be the degree of attenuation of the late-phase asthmatic response.

Conditions: Asthma
Being tested: 100 micrograms Fluticasone propionate, 500 micrograms Fluticasone propionate, lactose powder
Medical subject headings: Asthma

What participants receive

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

100 micrograms Fluticasone propionateDrug
Also called Flixotide
100 micrograms micronized drug blended with lactose in dry powder inhalator
500 micrograms Fluticasone propionateDrug
Also called Flixotide
500 micrograms micronized drug blended with lactose in dry powder inhalator
lactose powderDrug
lactose powder in dry powder device : placebo comparator

Study groups in NCT01400906
Study group	Role	What they receive
3 periods cross-over study	Placebo comparator	Each subject will receive each intervention BID during a 7 days period. The treatment periods are separated by 14 days washout. The sequence in which the interventions are administered are at random and double blind. Receives: Drug: 100 micrograms Fluticasone propionate; Drug: 500 micrograms Fluticasone propionate; Drug: lactose powder

What is being measured

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

Late Asthmatic Response (LAR) - Smokers: Absolute Change From Saline in Minimum Forced Expiratory Volume in One Second (FEV1) Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 6 of each treatment period (up to 11 weeks)
LAR - Non-smokers: Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 6 of each treatment period (up to 11 weeks)
LAR - Smokers: Absolute Change From Saline in Weighted Mean (WM) FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 6 of each treatment period (up to 11 weeks)
LAR - Non-smokers: Absolute Change From Saline in WM FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 6 of each treatment period (up to 11 weeks)

Secondary outcomes (5)

Early Asthmatic Response (EAR): Absolute Change From Saline in Minimum FEV1 and WM FEV1 Between 0-2 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 0-2 hrs post-allergen challenge (Minimum EAR) is the minimum value of all of the post-allergen challenge timepoints up to and including 2 hours post-allergen challenge (i.e., minimum over 5 minutes [min], 10 min, 15 min, 20 min, 30 min, 45 min and 1 hr, 1.5 hrs, and 2 hrs). The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 6 of each treatment period (up to 11 weeks)
Absolute Change From Baseline in FEV1 Post-dose on Day 1, Day 6 (Prior to Allergen Challenge), and Day 7
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Baseline FEV1 was measured on Day 1 pre-dose administration. FEV1 was measured on Day 1 post-dose, on Day 6 (prior to allergen challenge), and on Day 7 pre dose administration. Change from Baseline was calculated as the post-Baseline value minus the Baseline value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Baseline, Day 1, Day 6, and Day 7
Provocative Concentration of Methacholine Resulting in a 20% Reduction in FEV1 (PC20) on Day 7 of Each Treatment Period
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants inhaled doubling increments of methacholine until a >=20% decrease in FEV1 from the post-saline value was achieved.
Measured: Day 7 of each treatment period (up to 11 weeks)
Concentration of Exhaled Nitric Oxide (eNO) on Day 6 and Day 7 of Each Treatment Period
The concentration of eNO was measured on Day 6 pre-dose and on Day 7 post-study medication administration. eNO was measured 3 times at each time point, and all 3 measurements were recorded. The mean of the 3 measurements was calculated and was used in the derivation of summary statistics.
Measured: Day 6 and Day 7 of each treatment period (up to 11 weeks)
Neutrophil and Eosinophil Cell Counts in Induced Sputum on Day 7 of Each Treatment Period
Sputum induction was performed using hypertonic saline solution to collect an adequate sample of secretions from lungs. The collected sputum was analyzed for neutrophil and eosinophil counts. Sputum induction was performed after methacholine challenge and post-dose administration on Day 7. Zero values are imputed to 0.001 for this analysis. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
Measured: Day 7 of each treatment period (up to 11 weeks)

Timeline

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

20 Jul 201112 Dec 2012

First posted25 Jul 2011 (estimated)
Study start20 Jul 2011
Primary completion1 Dec 2012
Study completion12 Dec 2012

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 (23)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: Other
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 36 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01400906
Sponsor's protocol ID: 114748
Status last verified: Jun 2018
First submitted: 21 Jul 2011
Last updated: 13 Aug 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
Individual data sharing: Yes: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Publications

Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008 Aug;134(2):394-401. doi: 10.1378/chest.08-0440.
PubMed 18682458
Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002 Mar;57(3):226-30. doi: 10.1136/thorax.57.3.226.
PubMed 11867826
Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest. 2001 Dec;120(6):1917-22. doi: 10.1378/chest.120.6.1917.
PubMed 11742922
Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, Thomson NC. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med. 2006 Jul 15;174(2):127-33. doi: 10.1164/rccm.200510-1589OC. Epub 2006 Apr 27.
PubMed 16645173
Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol. 1987 May;79(5):734-40. doi: 10.1016/0091-6749(87)90204-1.
PubMed 3106449
Gauvreau GM, Wood LJ, Sehmi R, Watson RM, Dorman SC, Schleimer RP, Denburg JA, O'Byrne PM. The effects of inhaled budesonide on circulating eosinophil progenitors and their expression of cytokines after allergen challenge in subjects with atopic asthma. Am J Respir Crit Care Med. 2000 Dec;162(6):2139-44. doi: 10.1164/ajrccm.162.6.2001120.
PubMed 11112128
GlaxoSmithKline Document Number GM2003/00619/00 Study ID EL110002. A single-centre, randomised, double-blind, double-dummy, placebo-controlled, 3-period crossover study to evaluate the effect of pre-treatment with repeat doses of GW842470X (6mg inhaled once daily via the Cyclohaler for 7 days) on the allergen induced late asthmatic response in subjects with mild to moderate asthma, using fluticasone propionate (250 mcg twice daily for 7 days) as a positive control. Report Date 24-Jun-2004.
GlaxoSmithKline Document Number YM2009/00265/00 Study ID LPA111834. A randomised, double-blind, placebo-controlled, 2-period crossover study to evaluate the effect of treatment with GSK2190915 on the allergen-induced asthmatic response in subjects with mild asthma. Report Date 26-Mar-2010.
GlaxoSmithKline Document Number YM2010/00033/00 Study ID SIG110762. A randomised, placebo-controlled, incomplete block, three-way crossover study to evaluate the effect of treatment with repeat inhaled doses of GW870086 on the allergen-induced early and late asthmatic response in subjects with mild asthma. Report Date 10-May-2010.
Grzelewska-Rzymowska I, Gondorowicz K, Cieslewicz G, Rozniecki J. [Course of non-specific bronchial reactivity to histamine after bronchospasm induced by allergen challenge in patients with bronchial asthma]. Pneumonol Alergol Pol. 1995;63(5-6):273-80. Polish.
PubMed 7581057
Hansel TT, Erin EM, Barnes PJ. The allergen challenge. Clin Exp Allergy. 2002 Feb;32(2):162-7. doi: 10.1046/j.1365-2222.2002.01309.x. No abstract available.
PubMed 11929474
Horvath I, Donnelly LE, Kiss A, Balint B, Kharitonov SA, Barnes PJ. Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers. Respiration. 2004 Sep-Oct;71(5):463-8. doi: 10.1159/000080630.
PubMed 15467323
Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol. 2006 Mar;117(3):522-43. doi: 10.1016/j.jaci.2006.01.032.
PubMed 16522450
Johnston NW, Sears MR. Asthma exacerbations . 1: epidemiology. Thorax. 2006 Aug;61(8):722-8. doi: 10.1136/thx.2005.045161.
PubMed 16877691
Kidney JC, Boulet LP, Hargreave FE, Deschesnes F, Swystun VA, O'Byrne PM, Choudry N, Morris MM, Jennings B, Andersson N, Andreasson A, Cockcroft DW. Evaluation of single-dose inhaled corticosteroid activity with an allergen challenge model. J Allergy Clin Immunol. 1997 Jul;100(1):65-70. doi: 10.1016/s0091-6749(97)70196-9.
PubMed 9257789

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?

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Study at a glance

From the registry record, last updated by the sponsor on 13 Aug 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Randomized, Double Blind, Placebo-controlled Three-way Crossover Study in Mild Asthmatics to Evaluate the Effect of Smoking Status on the Attenuation by Inhaled Corticosteroids of the Allergen-induced Asthmatic Response.
ClinicalTrials.gov ID: NCT01400906
Acronym / sponsor ID: 114748
Conditions: Asthma
Phase: Phase 2
Study type: Interventional
Recruitment status: Completed
Enrolment: 36 participants (actual)
Lead sponsor: GlaxoSmithKlineIndustry (pharma, biotech, devices)
Study start: 20 Jul 2011
Primary completion: 1 Dec 2012 (actual)
Study completion: 12 Dec 2012 (actual)
First posted: 25 Jul 2011 (estimated)
Results: Posted 30 Sep 2013

Clinical summary

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

16 smokers and 16 non-smokers, aged 18-55 years will be enrolled in this study.

Subjects will take each of the following treatments:

100 micrograms Flixotide twice daily for 7 days;
500 micrograms Flixotide twice daily for 7 days; and
placebo (dummy medicine) twice daily for 7 days.

The order in which order the subjects will take the treatments is defined at random. Total study duration: about 11 weeks.

To test the effects of Flixotide, the subject's responses to :

an inhaled allergen test
a PC20 methacholine test
blood, urine and sputum PD markers will be analysed.

Detailed description

Smoking asthmatics have more severe disease requiring more therapy, have more hospital admissions and are more likely to die from asthma [Thomson, 2005].

Inhaled allergens are an important trigger of exacerbations in asthma [Johnston, 2006].

Study design

Primary purpose: Other
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 1

Arm	Type	Receives
3 periods cross-over study	Placebo comparator	Drug: 100 micrograms Fluticasone propionate, Drug: 500 micrograms Fluticasone propionate, Drug: lactose powderEach subject will receive each intervention BID during a 7 days period. The treatment periods are separated by 14 days washout. The sequence in which the interventions are administered are at random and double blind.

Who may qualify

Ages: 18 to 55 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult

Key inclusion criteria (14 listed)

males and females between 18 and 55 years of age inclusive
female subject of child-bearing potential and agrees to use one of the contraception methods; or of non-childbearing potential including pre-menopausal females with documented (medical report verification) hysterectomy or double oophorectomy or postmenopausal defined as 12 months of spontaneous amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels > 40 mIU/mL and estradiol < 40 pg/ml (<140 pmol/L) or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy.
male subjects with female partners of child-bearing potential must agree to use a contraception method
body weight ≥50 kg and BMI within the range (18.5-35) kg/m2 (inclusive)
documented history of bronchial asthma, first diagnosed at least 6 months prior to the first screening visit (according to the BTS guideline 2009), and currently being treated only with prn short-acting inhaled β2-agonist therapy

Key exclusion criteria (26 listed)

past or present disease (other than asthma)
respiratory tract infection and / or exacerbation of asthma within 4 weeks prior the first dose of study drug
history of life-threatening asthma
symptomatic with hay fever at screening or predicted to have symptomatic hay fever during the time of the study
administration of oral or injectable steroids within 5 weeks of the screening visit or intranasal and / or inhaled steroids within 4 weeks of the screening visit

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
100 micrograms Fluticasone propionateAlso: Flixotide100 micrograms micronized drug blended with lactose in dry powder inhalator	Drug	3 periods cross-over study
500 micrograms Fluticasone propionateAlso: Flixotide500 micrograms micronized drug blended with lactose in dry powder inhalator	Drug	3 periods cross-over study
lactose powderlactose powder in dry powder device : placebo comparator	Drug	3 periods cross-over study

Primary outcome

Late Asthmatic Response (LAR) - Smokers: Absolute Change From Saline in Minimum Forced Expiratory Volume in One Second (FEV1) Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
Time frame: Day 6 of each treatment period (up to 11 weeks)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
LAR - Non-smokers: Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
Time frame: Day 6 of each treatment period (up to 11 weeks)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hr after dosing on Day 6. Minimum FEV1 over 4-10 hours post-allergen challenge is the minimum value of all of the post-saline time points between 4 and 10 hrs post-allergen challenge, inclusive of the 4 hr and 10 hr timepoints (i.e., minimum over 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs). Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
LAR - Smokers: Absolute Change From Saline in Weighted Mean (WM) FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period
Time frame: Day 6 of each treatment period (up to 11 weeks)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.
LAR - Non-smokers: Absolute Change From Saline in WM FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period
Time frame: Day 6 of each treatment period (up to 11 weeks)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. Participants were exposed to an allergen 1 hour after dosing on Day 6. The WM FEV1 was derived by calculating the area under the curve, and then dividing the value by the relevant time interval. LAR WM FEV1 was measured at 4 hrs, 4.5 hrs, 5 hrs, 5.5 hrs, 6 hrs, 6.5 hrs, 7 hrs, 7.5 hrs, 8 hrs, 8.5 hrs, 9 hrs, 9.5 hrs, and 10 hrs post-allergen challenge on Day 6. Absolute change from saline at each time point was calculated as the highest allergen challenge FEV1 value minus the highest saline FEV1 value. Data were adjusted for the following covariates: period, smoking status, treatment, participant-level Baseline, period-level Baseline, and treatment by smoking status interaction.

5 secondary outcomes

Early Asthmatic Response (EAR): Absolute Change From Saline in Minimum FEV1 and WM FEV1 Between 0-2 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period
Time frame: Day 6 of each treatment period (up to 11 weeks)
Absolute Change From Baseline in FEV1 Post-dose on Day 1, Day 6 (Prior to Allergen Challenge), and Day 7
Time frame: Baseline, Day 1, Day 6, and Day 7
Provocative Concentration of Methacholine Resulting in a 20% Reduction in FEV1 (PC20) on Day 7 of Each Treatment Period
Time frame: Day 7 of each treatment period (up to 11 weeks)
Concentration of Exhaled Nitric Oxide (eNO) on Day 6 and Day 7 of Each Treatment Period
Time frame: Day 6 and Day 7 of each treatment period (up to 11 weeks)
Neutrophil and Eosinophil Cell Counts in Induced Sputum on Day 7 of Each Treatment Period
Time frame: Day 7 of each treatment period (up to 11 weeks)

Results and safety

Results posted to the registry on 30 Sep 2013, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Sequence 1: Placebo, FP 100 µg, FP 500 µg	6	6
Sequence 2: Placebo, FP 500 µg, FP 100 µg	6	6
Sequence 3: FP 100 µg, Placebo, FP 500 µg	6	6
Sequence 4: FP 100 µg, FP 500 µg, Placebo	6	6
Sequence 5: FP 500 µg, Placebo, FP 100 µg	6	6
Sequence 6: FP 500 µg, FP 100 µg, Placebo	5	5

Primary outcome: Late Asthmatic Response (LAR) - Smokers: Absolute Change From Saline in Minimum Forced Expiratory Volume in One Second (FEV1) Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period

Time frame: Day 6 of each treatment period (up to 11 weeks). Least squares mean (95% Confidence Interval). Unit: Liters

Measure	Placebo n = 16	FP 100 µg n = 17	FP 500 µg n = 17
Value	-0.592 (-0.793 to -0.391)	-0.420 (-0.617 to -0.224)	-0.431 (-0.627 to -0.234)

Placebo vs FP 100 µg: Mean Difference (Final Values): 0.172 (95% CI -0.037 to 0.380)
Placebo vs FP 500 µg: Mean Difference (Final Values): 0.161 (95% CI -0.047 to 0.370)

Population analysed: Pharmacodynamic (PD) Population: all participants in the All Subjects Population (all participants who received at least one dose of study medication) who had a post-dose FEV1 assessment in the same period. Only those participants who were smokers were analyzed.

Primary outcome: LAR - Non-smokers: Absolute Change From Saline in Minimum FEV1 Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period

Time frame: Day 6 of each treatment period (up to 11 weeks). Least squares mean (95% Confidence Interval). Unit: Liters

Measure	Placebo n = 18	FP 100 µg n = 18	FP 500 µg n = 18
Value	-1.034 (-1.225 to -0.843)	-0.396 (-0.587 to -0.205)	-0.373 (-0.563 to -0.182)

Placebo vs FP 100 µg: Mean Difference (Final Values): 0.638 (95% CI 0.440 to 0.836)
Placebo vs FP 500 µg: Mean Difference (Final Values): 0.661 (95% CI 0.463 to 0.859)

Population analysed: PD Population. Only those participants who were non-smokers were analyzed.

Primary outcome: LAR - Smokers: Absolute Change From Saline in Weighted Mean (WM) FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period

Time frame: Day 6 of each treatment period (up to 11 weeks). Least squares mean (95% Confidence Interval). Unit: Liters

Measure	Placebo n = 16	FP 100 µg n = 17	FP 500 µg n = 17
Value	-0.364 (-0.512 to -0.215)	-0.188 (-0.334 to -0.043)	-0.198 (-0.344 to -0.053)

Placebo vs FP 100 µg: Mean Difference (Final Values): 0.175 (95% CI 0.018 to 0.333)
Placebo vs FP 500 µg: Mean Difference (Final Values): 0.165 (95% CI 0.008 to 0.323)

Population analysed: PD Population. Only those participants who were smokers were analyzed.

Primary outcome: LAR - Non-smokers: Absolute Change From Saline in WM FEV1 Between 4-10 Hrs Following Post-treatment Allergen Challenge on Day 6 of Each Treatment Period

Time frame: Day 6 of each treatment period (up to 11 weeks). Least squares mean (95% Confidence Interval). Unit: Liters

Measure	Placebo n = 18	FP 100 µg n = 18	FP 500 µg n = 18
Value	-0.688 (-0.829 to -0.547)	-0.212 (-0.353 to -0.071)	-0.158 (-0.299 to -0.018)

Placebo vs FP 100 µg: Mean Difference (Final Values): 0.476 (95% CI 0.326 to 0.627)
Placebo vs FP 500 µg: Mean Difference (Final Values): 0.530 (95% CI 0.380 to 0.680)

Population analysed: PD Population. Only those participants were non-smokers were analyzed.

5 secondary outcomes are reported in the full results.

Adverse events

Time frame: Serious adverse events (SAEs) and non-serious AEs were collected from the start of study medication to the end of the treatment period (up to 16 weeks).. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Placebo	0 of 35 (0%)	11 of 35 (31.4%)	Not reported
FP 100 µg	0 of 35 (0%)	8 of 35 (22.9%)	Not reported
FP 500 µg	0 of 35 (0%)	11 of 35 (31.4%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 18682458Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008 Aug;134(2):394-401. doi: 10.1378/chest.08-0440.
Background: PubMed 11867826Chalmers GW, Macleod KJ, Little SA, Thomson LJ, McSharry CP, Thomson NC. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma. Thorax. 2002 Mar;57(3):226-30. doi: 10.1136/thorax.57.3.226.
Background: PubMed 11742922Chalmers GW, MacLeod KJ, Thomson L, Little SA, McSharry C, Thomson NC. Smoking and airway inflammation in patients with mild asthma. Chest. 2001 Dec;120(6):1917-22. doi: 10.1378/chest.120.6.1917.
Background: PubMed 16645173Chaudhuri R, Livingston E, McMahon AD, Lafferty J, Fraser I, Spears M, McSharry CP, Thomson NC. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med. 2006 Jul 15;174(2):127-33. doi: 10.1164/rccm.200510-1589OC. Epub 2006 Apr 27.
Background: PubMed 3106449Cockcroft DW, Murdock KY. Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol. 1987 May;79(5):734-40. doi: 10.1016/0091-6749(87)90204-1.
Background: PubMed 11112128Gauvreau GM, Wood LJ, Sehmi R, Watson RM, Dorman SC, Schleimer RP, Denburg JA, O'Byrne PM. The effects of inhaled budesonide on circulating eosinophil progenitors and their expression of cytokines after allergen challenge in subjects with atopic asthma. Am J Respir Crit Care Med. 2000 Dec;162(6):2139-44. doi: 10.1164/ajrccm.162.6.2001120.
BackgroundGlaxoSmithKline Document Number GM2003/00619/00 Study ID EL110002. A single-centre, randomised, double-blind, double-dummy, placebo-controlled, 3-period crossover study to evaluate the effect of pre-treatment with repeat doses of GW842470X (6mg inhaled once daily via the Cyclohaler for 7 days) on the allergen induced late asthmatic response in subjects with mild to moderate asthma, using fluticasone propionate (250 mcg twice daily for 7 days) as a positive control. Report Date 24-Jun-2004.
BackgroundGlaxoSmithKline Document Number YM2009/00265/00 Study ID LPA111834. A randomised, double-blind, placebo-controlled, 2-period crossover study to evaluate the effect of treatment with GSK2190915 on the allergen-induced asthmatic response in subjects with mild asthma. Report Date 26-Mar-2010.
BackgroundGlaxoSmithKline Document Number YM2010/00033/00 Study ID SIG110762. A randomised, placebo-controlled, incomplete block, three-way crossover study to evaluate the effect of treatment with repeat inhaled doses of GW870086 on the allergen-induced early and late asthmatic response in subjects with mild asthma. Report Date 10-May-2010.
Background: PubMed 7581057Grzelewska-Rzymowska I, Gondorowicz K, Cieslewicz G, Rozniecki J. [Course of non-specific bronchial reactivity to histamine after bronchospasm induced by allergen challenge in patients with bronchial asthma]. Pneumonol Alergol Pol. 1995;63(5-6):273-80. Polish.
Background: PubMed 11929474Hansel TT, Erin EM, Barnes PJ. The allergen challenge. Clin Exp Allergy. 2002 Feb;32(2):162-7. doi: 10.1046/j.1365-2222.2002.01309.x. No abstract available.
Background: PubMed 15467323Horvath I, Donnelly LE, Kiss A, Balint B, Kharitonov SA, Barnes PJ. Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers. Respiration. 2004 Sep-Oct;71(5):463-8. doi: 10.1159/000080630.
Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.Link provided by the sponsor.
Individual participant dataSharing planned: Yes. Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this 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

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

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing 100 micrograms Fluticasone propionate, 500 micrograms Fluticasone propionate and lactose powder in people with Asthma, run by GlaxoSmithKline at 2 sites in 2 countries.

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

Who may be eligible to take part?

The sponsor lists 14 inclusion and 26 exclusion criteria. 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 13 Aug 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Belgium, United Kingdom. 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. Some participants in this study may receive a placebo. 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 Sep 2013). 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?

Late Asthmatic Response (LAR) - Smokers: Absolute Change From Saline in Minimum Forced Expiratory Volume in One Second (FEV1) Between 4-10 Hours (Hrs) After Allergen Challenge on Day 6 of Each Treatment Period (time frame: Day 6 of each treatment period (up to 11 weeks)). The study lists 4 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 NCT01400906, which also lists 23 linked publications.

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 13 Aug 2018.