Last updated: 11/07/2018 08:15:50
Inhalation of corticosteroids in smoking and non-smoking asthmatics.
EudraCT ID
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Trial overview
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.
Trial description: 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.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 markerswill 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.
Primary purpose:
Other
Trial design:
Crossover Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: Day 6 of each treatment period (up to 11 weeks)
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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: 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
Timeframe: Day 7 of each treatment period (up to 11 weeks)
Interventions:
Enrollment:
36
Primary completion date:
2012-12-12
Observational study model:
Not applicable
Time perspective:
Not applicable
Clinical publications:
Adcock I. M and Peter J. Barnes. Molecular Mechanisms of Corticosteroid resistance Chest 2008;134;394-401.
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) 57(3):226-230.
Chalmers GW, MacLeod KJ, Thomson L. Little SA, McSharry NC: Smoking and airway inflammation in patients with mild asthma. Chest 2001 Dec;120 (6):1917-22.
Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006; 174:127–133.
Cockcroft D, Murdoch 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. Journal of Allergy and Clinical Immunology. 1987;79:734-740.
Gauvreau G.M., L. J. Wood, R. Sehmi, R. M. Watson, S. C. Dorman, R. P. Schleimer, J. A. Denburgh, and P. M. O'BYRNE. 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;162(6):2139-2144.
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-Rsymowska I, Gondorowicz K, Cieslewicz G, Rozniecki J. Course of nonspecific bronchial reactivity to histamine after bronchospasm induced by allergen challenge in patients with bronchial asthma. Pneumonol Alergol Pol. 1995;63:273-280.
Hansel TT; Erin EM; Barnes PJ. (Feb 2002). The allergen challenge. Clin Exp Allergy 32:162-167.
Horváth I, Donnelly LE, Kiss A, Balint B, Kharitonov SA, Barnes PJ: 18. Exhaled nitric oxide and hydrogen peroxide concentrations in asthmatic smokers. Respiration (2004) 71(5):463-468.
Ito K, Chung KF, Adcock IM. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006; 117:522–543.
Johnston NW, Sears MR. Asthma exacerbations. 1: epidemiology Thorax 2006 Aug; 61(8) 722-8.
Kidney JC, Boulet L, Hargreave FE, Deschesnes F, Swystun VA, O'Byrne VM, Choudry, V, Morrisa MM, Jennings B, Andersson N, Andreasson A, Cockcroft DW Evaluation of single dose inhaled corticosteroid activity with an allergen challenge model. The Journal of Allergy and Clinical Immunology. 1997;100:65-70.
Moerloose KB, Robays LJ, Maes T, Brusselle GG, Tournoy KG, Joos GF: 20. Cigarette smoke exposure facilitates allergic sensitization in mice. Respir Res (2006) 7:49.
O’ Shaughnessy KM, Wellings R, Giles B, Fuller RW. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion.Am Rev Resp Disease 1993 Jun;147(6 Pt 1):1472-6.
O’Byrne P. M., G. M. Gauvreau and J. D. Brannan, Provoked models of asthma: what have we learnt? Clinical and Experimental Allergy, 2009 (39) 181–192.
Singh D, Petavy F, Macdonald AJ, Lazaar AL4, O’Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respiratory Research, 2010, 11:26
Thomson, N.C., Spears, M. The influence of smoking on the treatment response in patients with asthma. Curr. Opin. Allergy Clin. Immunol 2005; 5: 57–63.
Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, 16. Thomson NC: Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax (2005) 60(4):282-287.
Van Hove CL, Moerloose K, Maes T, Joos GF, Tournoy KG. Cigarette smoke enhances Th-2 driven airway inflammation and delays inhalational tolerance. Respir Res. 2008 May 20;9:42
Medical condition
Asthma
Product
fluticasone propionate
Collaborators
Not applicable
Study date(s)
July 2011 to December 2012
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 55 years
Accepts healthy volunteers
No
- 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.
- 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
Inclusion and exclusion criteria
Inclusion criteria:
- 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
- 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
Exclusion criteria:
- 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
- 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 location(s)
Study documents
Clinical study report
Available language(s): English
Scientific result summary
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Study complete
Actual primary completion date
2012-12-12
Actual study completion date
2012-12-12
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
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