Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.

NCT01400906 | Completed Phase 2 Results

• 1 other identifier: 114748
• Study Type: interventional
• Target: 36
• Locations: 2 countries
• Sites: 2

Brief 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. 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.

Conditions

Asthma

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  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

  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

  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

  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

  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

  Day 7 of each treatment period (up to 11 weeks)

Study Arms (1)

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.

Drug: 100 micrograms Fluticasone propionate; Drug: 500 micrograms Fluticasone propionate; Drug: lactose powder

Interventions

100 micrograms Fluticasone propionate DRUG

100 micrograms micronized drug blended with lactose in dry powder inhalator

Also known as: Flixotide

3 periods cross-over study

500 micrograms Fluticasone propionate DRUG

500 micrograms micronized drug blended with lactose in dry powder inhalator

Also known as: Flixotide

3 periods cross-over study

lactose powder DRUG

lactose powder in dry powder device : placebo comparator

3 periods cross-over study

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (2)

GSK Investigational Site

Brussels, 1020, Belgium

Location

GSK Investigational Site

London, NW10 7EW, United Kingdom

Location

Related Publications (23)

• Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008 Aug;134(2):394-401. doi: 10.1378/chest.08-0440.

  PMID: 18682458 BACKGROUND

• 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.

  PMID: 11867826 BACKGROUND

• 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.

  PMID: 11742922 BACKGROUND

• 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.

  PMID: 16645173 BACKGROUND

• 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.

  PMID: 3106449 BACKGROUND

• 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.

  PMID: 11112128 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 7581057 BACKGROUND

• 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.

  PMID: 11929474 BACKGROUND

• 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.

  PMID: 15467323 BACKGROUND

• 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.

  PMID: 16522450 BACKGROUND

• Johnston NW, Sears MR. Asthma exacerbations . 1: epidemiology. Thorax. 2006 Aug;61(8):722-8. doi: 10.1136/thx.2005.045161.

  PMID: 16877691 BACKGROUND

• 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.

  PMID: 9257789 BACKGROUND

• Moerloose KB, Robays LJ, Maes T, Brusselle GG, Tournoy KG, Joos GF. Cigarette smoke exposure facilitates allergic sensitization in mice. Respir Res. 2006 Mar 29;7(1):49. doi: 10.1186/1465-9921-7-49.

  PMID: 16571114 BACKGROUND

• O'Shaughnessy KM, Wellings R, Gillies B, Fuller RW. Differential effects of fluticasone propionate on allergen-evoked bronchoconstriction and increased urinary leukotriene E4 excretion. Am Rev Respir Dis. 1993 Jun;147(6 Pt 1):1472-6. doi: 10.1164/ajrccm/147.6_Pt_1.1472.

  PMID: 8389108 BACKGROUND

• O'Byrne PM, Gauvreau GM, Brannan JD. Provoked models of asthma: what have we learnt? Clin Exp Allergy. 2009 Feb;39(2):181-92. doi: 10.1111/j.1365-2222.2008.03172.x.

  PMID: 19187330 BACKGROUND

• Singh D, Petavy F, Macdonald AJ, Lazaar AL, O'Connor BJ. The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res. 2010 Mar 1;11(1):26. doi: 10.1186/1465-9921-11-26.

  PMID: 20193079 BACKGROUND

• Thomson NC, Spears M. The influence of smoking on the treatment response in patients with asthma. Curr Opin Allergy Clin Immunol. 2005 Feb;5(1):57-63. doi: 10.1097/00130832-200502000-00011.

  PMID: 15643345 BACKGROUND

• Tomlinson JE, McMahon AD, Chaudhuri R, Thompson JM, Wood SF, Thomson NC. Efficacy of low and high dose inhaled corticosteroid in smokers versus non-smokers with mild asthma. Thorax. 2005 Apr;60(4):282-7. doi: 10.1136/thx.2004.033688.

  PMID: 15790982 BACKGROUND

• 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(1):42. doi: 10.1186/1465-9921-9-42.

  PMID: 18489797 BACKGROUND

• Cahn A, Boyce M, Mistry S, Musani N, Rambaran C, Storey J, Ventresca P, Michel O. Randomized trial of allergen-induced asthmatic response in smokers and non-smokers: effects of inhaled corticosteroids. Clin Exp Allergy. 2015 Oct;45(10):1531-41. doi: 10.1111/cea.12610.

  PMID: 26251958 DERIVED

Related Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

MeSH Terms

Conditions

Asthma

Interventions

Fluticasone

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Androstadienes; Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2011
• First Posted: July 25, 2011
• Study Start: July 20, 2011
• Primary Completion: December 1, 2012
• Study Completion: December 12, 2012
• Last Updated: August 13, 2018
• Results First Posted: September 30, 2013

Record last verified: 2018-06

Data Sharing

• IPD Sharing: Will share

Locations

GB (1); BE (1)