Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.

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)