Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.
Condition: Asthma
MeSH terms: Asthma
Intervention: 100 micrograms Fluticasone propionate; 500 micrograms Fluticasone propionate; lactose powder
Intervention description: 100 micrograms micronized drug blended with lactose in dry powder inhalator; 500 micrograms micronized drug blended with lactose in dry powder inhalator; lactose powder in dry powder device : placebo comparator
Intervention MeSH terms: Fluticasone; Xhance
Phase: Phase 2
Study type: Interventional
Primary purpose: Other
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No

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.
    

Eligibility 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)