Inhalation of Corticosteroids in Smoking and Non-smoking Asthmatics.
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): 100 micrograms Fluticasone propionate; 500 micrograms Fluticasone propionate; lactose powder
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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
Other intervention name(s): Flixotide; Flixotide
Intervention MeSH terms: Fluticasone; Xhance
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Other