Fluticasone/Salmeterol (FP/SM) Versus Double the Dose Fluticasone (FP) in Patients With Mild to Moderate Asthma
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to compare the effects of Fluticasone/ salmeterol combination
      and double the dose of fluticasone on airway hyper-responsiveness to methacholine in a
      randomised, double blind, double dummy, cross-over trial.
    

Detailed description: 
      The objective of pharmacotherapy in the treatment of asthma is restoration of pulmonary
      function. This is accomplished by reducing airway inflammation, stimulating bronchodilation
      or a combination of the two. The classes of drug that have proved effective in this regard
      are anti-inflammatory agents such as corticosteroids and mast cell-stabilising agents, and
      bronchodilators such as β2 adrenergic agonists.

      Inhaled corticosteroids (ICS) are used as a first-line anti-inflammatory prophylactic therapy
      for asthma. Current guidelines recommend initiating treatment with a medium to high dose,
      then reducing to the lowest effective dose for long-term maintenance.

      Corticosteroids are preferably inhaled from aerosol inhalers (commonly pMDIs: pressurised
      metered dose inhalers) using large-volume spacer devices for pMDI doses in excess of 800
      µg/day of BDP (Beclometasone Dipropionate), or equivalent. CFCs ((Chlorofluorocarbon)) (
      propellants in BDP pMDIs are being replaced with non-ozone-depleting propellants such as
      hydrofluoroalkane-134a (HFA).

      Comparison of steroid therapies in patients with asthma is rather difficult using
      conventional measures such as lung function parameters (FEV1/forced expiratory flow over one
      sencond or PEF/Peak expiratory flow) when chosen as the primary outcome variable, as these
      are relatively insensitive to ICS therapy, and are rather distant from the underlying
      inflammatory process. Measurements of airway responsiveness are frequently used to evaluate
      asthma treatments and methacholine or histamine challenge testing is recognized and
      recommended by regulatory authorities.

      Airway responsiveness is defined as the relative ease with which airways can be made to
      constrict when exposed to non-sensitising chemical or physical stimuli such as methacholine,
      histamine, cold air, exercise or hyperventilation. Methacholine challenge looks at the
      functional antagonism of long acting bronchodilators (LABA) against increased airway tone; as
      such there is always more room for potential improvement, and therefore treatment response,
      with protection against challenge than with spirometry alone. In addition the effect of ICS
      is more sensitive when measured with methacholine challenge testing than with lung function
      alone.

      In this study, which looked at the effect of both ICS alone and ICS with LABA, methacholine
      challenge was selected as it is more sensitive than lung function alone.

      The methacholine challenge test involves delivering doubling concentrations of methacholine
      over a period of time (usually 2 minutes) until a given level of bronchoconstriction is
      achieved (often a 20% fall in FEV1). The provocative concentration producing a 20% fall in
      FEV1 is termed the PC20. Previous studies have shown that treatment with 50µg salmeterol
      versus 100 µg Fluticasone plus 50 µg salbutamol showed a 1.15 doubling dose difference in
      response to methacholine challenge, which would indicate that a treatment response to the
      100µg fluticasone would be in the region of 1 doubling dose15. A similar study demonstrated a
      similar (0.9 dd difference between treatments) when comparing FPSM/fluticasone/ salmeterol
      (125/50µg) vs FP/Flutiocasone Propionate(250µg) alone.

      One doubling dose can therefore be shown to indicate a clinically relevant difference between
      the treatments (based upon either the ICS or the LABA component of the combination product)
      as shown in previous studies. Therefore 1 dd shift in treatment response was defined as the
      minimally important clinical difference for the purposes of the statistical calculations.

      In addition to the measures of efficacy, this study aimed to compare the effect of the two
      treatments on basal HPA-axis suppression in vivo, as measured by the ratio of overnight
      urinary cortisol to creatinine.

      The bioactivity of a corticosteroid is thought to be related to the relative degree of
      HPA-axis suppression as measured by the decrease in the ratio of overnight urinary cortisol
      to creatinine. This measure has been shown to be as sensitive as a 24-hour collection. An
      alternative, though less sensitive, assessment is plasma cortisol and creatinine production
      30 minutes after stimulation with ACTH19,20.

      The two formulations were administered for 2 weeks, which was thought to be sufficient to
      achieve steady state in terms of HPA-axis suppression. It had been shown previously that
      steady state plasma levels can be achieved in 3 days when using fluticasone propionate.

      Smokers have been shown to develop acquired steroid resistance, resulting in a diminished
      response. It has therefore been the practice of most studies on asthma to exclude smokers as
      a matter of course. Indeed current asthma guidelines are based on these studies. A recent
      subgroup analysis of the 'Gaining Optimal Asthma controL (GOAL) study' reported by Pedersen
      and colleagues has revealed some interesting results. They discovered that smokers gained
      more benefit from FPSM vs FP alone, as compared to non smokers, in terms of reduction in
      exacerbation rates over 12 months.

      To put the results of this study into a clinical context, in the majority of patients who
      were non smokers it would take 25 years to obtain an additional benefit to prevent an
      exacerbation by taking fluticasone/salmeterol vs fluticasone alone. In smokers it would take
      6.66 years to see the same benefit conferred by using combination therapy.

      The reasons for the apparent increased benefits of treatment with FP/SM in smokers are
      unclear. A potential explanation for this could be that, in the face of the relative steroid
      resistance seen in smokers, the smooth muscle stabilisation conferred by the LABA becomes of
      greater significance. Another possible explanation is that smoking induces greater
      hyper-reactivity in the airway smooth muscle, which responds well to the smooth muscle
      stabilisation offered by LABAs. A third possibility is that smoking might in some way
      up-regulate beta2- adrenoreceptor function. It was therefore felt important to include a
      cohort of smokers in this study.

      To enter Treatment Period 1, subjects must have had a provocative concentration of
      methacholine causing a 20% decrease in FEV1 (PC20) of less than 4mg/mL at randomisation and
      FEV1 at the end of the run-in period and wash-out must have remained within 15% of that
      recorded at screening, and ≥ 60% predicted.

      For entry into the second treatment period the PC20 after 2 to 3 weeks of the placebo washout
      must have been within ±1 doubling dilution of the initial placebo run in period.
    

Intervention name(s): fluticasone/salmeterol; fluticasone
Intervention type(s): Drug; Drug
Intervention description(s): 2 puffs twice a day for 2 weeks; 2 puffs twice a day for 2 weeks
Other intervention name(s): fluticasone/salmeterol combination; Flixotide
Intervention MeSH terms: Fluticasone; Xhance; Salmeterol Xinafoate; Fluticasone-Salmeterol Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: fluticasone; salmeterol; bronchoprotection