Add-on Salmeterol Versus Montelukast in Arg/Arg-16 Asthmatics
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional

Summary: 
      The purpose of this study is to determine whether patients with asthma who carry a genotype
      associated with adverse outcomes with long-acting beta-2 agonists like salmeterol show
      greater benefit from the use of an asthma drug that works via alternative pathways like
      montelukast.
    

Detailed description: 
      Background/Rationale:

      The presence of the homozygous Arg/Arg genotype at position 16 of the β2-receptor (prevalence
      15-17% in UK/US populations) confers relative protection against down-regulation by
      endogenous catecholamines, making individuals susceptible to down-regulation and
      desensitization by regular exogenous β2-agonists and thereby negating the benefits from the
      regular use of short and long acting β2-agonists in adults with asthma. We found that, in the
      children receiving salmeterol, the adjusted odds ratio showed a 9 fold (p=0.003) greater risk
      of school absences due to asthma in the Arg/Arg group in comparison to the Gly16 carriers,
      with an unadjusted odds ratio of 6 (p=0.009). In the cohort not receiving salmeterol, there
      was no evidence of any genotype-dependent increases in school absences due to asthma (odds
      ratio=1). In addition, the Arg/Arg children on salmeterol had a significantly increased risk
      of extended school absence of over 1 week from asthma with an adjusted odds ratio of 6 (p=
      0.019).

      Currently, British Thoracic Society/Scottish Intercollegiate Guidelines Network
      recommendations suggest the use of regular long-acting β2-agonists as add on therapy in
      children with asthma who are inadequately controlled on inhaled steroids. The guidelines
      suggest the use of leukotriene antagonists (e.g. montelukast) if a combination of inhaled
      salmeterol and inhaled steroids fail to control symptoms.

      There are 1 million children with asthma in the UK. 150,000-170,000 children carry the
      Arg/Arg-16 genotype.

      The Arg/Arg-16 children with asthma may constitute a significant population that is likely to
      show better asthma control with a leukotriene antagonist in comparison to long-acting
      β2-agonists. We have already demonstrated that school absences constitute a suitable primary
      outcome measure for the testing of this hypothesis.

      Hypothesis:

      Children with asthma carrying the Arg/Arg-16 genotype on step 2 of the BTS guidelines
      (inhaled steroids plus salbutamol according to need) have fewer school absences over a period
      of 1 year on oral montelukast compared to inhaled salmeterol

      Objectives:

      To perform a randomized controlled trial (parallel design) of oral montelukast versus inhaled
      salmeterol on children with a history of school absences/hospital admissions due to asthma
      over the past year using school absences from asthma over a period of 1 year as the primary
      outcome

      Treatment Groups and Duration:

      Inclusion/exclusion criteria- All children and adolescents (5-18 years) with asthma in
      Tayside (Scotland) known (a) to carry the Arg/Arg-16 genotype and (b) currently on inhaled
      steroids and (c) inhaled bronchodilators according to need will be telephoned or contacted
      through home visits to establish if they have had (a) any school absences from asthma or (b)
      out-of-hours visits to GP/hospital visits or admissions due to asthma over the previous 12
      months. The presence of serious respiratory or multi-system disease (e.g. cystic fibrosis,
      cancer under current treatment) will constitute exclusion criteria for the study. All
      patients fulfilling the above inclusion and exclusion criteria will be invited to participate
      in the study.

      Plan for each visit - First visit: (a) Documentation of patient details (b) Baseline
      spirometry; (c) Exhaled nitric oxide measurements (d) Respiratory quality-of-life (Juniper);
      (e) Saliva sample for eosinophilic cationic protein (f) discontinuation of current asthma
      medication for the period of the study; (g) randomization to receive either (a) Flixotide
      (fluticasone) as per current inhaled steroid dose (therapeutic ratio of 2:1 for
      beclomethasone / budesonide versus fluticasone) plus oral montelukast; or (b) Seretide
      (salmeterol plus equivalent dose of fluticasone) plus placebo for montelukast for a period of
      1 year.

      2nd -5th visits, month 3, 6, 9: 3-monthly spirometry, exhaled nitric oxide, saliva for
      eosinophilic cationic protein, document school absences for asthma, hospital
      admissions/hospital or out-of-hours GP visits over the 3-month period.

      Month 12: end of study - spirometry, exhaled nitric oxide, saliva for eosinophilic cationic
      protein, document school absences for asthma, hospital admissions/hospital or out-of-hours GP
      visits over final 3-month period, measure quality-of-life.

      Physical monitoring of compliance will be performed by using inhalers provided with counters
      and tablet dispensers that allow counting of number used.

      Doses and dosage regimens:

      The following doses and dosage regimens will be used for the study Seretide 100 Accuhaler 1
      dose twice daily plus 1 tablet daily of placebo montelukast Seretide 250 Accuhaler 1 dose
      twice daily plus 1 tablet daily of placebo montelukast Seretide 500 Accuhaler 1 dose twice
      daily plus 1 tablet daily of placebo montelukast Flixotide Accuhaler 50 micrograms per
      blister, 1 blister dose twice daily plus 1 tablet daily of montelukast Flixotide Accuhaler
      100 micrograms per blister; 1 blister dose twice daily plus 1 tablet daily of montelukast
      Flixotide Accuhaler 250 micrograms per blister; 1 blister dose twice daily plus 1 tablet
      daily of montelukast Flixotide Accuhaler 500 micrograms per blister; 1 blister dose twice
      daily plus 1 tablet daily of montelukast Doses of montelukast or placebo: upto 6 years 4 mg
      once daily; 6-14 years 5 mg once daily; 15 years and above 10 mg once daily.

      Rescue medication: Subjects will be advised treatment with inhaled salbutamol 200 to 1000
      micrograms via metered dose inhaler and volumatic device, if cough, breathlessness,
      increasing symptoms on exercise, or other symptoms of asthma occur. The dose will be advised
      to be repeated once every four to six hours. The regimen will be advised to be continued for
      3-4 days, and up to a week, in case of persistence of symptoms. The research nurse conducting
      the study will ensure that the subject has an adequate supply of salbutamol via metered dose
      inhaler and large volume spacer (volumatic) at the start of the study. This will be confirmed
      at each visit.

      Key Efficacy Parameters:

        1. Primary outcome: Oral montelukast is associated with reduced school absences in
           comparison to inhaled salmeterol over a period of 1 year in Arg/Arg-16 asthmatic
           children

        2. Secondary outcomes that will also be tested:

             -  Oral montelukast is associated with reduced out-of hours visits/hospital visits or
                admissions in comparison to inhaled salmeterol over a period of 1 year

             -  Oral montelukast is associated with a reduction in airway resistance in comparison
                to inhaled salmeterol over a period of 1 year

             -  Oral montelukast is associated with reduced exhaled nitric oxide levels in
                comparison to inhaled salmeterol over a period of 1 year

             -  Oral montelukast is associated with reduced salivary eosinophilic cationic protein
                levels in comparison to inhaled salmeterol over a period of 1 year

             -  Oral montelukast is associated with improved asthma specific quality-of-life in
                comparison to inhaled salmeterol over a period of 1 year

             -  Oral montelukast is associated with improved morning peak expiratory flow rate in
                comparison to inhaled salmeterol over a period of 1 year
    

Intervention name(s): Montelukast Placebo; Salmeterol, Montelukast
Intervention type(s): Drug; Drug
Intervention description(s): Seretide 100 Accuhaler 1 dose twice daily plus 1 tablet daily of placebo montelukast
Seretide 250 Accuhaler 1 dose twice daily plus 1 tablet daily of placebo montelukast
Seretide 500 Accuhaler 1 dose twice daily plus 1 tablet daily of placebo montelukast
Doses of montelukast or placebo: up to 6 years 4 mg once daily; 6-14 years 5 mg once daily; 15 years and above 10 mg once daily; Flixotide Accuhaler 50 micrograms per blister, 1 blister dose twice daily plus 1 tablet daily of montelukast
Flixotide Accuhaler 100 micrograms per blister; 1 blister dose twice daily plus 1 tablet daily of montelukast
Flixotide Accuhaler 250 micrograms per blister; 1 blister dose twice daily plus 1 tablet daily of montelukast
Flixotide Accuhaler 500 micrograms per blister; 1 blister dose twice daily plus 1 tablet daily of montelukast
Doses of montelukast or placebo: up to 6 years 4 mg once daily; 6-14 years 5 mg once daily; 15 years and above 10 mg once daily
Intervention MeSH terms: Salmeterol Xinafoate; Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment