Add-on Salmeterol Versus Montelukast in Arg/Arg-16 Asthmatics
Add-on Salmeterol Versus Montelukast in Arg/Arg-16 Asthmatics
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.
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
Inclusion Criteria:

 All children and adolescents (5-18 years) with asthma in Tayside (Scotland) known:

 -  To carry the Arg/Arg-16 genotype and

 -  Currently on inhaled steroids and

 -  Inhaled bronchodilators according to need will be telephoned or contacted through home
 visits to establish if they have had:

 -  Any school absences from asthma or

 -  Out-of-hours visits to GP/hospital visits or admissions due to asthma over the
 previous 12 months.

 Exclusion Criteria:

 -  The presence of serious respiratory or multi-system disease (e.g. cystic fibrosis,
 cancer under current treatment)