There is large heterogeneity in treatment response to asthma medication and a one-size fits all approach based on current guidelines might not fit all children with asthma. It is expected that children with one or more variant alleles (Arg16Arg and Arg16Gly) within the beta2 adrenergic receptor (ADRB2) gene coding for the beta2-receptor have a higher risk to poorly respond to long-acting beta2-agonists (LABA) comparing to the Gly16Gly wildtype. Aims To study whether ADRB2 genotype-guided treatment will lead to improvement in asthma control in children with uncontrolled asthma on inhaled corticosteroids compared with usual care. Design A multicentre, double-blind, precision medicine, randomized trial will be carried out within 20 Dutch hospitals. 310 asthmatic children (6-17 years of age) not well controlled on a low dose of inhaled corticosteroids (ICS) will be included and randomized over a genotype-guided and a non-genotype-guided(control) arm. In the genotype-guided arm children with Arg16Arg and Arg16Gly will be treated with double dosages of ICS and with the Gly16Gly wildtype with add on LABA. In the control arm children will be randomized over both treatment options. Lung function measurements, questionnaires focussing on asthma control (ACT/c-ACT) and quality of life, will be obtained in three visits within 6 months. The primary outcome will be improvement in asthma control based on repeated measurement analysis of c-ACT or ACT scores in the first three months of the trial. Additional cost effectiveness studies will be performed. Conclusion Currently, pharmacogenetics is not used in paediatric asthmas. This trial may pave the way to implement promising results for genotype-guided treatment in paediatric asthma in clinical practice.
Name: ADRB2-genotype guided treatment
Name: Randomisation
Description: Patients will fill in the (childhood-)Asthma Control Test at baseline, after 3 months [Range score: 0 - 27, 20 or more means asthma under control]
Measure: Asthma control based on (childhood-)Asthma Control Test scores in the first 3 months of the trial Time: 3 monthsDescription: Patients will fill in the (childhood-)Asthma Control Test at baseline after 6 months [Range score: 0 - 27, 20 or more means asthma under control]
Measure: Change in asthma control at t=6 months (childhood-)Asthma Control Test Time: 6 monthsDescription: Patients will fill in a questionnaire about asthma-related school absences [Minimum score 0 days, maximum score more than 10 days]
Measure: Change in asthma-related school absences Time: 6 monthsDescription: Patients will be questioned what kind of treatment they use at baseline visit, after three months
Measure: Change in therapy in t = 3 months Time: 3 monthsDescription: Patients will fill in the (childhood-)Asthma Control Test at baseline, every month [Range score: 0 - 27, 20 or more means asthma under control]
Measure: Time to reach asthma control (Asthma Control Test score ≥20) Time: 6 monthsDescription: Patients will fill in the Productivity Cost Questionnaire at 0, 3 and 6 months. The IPCQ measures: absenteeism (number of days missed from work in the 4 weeks due to ilness) -- minimum is 0, maximum (in theory) is 28 days Presenteism (productivity lost while at work due to ilness) -- minimum is 0, maximum is 224 hours. In absenteeism, a lower number of days missed from work represent a better outcome; In presenteism, a lower number of hours represent a better outcome For presenteism the number of hours productivity loss is calculated by the following formula using data from the questionnaire. presenteism = number of workingdays affected by illness * (1-efficiencyscore/10)*working hours per working day. This results in a monetary value for productivity loss.
Measure: Cost-effectiveness of ADRB2 genotype guided treatment measured by the Productivity Cost Questionnaire Time: 3 and 6 monthsDescription: Non-response to ICS treatment will be measured by analysing feces samples (microbiome) and nose swabs (epigenome). Nose swabs will be collected after 0, 3 and 6 months and feces after 1 month
Measure: In-depth integrative -omics analysis Time: 0, 3 and 6 monthsDescription: Measured by the Pediatric Asthma-related Quality of Life Questionnaire (PAQLQ). Children are asked to think about how they have been during the previous week and to respond to each of the 32 questions on a 7-point scale (7 = not bothered at all - 1 = extremely bothered). The overall PAQLQ score is the mean of all 23 responses and the individual domain scores are the means of the items in those domains. Subscales are summed.
Measure: Change in quality of life assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) score Time: 0, 3 and 6 monthsDescription: Measured by the PedsQL questionnaire, a 23 item generic score scale consisting of physiological functioning, emotional functioning, social functioning and school functioning questions with multidimensional scales. Subscales are summed. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 4 dimensions (physical, emotional, social, & school functioning) are scored.
Measure: Change in fatigue scores assessed by the PedsQL questionnaire Time: 0, 3 and 6 monthsDescription: FEV1 will be measured at 0 and 3 months, change in FEV1 will be calculated.
Measure: change in FEV1 at t = 3 months Time: 0 and 3 monthsDescription: FEV1 will be measured at t=0 and 6 months, change in FEV1 will be calculated
Measure: change in FEV1 at t = 6 months Time: 0, 3 and 6 monthsDescription: Exhaled nitric oxide measures will be performed using the Niox Vero at t=0 and 3 months
Measure: change in fraction of exhaled nitric oxide at t=3 months Time: 0 and 3 monthsDescription: Exhaled nitric oxide measures will be performed using the Niox Vero at t=0. 3 and 6 months
Measure: change in fraction of exhaled nitric oxide at t=6 months Time: 0,3 and 6 monthsAllocation: Randomized
Parallel Assignment
There is one SNP
It is expected that children with one or more variant alleles (Arg16Arg and Arg16Gly) within the beta2 adrenergic receptor (ADRB2) gene coding for the beta2-receptor have a higher risk to poorly respond to long-acting beta2-agonists (LABA) comparing to the Gly16Gly wildtype. --- Arg16Gly ---
In the genotype-guided arm children with Arg16Arg and Arg16Gly will be treated with double dosages of ICS and with the Gly16Gly wildtype with add on LABA. --- Arg16Gly ---
Furthermore, to test the hypothesis it is necessary to include enough children in the control group with Arg16Arg or Arg16Gly to be treated with LABA. --- Arg16Gly ---
This will lead to an estimated number of children with Arg16Arg or Arg16Gly of 51 who will get LABA add on. --- Arg16Gly ---