Pharmacogenetics Use For Further Treatment Improvement in childreN
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Enrollment
- 102
- Locations
- 42
- Primary Endpoint
- Asthma control based on (childhood-)Asthma Control Test scores in the first 3 months of the trial
Study Overview
Brief Summary
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.
Detailed Description
Study design: national, multi-centre, double-blind randomized controlled trial
Duration: 6 months, with 3 visits in the hospitals (at t=0, t=3 months and t=6 months)
Setting: Patients are recruited at out-patient asthma clinics in secondary and tertiary care hospitals in the Netherlands.
Description: Three hundred ten children (6 to 17 years of age) with a doctor's diagnosis of asthma and uncontrolled asthma symptoms despite adherent and adequate use of ICS for at least three months (step 2 asthma treatment) will be recruited by secondary and tertiary care centers in the Netherlands. All participants are eligible for step-up asthma treatment (from step 2 to step 3) as assessed by the treating paediatrician/paediatric pulmonologist. Participants will be randomized to a genotype-guided treatment arm (n=155) or to a usual care, non-genotype guided arm (n=155) and followed for 6 months.
Genotyping before start treatment During the baseline visit in the hospital, clinical data and biological samples (including a DNA sample) will be collected. Upon this visit, the DNA sample will be send to the Clinical Chemistry department of the Erasmus MC (Head: Prof. R. van Schaik) to perform genotyping of the ADRB2 gene within one week. The treating physician will adapt the treatment regime of the participant based on the treatment advice of the study coordinator (Table 1). For the children in the genotype-arm, this will be based on the genotype. The treating physician will not know (be blinded) whether the treatment advice was based on the genotype (intervention arm) or based on randomization (control arm). The participant will be followed for 6 months. If the participant is still uncontrolled at t=3 months, treatment will be adapted. All children will be genotyped, in order to assess the influence of the genotype on treatment outcome in the usual arm group retrospectively. The children should use the same inhalation device during the study to avoid confusion on how they should inhale their medication.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Care Provider)
Eligibility Criteria
- Ages
- 6 Years to 17 Years (Child)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Doctor's diagnosis of asthma (ever) based on patient history, FEV1 reversibility ≥ 12% and/or bronchial hyperresponsiveness
- •Current asthma symptoms (based on ACT (≥12 years) or C-ACT (<12 years) score ≤ 19
- •ICS use ≥ 3 months before inclusion (start dosage ICS, treatment step 2 according to childhood asthma guideline NVK, Table 3)
- •Adequate inhalation technique (based on validated checklist score [21])
- •Self-assessed good adherence to maintenance asthma treatment
- •Understanding of Dutch language
- •Internet access a home, willing to fill in internet questionnaires
Exclusion Criteria
- •Active smoking
- •Congenital heart disease
- •Serious lung disease other than asthma (Cystic Fibrosis, Primary Ciliary Dyskinesia, congenital lung disorders, severe immune disorders)
- •LABA use in past 6 months
- •Omalizumab use
- •ICU admission in the previous year
Outcomes
Primary Outcomes
Asthma control based on (childhood-)Asthma Control Test scores in the first 3 months of the trial
Time Frame: 3 months
Patients will fill in the (childhood-)Asthma Control Test at baseline, after 3 months \[Range score: 0 - 27, 20 or more means asthma under control\]
Secondary Outcomes
- Change in fatigue scores assessed by the PedsQL questionnaire(0, 3 and 6 months)
- Change in therapy in t = 3 months(3 months)
- Time to reach asthma control (Asthma Control Test score ≥20)(6 months)
- Change in asthma-related school absences(6 months)
- Cost-effectiveness of ADRB2 genotype guided treatment measured by the Productivity Cost Questionnaire(3 and 6 months)
- Change in quality of life assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) score(0, 3 and 6 months)
- change in FEV1 at t = 3 months(0 and 3 months)
- change in FEV1 at t = 6 months(0, 3 and 6 months)
- Change in asthma control at t=6 months (childhood-)Asthma Control Test(6 months)
- In-depth integrative -omics analysis(0, 3 and 6 months)
- change in fraction of exhaled nitric oxide at t=6 months(0,3 and 6 months)
- change in fraction of exhaled nitric oxide at t=3 months(0 and 3 months)
Investigators
Prof. dr. A.H. Maitland-van der Zee
Prof. dr. A.H. Maitland-van der Zee
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)