Clinical trial NCT03654508: Pharmacogenetics Use For Further Treatment Improvement in childreN
Official title: Pharmacogenetics Use For Further Treatment Improvement in childreN
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Asthma in Children
Keywords: long-acting beta2-agonist
pharmacogenetics
Lead sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Sponsor class: OTHER
Collaborators: name: Dutch Lung Foundation
First posted: 2018-08-31
Enrollment: 102
Sex: ALL
Minimum age (years): 6
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: multicentre, double-blind, precision medicine, randomized trial
Primary purpose: TREATMENT

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.

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. The amount of children treated with LABA and ICS should be equal in the control group. Therefore children are randomized in the control group over doubling ICS (n=77) and adding LABA (n=77). This will lead to an estimated number of children with Arg16Arg or Arg16Gly of 51 who will get LABA add on. In this way the power is high enough to determine the effectivity of both treatment options in the three genotypes. The investigators find it important to define effectivity next to the question whether genotyping benefits children with asthma. In the control group DNA samples will be obtained for retrospective analysis.

It is safe to randomise the children again who are randomised within the control arm, because treatment with a double dose of ICS and adding a LABA are both standard of care. A Cochrane review from 2009 has shown that both treatments have proven to be equally effective in both children and adults Randomisation in the control arm is important because it would be futile if the children in this arm would be treated with the same therapy by accident. Randomisation is necessary to make the trial as small and effective as possible. At this moment physicians do not have the tools to determine which therapy is the best for every child. This is why the investigators think it is correct to randomise in the control arm.

Eligibility criteria: 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

Primary outcomes:
measure: Asthma control based on (childhood-)Asthma Control Test scores in the first 3 months of the trial
timeFrame: 3 months
Secondary outcomes:
measure: Change in asthma control at t=6 months (childhood-)Asthma Control Test
timeFrame: 6 months
measure: Change in asthma-related school absences
timeFrame: 6 months
measure: Change in therapy in t = 3 months
timeFrame: 3 months
measure: Time to reach asthma control (Asthma Control Test score ≥20)
timeFrame: 6 months
measure: Cost-effectiveness of ADRB2 genotype guided treatment measured by the Productivity Cost Questionnaire
timeFrame: 3 and 6 months
measure: In-depth integrative -omics analysis
timeFrame: 0, 3 and 6 months
measure: Change in quality of life assessed by the Paediatric Asthma Quality of Life Questionnaire (PAQLQ) score
timeFrame: 0, 3 and 6 months
measure: Change in fatigue scores assessed by the PedsQL questionnaire
timeFrame: 0, 3 and 6 months
measure: change in FEV1 at t = 3 months
timeFrame: 0 and 3 months
measure: change in FEV1 at t = 6 months
timeFrame: 0, 3 and 6 months
measure: change in fraction of exhaled nitric oxide at t=3 months
timeFrame: 0 and 3 months
measure: change in fraction of exhaled nitric oxide at t=6 months
timeFrame: 0,3 and 6 months
Other outcomes:
Locations:
city: Edegem
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Drachten
country: Netherlands
facility: Nij Smellinghe
state: Drenthe
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
state: Friesland
city: Arnhem
country: Netherlands
facility: Rijnstate
state: Gelderland
city: Nijmegen
country: Netherlands
facility: RadboudUMC
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
state: Gelderland
city: Breda
country: Netherlands
facility: Amphia ziekenhuis
state: Noord-Brabant
city: Eindhoven
country: Netherlands
facility: Catharina ziekenhuis
state: Noord-Brabant
city: Amsterdam-Zuidoost
country: Netherlands
facility: Academic Medical Center, Department of Respiratory Disease
state: Noord-Holland
city: Amsterdam
country: Netherlands
facility: VUmc locatie Boelelaan
state: Noord-Holland
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
state: Noord-Holland
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
state: Twente
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
state: Zuid-Holland
city: Den Haag
country: Netherlands
facility: Haga ziekenhuis
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Sint Franciscus Gasthuis
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Maasstadziekenhuis
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Groningen
country: Netherlands
facility: Martini ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi ziekenhuis
city: Zürich
country: Switzerland
facility: Kinderspital
Study officials:
affiliation: Academic Medical Center, Department of Respiratory Medicine
name: Anke-Hilse Maitland-van der Zee, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References: