Pharmacogenetics Use For Further Treatment Improvement in childreN

NCT ID: NCT03654508

Last Updated: 2023-11-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 102 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-12
• Study Completion Date: 2023-10-18

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.

Conditions

Asthma in Children

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

ADRB2-genotype guided treatment arm

In the genotype-stratified arm, children will be treated based on their ADRB2 genotype. Children homozygous for the risk variant Arg16 and heterozygotes (Arg16Gly) will be treated with doubling dosages of their ICS. Children homozygous for the wild type allele (Gly16Gly) will receive LABA.

Group Type: ACTIVE_COMPARATOR

ADRB2-genotype guided treatment

Intervention Type: GENETIC

This intervention assesses whether ADRB2 genotype-guided treatment leads to better asthma control after 3 months compared to usual care in children who are uncontrolled despite adherent and adequate use of ICS.

Control arm

In the control arm, genotyping will be performed for retrospective analysis, but the genotype information will not be used to guide treatment. Children in this study arm will proceed randomisation between doubling ICS dosage (n=75) or LABA treatment (n=75), the two most commonly preferred add-on options among paediatric pulmonologists in the Netherlands. The investigators choose to randomize between both treatments options, since international guidelines do not agree on the preferred treatment option.

Group Type: ACTIVE_COMPARATOR

Randomisation

Intervention Type: OTHER

In the control arm, children will be randomised over double dose ICS or ICS+LABA instead of treatment according to their genotype.

Interventions

ADRB2-genotype guided treatment

This intervention assesses whether ADRB2 genotype-guided treatment leads to better asthma control after 3 months compared to usual care in children who are uncontrolled despite adherent and adequate use of ICS.

Intervention Type: GENETIC

Randomisation

In the control arm, children will be randomised over double dose ICS or ICS+LABA instead of treatment according to their genotype.

Intervention Type: OTHER

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

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dutch Lung Foundation

UNKNOWN

Sponsor Role: collaborator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role: lead

Responsible Party

Prof. dr. A.H. Maitland-van der Zee

Prof. dr. A.H. Maitland-van der Zee

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Anke-Hilse Maitland-van der Zee, Prof. Dr.

Role: PRINCIPAL_INVESTIGATOR

Academic Medical Center, Department of Respiratory Medicine

Locations

Universitair Ziekenhuis Antwerpen

Edegem, , Belgium

Nij Smellinghe

Drachten, Drenthe, Netherlands

Rijnstate

Arnhem, Gelderland, Netherlands

RadboudUMC

Nijmegen, Gelderland, Netherlands

Canisius Wilhelmina Ziekenhuis

Nijmegen, Gelderland, Netherlands

Amphia ziekenhuis

Breda, North Brabant, Netherlands

Catharina ziekenhuis

Eindhoven, North Brabant, Netherlands

VUmc locatie Boelelaan

Amsterdam, North Holland, Netherlands

Academic Medical Center, Department of Respiratory Disease

Amsterdam-Zuidoost, North Holland, Netherlands

Spaarne Gasthuis

Hoofddorp, North Holland, Netherlands

Medisch Centrum Leeuwarden

Leeuwarden, Provincie Friesland, Netherlands

Reinier de Graaf Gasthuis

Delft, South Holland, Netherlands

Erasmus Medical Center

Rotterdam, South Holland, Netherlands

Sint Franciscus Gasthuis

Rotterdam, South Holland, Netherlands

Maasstadziekenhuis

Rotterdam, South Holland, Netherlands

Haga ziekenhuis

The Hague, South Holland, Netherlands

Medisch Spectrum Twente

Enschede, Twente, Netherlands

University Medical Center Groningen

Groningen, , Netherlands

Martini ziekenhuis

Groningen, , Netherlands

Tergooi ziekenhuis

Hilversum, , Netherlands

Kinderspital

Zurich, , Switzerland

Countries

Belgium; Netherlands; Switzerland

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NL63849.018.17

Identifier Type: -

Identifier Source: org_study_id