Pharmacogenetics Use For Further Treatment Improvement in childreN

NCT03654508 | Completed DMC

• 1 other identifier: NL63849.018.17
• Study Type: interventional
• Target: 102
• Locations: 3 countries
• Sites: 21

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.

Conditions

Asthma in Children

Keywords

long-acting beta2-agonist; pharmacogenetics

Outcome Measures

Primary Outcomes (1)

• Asthma control based on (childhood-)Asthma Control Test scores in the first 3 months of the trial

  Patients will fill in the (childhood-)Asthma Control Test at baseline, after 3 months \[Range score: 0 - 27, 20 or more means asthma under control\]

  3 months

Secondary Outcomes (12)

• Change in asthma control at t=6 months (childhood-)Asthma Control Test

  6 months

• Change in asthma-related school absences

  6 months

• Change in therapy in t = 3 months

  3 months

• Time to reach asthma control (Asthma Control Test score ≥20)

  6 months

• Cost-effectiveness of ADRB2 genotype guided treatment measured by the Productivity Cost Questionnaire

  3 and 6 months

Study Arms (2)

ADRB2-genotype guided treatment arm

ACTIVE COMPARATOR

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.

Genetic: ADRB2-genotype guided treatment

Control arm

ACTIVE COMPARATOR

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.

Other: Randomisation

Interventions

ADRB2-genotype guided treatment 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.

ADRB2-genotype guided treatment arm

Randomisation OTHER

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

Control arm

Eligibility Criteria

• Age: 6 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Dutch Lung Foundation: collaborator

Study Sites (21)

Universitair Ziekenhuis Antwerpen

Edegem, B-2650, Belgium

Location

Nij Smellinghe

Drachten, Drenthe, 9202NN, Netherlands

Location

Rijnstate

Arnhem, Gelderland, 6815 AD, Netherlands

Location

RadboudUMC

Nijmegen, Gelderland, 6525GA, Netherlands

Location

Canisius Wilhelmina Ziekenhuis

Nijmegen, Gelderland, 6532 SZ, Netherlands

Location

Amphia ziekenhuis

Breda, North Brabant, 4818CK, Netherlands

Location

Catharina ziekenhuis

Eindhoven, North Brabant, 5623 EJ, Netherlands

Location

VUmc locatie Boelelaan

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Academic Medical Center, Department of Respiratory Disease

Amsterdam-Zuidoost, North Holland, 1105AZ, Netherlands

Location

Spaarne Gasthuis

Hoofddorp, North Holland, 0031232245730, Netherlands

Location

Medisch Centrum Leeuwarden

Leeuwarden, Provincie Friesland, 8934AD, Netherlands

Location

Reinier de Graaf Gasthuis

Delft, South Holland, 2625 AD, Netherlands

Location

Erasmus Medical Center

Rotterdam, South Holland, 3015CN, Netherlands

Location

Sint Franciscus Gasthuis

Rotterdam, South Holland, 3045 PM, Netherlands

Location

Maasstadziekenhuis

Rotterdam, South Holland, 3079 DZ, Netherlands

Location

Haga ziekenhuis

The Hague, South Holland, 2545 AA, Netherlands

Location

Medisch Spectrum Twente

Enschede, Twente, 7512 KZ, Netherlands

Location

University Medical Center Groningen

Groningen, 9700RB, Netherlands

Location

Martini ziekenhuis

Groningen, 9728NT, Netherlands

Location

Tergooi ziekenhuis

Hilversum, 1213 XZ, Netherlands

Location

Kinderspital

Zurich, CH-8032, Switzerland

Location

Study Officials

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

  Academic Medical Center, Department of Respiratory Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. dr. A.H. Maitland-van der Zee

Model Details: multicentre, double-blind, precision medicine, randomized trial

Study Record Dates

• First Submitted: May 14, 2018
• First Posted: August 31, 2018
• Study Start: June 12, 2018
• Primary Completion: October 18, 2023
• Study Completion: October 18, 2023
• Last Updated: November 7, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

NL (19); BE (1); CH (1)