Systems Pharmacology Approach to Uncontrolled Pediatric Asthma

Systems Pharmacology Approach to Uncontrolled Pediatric Asthma (SysPharmPediA)

Background:

Asthma is a heterogeneous respiratory disease and the most common chronic disease in children. A small subset of children has continuous poor asthma control despite appropriate adherence to asthma medication. There is a clinical need to identify these children as early as possible to optimize treatment and/or to find therapeutic alternatives. Therefore, the "Systems Pharmacology approach to uncontrolled Pediatric Asthma" (SysPharmPediA) study was set up.

Objective:

To establish a cohort of pediatric moderate-to-severe uncontrolled and controlled patients with asthma in order to investigate pathophysiological mechanisms underlying uncontrolled moderate-to-severe asthma in children on maintenance treatment, using a multi-omics systems medicine approach.

Methods:

In this multicenter observational case-control study, moderate-to-severe asthmatic children (n=145, age 6-17 years), were included in specialized hospitals in four European countries (Netherlands, Germany, Spain and Slovenia). Recruited subjects were selected based on good asthma control (controlled asthmatics, n=54) or poor asthma control / recurrent exacerbations (uncontrolled asthmatics, n=91). Comprehensive details concerning demographics, current and past patient/family history and clinical characteristics were collected. In addition, systems-wide omics layers, including epi(genomics), transcriptomics, microbiome, proteomics and metabolomics will be evaluated from multiple collected, relatively non-invasive, samples of from the recruited individuals, such as: blood, feces, saliva, nasal swabs and exhaled breath. Follow-up visits were performed 6 and 12 months after inclusion.

Study Overview

• Status: Completed
• Conditions: Pediatric Asthma; Uncontrolled Asthma

• Study Type: Observational
• Enrollment (Actual): 145

Contacts and Locations

Study Locations

• Germany
  • Regensburg, Germany
    • University Regensburg
• Netherlands
  • Utrecht, Netherlands
    • Utrecht University
• Slovenia
  • Maribor, Slovenia
    • University of Maribor
• Spain
  • San Sebastián, Spain
    • University of the Basque Country
  • Santa Cruz De Tenerife, Spain
    • Universidad de la Laguna
• Sweden
  • Stockholm, Sweden
    • Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Four tertiary care centers from four European countries (the Netherlands, Germany, Spain, and Slovenia) recruited 145 asthmatic children and adolescents (6-17 years old). All centers obtained approval from their local medical ethics committee (ethics committee of University Regensburg, Germany (18-1034-101); Clinical Research Ethics Committee of the Basque Country, Spain (PI2015075 (SO)); Medical Ethics Committee of the University Medical Center Utrecht (UMC Utrecht), Utrecht, the Netherlands (NL55788.041.15); National Medical Ethics Committee, Slovenia (0120-569/2017/4)) and written informed consents were collected from the parents/caregivers and/or the recruited children when appropriate.

Description

Inclusion Criteria:

General:

• Between 6-17 years of age
• Doctor diagnosis of asthma

In addition to the general criteria, a case with uncontrolled asthma (case group A) should meet:

• Asthma treatment Global INitiative of Asthma (GINA) step 3 or higher

  ≥ 1of the following criteria (based on the guideline 'Childhood Asthma' of the section paediatric pulmonology of the Dutch Society of Paediatricians, 2007):

• Frequent exacerbations requiring OCS use (≥1 in the past year) and/or
• Severe exacerbations requiring hospitalization or ER visits in the past year and/or
• ACQ/ACT scores indicating uncontrolled asthma

In addition to the general criteria, a case with an acute exacerbation (case group B) should meet:

• Asthma treatment Global INitiative of Asthma (GINA) step 2 or higher
• Current severe asthma exacerbation requiring hospitalization

In addition to the general inclusion criteria, a control (controlled asthma) should meet the following criteria:

• Asthma treatment Global INitiative of Asthma (GINA) step 3 or higher
• Lack of severe exacerbations requiring OCS use or hospitalizations or ER visits in the past year
• ACQ/ACT scores indicating well controlled asthma or few reported asthma symptoms during asthma checks in the past year.

Exclusion Criteria:

• Recent use of a course of antibiotics (< 1 month). This will affect the microbiome analyses.

A patient can be re-screened 1 month after the use of the antibiotic treatment has finished.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
controlled asthmatics; moderate-to-severe asthmatic children with good asthma control
uncontrolled asthmatics; moderate-to-severe asthmatic children with poor asthma control / recurrent exacerbations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Saliva and stool microbiome	Differences in 16S rRNA microbial α- and ß- diversities between cases and controls	Baseline
Exhaled breath metabolome	Differences in presence and levels of volatile organic compounds between cases and controls	Baseline

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Age	Age in years	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Sex	Female/Male	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
BMI	kg/m2	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Uncontrolled asthma	according to the Asthma Control Test (ACT) questionnaire (<19 score) and frequent exacerbation within the past 12 months (>n of exacerbation in the past 12 months	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Exacerbations	Exacerbation requiring OCS use, hospitalization or ER visit	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Spirometry	FEV1 (L, percent predicted value)	Baseline
Pediatric Asthma Quality of Life Questionnaire (PAQLQ)	Questionnaire including 23 questions in 3 domains (symptoms, activity limitation, emotional function) and a 7-point scale (7 = not bothered at all; 1 = extremely bothered)	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Atopy	Questionnaire on history of allergic diseases	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Current asthma medication intake	ICS: inhaled corticosteroids, LTRA: leukotriene antagonist, SABA: short-acting beta agonist, LABA: long-acting beta agonist, OCS: oral corticosteroids, Omalizumab, Mepolizumab	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)
Asthma severity	Asthma Control Test (ACT)	Baseline (+ follow-up at 6 and 12 months after baseline inclusion)

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Collaborators: Karolinska Institutet; University of the Basque Country (UPV/EHU); Instituto de Salud Carlos III; Karolinska Institutet, Stockholm, Sweden; University of Maribor, Maribor, Slovenia.; University Children's Hospital, University of Regensburg, Regensburg, Germany; Universidad de La Laguna, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Spain.; Hospital Universitario Donostia, San Sebastián, Spain.; Utrecht University, Utrecht, the Netherlands.

Study record dates

Study Major Dates

• Study Start (Actual): January 12, 2018
• Primary Completion (Actual): October 31, 2019
• Study Completion (Actual): October 31, 2020

Study Registration Dates

• First Submitted: April 21, 2021
• First Submitted That Met QC Criteria: April 26, 2021
• First Posted (Actual): April 29, 2021

Study Record Updates

• Last Update Posted (Actual): April 29, 2021
• Last Update Submitted That Met QC Criteria: April 26, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Keywords: Omics; Systems Pharmacology
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Asthma
• Other Study ID Numbers: NL55788.041.15

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

In case other researchers are interested to work with data that is collected within SysPharmPediA; we kindly request to contact the PI of the study (Prof. dr. A.H. Maitland-van der Zee - a.h.maitland@amsterdamumc.nl)

1. The PIs will refer to an up-to-list of planned publications, which includes ongoing and planned analysis work from SysPharmPediA partners and from those granted access to specific data, to determine potential duplication of work.
2. To understand and draw sound scientific results those groups planning to work on SysPharmPediA data should engage with the SysPharmPediA members who have generated the data in question.
3. A summary of the Data Analysis Plan (DAP) must be attached to the data access request form.
4. If the analysis deviates substantially from the summary DAP or provides results which the SysPharmPediA group feel mis-represent the data, the SysPharmPediA group may raise an objection with the publication concerned.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No