Bronchodilators for Wheeze in Young Children Presenting to Primary Care: a Randomised, Placebo-controlled, Multicentre, Parallel Group Trial (KIWI)

Ten percent of infants are prescribed short-acting bronchodilators (i.e. salbutamol) for wheezing every year, yet evidence to support this treatment in children younger than two years old is scarce. The aim of this study is to evaluate the effectiveness and safety of salbutamol for treatment of wheezing in young children who present to their primary care physician.

In this study, the investigators will compare the effect of a 7-day treatment with salbutamol to the effect of 7-day treatment with a placebo. The main effect will be measured by evaluating a parent-reported symptom score. Additionally, the investigators will look at the presence of wheeze after 5 days, time to recovery, adverse events, healthcare utilisation, medication prescriptions, cost-effectiveness, and parent satisfaction with treatment.

Study Overview

• Status: Withdrawn
• Conditions: Wheezing
• Intervention / Treatment: Drug: Salbutamol; Drug: Placebo

Detailed Description

BACKGROUND: Worldwide, 30% of all infants and young children experience an episode of wheezing (Matricaldi et al. 2008; Mallol at al. 2010; Martinez et al. 1995). Currently, there is no evidence to underpin the management of these children. National Belgian and Dutch primary care professional guidelines propose 'a trial of treatment' with short acting bronchodilators (i.e. salbutamol) for wheezing children below the age of six years and to evaluate treatment effect after 1 to 2 weeks, but convincing evidence is lacking (Chavasse et al. 2002).

The effect of salbutamol has been studied well in children with proven asthma and is considered the first-line treatment in all patients in international asthma guidelines. However, trial findings of children with asthma are not applicable to primary care infants and young children with acute wheeze for several reasons; the anatomy and physiology in younger children differs significantly from those in older children and many infants and young children with an acute episode of wheezing do not experience further wheezing episodes later in life. As a result, it is at present unclear whether salbutamol inhalation therapy confers any benefit in young children who wheeze.

OBJECTIVE: To evaluate the (cost-)effectiveness of salbutamol inhalations (4x200μg for 7 days) versus placebo in children aged 6-24 months presenting to their primary care physician with wheezing.

DESIGN: A primary care based, randomised, placebo-controlled, multicentre, parallel group trial in 40 general practices and community paediatric practices in Belgium and the Netherlands.

• Study Type: Interventional
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 2 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Presenting to their primary care physician because of wheezing as confirmed by clinical examination (chest auscultation)
• A baseline score of 7 or higher on a parent-reported respiratory symptom score

Exclusion Criteria:

• Prematurity (<37 weeks)
• Major congenital malformations
• Pre-existing pulmonary disease as diagnosed by a paediatrician
• Continuous use of inhalation medication
• Physician visit because of wheezing in previous two weeks
• Use of inhalation medication in the previous two weeks
• Wheezing as a result of upper airway obstruction (i.e. laryngitis subglottica/pseudocroup)
• Severe illness requiring inhalation medication, prescription of antibiotics, or hospital referral during the consultation of inclusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Salbutamol; Salbutamol inhalation 4x200ug daily for 7 days, delivered using a Babyhaler	Drug: Salbutamol; Salbutamol will be delivered using a Babyhaler spacer device. Ventolin will be used, brandname for Salbutamol sulfate. Ventolin contains the propellant HFA 134a.; Other Names: Ventolin; Bronchodilator; β2-adrenoceptor agonist; Salbutamol sulfate
Placebo Comparator: Placebo; Placebo 4 x 2 inhalations daily for 7 days, delivered using a Babyhaler	Drug: Placebo; The placebo will be delivered using a Babyhaler spacer device. The placebo will contain only the propellant HFA 134a.; Other Names: Mock inhaler

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Course of the parent reported respiratory symptom score	Scores on an arbitrary ordinal scale of 0 to 3 (0= no symptoms, 1= a bit (mild), 2= quite bad (moderate), 3= very bad (severe)) are recorded by parents for wheeze, cough and difficulty in breathing for both day and night, giving a maximum possible symptom score of 18 for each day.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse effects		7 days
Time to recovery	Recovery defined as a respiratory symptom score of 5 or lower indicating only trivial symptoms	28 days
Health care resource use	Primary care physician re-consultations, medication prescriptions (e.g. antibiotics), specialist consultations and hospital admissions	28 days
Persistent wheezing on auscultation on day 5	To maximise objectivity, lung sounds will be recorded (digital stethoscope) and evaluated by an expert panel at a later date	on day 5
Day of parent reported recovery	The number of the day on which parents felt their child was recovered	28 days
Parent satisfaction with care	Single direct question "How satisfied are you with the treatment with study medication on a scale from 1 to 4 (very satisfied, satisfied, unsatisfied, very unsatisfied)?	on day 28
Out-of-pocket expenses	Parent reported expenses for over-the-counter medication, additional travel, parking and child care, recorded in the study diary	14 days
Parent productivity losses	Assessed using the iMTA Productivity Cost questionnaire (iPCQ)	14 days

Collaborators and Investigators

• Sponsor: UMC Utrecht
• Collaborators: KU Leuven; Maastricht University Medical Center; Universiteit Antwerpen; Université de Liège
• Investigators: Principal Investigator: Roger AMJ Damoiseaux, Professor, Julius Center, UMC Utrecht; Principal Investigator: Ann van den Bruel, Professor, KU Leuven

Publications and helpful links

General Publications

• Martinez FD, Wright AL, Taussig LM, Holberg CJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995 Jan 19;332(3):133-8. doi: 10.1056/NEJM199501193320301.
• Matricardi PM, Illi S, Gruber C, Keil T, Nickel R, Wahn U, Lau S. Wheezing in childhood: incidence, longitudinal patterns and factors predicting persistence. Eur Respir J. 2008 Sep;32(3):585-92. doi: 10.1183/09031936.00066307. Epub 2008 May 14.
• Mallol J, Garcia-Marcos L, Sole D, Brand P; EISL Study Group. International prevalence of recurrent wheezing during the first year of life: variability, treatment patterns and use of health resources. Thorax. 2010 Nov;65(11):1004-9. doi: 10.1136/thx.2009.115188. Epub 2010 Sep 20.
• Chavasse R, Seddon P, Bara A, McKean M. Short acting beta agonists for recurrent wheeze in children under 2 years of age. Cochrane Database Syst Rev. 2002;2002(3):CD002873. doi: 10.1002/14651858.CD002873.

Study record dates

Study Major Dates

• Study Start (Anticipated): September 1, 2021
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: September 3, 2020
• First Submitted That Met QC Criteria: October 8, 2020
• First Posted (Actual): October 12, 2020

Study Record Updates

• Last Update Posted (Actual): July 23, 2021
• Last Update Submitted That Met QC Criteria: July 16, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: Primary care; General practice; Bronchodilators; Salbutamol; Wheeze; Viral respiratory illnesses; Pre-school age children; Therapeutic trial
• Additional Relevant MeSH Terms: Signs and Symptoms, Respiratory; Respiratory Sounds; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Adrenergic beta-2 Receptor Agonists; Adrenergic beta-Agonists; Tocolytic Agents; Albuterol; Bronchodilator Agents
• Other Study ID Numbers: NL72651

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: We will make our data accessable for verification and future research (other researchers / spin-off projects), yet these will be shared under restrictions. Data cannot be reused without consulting the research team.
• IPD Sharing Time Frame: Data will only be accessable after publication of trial results. Data will be stored for at least 25 years.
• IPD Sharing Access Criteria: On request, after approval of principle investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes