Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial

Elianne J L E Vrijlandt; Georges El Azzi; Mark Vandewalker; Ned Rupp; Thomas Harper; LeRoy Graham; Stanley J Szefler; Petra Moroni-Zentgraf; Ashish Sharma; Sebastian D Vulcu; Ralf Sigmund; Bo Chawes; Michael Engel; Hans Bisgaard

doi:10.1016/S2213-2600(18)30012-2

Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial

Elianne J L E Vrijlandt, Georges El Azzi, Mark Vandewalker, Ned Rupp, Thomas Harper, LeRoy Graham, Stanley J Szefler, Petra Moroni-Zentgraf, Ashish Sharma, Sebastian D Vulcu, Ralf Sigmund, Bo Chawes, Michael Engel, Hans Bisgaard

Department of Clinical Medicine

43 Citations (Scopus)

Abstract

BACKGROUND: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.

METHODS: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.

FINDINGS: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.

INTERPRETATION: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.

FUNDING: Boehringer Ingelheim.

Original language	English
Journal	The Lancet Respiratory Medicine
Volume	6
Issue number	2
Pages (from-to)	127-137
ISSN	2213-2600
DOIs	https://doi.org/10.1016/S2213-2600(18)30012-2
Publication status	Published - Feb 2018

Keywords

Asia
Asthma/drug therapy
Bronchodilator Agents/therapeutic use
Child, Preschool
Double-Blind Method
Europe
Female
Humans
Infant
Male
North America
Tiotropium Bromide/therapeutic use
Treatment Outcome

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10.1016/S2213-2600(18)30012-2

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Vrijlandt, E. J. L. E., El Azzi, G., Vandewalker, M., Rupp, N., Harper, T., Graham, L., Szefler, S. J., Moroni-Zentgraf, P., Sharma, A., Vulcu, S. D., Sigmund, R., Chawes, B., Engel, M., & Bisgaard, H. (2018). Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial. The Lancet Respiratory Medicine, 6(2), 127-137. https://doi.org/10.1016/S2213-2600(18)30012-2

Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms : a randomised, double-blind, placebo-controlled trial. / Vrijlandt, Elianne J L E; El Azzi, Georges; Vandewalker, Mark et al.

In: The Lancet Respiratory Medicine, Vol. 6, No. 2, 02.2018, p. 127-137.

Research output: Contribution to journal › Journal article › Research › peer-review

Vrijlandt, EJLE, El Azzi, G, Vandewalker, M, Rupp, N, Harper, T, Graham, L, Szefler, SJ, Moroni-Zentgraf, P, Sharma, A, Vulcu, SD, Sigmund, R, Chawes, B, Engel, M & Bisgaard, H 2018, 'Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial', The Lancet Respiratory Medicine, vol. 6, no. 2, pp. 127-137. https://doi.org/10.1016/S2213-2600(18)30012-2

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title = "Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial",

abstract = "BACKGROUND: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.METHODS: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.FINDINGS: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.INTERPRETATION: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.FUNDING: Boehringer Ingelheim.",

keywords = "Asia, Asthma/drug therapy, Bronchodilator Agents/therapeutic use, Child, Preschool, Double-Blind Method, Europe, Female, Humans, Infant, Male, North America, Tiotropium Bromide/therapeutic use, Treatment Outcome",

author = "Vrijlandt, {Elianne J L E} and {El Azzi}, Georges and Mark Vandewalker and Ned Rupp and Thomas Harper and LeRoy Graham and Szefler, {Stanley J} and Petra Moroni-Zentgraf and Ashish Sharma and Vulcu, {Sebastian D} and Ralf Sigmund and Bo Chawes and Michael Engel and Hans Bisgaard",

year = "2018",

month = feb,

doi = "10.1016/S2213-2600(18)30012-2",

language = "English",

volume = "6",

pages = "127--137",

journal = "The Lancet Respiratory Medicine",

issn = "2213-2600",

publisher = "The Lancet Publishing Group",

number = "2",

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TY - JOUR

T1 - Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms

T2 - a randomised, double-blind, placebo-controlled trial

AU - Vrijlandt, Elianne J L E

AU - El Azzi, Georges

AU - Vandewalker, Mark

AU - Rupp, Ned

AU - Harper, Thomas

AU - Graham, LeRoy

AU - Szefler, Stanley J

AU - Moroni-Zentgraf, Petra

AU - Sharma, Ashish

AU - Vulcu, Sebastian D

AU - Sigmund, Ralf

AU - Chawes, Bo

AU - Engel, Michael

AU - Bisgaard, Hans

PY - 2018/2

Y1 - 2018/2

N2 - BACKGROUND: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.METHODS: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.FINDINGS: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.INTERPRETATION: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.FUNDING: Boehringer Ingelheim.

AB - BACKGROUND: Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1-5 years with persistent asthmatic symptoms.METHODS: This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1-5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.FINDINGS: Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was -0·080 (95% CI -0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was -0·048 (-0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.INTERPRETATION: To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.FUNDING: Boehringer Ingelheim.

KW - Asia

KW - Asthma/drug therapy

KW - Bronchodilator Agents/therapeutic use

KW - Child, Preschool

KW - Double-Blind Method

KW - Europe

KW - Female

KW - Humans

KW - Infant

KW - Male

KW - North America

KW - Tiotropium Bromide/therapeutic use

KW - Treatment Outcome

U2 - 10.1016/S2213-2600(18)30012-2

DO - 10.1016/S2213-2600(18)30012-2

M3 - Journal article

C2 - 29361462

SN - 2213-2600

VL - 6

SP - 127

EP - 137

JO - The Lancet Respiratory Medicine

JF - The Lancet Respiratory Medicine

IS - 2

ER -

Safety and efficacy of tiotropium in children aged 1-5 years with persistent asthmatic symptoms: a randomised, double-blind, placebo-controlled trial

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Keywords

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