Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial)

a multicentre, randomised, placebo-controlled trial

Chinedu Nwokoro, Hitesh Pandya, Stephen William Turner, Sandra Eldridge, C Griffiths, Tom Vulliamy, David Brendan Price, Marek Sanak, John W Holloway, Rossa Brugha, Lee Koh, Iain Dickson, Clare Rutterford, Jonathan Grigg

Research output: Contribution to journalArticle

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Abstract

BACKGROUND: The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.

METHODS: We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.

FINDINGS: We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.

INTERPRETATION: Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.

FUNDING: Medical Research Council (UK) and National Institute for Health Research.

Original languageEnglish
Pages (from-to)796-803
Number of pages8
JournalThe Lancet. Respiratory medicine
Volume2
Issue number10
Early online date8 Sep 2014
DOIs
Publication statusPublished - 9 Sep 2014

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montelukast
Multicenter Studies
Randomized Controlled Trials
Placebos
Respiratory Sounds
Genotype
Parents
Arachidonate 5-Lipoxygenase
Secondary Care
Intention to Treat Analysis
Incidence
National Institutes of Health (U.S.)
Scotland

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Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial) : a multicentre, randomised, placebo-controlled trial. / Nwokoro, Chinedu; Pandya, Hitesh; Turner, Stephen William; Eldridge, Sandra; Griffiths, C; Vulliamy, Tom; Price, David Brendan; Sanak, Marek; Holloway, John W; Brugha, Rossa; Koh, Lee; Dickson, Iain; Rutterford, Clare; Grigg, Jonathan.

In: The Lancet. Respiratory medicine, Vol. 2, No. 10, 09.09.2014, p. 796-803.

Research output: Contribution to journalArticle

Nwokoro, C, Pandya, H, Turner, SW, Eldridge, S, Griffiths, C, Vulliamy, T, Price, DB, Sanak, M, Holloway, JW, Brugha, R, Koh, L, Dickson, I, Rutterford, C & Grigg, J 2014, 'Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial): a multicentre, randomised, placebo-controlled trial', The Lancet. Respiratory medicine, vol. 2, no. 10, pp. 796-803. https://doi.org/10.1016/S2213-2600(14)70186-9
Nwokoro, Chinedu ; Pandya, Hitesh ; Turner, Stephen William ; Eldridge, Sandra ; Griffiths, C ; Vulliamy, Tom ; Price, David Brendan ; Sanak, Marek ; Holloway, John W ; Brugha, Rossa ; Koh, Lee ; Dickson, Iain ; Rutterford, Clare ; Grigg, Jonathan. / Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial) : a multicentre, randomised, placebo-controlled trial. In: The Lancet. Respiratory medicine. 2014 ; Vol. 2, No. 10. pp. 796-803.
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abstract = "BACKGROUND: The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.METHODS: We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.FINDINGS: We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1{\%}) children. Primary outcome data were available for 1308 (96{\%}) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95{\%} CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95{\%} CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.INTERPRETATION: Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.FUNDING: Medical Research Council (UK) and National Institute for Health Research.",
author = "Chinedu Nwokoro and Hitesh Pandya and Turner, {Stephen William} and Sandra Eldridge and C Griffiths and Tom Vulliamy and Price, {David Brendan} and Marek Sanak and Holloway, {John W} and Rossa Brugha and Lee Koh and Iain Dickson and Clare Rutterford and Jonathan Grigg",
note = "Acknowledgments This study was funded by the Medical Research Council (UK), in partnership with the National Institute for Health Research (reference number 08/43/03). We thank independent members of the trial steering committee (listed in appendix), centres responsible for primary care recruitment (appendix), and the National Institute for Health Research (NIHR) Medicines for Children Network for helping with recruitment.",
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TY - JOUR

T1 - Intermittent montelukast in children aged 10 months to 5 years with wheeze (WAIT trial)

T2 - a multicentre, randomised, placebo-controlled trial

AU - Nwokoro, Chinedu

AU - Pandya, Hitesh

AU - Turner, Stephen William

AU - Eldridge, Sandra

AU - Griffiths, C

AU - Vulliamy, Tom

AU - Price, David Brendan

AU - Sanak, Marek

AU - Holloway, John W

AU - Brugha, Rossa

AU - Koh, Lee

AU - Dickson, Iain

AU - Rutterford, Clare

AU - Grigg, Jonathan

N1 - Acknowledgments This study was funded by the Medical Research Council (UK), in partnership with the National Institute for Health Research (reference number 08/43/03). We thank independent members of the trial steering committee (listed in appendix), centres responsible for primary care recruitment (appendix), and the National Institute for Health Research (NIHR) Medicines for Children Network for helping with recruitment.

PY - 2014/9/9

Y1 - 2014/9/9

N2 - BACKGROUND: The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.METHODS: We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.FINDINGS: We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.INTERPRETATION: Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.FUNDING: Medical Research Council (UK) and National Institute for Health Research.

AB - BACKGROUND: The effectiveness of intermittent montelukast for wheeze in young children is unclear. We aimed to assess whether intermittent montelukast is better than placebo for treatment of wheeze in this age group. Because copy numbers of the Sp1-binding motif in the arachidonate 5-lipoxygenase (ALOX5) gene promoter (either 5/5, 5/x, or x/x, where x does not equal 5) modifies response to montelukast in adults, we stratified by this genotype.METHODS: We did this multicentre, parallel-group, randomised, placebo-controlled trial between Oct 1, 2010, and Dec 20, 2013, at 21 primary care sites and 41 secondary care sites in England and Scotland. Children aged 10 months to 5 years with two or more wheeze episodes were allocated to either a 5/5 or 5/x+x/x ALOX5 promoter genotype stratum, then randomly assigned (1:1) via a permuted block schedule (size ten), to receive intermittent montelukast or placebo given by parents at each wheeze episode over a 12 month period. Clinical investigators and parents were masked to treatment group and genotype strata. The primary outcome was number of unscheduled medical attendances for wheezing episodes. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01142505.FINDINGS: We randomly assigned 1358 children to receive montelukast (n=669) or placebo (n=677). Consent was withdrawn for 12 (1%) children. Primary outcome data were available for 1308 (96%) children. There was no difference in unscheduled medical attendances for wheezing episodes between children in the montelukast and placebo groups (mean 2·0 [SD 2·6] vs 2·3 [2·7]; incidence rate ratio [IRR] 0·88, 95% CI: 0·77-1·01; p=0·06). Compared with placebo, unscheduled medical attendances for wheezing episodes were reduced in children given montelukast in the 5/5 stratum (2·0 [2·7] vs 2·4 [3·0]; IRR 0·80, 95% CI 0·68-0·95; p=0·01), but not in those in the 5/x+x/x stratum (2·0 [2·5] vs 2·0 [2·3]; 1·03, 0·83-1·29; p=0·79, pinteraction=0·08). We recorded one serious adverse event, which was a skin reaction in a child allocated to placebo.INTERPRETATION: Our findings show no clear benefit of intermittent montelukast in young children with wheeze. However, the 5/5 ALOX5 promoter genotype might identify a montelukast-responsive subgroup.FUNDING: Medical Research Council (UK) and National Institute for Health Research.

U2 - 10.1016/S2213-2600(14)70186-9

DO - 10.1016/S2213-2600(14)70186-9

M3 - Article

VL - 2

SP - 796

EP - 803

JO - The Lancet. Respiratory medicine

JF - The Lancet. Respiratory medicine

SN - 2213-2600

IS - 10

ER -