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Methods |
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Participants |
Population 290 participants were randomised; 98 participants experienced an exacerbation and contributed to the analysis. Participants were 13 years of age or older; mean age was 32 years; 28% were male; 86% were non-smokers, and 14% were ex-smokers of fewer than 10 pack-years. Inclusion criteria Age ≥ 13 years; documentation of the diagnosis of asthma within the previous year based on FEV1 reversibility postbronchodilator, methacholine provoking a fall in FEV1 and/or diurnal PEF variability; at least 1 previous asthma exacerbation (with mean duration from recent exacerbation to visit 1 of 131 day); stable dose of ICS (< 1200 μg/d of beclomethasone or equivalent twice daily) for 1 month before visit 1 Exclusion criteria Severe or near-fatal asthma; current smokers and ex-smokers > 10 pack-years; baseline use of LABA; pregnant or lactating women; women of childbearing potential not on effective birth control; exacerbation due to chronic sinusitis; hospitalisation in previous 3 months; respiratory tract infection ≤ 1 month before visit 1 Baseline asthma severity See Table 1. |
Interventions |
Run-in period 3- to 6-week period whereby participants using other forms of inhalers were switched to budesonide Turbuhaler at an equivalent dose and placed on a twice-daily dose regimen Study period Control arm: maintenance inhaler of budesonide (100, 200, or 400 μg twice daily) + placebo inhaler twice daily for exacerbations Study arm: maintenance inhaler of budesonide + inhaler with budesonide to double dose of ICS (200, 400, or 800 μg twice daily) for exacerbations Other medications allowed Terbutaline sulfate inhaler as rescue medication; theophylline; anticholinergics; nasal corticosteroids |
Outcomes |
Primary outcome The proportion of participants with treatment failure as judged by the need for treatment with oral methylprednisolone or an unscheduled visit to a physician or medical emergency department due to asthma or unstable asthma after 14 days of treatment Secondary outcomes None |
Notes |
Funding source: AstraZeneca Canada Inc Funder role: author with AstraZeneca affiliation involved in drafting the protocol and manuscript and not on the trial steering committee or involved in designing the trial. No other details about funder's role reported. Registration: not registered Ethics approval: approved by institutional ethics committees at each research site Consent to participate: reports all participants provided written informed consent prior to enrolment Trial reporting vs review analysis: study reports need for oral steroids only for those who took their study inhaler, which is suitable for the per protocol treatment failure outcome. To include in the ITT treatment failure outcome, we used the same number of events with the full population denominators. |
Methods |
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Participants |
Population 213 participants were randomised to 3 treatment groups; 47 participants experienced an exacerbation; Groups 2 and 3 accounted for 36 exacerbations and contributed to the analysis. Participants were 18 to 65 years of age; mean age was 39 years; 47% were male; 70% were non-smokers, 22% ex-smokers, and 8% smokers. Inclusion criteria Age 18 to 65 years; baseline FEV1 ≥ 50% and ≤ 90% of predicted values; daily PEF variability ≥ 20% on at least 4 different days during a 2-week period; daily requirement of inhaled beta-2 agonist; presence of wheeze, cough, chest tightness, shortness of breath that interfered with normal daily activity during a 2-week pre-study observation period Exclusion criteria Treatment with a high dose of beclomethasone (> 1000 μg/d); history of seasonal asthma Baseline asthma severity See Table 1. |
Interventions |
Run-in period 4-week pre-study treatment period whereby participants were asked to inhale budesonide 800 μg twice daily Study period Control arm (Group 3): maintenance inhaler of budesonide 100 μg twice daily + placebo inhaler 4 times daily for exacerbations (total 200 μg per day) Study arm (Group 2): maintenance inhaler of budesonide 100 μg twice daily + budesonide 200 μg 4 times daily for exacerbations (total 1000 μg per day) Other medications allowed Inhaled beta-2 agonist; LABA; theophylline; anticholinergics |
Outcomes |
Primary outcome: not specified Secondary outcomes
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Notes |
Funding source: Astra Farmaceutici Funder role: no details about funder's role reported. Registration: not registered Ethics approval: approved by ethics committees at all clinics Consent to participate: reports all participants provided informed consent Trial reporting vs review analysis: reports the number of participants having exacerbations defined by PEF reduction and the number of days participants had exacerbations and required OCS, but not the number of participants. Cannot be included in either treatment failure outcome (ITT and per protocol) |
Methods |
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Participants |
Population 28 participants were randomised; 18 pairs of exacerbations in both cross-over periods contributed to the analysis. Participants were 6 to 14 years old; mean age was 8.2 years; 67% were male; smoking status not reported as paediatric trial (likely all non-smokers). Inclusion criteria Age 6 to 14 years; currently taking inhaled corticosteroid prophylaxis (not exceeding 800 μg/d) Exclusion criteria Taking oral corticosteroids, sodium cromoglycate, or LABA; any previous intensive care admission, recent inpatient care for asthma, or any change in dose of inhaled corticosteroids in the past 2 months; any concurrent illness Baseline asthma severity See Table 1. |
Interventions |
Run-in period 2-week run-in period during which participants were required to use beclomethasone via MDI and spacer and a salbutamol MDI. Participants previously taking budesonide were switched to beclomethasone, but the child's daily dose was not changed. Study period Sequence 1: maintenance beclomethasone inhaler (< 800 μg/d) + placebo inhaler for exacerbation 1, followed by maintenance beclomethasone inhaler + inhaler with beclomethasone to double dose of ICS for exacerbation 2 Sequence 2: maintenance beclomethasone inhaler + inhaler with beclomethasone to double dose of ICS for exacerbation 1. Maintenance beclomethasone inhaler (< 800 μg/d) + placebo inhaler for exacerbation 2 Other medications allowed Salbutamol MDI |
Outcomes |
Primary outcome: not specified Secondary outcomes
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Notes |
Funding source: New Zealand Asthma Society Funder role: no details about funder's role reported Registration: not registered Ethics approval: approved by Southern Regional Health Authority ethics committee Consent to participate: reports all participants and their parent provided informed consent Trial reporting vs review analysis: study reports need for oral steroids only for those who took their study inhaler, which is suitable for the per protocol treatment failure outcome. To include in the ITT treatment failure outcome, we used the same number of events with the full population denominators. |
Methods |
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Participants |
Population 390 participants were randomised; 207 experienced an exacerbation and contributed to the analysis. Participants were 16 years or older; mean age was 49 years; 33% were male; 61% were non-smokers, 36% ex-smokers, and 3% smokers. Inclusion criteria Age ≥ 16 years; clinical diagnosis of asthma; taking an inhaled corticosteroid (100 to 2000 μg/d) on a regular basis; previous course of oral corticosteroids or doubled dose of inhaled corticosteroid in the previous 12 months for treatment or prevention of an asthma exacerbation Exclusion criteria History of smoking > 10 pack-years; unstable asthma during a 2-week run-in period Baseline asthma severity See Table 1. |
Interventions |
Run-in period 2-week period whereby participants continued their usual dose of inhaled corticosteroid and recorded morning peak flow and daytime symptom scores to ensure asthma stability Study period Control arm: maintenance inhaled corticosteroid (100 to 2000 μg/d) + identical placebo inhaler for exacerbations Study arm: maintenance inhaled corticosteroid (100 to 2000 μg/d) + identical inhaler with corticosteroid to double dose of ICS for exacerbations Participants were to use study inhaler for 14 days in addition to usual treatment when peak flow or symptoms deteriorated. Other medications allowed Not specified |
Outcomes |
Primary outcome Proportion of participants who needed prednisolone in each group Secondary outcomes
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Notes |
Funding source: NHS Executive (through National Asthma Campaign) Funder role: provided critical review of the protocol but no role in study design, data collection, data analysis, data interpretation, or writing of the report Registration: not registered Ethics approval: approved by Nottingham City Hospital ethics committee Consent to participate: reports all participants provided written informed consent Trial reporting vs review analysis: study reports need for oral steroids separately for those who took their study inhaler (suitable for the per protocol treatment failure outcome) and all randomised participants (suitable for the ITT treatment failure outcome) |
Methods |
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Participants |
Population 254 participants were randomised; 168 participants experienced an exacerbation, with 68 resulting in treatment failure. Participants were 5 to 11 years old; mean age was 8 years; 64% were male; 38% had tobacco smoke exposure. Inclusion criteria 5 to 11 years of age; doctor-diagnosed asthma mild to moderate; persistent asthma and had had at least 1 asthma exacerbation treated with systemic glucocorticoids in the previous year Exclusion criteria Asthma too severe (> 5 exacerbations in the previous year that had been treated with systemic glucocorticoids or a history of life-threatening asthma) Baseline asthma severity See Table 1. |
Interventions |
Run‐in period 4 weeks to establish adherence of 1) more than 75% to the use of open-label trial medication (fluticasone propionate at a dose of 44 μg per inhalation, 2 inhalations twice daily); 2) daily completion of an electronic diary; and 3) asthma control (C-ACT score > 19) at the randomisation visit Study period Control arm: maintenance inhaler of budesonide (88 μg twice daily) + control inhaler budesonide (88 μg twice daily) for exacerbations for 7 days at the early signs of loss of asthma control Study arm: maintenance inhaler of budesonide (88 μg twice daily) + study inhaler budesonide (440 μg twice daily) for exacerbations for 7 days at the early signs of loss of asthma control Other medications allowed Albuterol sulfate 90 μg/inhalation; rescue therapy oral prednisone will be administered for the treatment of impending episodes of severe asthma when bronchodilator therapy is inadequate |
Outcomes |
Primary outcome Rate of severe asthma exacerbations treated with systemic glucocorticoids during the blinded treatment period Secondary outcomes Time to first asthma exacerbation, treatment failure, area under the curve for symptom scores during yellow-zone episodes, albuterol use during yellow-zone episodes, unscheduled emergency department or urgent care visits for asthma, hospitalisations for asthma, total glucocorticoid exposure (inhaled glucocorticoids plus systemic glucocorticoids), and linear growth. Exploratory outcomes included peak expiratory flows and number of days of asthma control. |
Notes |
Funding source: National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) Funder role: Program Officers from NHLBI serve on the steering committee for oversight of the interests/priorities of the NIH as well as applicable regulations. GlaxoSmithKline, who donated the trial medication, was not involved in trial design, data collection or interpretation. They were given the opportunity to read the draft manuscript, but did not provide any comments. Registration: NCT02066129 Ethics approval: approved by AsthmaNet steering committee, protocol review committee, and data and safety monitoring board Consent to participate: reports parents or legal guardians provided written informed consent, and children provided assent Trial reporting vs review analysis: number of participants needing oral steroids reported for the full population (suitable for the ITT treatment failure outcome). Study reports the number of treatment failures out of total number of yellow-zone episodes and the number of participants with at least 1 yellow-zone episode (i.e. those who took their study inhaler; 80 and 88), but not the number of participants in that population who needed oral steroids, so data could not be included in the per protocol treatment failure outcome. Also reports mean number per year (primary method of analysis in the study), which could be reported narratively with the results |
Methods |
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Participants |
Population 288 participants were randomised to 1 of 4 groups, of which 143 contributed to this analysis (71 combined group, 72 daily group). Participants were aged between 5 and 18 years; mean age was 11.2 years; 56.6% were male; smoking status not reported, as paediatric trial (likely all non-smokers). Inclusion criteria Children and adolescents 6 to 18 years of age, history of mild persistent asthma during the previous 2 years, qualified for interruption or discontinuation of controller treatment because their illness was well-controlled (as defined in US National Asthma Education and Prevention Program asthma care guidelines), naive to controller treatment with a history of 1 to 2 exacerbations in the previous year, those treated for the previous 8 weeks with monotherapy other than inhaled corticosteroids, and those whose illness was controlled for the previous 8 weeks on low-dose corticosteroids as monotherapy (≤ 160 μg daily with a beclomethasone equivalent) Exclusion criteria Pre-bronchodilator FEV1 < 60% predicted at the first visit; admitted to hospital for asthma in the previous year; any asthma exacerbation in the previous 3 months or more than 2 in the previous year; history of life-threatening asthma exacerbations that required intubation or mechanical ventilation, or that resulted in a hypoxic seizure Baseline asthma severity See Table 1. |
Interventions |
Run-in period 4-week run-in period, during which participants received twice-daily treatment with 1 puff of beclomethasone dipropionate and rescue treatment with a placebo inhaler added to rescue albuterol every time they needed albuterol Study period Control arm: maintenance inhaler of beclomethasone 40 μg twice daily + placebo twice-daily inhaler and albuterol as rescue for exacerbations Study arm: maintenance inhaler of beclomethasone 40 μg twice daily + 40 mg beclomethasone twice daily and albuterol as rescue for exacerbations (combined group) Other medications allowed Low-dose ICS or other monotherapy in previous 8 weeks. ICS > 160 μg beclomethasone equivalent was not allowed (daily beclomethasone group). Definition of exacerbation: use of more than 12 puffs of albuterol in 24 hours (excluding preventive use before exercise), PEF < 70% of consecutive days, PEF < 50% of reference value despite relief treatment, emergency room visit due to worsening of asthma symptoms |
Outcomes |
Primary outcome Time to first exacerbation that required treatment with prednisone Secondary outcomes Spirometry FEV1, FENO, symptom diaries and control and quality of life questionnaires, linear growth |
Notes |
Funding source: grants from the National Heart, Lung and Blood Institute (NHLBI); TEVA Pharmaceutical Industries Ltd provided beclomethasone dipropionate-HFA and placebo Funder role: the NHLBI established and managed the independent data and safety monitoring board. Reports that the authors had complete independence over the conduct, integrity, and publication of the study Registration: NCT00394329 Other study identifier(s): TREXA Ethics approval: approved by local institutional review boards Consent to participate: reports that parents or guardians provided written informed consent, and children provided verbal or written assent Trial reporting vs review analysis: study design implies that everyone took their study inhaler, so there is no difference between the all-randomised (the ITT treatment failure outcome) and treated population (the per protocol treatment failure outcome). The study used a factorial design, which had implications for the independence of treatments and subsequent analysis of results. |
Methods |
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Participants |
Population 403 participants were randomised; 94 participants experienced an exacerbation, for a total of 121 exacerbations that contributed to the analysis. Participants were 16 years of age or older; mean age was 56 years; 32% of participants were male; 69% were never-smokers, 21% were ex-smokers, and 10% were smokers. Inclusion criteria: age > 16 years, stable asthma, treated with ICS (200 to 1000 μg budesonide or equivalent), taken a course of oral corticosteroid or doubled dose of ICS in the previous 12 months but not in the preceding 4 weeks Exclusion criteria: > 20 pack-year smoking history, other clinically significant medical conditions, pregnant or lactating Baseline asthma severity See Table 1. |
Interventions |
Run-in period: 2-week period whereby participants continued their usual dose of inhaled corticosteroid and recorded morning peak flow and daytime symptom scores to ensure asthma stability Study period Control arm: maintenance inhaled corticosteroid (200 to 1000 μg/d) + identical placebo inhaler for exacerbations Study arm: maintenance inhaled corticosteroid (200 to 1000 μg/d) + identical inhaler with corticosteroid to quadruple dose of ICS for exacerbations Participants were to use study inhaler for 14 days in addition to usual treatment when peak flow or symptoms deteriorated. Other medications allowed Not specified |
Outcomes |
Primary outcome Number of participants who had exacerbations of asthma treated with oral corticosteroids (ITT analysis) Secondary outcomes Number of participants who started the study inhaler and went on to require treatment with oral corticosteroids (treated population) |
Notes |
Funding source: Asthma UK Funder role: not reported Registration: ISRCTN46018181 Ethics approval: approved by Nottingham Research Ethics Committee and relevant Research and Development departments in Nottinghamshire and Derbyshire Consent to participate: reports that participants provided written informed consent Trial reporting vs review analysis: study reports the need for oral steroids separately for those who took their study inhaler (suitable for the per protocol treatment failure outcome) and all randomised participants (suitable for the ITT treatment failure outcome) |
Methods |
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Participants |
Population 22 participants were randomised; 18 experienced an exacerbation in both phases and contributed to the analysis. Participants were 18 years of age or older; mean age was 46.5 years; 40.9% were male; smoking status not reported. Inclusion criteria: consenting adults ≥ 18 years of age; physician-diagnosed asthma; reversible airways obstruction evidenced by (i) ≥ 15% reversibility in FEV1; or (ii) ≥ 20% variability in PEF over the 2- to 4-week run-in period (% variability defined as highest PEF–lowest PEF/highest PEF 3100); assessment by investigator that ongoing treatment with ICS was appropriate; participant did not meet any exclusion criteria Exclusion criteria: mild asthma when exacerbations with PEF < 80% of best were thought to be unlikely during the course of the study; demonstration by potential volunteers of erroneous or falsified PEF entries during a 2– to 4-week reliability check; reliability was determined by comparison of self-recorded PEF with actual PEF as recorded on personal Vitalograph 2110 electronic PEF/FEV1 diaries (Vitalograph, Buckingham, UK); participants were unaware that the diaries recorded all PEF values; asthma requiring continuous oral steroids or immunosuppressive-type therapies; concomitant use of LABA, theophylline, or LTRA did not exclude individuals from participating Baseline asthma severity See Table 1. |
Interventions |
Run-in period: 2- to 4-week run-in period to ensure inclusion criteria, demonstrate competence in taking ICS via spacer, and ensure that asthma was stable Study period Control phase: maintenance ICS inhaler (usual type/dose) + same number of placebo inhalations for 14 days during exacerbations Study phase: maintenance ICS inhaler (usual type/dose) + same number of ICS inhalations for 14 days during exacerbations Participants also received placebo oral steroids for 7 days during these phases and their usual SABA inhaler. Other medications allowed: concomitant use of LABA, theophylline, or LTRA was not exclusionary |
Outcomes |
Treatment failure rates; PEF at endpoint; adverse events. The endpoint was assessed at 7 days if no treatment failure, or at time of treatment failure in the event of failure. Outcomes were not defined as primary and secondary. |
Notes |
Funding source: Asthma Foundation of Queensland Funder role: no details about funder's role reported Registration: not registered Ethics approval: approved by institutional ethics committees of the participating unit Consent to participate: reports that all participants had to give consent Trial reporting vs review analysis: study population is defined by those who took the study inhaler in order to have matched pairs for analysis, so the same data were used in both treatment failure outcomes (ITT and per protocol). |
Methods |
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Participants |
Population 251 children were randomised; 187 participants experienced an exacerbation and contributed to the analysis. Participants were between 3 and 14 years old; 38% of children were 3 to 5 years of age; 43% between 6 and 11 years; and 19% between 12 and 14 years. 60% of participants were male. Smoking status not reported (likely all never-smokers, as paediatric study). Inclusion criteria: informed consent obtained from parent/carer and assent from child when possible. Age between 3 and 14 years, doctor diagnosis of asthma and taking regular ICS (minimum 125 μg fluticasone/d), at least 1 exacerbation in previous 12 months requiring admission to hospital, presentation to emergency department + use of oral steroids Exclusion criteria: children with comorbidities that may affect growth; children with other respiratory illness; unable to obtain informed consent; unable to speak English Baseline asthma severity See Table 1. |
Interventions |
Run-in period: 3-month run-in period including 2 weeks of peak flow measurement Study period Control arm: maintenance fluticasone inhaler at child's usual dose + placebo inhaler to keep dose stable during exacerbations Study arm: maintenance fluticasone inhaler at child's usual dose + study puffer to double dose during exacerbations. Continued until back to baseline Other medications allowed: not reported |
Outcomes |
Primary outcome: use of oral steroid rescue and admission to hospital Secondary outcomes: growth over 12 months; time off work for parents, school for children; time for peak flow to return to baseline |
Notes |
Funding source: Asthma Foundation Queensland; RCH Foundation Brisbane; fluticasone propionate, placebo, and peak flow metres provided by GlaxoSmithKline Funder role: details about funder's role reported. Registration: ACTRN12605000631606 Ethics approval: approved by Royal Children's Hospital & Health Service District (see registration details) Consent to participate: reports parents or carers provided informed consent, and children provided assent where possible Trial reporting vs review analysis: study reports need for oral steroids as a percentage with unclear denominators (43.8% increased group, 50.2% usual group). Number of events calculated using those who started the inhaler as the denominator (93 and 94), giving 41 and 47 events for the per protocol treatment failure outcome. To include in ITT treatment failure outcome, the same number of events was used with the number of participants in the full population. |
d = day.
FEF = forced expiratory flow.
FENO = fractional exhaled nitric oxide.
FEV1 = forced expiratory volume in one second.
FVC = forced vital capacity.
HFA = hydrofluoroalkane
ICS = inhaled corticosteroids.
ITT = intention-to-treat.
LABA = long-acting beta agonist.
LTRA = leukotriene receptor antagonist.
MDI = metered dose inhaler.
NR = not reported.
OCS = oral corticosteroids
PEF = peak expiratory flow.
PEFR = peak expiratory flow rate.
SABA = short-acting beta-agonist.
[ACTRN: ACTRN12605000631606]