Martinez 2011.

Methods	This 44‐week, randomised, double‐blind, placebo‐controlled, 4‐treatment trial used a 2‐by‐2 factorial design (2 arms were not relevant to the review and were not included) The study was conducted at 5 clinical centres in the USA
Participants	Population Participants were recruited from 5 clinical centres 288 were randomised to 1 of 4 groups, of which 143 contributed to this analysis (71 combined group, 72 daily group) Aged between 5 and 18 years. Mean age was 11.2. 56.6% were male Baseline asthma severity Mean dose of budesonide: NR (≤ 160 μg daily equivalent) Mean FEV1 (pre‐BD): 101.5 (11.7) active, 100.1 (10.8) control Mean PEFR: 321.0 (113.1) active, 301.8 (125.9) control Approx 5% were taking long‐acting beta‐agonists. In the previous year, 82% had taken ICS, 10% had taken a leukotriene inhibitor, 1% had taken salmeterol and none had taken theophylline or sodium cromoglycate. Participants were required to have had 1 or 2 exacerbations in the previous year 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 mcg 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
Interventions	Run‐in period Four‐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 mcg BID + placebo BID inhaler and albuterol as rescue for exacerbations Study arm: maintenance inhaler of beclomethasone 40 mcg BID + 40 mg beclomethasone BID and albuterol as rescue for exacerbations (combined group) Other medications allowed Low‐dose ICS or other monotherapy in previous 8 weeks. ICS > 160 mcg beclomethasone equivalent not allowed (daily beclomethasone group) Definition of exacerbation: use of more than 12 puffs of albuterol in 24 hours (excluding preventive use before exercise), peak expiratory flow < 70% of consecutive days, peak expiratory flow < 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, fractional exhaled nitric oxide (FENO), symptom diaries and control and quality of life questionnaires, linear growth
Notes	Funding source: grants from the National Heart, Lung and Blood Institute; TEVA Pharmaceutical Industries Ltd provided beclomethasone dipropionate‐HFA and placebo Study identifiers: TREXA, NCT00394329 The study used a factorial design, which had implications for the independence of treatments and subsequent analysis of results
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"A computer‐generated randomisation sequence, stratified by clinical centre and age group, was used to randomly assign participants to one of four treatment groups" ‐ "The Data Coordinating Center (DCC; Penn State Hershey College, PA, USA) generated the random allocation sequence"
Allocation concealment (selection bias)	Low risk	"The DCC had no interaction with participants, but was responsible for management of data and statistical analyses" ‐ "A pharmaceutical vendor was selected to package, code, and ship the drug packets to each clinical centre. When a clinical centre deemed that a participant was eligible for randomisation, the clinical centre coordinator logged onto the secure CARE Network website, entered the relevant information to confirm participant eligibility, and received the appropriate drug packet code to be assigned to the participant"
Blinding (performance bias and detection bias) All outcomes	Low risk	"double‐blind, placebo‐controlled trial" ‐ "Drug groups were labelled as A, B, C, and D to mask statisticians to treatment group during the first complete run‐through of data analyses"
Incomplete outcome data (attrition bias) All outcomes	Low risk	Withdrawals from the study were relatively low and even between the 2 groups included in this review: 11.3% in the intervention group (double ICS) and 12.5% in the control group (stable ICS)
Selective reporting (reporting bias)	Low risk	The study was prospectively registered (NCT00394329) and results were well reported in accordance with the protocol