Sher 2017

Methods	A randomised, double‐blind, multi‐centre, parallel‐group study carried out over 12 weeks
Participants	Population: 728 adults and older children (> 12 years) with persistent asthma who previously took an ICS with or without a LABA Baseline characteristics: mean age was 44.7 years; 45% were receiving inhaled glucocorticoids at baseline and 55% were on combined IC/LABA; 40% of the cohort were male and 81% were white Inclusion criteria: patients were eligible if they had FEV₁ of 40% and 85% of predicted value for age, height, sex, and race per National Health and Nutrition Examination Survey III reference values; 15 exhibited 15% reversibility in FEV₁ (all patients) and 200‐mL increase in FEV₁ from baseline (patients 12 years of age) within 30 minutes of exposure to a short‐acting agonist, and had a treatment regimen that included albuterol or salbutamol for use as needed for 8 weeks before screening and an ICS (either ICS monotherapy or ICS/LABA) at a qualifying dose of fluticasone DPI 200 g/d or equivalent for 1 month. Patients who received ICS/LABA therapy had a pre‐screening visit to change to a comparable dose of ICS monotherapy Exclusion criteria: history of life‐threatening asthma exacerbation, asthma exacerbation that required systemic corticosteroids within 30 days before screening, any hospitalisation for asthma within 2 months before screening
Interventions	• Fluticasone propionate and salmeterol (100 or 200 μg/12.5 μg salmeterol) twice daily • Fluticasone propionate (100 or 200 μg) twice daily A novel, inhalation‐driven, multi‐dose dry powder inhaler (RespiClick MDPI; Teva Pharmaceuticals, Inc., Frazer, PA) was used in all arms of the study
Outcomes	Safety was assessed by monitoring of vital signs, physical and oropharyngeal examinations, electrocardiograms, concomitant medication usage, and AEs. An SAE was defined as an AE that occurred at any dose and resulted in death, a life‐threatening AE, inpatient hospitalisation or prolongation of existing hospitalisation, persistent or significant disability or incapacity, congenital anomaly, or a birth defect. An asthma exacerbation was defined as worsening asthma that required any significant treatment other than study medication or rescue albuterol/salbutamol, including systemic corticosteroids, urgent care and/or emergency department visit, or hospitalisation. An asthma exacerbation was considered an AE only if it met the criteria for an SAE
Notes	Sponsored by Teva Pharmaceuticals
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"For the double‐blind treatment period, the patients were randomized in a 1:1:1:1:1 ratio to one of five double‐blind treatment groups"; how they were assigned to each was not specified
Allocation concealment (selection bias)	Unclear risk	No details
Blinding (performance bias and detection bias) All outcomes	Unclear risk	Reported to be carried out in a double‐blind manner, but further information detailing how this was maintained throughout the study was not readily available in the publication
Independent Assessment of causation (detection bias) Asthma‐related events	High risk	No clear documentation of independent assessment of causation
Incomplete outcome data (attrition bias) All outcomes	Low risk	Clear reasons for participant withdrawal were detailed in the study report: "Overall, 78 patients (11%) discontinued the study, most frequently from the placebo group and most commonly due to disease progression (n=24 [3%]) or lack of efficacy (n 9 [1%])" With attrition rates of 0.3% in the fluticasone propionate treatment arm and 1% in the fluticasone propionate and salmeterol arm in a population of 583 Safety outcomes were reported in all included participants apart from 8 patients, including 2 (1.4%) in the placebo group and 6 (1.0%) in the active treatment groups who discontinued due to AEs
Selective reporting (reporting bias)	Low risk	Study was registered with an NCT number and had clearly pre‐specified primary and secondary outcomes. All safety‐related outcomes were reported and were easily attainable