Ploszczuk 2014

Methods	A randomised, double‐blind, parallel‐group, multi‐centre study over 12 weeks from March 2012 to November 2013, across multiple sites (Bulgaria, Czech Republic, Hungary, India, Poland, Romania, Russian Federation, Ukraine). Run in 2 to 4 weeks of ICS
Participants	Population: 512 children 5 to < 12 years of age with asthma Baseline characteristics: 66% males, 33% females included in the study Inclusion criteria: male and female children 5 to < 12 years of age with a known history of moderate to severe persistent reversible asthma for ≥ 6 months before screening visit, FEV₁ ≥ 60% to ≤ 90% predicted during the screening period followed by appropriate withholding of asthma medications (no LABA within 12 hours and/or no SABA within 6 hours of PFT; no ICS on the day of screening), documented reversibility ≥ 15% FEV₁ in the screening period, current ICS use at a stable dose for ≥ 4 weeks before screening, inadequate asthma control on ICS alone at ≤ 500 µg fluticasone equivalents per day or controlled asthma on ICS‐LABA combination at ICS dose ≤ 200 µg fluticasone equivalents per day, demonstrated satisfactory pMDI and spacer technique, adequate spirometry performed, willing and able to add information in electronic diary with help of parent or guardian, attending all study visits, willing and able to substitute pre‐study inhaler medication for entire study duration; if female post menarche, a urine pregnancy test may be undertaken at the discretion of the investigator and parents/legal representative (test must be negative); written informed consent and assent obtained as per national law Exclusion criteria: near fatal or life‐threatening asthma within past year (including intubation), hospitalisation or emergency visit for asthma within past 6 months, history of systemic (injectable/oral) corticosteroid medication within 1 month of screening visit, current or prior non‐response or partial response only to ICS/LABA combination, evidence of clinically unstable disease (determined by medical history, clinical laboratory tests, physical examination), clinically significant upper and lower respiratory infection within 4 weeks before screening, significant non‐reversible active pulmonary disease, known HIV positive status, current smoking history within 12 months before screening, current alcohol//substance abuse within 12 months before screening, beta‐blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, astemizole (Hismanal), quinidine‐type antiarrhythmics, or potent CYP 3A4 inhibitors such as ketoconazole within 1 week before screening; current use of medications that may affect outcomes of study; hypersensitivity/idiosyncratic reactions to test medications/components; investigational medicinal product within 30 days of screening; current participation in a clinical study
Interventions	• Fluticasone propionate and salmeterol 100/50 µg twice daily (total 200/100 µg/d) • Fluticasone propionate 100 µg twice daily (total 200 µg/d) • Fluticasone propionate /formoterol 100/10 µg twice daily (total 200/20 µg/d); this arm was not used in the analysis of this review
Outcomes	Primary efficacy variables: change from baseline in pre‐dose to 2 hour post‐dose FEV₁ over 12 weeks Safety and tolerability profiles were reported to be similar in all treatment groups, but data were not reported
Notes	This is a conference abstract that was also published in another journal (Ploszczuk 2014a). This trial was published at clinicatrials.gov and EudraCT websites. Sponsored by Mundipharma Research Ltd.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Not clearly reported but trial was conducted for regulatory purposes
Allocation concealment (selection bias)	Low risk	Randomisation schedule was filed securely by Interactive response technology
Blinding (performance bias and detection bias) All outcomes	Low risk	Blinding was properly maintained throughout the study. Each participant received 2 inhalers (double‐dummy)
Independent Assessment of causation (detection bias) Asthma‐related events	High risk	No independent assessment of causation was reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants who took at least 1 dose of treatment were included in the safety analysis
Selective reporting (reporting bias)	Low risk	Serious adverse events were reported on the EU Clinical Trials register