Ulrik 2009.

Methods	Design: open‐label, parallel‐group randomised controlled trial Duration: 12 weeks Setting: 29 GSK investigational sites in Denmark and Switzerland Trial registration: NCT00351143; EudraCT no. 2005‐0003374‐48; ACE104325
Participants	Population: 274 adults with asthma randomised to adherence education and study medication (n = 140) or study medication only (n = 134) Age: over 18 years of age; mean (SD) age in the intervention group 40.5 (13.9) years and in the control group 38.7 (14.6) years Baseline asthma severity: Across the 2 groups, most randomised participants had mild persistent (51%) or moderate persistent (34%) asthma Inclusion criteria: ≥ 18 years of age; diagnosis of persistent asthma; treatment with at least 250 mg fluticasone propionate bid (or equivalent for other ICS) 4 weeks before the study and/or LABA bid or monotherapy with a short‐acting beta2‐agonist; ability to comply with use of the Asthma Monitor 2 (AM2) and the Asthma Quality of Life Questionnaire (AQLQ). Participants who had an exacerbation during the study period were allowed to remain in the study Exclusion criteria: known or suspected chronic obstructive pulmonary disease (COPD); pregnancy or lactation; smoking history > 10 pack‐years; clinical or laboratory evidence of serious uncontrolled systemic disease; microbiologically verified upper or lower respiratory tract infection within 1 month before screening visit; acute asthma exacerbation requiring hospitalisation/emergency department treatment/treatment with systemic corticosteroids within 3 months before screening visit; furthermore, for entry into treatment period 1 and treatment period 2: changes in asthma medication, including treatment with systemic corticosteroid, during the preceding period; more than 1 week of guideline‐defined asthma control before baseline visit/during treatment period 1; achieving total control in treatment period 1 (participants randomised at end of treatment period 1 and before entry into treatment period 2) Percentage withdrawn: not reported Other allowed medication: Those who had been treated with oral corticosteroids in the preceding 3 months were excluded from enrolling, and those who needed a change in asthma medication during period 1 were excluded from period 2
Interventions	Intervention summary: given salmeterol/fluticasone propionate 50/250 mg (Diskus®) bid and salbutamol prn for 12 weeks before randomisation (period 1). Then for 12 weeks (period 2), those who did not achieve total control were randomised and were given 5 patient‐centred teaching modules that included education about asthma, risk factors, prognosis, expectations of treatment, correct ways of taking controller and rescue medication and mnemonics as an aid for optimal dosing/timing of medication. Based on both written and oral information. Coaches were trained to use the standardised material at all centres Control summary: given salmeterol/fluticasone propionate 50/250 mg (Diskus®) bid and salbutamol prn for 12 weeks before randomisation (period 1). Then for 12 weeks (period 2), those who did not achieve total control were randomised and continued with the same study medication Complex intervention: yes
Outcomes	Outcomes measured: total asthma control; PEF; symptom scores; rescue medication use; number of nights awakenings due to asthma; adverse events; quality of life (AQLQ); medication compliance; asthma severity; adverse events (including exacerbations, emergency visits and hospitalisations); vital signs. The asthma monitor AM2 medical device was used to collect the following data on a daily basis: FEV1; pre‐dose morning PEF; symptoms; use of rescue medication; night‐time awakenings; exacerbations; change of medication due to side effects and emergency doctor visits Adherence calculation: Treatment compliance was assessed by counting the number of doses in the returned investigational product
Notes	Type of publication: single peer‐reviewed journal article Funding: GlaxoSmithKline NB: Period 2 of interest. During study period 1, all participants were treated with salmeterol/fluticasone 50/250. Those who did not achieve total asthma control in treatment period 1 were randomised to continued treatment with or without adherence education concomitantly for a further 12 weeks (period 2)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"subjects who did not achieve total asthma control in treatment period 1 were randomised to continued treatment with or without compliance enhancement training concomitantly for a further 12 weeks" ‐ no further details
Allocation concealment (selection bias)	Unclear risk	No details
Blinding of participants and personnel (performance bias) All outcomes	High risk	Trial is described as open‐label; although adherence was measured objectively with a device counter, knowledge of group allocation and monitoring may have affected adherence behaviour. In addition, patient‐reported outcomes, such as quality of life, are susceptible to risk of performance bias
Blinding of outcome assessment (detection bias) All outcomes	High risk	Trial is described as open‐label; although adherence was measured objectively with a device counter, knowledge of group allocation and monitoring may have affected patient‐reported outcomes, such as quality of life, for which the participant is the outcome assessor
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	All efficacy analyses were performed by intent‐to‐treat (ITT) analysis on all participants with data entered into the database, who had received at least 1 single dose of trial medication in treatment period 2 (randomised portion of the trial); therefore, this was the population for analysis of the primary endpoint. Sensitivity analyses were performed for the per‐protocol population for treatment period 2, which comprised all participants in the ITT‐2 population who did not have major protocol violations. The safety population comprised all participants who had received at least 1 single dose of study medication. However, no flow diagram was presented and drop‐out was not clearly reported
Selective reporting (reporting bias)	High risk	Prospectively registered trial (NCT00351143; EudraCT no. 2005‐0003374‐48). However, many outcomes of interest were not reported numerically, so could not used in the meta‐analysis
Other bias	Low risk	None noted