Slankard 2016

Methods	A randomised, double‐blind, multi‐centre study conducted in patients with moderate to severe asthma who were being treated with combined inhaled corticosteroids/LABA over 16 weeks
Participants	Population: 61 (67 randomised) participants age 18 years or older with physician‐diagnosed moderate or severe persistent asthma who were receiving treatment with combined ICS/LABA Baseline characteristics: mean age of participants with Arg/Arg genotype (n = 28) was 47.2, and for those with Gly/Gly genotype (n = 33) 43.1. 23% of the Arg/Arg subgroup and 24% of the Gly/Gly subgroup were female. 15% (Arg/Arg) and 17% (Gly/Gly) were of white ethnic origin, and 8% (Arg/Arg) and 10% (Arg/Arg) were of African American origin Inclusion criteria: after providing informed consent, all potential study participants underwent genetic screening for beta₂‐adrenergic receptor genotype, and those homozygous for the arginine or glycine variant at the 16th amino acid position (Arg/Arg or Gly/Gly) were eligible to participate Exclusion criteria: pregnancy at the time of enrolment, active tobacco use or > 10‐pack‐year history of tobacco use, history of intubation for asthma within past 10 years, FEV₁ < 60% of predicted on screening spirometry before the run‐in or < 70% predicted at the randomisation visit, major comorbidity (symptomatic coronary artery disease, ongoing treatment for malignancy, poorly controlled diabetes)
Interventions	• Fluticasone propionate and salmeterol (Advair HFAR, 45 μg, 115 μg, or 230 μg of fluticasone propionate with 21 μg of salmeterol, 2 puffs every 12 hours) • Fluticasone propionate (Flovent HFAR, 44 μg, 110 μg, or 220 μg) twice daily Advair HFA devices were used to deliver ICS/LABA fixed dose and Flovent HFA for fluticasone propionate alone
Outcomes	Participants who experienced more than 2 exacerbations during the course of the study were withdrawn according to pre‐determined safety parameters. (Exacerbation is defined in Selected Methods of the Supplementary Appendix.) Adverse events were defined as any untoward events or symptoms reported by the participant, whether related or not related to the study drug
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Randomization was carried out by the Columbia University Research Pharmacy using the Microsoft Excel random number generator"
Allocation concealment (selection bias)	Unclear risk	Further details regarding allocation concealment were not described, but it appears that participants were blinded to their allocation
Blinding (performance bias and detection bias) All outcomes	Low risk	"Investigators and research staff were kept blinded to the genotype and study drug assignment. HFA devices were blinded and distributed by the Columbia University Research Pharmacy"
Independent Assessment of causation (detection bias) Asthma‐related events	High risk	Independent assessment of causation was not clearly documented
Incomplete outcome data (attrition bias) All outcomes	Low risk	Attrition rates were quite high due to the small overall sample size (N = 90), but most withdrawals occurred following initial (genotype) screening, whereas the level of attrition was much lower following treatment allocations, suggesting this was less likely to influence subsequent outcomes. Furthermore, reasons for withdrawal were clearly detailed in the trial flow chart (Fig. 2 of the paper)
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