Carruthers 2005a.

Study characteristics
Methods	Study design‐ single‐centre, double‐blind, randomised, parallel‐design, dose‐ranging in glabellar lines in men Study date‐ no information Study setting‐ outpatients, one centre (Canada)
Participants	Randomised 80 men, with a mean age of 44.2 ± 14.6 years in BontA 20u group; 38.6 ± 8.2 years in BontA 40u group; 44.0 ± 12.8 years in BontA 60u group; 39.6 ± 13.2 years in BontA 80u group. Gender 100% male Inclusion criteria Males between 18 and 65 years of age with moderate to severe (grade 2 and 3‐ FWS) glabellar at maximum contraction Exclusion criteria Use of any agent (e.g. aminoglycoside antibiotics) that could interfere with neuromuscular transmission or any condition(e.g. Eaton‐Lambert syndrome, myasthenia gravis., excessive weakness, or atrophy of target muscles that could amplify the effects of treatment with botulinum toxin type A. Allergy or sensitivity to any component of the study medication Prior cosmetic procedures, soft tissue augmentation, or visible scars on the treatment area; or had received treatment with botulinum toxin within 1 year of baseline evaluation Severity of disease‐ moderate to severe glabellar lines at maximum frown Ethnicity‐ BontA 20 U‐ 100% white; 40 U‐ 18/20 white, 2/20 other; 60 U‐ 19/20 white and 1/20 other; 80 U 16/20 white, 1/20 Hispanic and 3/20 other
Interventions	Duration of study‐ 52 weeks Intervention/Comparator OnabotulinumtoxinA (20 U), in seven points 20% of total dose in procerus muscle, 15% in each corrugator muscle, 50% over orbicularis muscle (15% each two in the medial canthus and 10% into each above mid pupillary line) (N = 20) OnabotulinumtoxinA (4 0U, in seven points 20% of total dose in procerus muscle, 15% in each corrugator muscle, 50% over orbicularis muscle (15% each two in the medial canthus and 10% into each above mid pupillary line) (N = 20) OnabotulinumtoxinA (60 U), in seven points 20% of total dose in procerus muscle, 15% in each corrugator muscle, 50% over orbicularis muscle (15% each two in the medial canthus and 10% into each above mid pupillary line) (N = 20) OnabotulinumtoxinA (80 U), in seven points 20% of total dose in procerus muscle, 15% in each corrugator muscle, 50% over orbicularis muscle (15% each two in the medial canthus and 10% into each above mid pupillary line) (N = 20)
Outcomes	Primary outcome Observer assessment, severity of wrinkles at maximum frown (FWS) compared to baseline Secondary outcomes Maximum treatment effect(observer assessment) Response rate (peak between 2weeks to 4 weeks) by investigator Duration of effect Relapse time by investigator Responders rate(any improvement). Self assessment (scale 0 to 6) Global assessment Adverse events
Notes	Drs Carruthers are consultants of Allergan
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "prospective, double‐blind, randomised" page 1297 "participants were randomly assigned into one of four possible treatment groups using a block‐of‐eight design" page 1298 Comment: we considered this unclear risk of bias because the authors did not explain how they randomised the participants
Allocation concealment (selection bias)	Unclear risk	No information available to allow a judgment Comment: we considered this unclear risk of bias
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "to maintain blind, vials were prepared by a registered nurse who took no further part in the study" page 1298 Comment: we considered this unclear risk of bias due to the visual aspect of intervention and placebo was not detailed
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "to maintain blind, vials were prepared by a registered nurse who took no further part in the study" page 1298 Comment: we considered this unclear risk of bias due to the visual aspect of intervention and placebo was not detailed.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Two participants withdrew consent, and one discontinued without providing information" page 1299 Comment: we considered this unclear risk of bias, because the authors did not mention the reason of drop out neither which group these patients came from
Selective reporting (reporting bias)	High risk	Patient self assessment no data, only P value. Comment: e‐mail sent on 24 June 2015, answer on 25 June 2015 "The study was done almost 10 years ago. The data will be buried in our basement. Getting out the raw data would be very labor intensive. Alastair."
Other bias	Low risk	We considered this study at low risk of other bias