Carruthers 2002.

Study characteristics
Methods	Study design‐ multicentre, double‐blind, randomised, placebo‐controlled parallel design study in glabellar lines Study date‐ no information Study setting‐ outpatients of 14 centres
Participants	Randomised‐ 264 participants, with a mean age of 44.7 ± 11 years in BontA group; 44.3 ± 11.3 years in placebo group. Gender: 173/203 (85.2%) female, 30/203 (14.8%) male in BontA group; female 47/61 (77%), 14/61 (23%) male in placebo group Inclusion criteria Patients had to be between 18 and 75 years of age with glabellar lines of at least moderate severity at maximum frown (graded on a 4‐point scale, ranging from 0 = none to 3 = severe). There was no requirement for a minimum severity rating for glabellar lines at rest. Patients may have had prior BTX‐A treatment for glabellar lines, provided that they met this severity requirement. Patients also had to be in medically stable condition, able to complete the entire study, and able to comply with study instruction. Exclusion criteria Any disorder (e.g. myasthenia gravis or Eaton‐Lambert syndrome) or use of any agent (e.g. aminoglycoside antibiotics) that might interfere with neuromuscular function Any other condition or situation that might put the patient at significant risk, confound the study results (e.g. significant pre‐existing brow or eyelid ptosis), or interfere with the patient’s participation in the study Allergy or sensitivity to either study treatment Had participated in another clinical study within 30 days of the study start date Patients planning other facial cosmetic procedures during the study period Pregnancy, lactating, or planning a pregnancy. Severity of disease‐ moderate to severe glabellar lines at maximum frown Ethnicity‐ 174/203 (85.7%) white, Hispanic 16/203 (7.9%), black 7/203 (3.4%), Asian 3/203 (1.5%), other 3/203(1.5%) in BontA; 49/61 (80.3%) white, Hispanic 6/61 (9.8%), black 1/61 (6.6%), Asian 4/61 (6.6%), other 1/61(1.6%) in placebo
Interventions	Duration of study‐ 4 weeks Intervention OnabotulinumtoxinA 20 U, 0.1mL/site, 5 points in glabellar lines (N = 203) Comparator Placebo 0.5mL, 0.1mL/site, 5 points in glabellar lines (N = 61)
Outcomes	Primary outcome Physician’s assessment: physicians graded glabellar line severity during every visit, both at maximum frown and at rest on a scale of 0 to 3. Secondary outcomes Patients' assessment: patients graded the change in appearance of glabellar lines at every post‐injection visit by responding to the question, “How would you rate the change in the appearance of your glabellar lines compared with immediately before your injection?” The patients scored the change on a 9‐point scale. Adverse events.
Notes	"Funding sources: Allergan, Inc. Disclosure: Drs Carruthers and Lowe are paid consultants of Allergan"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "At each study centre, randomisation to treatment was stratified by age group (≤50 years and ≥ 51 years). Within each age group, patients were randomly assigned in blocks of 8, with a ratio of 3:1 (BTX‐A/placebo)." page 842 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	Quote: "At each study centre, randomisation to treatment was stratified by age group (≤50 years and ≥ 51 years). Within each age group, patients were randomly assigned in blocks of 8, with a ratio of 3:1 (BTX‐A/placebo)." page 842 Comment: we considered this unclear risk of bias because the authors did not explain the methods used for maintaining the allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Randomization block size was not divulged to the physician investigators to help maintain blinding. In addition, two investigators co‐evaluated each patient on day 0, one of whom was to do the day 7 assessment, while the other was to do the day 30 assessment. This prevented the evaluation on day 30 from being influenced by the patient’s appearance on day 7." page 842 Comment: we considered this unclear risk of bias due to the visual aspect of BontA and placebo was not described.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Randomization block size was not divulged to the physician investigators to help maintain blinding. In addition, two investigators co‐evaluated each patient on day 0, one of whom was to do the day 7 assessment, while the other was to do the day 30 assessment. This prevented the evaluation on day 30 from being influenced by the patient’s appearance on day 7." page 842 Comment: we considered this low risk of bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "two patients (both in the BTX‐A group) did not complete the study. One moved out of state, and the other was unable to keep to scheduled appointments for personal reasons. A third patient was randomly assigned (placebo group) but declined treatment because of the visit schedule requirements." page 841 Comment: we considered this low risk of bias
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported Comment: we considered this low risk of bias
Other bias	Low risk	We considered this study at low risk of other bias