Carruthers 2004.

Study characteristics
Methods	Study design‐ multicentre, randomised, placebo‐ controlled, parallel ‐design in glabellar lines. Phase one‐ randomised clinical trial, double‐blind, duration 4 months two arms (BontA versus placebo), and phase two‐ open‐label, duration 8 months Study date‐ start (Feb 1999), end (June 2000) Study setting‐ outpatients from 30 centres
Participants	Randomised‐ 537 participants, with a mean age of 46.2 years in BontA group; 45.5 years in placebo group; and 46 years total population. Gender 334/405 (82.5%) female, 71/405 (17.5%) male in BontA group; 106/132 (80.3%) female, 26/132 (19.7%) in placebo group; 440/537 (81.9%) female, 97/537 (18.1%) total population Inclusion criteria Patients aged 18 to 75 years with moderate to severe glabellar frown lines at maximum frown (severity score of 2 or 3 on the facial wrinkle scale [FWS]), as assessed by the investigator, were eligible for inclusion in the study. The FWS rates the severity of glabellar frown at rest as 0 (none), 1 (mild), 2 (moderate), or 3 (severe) Exclusion criteria Patients were not eligible if they have any disorder (such as myasthenia gravis, Eaton‐Lambert Syndrome) or agent (such as aminoglycoside) that might interfere with neuromuscular function, or any condition that might put the patient at risk or confound outcome(such as significant pre‐existing brow or eyelid ptosis), or interfere with patient's participation in the study Also excluded were individuals who had glabellar lines that were so severe that they could not be lessened by spreading them apart with the fingers Allergy or sensitivity to any study component Participated in another clinical trial within 30 days of the study start date Patients planning other facial cosmetic procedures during the study period Pregnancy, breastfeeding, or planning a pregnancy during the study Facial surgery recently Severity of the disease‐ moderate to severe glabellar frown lines at maximum frown Ethnicity‐ BontA: 341/405 (84.2%) Caucasian, 21/405 (5.2%) black, 9/405 (2.2%) Asian, 30/405 (7.4%) Hispanic, 4/405 (1%) other; placebo: 109/132 (82.6%) Caucasian, 28/132 (5.3%) black, 4/132 (3%) Asian, 11/132 (8.3%) Hispanic,1/132 (0.8%) other; total 450/537 (83.8%) Caucasian, 28/537(5.2%) black, 13/537(2.4%) Asian, 41/537 (7.6%) Hispanic, 5/537 (0.9%) other
Interventions	Duration of study‐ Phase one‐ 16 weeks, phase two 32 weeks Intervention OnabobulinumtoxinA (20 U), 0,1mL/site, 5 points glabellar lines (N = 405) Comparator  Placebo, 0.5m, 0,1mL/site, 5 points in glabellar lines (N = 132)
Outcomes	Primary outcome Physician's assessment of glabellar lines (FWS) at maximum frown, and at rest Secondary outcome Patient self assessment response rate in contraction and repose, subgroup analysis (moderate/severe), antibody Adverse events
Notes	The first phase of this study was previous published as Carruthers 2002; Carruthers 2003b so this first phase was not reconsidered double count of patients
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "4‐month, randomised, double‐blind" page2 Comment: we considered this unclear risk of bias because the authors did not show how they randomised the participants (phase 1). Phase 2 was open‐label
Allocation concealment (selection bias)	Unclear risk	No information available to allow a judgment Comment: we considered this an unclear risk of bias
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "vials of botulinum toxin patients and placebo were identical,identified only by patient number and study number, and required identical dilution and injection procedure" page 3‐4 Comment: we considered this low risk of bias (Phase 1). Phase 2 was open‐label.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "vials of botulinum toxin patients and placebo were identical,identified only by patient number and study number, and required identical dilution and injection procedures.To help maintain blinding randomisation block size was not divulged to the physician investigator" page2 Comment: we considered this low risk of bias (Phase 1). Phase 2 was open‐label
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	At phase 1, there were 4 withdraws at BontA group due to the following reasons: lost of follow‐up (2), personal reasons (1) and other (1). For placebo group, the chart showed 4 withdraws but in table 2, there were 5 patients (inconsistence) due to the following reasons: lost of follow‐up (1), personal reasons (2), other (2). Comment:we considered an unclear risk of bias. Despite a low number of withdraw and a balance between interventions group regarding number and reason of withdraw, we are not sure about in which extension the inconsistence stated below could affect the results An 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."
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported. Comment: we considered this a low risk of bias
Other bias	Low risk	We considered this study at low risk of other bias