Cohen 2012.

Study characteristics
Methods	Study design‐ multicentre, randomised, double‐blind, parallel‐design, in perioral lines Study date‐ no information Study setting‐ no information
Participants	Randomised‐ 60 women, with a mean age of 41. 9 ± 8 years total population; 40.8 ± 7.1 years in BontA 7.5 U group; 43.2 ± 8.7 years in BontA 12 U group. Gender 100% female Inclusion criteria Women of any race aged 25 to 60 with a perioral line (POL) score of 2 or 3 (moderate or severe) at maximal attempted muscle contraction based on a 4‐point scale that considered the upper and lower lips Exclusion criteria Participants were excluded if they had undergone prior cosmetic surgery or exhibited facial scars that may have affected evaluation of response or the quality of photography Asymmetric line severity between the upper and lower lips; imprinted etched‐in lines at rest in the perioral area; the presence of facial hair affecting the evaluation of response or quality of photography; Injection of nonpermanent lip filler into the perioral area in the 18 months preceding visit 1 Previous botulinum toxin therapy in the mid or lower face within the 12 months preceding visit 1 Previous permanent procedure or treatment in the lower face Any medical condition or use of concurrent medication that might increase their risk of exposure to botulinum toxin medical or psychiatric problems that severe enough to interfere with the study results Allergy or sensitivity to any component of the study medication Severity of disease‐ POL score of 2 or 3 (moderate or severe) at maximal attempted muscle contraction based on a 4‐point scale that considered the upper and lower lips Ethnicity‐ 54/60 (90%) Caucasian, 3/60 (5%) black, 3/60 (5%) Hispanic total population; 30/31 (96.8%) Caucasian, 1/31 (3.2%) black, 0% Hispanic in BontA 7.5u group; 24/29 (82.8%) Caucasian, 2/29 (6.9%) black, 3/29 (10.3%), Hispanic in BontA 12u group
Interventions	Duration of study‐ 20 weeks. Intervention OnabotulinumtoxinA (7.5 U), 2 sites per lip:5 U upper lip; 2.5 U lower lip (N = 31) Comparator OnabotulinumtoxinA (12 U), 2 sites per lip: 8 U upper lip; 4 U lower lip (N = 29)
Outcomes	Primary outcome Investigator‐assessed POL severity scale at maximal contraction, reduction of at least 1 point in perioral lines Secondary outcomes Investigator satisfaction, baseline of at least 1 grade in CFL severity at rest, among subjects who rated themselves at least mild at baseline Adverse events.
Notes	The authors received research grant support from Allergan Inc. for this study and for manuscript preparation.  Dr Cohen and two other authors are consultants and investigators for Allergan Inc. This study finished in 2016 ‐ results added to clinical trial register May 28, 2019.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "this study was a multicenter, randomised... parallel‐design, in which subjects were randomised in a 1:1 ratio" page 1498. Comment: we considered this unclear risk of bias because the authors did not show how they randomised the participants
Allocation concealment (selection bias)	Unclear risk	No information Comment: we considered this unclear risk of bias because the authors did not show the methods used for maintaining the allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "this study was...double‐blind.Onabotulinumtoxin A was reconstituted in preserved saline. The volume of reconstituted toxin in each syringe was 0.30mL to maintain the blind." page 1498 Comment: we considered this low risk of bias
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "this study was...double‐blind..Onabotulinumtoxin A was reconstituted in preserved saline. The volume of reconstituted toxin in each syringe was 0.30mL to maintain the blind." page 1498 Comment: we considered this low risk of bias
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "Fifty‐one subjects (85%) completed the study, of whom 26 and 25 subjects were from the 12.0‐U and 7.5‐U arms, respectively." page 1499 Comment: we consider unclear risk of bias, the authors did not mention the reason of drop outs An e‐mail was sent to the authors on 21 November 2015. Answer on 22 November 2015: "I'm not sure I actually remember this. And the study was done so long ago, that I'm not sure we have these records on site any longer. You might want to inquire with Allergan, as they have the documents. I would imagine several patients were simply lost to follow up between the 3 sites"
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