Cheon 2019.

Study characteristics
Methods	Study design‐ multicentre, double‐blind, randomised, active‐drug controlled, phase I/III study designed to determine the non‐inferiority of Neuronox® compared to Onabotulinumtoxin A in the treatment of moderate to severe lateral canthal lines. NCT03317574 Study date‐ no information Study setting‐ outpatients, 5 centres (South Korea)
Participants	Randomised 220 participants with a mean age of 47.14 ±7.87yearsinn Nuronox® group and 49.03± 8.28 years in onabotulinumtoxinA group. Gender 88/110 (80%) female and 22/110 (20) males in Neuronox® group, and 92/110 (83.64%) female and 18/110(16.36%) male in onabotulinumtoxinA group. Previous BontA treatment 14/110(12.73%) in Neuronox® group and 17/110 (15.45%) in OnabotulinumtoxinA group. Inclusion criteria Males or females Aged 20 to 65 years With moderate to severe LCL at maximum smile as assessed by the investigator using an LCL severity scale Exclusion criteria Neuromuscular disorders, Specified facial surgery or permanent aesthetic treatments within the past 6 months to a year that would affect the assessment of LCL, Deep LCL Difficult to lessen even by physical methods, BoNT‐A treatment in the past 3 months or plans to receive BoNT‐A treatment during study participation, Hypersensitivity to any components of the investigational product, or infection at the injection site. Severity of the disease‐ moderate 29/110(26%), severe 81/110 (74%) in Neuronox® group; moderate 35/110 (32%), severe 75/110 (68%) in onabotulinumtoxinA group.
Interventions	Duration of study‐ 16 weeks Intervention Neuronox® 24u (N=110)‐ 4 U (0.1 mL), 3 sites each side Comparator OnabotulinumtoxinA 24 U (N=110)‐ 4 U (0.1 mL), 3 sites each side
Outcomes	Primary outcome Responder rate at a maximum smile as assessed by the investigators at Week 4 Secondary outcomes Responder rate at maximum smile at Weeks 8, 12, and 16 as assessed by the investigators independently Responder rate at rest at Weeks 4, 8, 12, and 16 as assessed by the investigators independently Responder rate at rest and at maximum smile at Weeks 4, 8, 12, and 16 as assessed by the participant Proportion of participants with more than 1‐grade point and 2‐grade point improvements from baseline on the LCL severity scale at maximum smile and at rest as assessed by the investigators at Weeks 4, 8, 12, and 16 Proportion of participants with Grade+2 (moderate improvement) or more on the subjective global assessment (9‐point grading scale; from +4, complete improvement, to ‐4, very marked worsening) at Weeks 4, 8, 12, and 16 Proportion of participants with Grade 6 (satisfied) or above on the subject satisfaction assessment (7‐point grading scale; from 7, very satisfied, to 1, very dissatisfied) at Weeks 4, 8, 12, and 16. Duration of the treatment Adverse events
Notes	"This study was sponsored by Medytox Inc., Korea. W.S. Lee is an employee of Medytox Inc."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote:"Dynamic Allocation was used to randomize eligible subjects"...page no number Comment: we considered this an unclear risk of bias because the authors did not explain how thy randomise the participants
Allocation concealment (selection bias)	Unclear risk	Quote:"Dynamic Allocation was used to randomize eligible subjects"...page no number Comment: we considered this an unclear risk of bias because the authors did not explain how thy randomise the participants
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "The pharmacist or designee responsible for the reconstitution was kept unblinded, and performed the dilution and preparation of the syringe in a separate room. All other individuals, including investigators and subjects were kept blinded throughout the study."... page no information. Comment: we considered this low risk of bias.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "The pharmacist or designee responsible for the reconstitution was kept unblinded, and performed the dilution and preparation of the syringe in a separate room. All other individuals, including investigators and subjects were kept blinded throughout the study."... page no information. Comment: we considered this low risk of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote:" due to major protocol deviation by seven subjects (two from Neuronox® and five from ONA (Figure 2)."...pgae no information Comment; we considered this a 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	Quote:"This study was sponsored by Medytox Inc., Korea. W.S. Lee is an employee of Medytox Inc."..page no information Comment: we considered this a low risk of bias