Costa 2016.

Study characteristics
Methods	Study design‐ multicentre, double‐blind, randomised, parallel‐design in glabellar lines Study date‐ started 2012, ended 2014 Study setting‐ outpatients three centres
Participants	Randomised‐ 157 female participants with mean age of 43.9 years in BontA1 (Prosigne®) group and 43.7 years in OnabotulinumtoxinA group Inclusion criteria Healthy females, age between 35 and 50 years, photo type from I to IV, BontA naive with moderate to severe glabellar lines at maximum contraction and mild to moderate glabellar lines at rest according 4‐point scale Exclusion criteria Bleeding disorders or previous use of any medication that can interfere in coagulation process Previous use of any type of botulinum toxin Antibiotics, cyclosporine, or any substance that interfere in neuromuscular function Local infection Allergy or sensitivity to any component of the study medication Prior upper or midfacial surgery or permanent aesthetic procedures/treatments Current enrolment in an investigational drug or device study or participation in such a study within 30 days of entry into this study Severity of disease‐ moderate to severe glabellar lines at maximum contraction and mild to moderate glabellar lines at rest Ethnicity‐ no information
Interventions	Duration of study‐ 12 weeks Intervention BontA [Prosigne®] (20 U), 4U per site, five sites (N = 85) Comparator OnabotulinumtoxinA (20 U), 4U per site, five sites (N = 72)
Outcomes	Primary outcome One point improvement in 4‐point scale at maximum contraction at day 15 by investigator and photographic assessment evaluated by three independent investigator. Secondary outcomes Duration of the treatment by photographic assessment evaluated by three independent investigators; at least one‐point improvement at rest at 120 days; pain tolerability by visual analogic scale during BontA injection Adverse events
Notes	Pharmaceutical support
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Realizou‐se a aleatorização em blocos de quatro, utilizando‐se o Random Allocation Software 1.0 para alocar os pacientes nos grupos" page 35 Comment: we consider low risk of bias (translation of quote: the authors wrote they use a software to randomise the patients)
Allocation concealment (selection bias)	Unclear risk	Quote: "Realizou‐se a aleatorização em blocos de quatro, utilizando‐se o Random Allocation Software 1.0 para alocar os pacientes nos grupos." page 35 Comment: we considered unclear risk of bias because the authors did not explain how the methods used for maintaining the allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Um investigador reconstituiu os frascos da Toxina 1 e da Toxina 2, aspirou 20 unidades de cada produto com seringa BD com capacidade para 1ml, agulha curta, e entregou para o segundo investigador que injetou a toxina já diluída sem saber qual produto havia na seringa."... page 35 (translation‐ one of the investigator reconstituted toxin 1 and toxin 2, he used 20u for each toxin, seringe BD, 1mL, short needle, and delivered to the second blinded investigator that injected the diluted toxin )Comment: we considered unclear risk of bias due to the authors did not reported methods for blinding visual aspect of interventions
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "Três avaliadores independentes analisaram todas as fotografias realizadas durante o estudo e classificaram a gravidade das rugas glabelares".. page 35 (translation‐ Three independents investigators evaluated all the study pictures and they classified all of them) Comment: we consider unclear risk of bias due to the due to the authors did not reported methods for blinding visual aspect of interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Houve seis perdas de seguimento na visita 2 (V2) (uma da Toxina 1, e cinco da Toxina 2), pela dificuldade de as pacientes seguirem as datas de retorno do protocolo. Da visita V2 (15 dias) até a V6 (120 dias), 16 sujeitos de pesquisa perderam o seguimento por faltar às visitas, mesmo após inúmeras tentativas de contato pelo centro do estudo (também por dificuldade de seguir o calendário do estudo). Completaram o estudo 119 pacientes (63 e 56 nos braços Toxina 1 e Toxina 2, respectivamente."... page 36 (translation‐ There was six drop outs in visit 2 (one in toxin 1 group and five in toxin 2 group), because the patients lost their follow‐up visit. From visit 2(15 days) to visit 6 (120 days), 16 patients did not show up, even though several previous contact. 119 subjects (63 and 56 in toxin1 and toxin 2 groups, respectively) completed the study Comment: we consider low risk of bias
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported Comment: we consider low risk of bias
Other bias	High risk	High number of protocol violation (17 in BontA (Prosigne®) group and 4 in OnabotulinumtoxinA group). Comment: we consider this high risk of bias