De Boulle 2018.

Study characteristics
Methods	Study design‐ multicentre, double‐blind, randomised, multicentre, placebo‐controlled, parallel‐design in upper facial lines, forehead lines, and crow’s feet lines. Period 1 (Days 1–180) comprised a double‐blind, placebo‐controlled, single‐treatment parallel‐group study design comparing onabotulinumtoxinA and placebo. Period 2 (Days 180–360), participants could receive up to 2 additional open‐label treatments (Cycles 2 and 3, >= 84 days apart) with onabotulinumtoxinA 64 U, administered using the same 16‐point pattern Study date‐ started October 2014 and finished April 2016 Study setting‐ outpatient 24 sites (10 in the USA, 14 in Europe)
Participants	Randomised 787 participants. Age ranging: Onabot40 U group‐47.6 years old (range 21‐75), Onabot 64 U group‐45.5 years old (range 21‐76), placebo group‐ 48.1 (range 22‐73). Gender: Onabot40 U group 87.4% female, Onabot64 U group 90.7% female, placebo group 88.7% female. Inclusion criteria Moderate to severe FHL at maximum eyebrow elevation based on investigator and subject assessments using the Facial Wrinkle Scale with Photo numeric Guide (FWS; 0 = none, 3 = severe) Exclusion criteria Eyelid ptosis or excessive forehead and eyebrow skin laxity;eyelid folds that reached the pupil or touched the upper lash line; use of the frontalis muscle to move the upper eyelid Periocular and eyebrow asymmetry Marked dermatochalasis Deep dermal scarring Excessively thick sebaceous skin Inability to substantially lessen facial lines, even by physically spreading them apart Women of childbearing potential had a negative urine pregnancy test on Day 1 pretreatment Severity of disease (according investigator rating of FHL severity eyebrow elevation in baseline): Onabot40U group 54.1% (moderate), 45.9%(severe); Onabot64U group 51.8% (moderate), 48.2%(severe); placebo group 51.9% moderate, 48.1% severe Ethnicity‐ 90.3% Caucasian in Onabot40U group; 91.1% Caucasian in Onabot64U group; 92.9% Caucasian in placebo group
Interventions	Duration of study: Period 1 (Days 1–180). Period 2 (Days 180–360) Intervention OnabotulinumtoxinA 64 U(FHL 20 U, GL 20 U, and CFL 24 U), OnabotulinumtoxinA 40 U(FHL 20 U,GL20 U, placebo [saline] in CFL Comparator Placebo (FHL, GL, and CFL). were administered as 0.1 mL injections distributed over 16 sites: 5 in FHL, 5 in GL, and 3 in CFLon each side Ratio: period 1 (2:2:1 Onabot44 U:Onabot64 U: placebo) Period 2 no information
Outcomes	Primary outcomes FDA‐proportion of participants (ITT population) who achieved at least a 2‐grade improvement from baseline on both investigator and subject FWS ratings of FHL severity at maximum eyebrow elevation on Day 30 of the double‐blind period European agency ‐the proportion of participants (mTT) population achieving an investigator‐assisted and a participant‐assisted FWS rating of none/mild for FHL severity at maximum eyebrow elevation at Day 30 o the double‐blind period  Secondary outcomes Investigator FWS rating of none/mild for FHL severity at maximum eyebrow elevation at Day 30, At least a 1‐grade improvement from baseline in investigatorFWSrating of FHLseverity at rest at Day 30, At least a 3‐point improvement from baseline on FLO‐11 Item 4 (looking older than actual age) Adverse events
Notes	"This study was sponsored by Allergan plc. Writing and editorial assistance was provided by K.E. Larsen and J. Street of PelotonAdvantage, Parsippany, NJ, and was funded by Allergan plc Dublin, Ireland. K. De Boulle has served as a consultant on an advisory board and speakers’ bureau, and has received honoraria from Allergan plc. W.P. Werschler has served on an advisory board, as a speaker, and as a consultant and/or received research funding from Allergan plc.M.H. Gold serves as a consultant and has received research funding from Allergan plc. S. Bruce has served on an advisory board and on a speakers’ bureau, has received research grants, and serves as an investigator trainer forAllergan plc. G. Sattler has received a research grant for participation in this study. P. Ogilvie received research grants from Allergan plc and serves as a consultant, advisory board member, and trainer for Allergan plc. D. Vitarella was an employee of Allergan plc at the time of this study. J. Street and K.E. Larsen serve as medical writers forPeloton Advantage, which received funding for editorial services from Allergan plc. E. Lee, X. Lei, C. Mao, and I.Yushmanova are employees of Allergan plc and may own stock or options in the company."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "On Day 1, after randomization (2:2:1), subjects"...page 1438 Comment: we considered unclear risk of bias because the authors did not mention how they randomise the participants
Allocation concealment (selection bias)	Unclear risk	Quote:"On Day 1, after randomization (2:2:1), subjects"...page 1438 Comment: we considered unclear risk of bias because the authors did not mention how they randomise the participants
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote:"Period 1 (Days 1–180) comprised a double‐blind, placebo‐controlled"...page 1438 Comment: we considered unclear risk of bias because the authors did not mention how they blind the participants
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote:"Period 1 (Days 1–180) comprised a double‐blind, placebo‐controlled"...page 1438 Commet: we considered unclear risk of bias because the authors did not mention how they keep the participants blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: Figure 2 ...page1440 Coment: we considered low risk of bias
Selective reporting (reporting bias)	Unclear risk	All prespecified outcomes were reported Comment: e consider a low risk of bias
Other bias	Unclear risk	Quote:"E. Lee, X. Lei, C. Mao, and I.Yushmanova are employees of Allergan plc and may own stock or options in the company"....page1437 Comment: we consider unclear risk of bias because professional aspects of some authors