Carruthers 2015.

Study characteristics
Methods	Study design‐ multicentre, double‐blind, randomised, parallel‐design, placebo‐controlled extension study of participants who completed the 7‐ month phase 3 study (Study 191622‐099;  www. clinicaltrials.gov identifier: NCT01224015) in crow's feet and/or glabellar lines Study date‐ no information Study setting‐ outpatients
Participants	Randomised‐ 684 participants, with a mean age of 49.7 ± 9.48 years in BontA 44 U/44U group; 49.4 ± 9.35 years in BontA 24 U/24 U group; 49.4 ± 9.23 in Placebo/BontA 0/44 U group; 49.1 ± 9.32 in Placebo/placebo group; 49.4 ± 9.36 years total population. Gender: 226/260 (86.9%) female, 34/260 (13.1%) male BontA 44 U/44 group; 203/227 (89.4%) female, 24/227 (11.9%) male in BontA 24 U/24 U group; 89/101 (88.1%) female, 12/101 (11.9%) male in Placebo/BontA 0/44 U group; 80/96 (83.3%) female, 16/96 (16.7%) male in Placebo/placebo group; 598/684 (87.4%) female, 86/684 (12.6%) male total population Inclusion criteria Male or female at least 18 years of age, bilaterally symmetrical moderate‐to‐severe crow’s feet lines at maximum smile on the FWS as rated by both investigator and participant on day 1 (before study), sufficient visual acuity without the use of eyeglasses (contact lens use acceptable), to accurately assess their facial wrinkles, female participants of childbearing potential must have had a negative urine pregnancy test at day 1 prior to study treatment; must be using a reliable means of contraception Exclusion criteria Concurrent or previous botulinum toxin treatment of any serotype Specified facial treatments or procedures within particular time points prior to study that could interfere with treatments in this study or with interpretation of results Prior upper or midfacial surgery or permanent aesthetic procedures/treatments Marked facial asymmetry, dermatochalasis, deep dermal scarring, excessively thick sebaceous skin, or the inability to substantially lessen lateral canthal rhytides even by physically spreading them apart, as determined by the investigator Presence of any clinically relevant abnormal finding as observed from the neurologic assessment Any eyebrow or eyelid ptosis at baseline as determined by the investigator History of facial nerve palsy Pregnancy, nursing, or planning a pregnancy Any uncontrolled systemic disease 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 bilaterally symmetrical CFL at maximum smile and moderate‐to‐severe GL at maximum frown Ethnicity‐ white 232/260 (89.2%), non‐white 28/260 (10.8%) in Botox 44/44 U, white 200/227 (88.1%), non‐white 27/227 (11.9%) in BontA 24/24 U group; white 89/101 (88.1%, non‐white 12/101 (11.9%) in placebo group; BontA44 U group; white 84/96 (87.5%), non‐white 12/96 (12.5%) in placebo/placebo group; white 605/684 (88.5%), non‐white 79/684 (11.5%) in total population
Interventions	Duration of study‐ 20 weeks Intervention/ Comparator OnabotulinumtoxinA crow's feet (24 U), glabella (20U) (N = 260) OnabotulinumtoxinA (24 U) Crow's feet lines, Glabellar lines (zero U) (N = 227) Placebo to onabotulinumtoxinA (44 U, 24u crow's feet lines, 20u glabellar lines)(N = 101) Placebo crow's feet lines and Glabellar lines (N = 96) Total (N = 684) Placebo crow's feet (0.6 mL), glabella (0.5 mL)
Outcomes	Primary outcome Proportion of participants achieving a grade of none or mild at maximum smile on Day 30 of treatment cycle 3 based on investigator’s Facial Wrinkle Scale (FWS) ratings Secondary outcomes  Proportion of participants achieving none or mild at other time points (maximum smile), the proportion achieving an improvement from baseline of at least 1 grade in CFL severity at maximum smile, and the proportion achieving an improvement from baseline of at least 1 grade in CFL severity at rest, among participants who were rated at least mild at baseline Participant‐rated end points included the proportion of participants achieving a grade of none or mild in CFL severity at maximum smile The proportion achieving an improvement from baseline of at least 1 grade in CFL severity at maximum smile, and the proportion achieving an improvement from baseline of at least 1 grade in CFL severity at rest, among participants who rated themselves at least mild at baseline Participant’s Global Assessment of Change in Crow’s Feet, Lines (SGA‐CFL), the validated Facial Line Outcomes Questionnaire (FLO‐11) psychological impact (Items 2, 5, and 8), and Self‐Perception of Age (SPA) and the Subject Satisfaction of Appearance Adverse events
Notes	"J. Carruthers and A. Rivkin are consultants and investigators for Allergan, Inc. L. Donofrio is an investigator for Allergan, Inc. V. Bertucci is a speaker, consultant, and investigator for Allergan, Inc. X. Lei is an employee of Allergan, Inc., and receives compensation in salary, as well as stock or stock options (or both). C. Somogyi and F. C. Beddingfield were employees of Allergan, Inc. at the time of this study and received compensation in salary, as well as stock or stock options (or both). The other authors have indicated no significant interest with commercial supporters." This RCT was a continuation of previous RCT published (Moers‐Carpi 2015), so we will consider only the patients that received placebo (Moers‐Carpi 2015) and were re randomised for BotoxR 44u and placebo in this study to avoid double count of participants.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Randomization took place on Day 1 of this study, corresponding to the last day of Study 191622‐099. Subjects who had received onabotulinumtoxinA in Study 191622‐099 continued to receive the same dose (44 U for CFL + GL, 24 U for CFL alone) in this study. Subjects who had received placebo in Study 191622‐ 099 were re randomised in a double‐blind fashion to either 44 U onabotulinumtoxinA (CFL + GL) or to placebo in a 1:1 ratio" page 703 Comment: we considered this unclear risk of bias because the authors did not explain how they randomised the participants
Allocation concealment (selection bias)	Unclear risk	Quote: "Randomization took place on Day 1 of this study, corresponding to the last day of Study 191622‐099. Subjects who had received onabotulinumtoxinA in Study 191622‐099 continued to receive the same dose (44 U for CFL + GL, 24 U for CFL alone) in this study. Subjects who had received placebo in Study 191622‐ 099 were re‐randomized in a double‐blind fashion to either 44 U onabotulinumtoxinA (CFL + GL) or to placebo in a 1:1 ratio" page 703 Comments: we considered this unclear risk of bias because the authors did not explain the methods used for maintaining the allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "To maintain the blind, all medications were reconstituted and prepared by individuals who had no interactions with subjects." page 104 (from Moers‐Carpi 2015) Comment: we considered this unclear risk of bias due to the visual aspect of BontA and placebo was not described
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "To maintain the blind, all medications were reconstituted and prepared by individuals who had no interactions with subjects." (from Moers‐Carpi 2015) Comment: we considered this unclear risk of bias due to the author did not provide information about blinding of outcome assessor
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of 684 subjects enrolled, 641 (93.7%) completed this study A total of 667 subjects (97.5%) received the third treatment. Most subjects who received a third dose (80.2%; 535/667) received their dose at Day 1 visit of Study 191622‐104. A total of 414 subjects (60.5%) received 2 treatments (treatment cycles 3 and 4): 149 onabotulinumtoxinA 24 U/24 U, 123 onabotulinumtoxinA 44 U/44 U, 69 placebo/ onabotulinumtoxinA 44 U, and 73 placebo/placebo. In this study, 253 subjects (37.0%) received only 1 treatment (treatment cycle 3): 74 onabotulinumtoxinA 24 U/24 U, 126 onabotulinumtoxinA 44 U/44 U, 31 placebo/onabotulinumtoxinA 44 U, and 22 placebo/placebo. Seventeen subjects failed to meet re‐treatment criteria after they received treatment 2 in Study 191622‐099 and therefore did not receive any treatment in this study: 4 onabotulinumtoxinA 24 U/ 24 U, 11 onabotulinumtoxinA 44 U/44 U, 1 placebo/ onabotulinumtoxinA 44 U, and 1 placebo/placebo" page 705 Comment: we considered this 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	High risk	Comment: we considered a high risk of bias because C. Somogyi and F. C. Beddingfield were employees of Allergan and conducted this trial