Kane 2009.

Study characteristics
Methods	Study design‐ multicentre, randomised, double‐blind, placebo‐controlled study, parallel‐design, phase III Study date‐ no information Study setting‐ outpatients from 27 centres
Participants	Randomised‐ 816 participants, with mean age of 49.2 ± 10.31 years in placebo group, 48.7 ± 10.33 years in AbobotulinumtoxinA group. Gender: 238/272 (88%) female, 34/272 (13%) male in placebo group; 481/544 (88%) female, 63/544 (12%) male in BontA group. Patients stratified by race/ethnicity. Severity of disease‐ moderate to severe glabellar lines Other demographic data‐ Fitzpatrick skin type: Placebo‐ 1 (extremely fair, always burns, never tans) 7/272 (3%), 2 (white, always burns, sometimes tans) 91/272 (33%), 3 (white, sometimes burns, always tans) 79/271 (29%), 4 (olive brown, rarely burns, always tans) 47/272 (17%), 5 (brown, never burns) 30/272 (11%), 6 (heavily pigmented or black, never burns) 18/272 (7%). Dysport‐ 1 (extremely fair, always burns, never tans) 19/544 (3%), 2 (white, always burns, sometimes tans) 161/544(30%), 3 (white, sometimes burns, always tans) 185/544 (34%), 4 (olive brown, rarely burns, always tans) 86/544 (67%), 5 (brown, never burns) 53/544 (10%), 6 (heavily pigmented or black, never burns) 140/544 (7%). BontA naive 221/272 (81%) in placebo group; 51/272 (10%) not naive in placebo group. BontA naive in AbobotulinumtoxinA group 437/544 (80%) BontA naive; 107/544(20%) not BontA naive Inclusion criteria Patients aged 18 years or older with moderate to severe glabellar lines Exclusion criteria Previous treatment with Dysport® within 150 days of entry and were prohibited from treatment to areas other than the glabellar area during the study Were unable to substantially reduce glabellar lines by manually spreading them Previous facial plastic surgery procedures such as tissue augmentation or brow lifts, or any procedure or concurrent therapy that the investigator considered would interfere with the evaluation of Dysport® Any active infection in the glabellar area Chronic drug or alcohol abuse Clinically diagnosed anxiety or depression Current facial palsy or neuromuscular junction disorders, or any other condition or circumstance that might pose a risk to the patient or interfere with the ability to acquire satisfactory clinical data Severity of disease‐ patients with grade 2 or 3, corresponding to moderate to severe wrinkles at maximum contraction Ethnicity‐ 191/271 (70%) Caucasian, 54/272 (20%) African American, 19/271 (7%) Hispanic, 2/272 (<1%) Asian, 2/272(<1%) Native American, 3/272 (<1%) other in placebo group; 364/544 (67%) Caucasian, 106/544 (19%) African American, 57/544 (10%) Hispanic, 8/544 (1%) Asian, 1/544 (<1%) Native American, 8/544 (1%) other in BontA group
Interventions	Duration of study‐ 20 weeks Intervention AbobotulinumtoxinA, women received 50 U, 60 U, or 70 U and men received 60 U, 70 U, 80 U, 5‐point of injection. "Procerus: This injection was located at a point inferior to a line joining the eyebrows and superior to the root of the nose. Corrugator: These two injections were administered bilaterally directly above the inner canthus and above the bony orbital rim. Lateral corrugator/orbicularis: These two injections were the most crucial because of the possibility of producing eyelid ptosis. The injection site was directly above the pupil and approximately 1 cm above the bony orbital rim, bilaterally" (N = 544) Comparator‐ Placebo, women 0.4 mL to 0.6 mL, men 0.5 mL to 0.7mL, 5 points of injection. Quote: "Procerus: This injection was located at a point inferior to a line joining the eyebrows and superior to the root of the nose. Corrugator: These two injections were administered bilaterally directly above the inner canthus and above the bony orbital rim. Lateral corrugator/orbicularis: These two injections were the most crucial because of the possibility of producing eyelid ptosis. The injection site was directly above the pupil and approximately 1 cm above the bony orbital rim, bilaterally" (N = 272)
Outcomes	Primary outcome‐ Evaluator and patient self‐assessment at maximum frown using the Glabellar Line Severity Score. Secondary outcome‐ Onset of the treatment Duration of treatment effect Subgroup analysis by ethnicity, gender, BontA naivety Adverse events.
Notes	"Medicis Aesthetics, Inc. (Scottsdale, Ariz.) provided Dysport and study funding to the authors. Michael A. C. Kane is a consultant, speaker, stockholder, and investigator for Medicis; a consultant, speaker, and stockholder for Allergan; a consultant and stockholder for Mentor; a consultant and speaker for QMed; and a consultant, investigator, and stock option holder for Revan"
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "Patients were randomised in a 2:1 ratio to one treatment of variably dosed" page 1620 Comment: we considered unclear risk of bias because the authors did not explain how they randomised the participants
Allocation concealment (selection bias)	Unclear risk	Quote: "Patients were randomised in a 2:1 ratio to one treatment of variably dosed" page 1620 Comment: we considered unclear risk of bias because the authors did not explain the methods used for maintain the allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "Double‐Blind, Placebo‐Controlled" page 1620 Comment: we considered unclear risk of bias because the authors did not explain how they blinded the participants
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "Double‐Blind, Placebo‐Controlled" page 1620. "Duration of Response Assessed by Blinded Evaluator at Maximum Frown"page 1623 Comment: we considered low risk of bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Patient disposition can be seen in Table 3. No patient discontinued because of an adverse event or lack of product efficacy". Placebo completed 265/272 (97%). Withdraw reasons: lost of follow‐up 1/272(<1%), patient decision 6/272 (2%), patient not compliant study requirements 0%. Dysport completed 534/544 (98%). Withdraw reasons: lost of follow‐up 7/544 (1%), patient decision 2/544 (<1%), patient not compliant study requirement 1/544 (<1%) page 1622 Comment: we considered this low risk of bias
Selective reporting (reporting bias)	Low risk	Duration of Response Assessed by Blinded Evaluator at Maximum Frown (table 4). In the second row: No. (%) of patients who became non responders during the study observation period, the authors reported 30/272 = 97%, but the correct percentage was 30/272 = 11% Comment: we considered this low risk of bias. We sent an e‐mail on 1st November 2015. No answer to date
Other bias	High risk	One of the authors was stockholder of pharmaceutical company Comment: we considered this high risk of bias