Rzany 2006.

Study characteristics
Methods	Study design‐ multicentre, randomised, double‐blind, placebo‐controlled, parallel‐design in forehead lines Study date‐ no information Study setting‐ outpatients from 23 centres
Participants	Randomised‐ 221 participants, with mean age of 6.6 ± 9.2 years in arm 1; 46.4 ± 8.1 years in arm 2. Gender: 98/ 109(89.9%) female in arm 1, 100/111 (90.1%) female in arm 2 Inclusion criteria Aged 18 to 75 years; had moderate or severe vertical or diagonal glabellar wrinkles (scores of 2 or 3 on a standardised 4‐point clinical scale ranging from 0 [no wrinkles] to 3 [severe wrinkles]) at maximum frown; and had mild, moderate, or severe (scores of 1, 2, or 3) vertical or diagonal glabellar wrinkles at rest Women of childbearing potential with a negative pregnancy test result before enrolment in the study Exclusion criteria‐ no information Severity of disease‐ moderate or severe vertical or diagonal glabellar wrinkles (scores of 2 or 3 on a standardised 4‐point clinical scale ranging from 0 [no wrinkles] to 3 [severe wrinkles]) at maximum frown; and had mild, moderate, or severe (scores of 1, 2, or 3) vertical or diagonal glabellar wrinkles at rest. Ethnicity‐ Quote:Quote: "Only 1 patient, in study arm 2, was not white"
Interventions	Duration of study‐ 16 weeks Arm 1‐ 3 injections (N = 110) Intervention AbobotulinumtoxinA (30 U), 3 injection sites covered the medial parts of the corrugator muscles and parts of the procerus muscle (N = 73) Comparator  Placebo 0.05 mL/site, 3 injection sites covered the medial parts of the corrugator muscles and parts of the procerus muscle (N = 37) Arm 2‐ 5 injections (N = 111) Intervention AbobotulinumtoxinA (50 U), 3 injection sites covered the medial parts of the corrugator muscles and parts of the procerus muscle and two additional ones in frontalis muscle (N = 73) Comparator Placebo 0.05 mL per site, 3 injection sites covered the medial parts of the corrugator muscles and parts of the procerus muscle and two additional ones in frontalis muscle (N = 38)
Outcomes	Primary outcome Percentage of responder rates at maximum glabellar frown between weeks 0 and 4 Secondary outcomes Scores at maximum frown (evaluated by the committee) at weeks 0, 2, 4, 12, and 16 (data not show) Scores at rest (evaluated by the committee) at weeks 0, 2, 4, 12, and 16 Scores at maximum frown and at rest (evaluated by the investigator) at weeks 0, 2, 4, 12, and 16 Subjective assessment of improvement since the first visit (evaluated by the patient) at weeks 2, 4, 12, and 16 Assessment of patients’ global satisfaction with the treatment at week 16 Adverse events
Notes	"Financial Disclosure: Dr Rzany has received grants from Ipsen Pharma, Ettlingen, as well as from Pharma Allergan, Ettlingen, for other clinical trials not related to this study. Dr Rzany also has received honoraria from Ipsen Pharma for consulting and for conducting educational workshops. Funding/Support: This study was supported by a grant from Ipsen Pharma."
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "This was a double‐blind, placebo‐controlled, randomised" page 321 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: "Within each centre, patients were randomised 2:1 to receive botulinum toxin A or placebo" page 321 Comment: we considered this unclear risk of bias because the authors did not explain the methods for allocation concealment
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Quote: "This was a double‐blind, placebo‐controlled,"page 321 Comment: we considered this unclear risk of bias because the authors did not explain how they blinded the participants (patients)
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Quote: "This was a double‐blind, placebo‐controlled" page 321 Comment: we considered this unclear risk of bias because the authors did not explain how they blinded the participants (patients)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Quote: "All but 1 patient (in study arm 1) were included in the intention‐to‐treat analysis." page 322 Comment: we considered this unclear risk of bias, because the authors did not explain the reason of drop outs
Selective reporting (reporting bias)	High risk	Quote: "the scores at maximum frown and at rest (evaluated by the investigator) at weeks 0, 2, 4, 12, and 16 (data not shown); the subjective assessment of improvement since the first visit (evaluated by the patient) at weeks 2, 4, 12, and 16 (data not shown)" page 322 Comment: we considered a high risk of bias. We sent an e‐mail on 28 November 2015. He answer on 14 December 2015: "Concerning the data. This was an IPSEN initiated trial. All analysis was done through IPSEN. I would suggest that you contact IPSEN directly. I cced Dr. Caird in who was at that time responsible for the study."
Other bias	High risk	Pharmaceutical support: "Concerning the data. This was an IPSEN initiated trial. All analysis was done through IPSEN. I would suggest that you contact IPSEN directly. I cced Dr. Caird in who was at that time responsible for the study." Comment: we considered this high risk of bias