Jankovic 2011.

Study characteristics
Methods	Randomised, double‐blind, parallel design Randomisation: carried out in blocks of four; RANCODE Setting: multicentre Duration: 20 weeks
Participants	129 participants enrolled (BtA group = 75; placebo group = 34) % Female: BtA: 65%; placebo: 65% Mean age (range): BtA: 61.5 years (SD 11); placebo: 62.6 years (SD 8.7) Mean blepharospasm duration: BtA: 233.2 months; placebo: 278 months Mean blepharospasm severity (SD) using JRS total score: BtA: 5.87 (1.49); placebo: 5.76 (1.23) Inclusion criteria: 18 years to 80 years of age blepharospasm diagnosis, with a minimum JRS severity subscore ≥ 2 stable satisfactory therapeutic response directly prior to trial entry Exclusion criteria: atypical variant of benign essential blepharospasm caused by inhibition of levator palpebrae muscle myotomy or denervation surgery in the affected muscles (e.g. peripheral denervation and/or spinal cord stimulation) previous two injections with BtA with more than 50 units per eye treatment with BtA for any indication other than benign essential blepharospasm within 4 months prior to baseline assessment and during the trial medical conditions or treatments known to be contraindicated for the injection of onabotulinumtoxinA
Interventions	BtA dose, dilution, volume, and injection site were selected based on the last 2 BtA treatments (± 10%) prior to the start of the study, up to a maximum of 50 units per eye. Each participant received only one treatment in each eye. BtA: Xeomin (incobotulinumtoxinA); vials were reconstituted with 0.9% sodium chloride up to 50 units per eye Placebo: matching Study drug preparation: BtA provided in vials by Merz EMG guidance: no
Outcomes	Primary outcome: Jankovic Rating Scale severity subscore Secondary outcomes: Blepharospasm Disability Index participant evaluation of global response at final visit global assessment of efficacy and tolerability at the end of the trial using a 4‐point Likert scale ranging from 1 to 4 time from injection to onset of treatment effect time to waning of treatment effect based on participants’ subjective assessments time from injection to re‐treatment (the difference between treatment effect onset and treatment effect waning)
Notes	Merz Pharmaceuticals GmbH (Frankfurt, Germany) was responsible for the funding, conduct, data collection, and statistical analysis of the study. Authors had full access to all study data.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	‘Patients were randomised by personnel not involved in other study procedures (…) using RANCODE version 3.6 (IDV, Gauting, Germany) for blockwise randomization (…), ensuring stratification by center.’
Allocation concealment (selection bias)	Low risk	Comment: method of concealment not specified
Blinding of participants and personnel (performance bias) All outcomes	Low risk	‘Investigators and patients were blinded to the treatment assignment: placebo and incobotulinumtoxinA vials had the same appearance, and neither the investigator nor other medical staff or any subject knew the identity of individual study medication.’
Blinding of outcome assessment (detection bias) Objective outcomes	Low risk	‘JRS (both subscores) and the BSDI assessments were performed at each visit by the same blinded, independent rater, who was not involved in any other trial procedure.’
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	‘A second investigator was responsible for all other assessments and procedures during the course of the trial.’ Comment: Investigator blinding not specified. Although placebo was identical to intervention, the fact that all of the participants were previously treated with botulinum toxin could have led to a degree of bias.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: post‐randomisation exclusions were low and roughly distributed evenly between groups (BtA group = 5/75; Placebo group = 2/34). The reasons are described and ‘no patient discontinued prematurely because of adverse events or insufficient efficacy’.
Selective reporting (reporting bias)	Low risk	‘Efficacy was analyzed using the full analysis set (FAS) population, which included all randomised patients.’ ‘All patients who received the trial medication were included in the descriptive safety analysis.’ Comment: The outcomes mentioned in the study protocol matched the outcomes reported in the study.
Enriched population ‐ predominant enrolment of positive responders	High risk	Enriched population due to exclusive enrolment of people responsive to previous botulinum toxin treatment. ‘A documented stable therapeutic response to the last 2 consecutive injections with onabotulinumtoxinA.’
Enriched population ‐ exclusion of poor responders	Low risk	Exclusion of people known to have poorer response to treatment, such as eyelid ataxia.
For‐profit bias	High risk	Comment: study funded by Merz Pharmaceuticals GmbH