Charles 2012.

Methods	Randomised, double‐blind, parallel design Randomisation: carried out in blocks of four; method not described Setting: multicentre (22 centres in the USA, 1 in Canada) Duration: 10 weeks
Participants	170 participants enrolled (BtA group = 88; placebo group = 82) % Female: BtA: 70%; placebo: 80% Mean age, range: BtA: 55 years; placebo: 55 years Mean CD duration: BtA: 11.2 years; placebo: 9.1 years Mean CD severity, SD (CDSS): BtA: 9.2, 4.8; placebo: 9.3, 4.2 Inclusion criteria: 21‐75 years of age idiopathic CD with a minimum score of 4 on the CDSS ≥ 2 previous successful treatments with ≤ 360 U of Botox administered at 12‐ to 16‐week intervals Exclusion criteria: previous treatment with onabotulinumtoxinA for any other indication pure anterocollis or isolated head shift pregnancy profound atrophy of cervical musculature medical conditions or treatments known to be contraindicated for the injection of onabotulinumtoxinA
Interventions	BtA: Botox (onabotulinumtoxinA); 25 ng of neurotoxin complex protein per 100 U, diluted with 1 mL sterile solution Placebo: 0.5 mg of human serum albumin and 0.9 mg of sodium chloride Study drug preparation: BtA provided in vials by Allergan Muscles injected: the doses and muscles injected were determined by the physician based on clinical assessment EMG guidance: no BtA dose per participant: maximum: 360 U; mean, range: 236 U, 91 U‐360 U
Outcomes	Primary outcomes: CDSS (range, 0‐54) at week 4 Physician GAS (range, ‐4 to +4; ‐4: very marked worsening, +4: complete remission) at week 6 Secondary outcomes: Functional disability (range, 0‐4; 0: no disability, 4: extreme disability) Range of cervical motion Participant assessment of pain (5‐point scale for both frequency and intensity) Frequency of pain (range, 0‐4; 0: never, 4: constant) Intensity of pain (range, 0‐4; 0: none, 4: very severity) Participant GAS (range, ‐4 to +4; ‐4: very marked worsening, +4: complete remission) Adverse events Time to treatment failure Plasma neutralising antibodies
Notes	This was a 2‐period clinical trial consisting of a 10‐week open‐label period followed by a 10‐week double‐blind period, with up to 6 weeks between periods. Participants who successfully completed the open phase (i.e. responded to BtA and were compliant with the study protocol) were enrolled into the blinded phase. 214 participants were enrolled in Period I, of whom 170 continued into Period II. We only considered the results of the blinded phase in this review. Study discontinuations, reasons: BtA: n = 11 (13%), lack of efficacy: n = 8, unrelated reasons: n = 3 Placebo: n = 24 (29%), lack of efficacy: n = 19, unrelated reasons: n = 5
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Comment: method of randomisation not specified
Allocation concealment (selection bias)	Unclear risk	Comment: method of concealment not specified
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Comment: blinding not specified although study described as double‐blind
Blinding of outcome assessment (detection bias) Objective outcomes	Unclear risk	Comment: blinding not specified although study described as double‐blind
Blinding of outcome assessment (detection bias) Subjective outcomes	Unclear risk	Comment: blinding not specified although study described as double‐blind
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: post‐randomisation exclusions were described as related to lack of efficacy or administrative reasons
Selective reporting (reporting bias)	Low risk	Comment: the expected outcomes that are usually evaluated in intervention trials for this condition were reported in this study
For‐profit bias	High risk	The study was supported by Allergan.
Enriched population – preferential enrolment of positive responders	High risk	Comment: to enrol in the study, participants had to have had at least 2 previous successful treatments with ≤ 360 U of Botox administered at 12‐ to 16‐week intervals. Also, all participants enrolled in phase II were compliant to treatment during phase I trial.
Enriched population – exclusion of poor responders	High risk	Quote: "Pure anterocollis and isolated head shift was exclusionary"