Brin 1999.

Methods	Randomised, multicenter, placebo‐controlled, double‐blind, two‐arm, parallel, phase III study Method of randomisation: master randomisation tables generated by an independent organisation Data analysed on an intention‐to‐treat basis Location: seven centres in the USA Duration: 16 weeks
Participants	77 participants were enrolled Placebo arm: 38 participants (1 withdrawal: 2.6%); 26 participants were female and 12 were male; mean age was 52.6 ± 13.3 (SD) years; ethnicity: all participants were White; mean duration of symptoms not stated; mean TWSTRS‐Total score at baseline: 51.2 ± 9.5 (SD). BtB 10,000 U arm: 39 participants (0 withdrawals); 27 participants were female and 12 were male; mean age was 56.6 ± 11.7 (SD); ethnicity: all participants were White; mean duration of symptoms not stated; mean TWSTRS‐Total score at baseline: 52.8 ± 8.6 (SD). Inclusion criteria: Cervical Dystonia (CD) for at least one year of duration with involvement of two or more neck muscles, and considered clinically non‐responsive to BtA treatment with an appropriate frontalis‐type A test result; TWSTRS‐Total score at baseline of at least 20 with a TWSTRS‐Severity score of at least 10, a TWSTRS‐Disability score of at least 3, and a TWSTRS‐Pain score of at least 1 Age more than 17 years‐old Weight more than 45 Kg Physical and neurological examinations and laboratory tests acceptable clinically Informed consent Exclusion criteria: Bt injections in the previous four months for CD; previous participation in a BtB trial; neck contractures or cervical spine disease that limit range of motion; pure retrocollis or anterocollis; use of drugs that could interfere with efficacy and security evaluations (e.g., narcotics, benzodiazepines); previous tetanus toxoid in the last 4 months; use of any investigational drug or device within 30 days of entry into the study; current acute or chronic medical condition or known drug hypersensitivity to the study drug that would preclude Bt injections; history of myotomy or denervation surgery of the neck; history of clinically persistent neurological or neuromuscular disorder; and women of child‐bearing potential who were pregnant or breast‐feeding
Interventions	The study drug (BtB) was provided by Athenas Neurociences, Inc in vials that contained placebo or 5000 U of BtB in a 1 ml sterile solution. Each participant was randomly assigned to one of the 2 groups: placebo or 10,000 U BtB. A total of 2 ml of the study drug was injected into 2 to 4 involved CD muscles selected by the investigator with or without the use of electromyography. Based on the investigator judgement, the proportionate volume per muscle was divided and injected into one to five sites. Each participant received only one treatment
Outcomes	The primary efficacy outcome was the change in TWSTRS‐Total score at week 4 Secondary efficacy outcomes included changes in two visual analogue scales (Patient Global Assessment of Change and Principal investigator Global Assessment of Change) at week 4, and change in TWSTRS‐Total score at weeks 8 and 12 Tertiary efficacy outcomes included change in visual analogue scale Patient Analog Pain Assessment at week 4, changes in the TWSTRS subscales scores at week 4, and change in TWSTRS‐Total score at week 16 All outcomes data were collected at treatment visit (day 1), and at weeks 2, 4, 8, 12, and 16 (termination). The results of the primary outcome were used to assess the duration of clinical benefit. Adverse events data were collected at each visit
Notes	Reasons for withdrawal: in the placebo group 1 discontinued the study because of an adverse effect Results are presented as variance of the means of the various outcome scales scores without individual data. An estimation of duration of treatment effect was made based on time to return to baseline TWSTRS‐Total score
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Master randomisation tables were generated by an independent organisation (Pharmaceutical Research Associates)." Method of randomisation not specified
Allocation concealment (selection bias)	Low risk	"Investigators, patients, and the sponsor were blinded to drug assignment until after the database was locked and analyzed"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"The study drug, provided by Athena Neurosciences, Inc. in 3.5‐mL vials containing either 5000 U of NeurBloc or placebo (same solution without toxin)." Study described as double blind
Blinding of outcome assessment (detection bias) Objective Outcomes	Low risk	"The principal investigator (PI) performed all screening assessments, (...) and performed the injection, in addition to acquiring all TWSTRS scores and the PI Global Assessment of Change."
Blinding of outcome assessment (detection bias) Subjective Outcomes	Unclear risk	"The administrative investigator (...) performed all other activities for each visit (including adverse events collection and assessment. Patients were instructed not to divulge any AE information to the principal investigator." Although placebo was identical to intervention, the fact that all of the participants had previously been treated with botulinum toxins could have led to a degree of bias
Incomplete outcome data (attrition bias) All outcomes	Low risk	Post‐randomisation exclusions were low (Placebo group = 1), and the reasons were described.
Selective reporting (reporting bias)	Low risk	"The ITT dataset was used for all analyses." The usual and more clinically relevant outcomes that are usually evaluated in intervention trials for this condition were reported in this study
Enriched population – preferential enrolment of positive responders	Low risk	Trial in botulinum toxin type A‐non‐responsive CD
Enriched population – exclusion of poor responders	High risk	"Patients were excluded if they (...) had pure anterocollis or retrocollis."
Other issues	High risk	“Supported by a grant from Athena Neurosciences, Inc.”