Gracies 2015.

Methods	Randomised controlled trial (3 arms). Setting: 34 neurology or rehabilitation clinics in 9 countries (Belgium, Czech Republic, France, Hungary, Italy, Poland, Russia, Slovakia, USA). Funding: Ipsen (pharmaceutical company).
Participants	Total participants: 243 overall study, including 23 with TBI (65% male), for whom results were presented separately. Number of participants in each study arm: 9 (placebo), 8 (abobotulinumtoxinA 500 U) and 6 (abobotulinumtoxinA 1000 U). Adults: 23, children: 0. People with TBI: mean age 35 years (SD 13, range not reported). Inclusion criteria: aged 18‐80 years; hemiparesis for at least 6 months post TBI (or stroke); Modified Ashworth Scale score in the target muscle group ≥ 2 (if never had botulinum toxin injection) or ≥ 3 (if had botulinum toxin A injection before); Disability Assessment Scale score ≥ 2 on the principal target of treatment; spasticity angle of least 10° in the primary target muscle group and mean Modified Frenchay Score of 1‐8 (out of possible 10). Exclusion criteria: major limitations of passive range of motion in the paretic limb; intrathecal baclofen or physiotherapy initiated < 4 weeks prior to expected enrolment; anticipated botulinum toxin A treatment during study period; administration of any alcohol or phenol in the study limb any time before the study; previous primary or secondary non‐response to any botulinum toxin for the targeted condition; previous surgery to treat spasticity of the affected upper limb; any medical disorder increasing the risk of adverse events from botulinum toxin A administration; major additional neurological impairment that could affect functional performance; known disease of the neuromuscular junction; known sensitivity to botulinum toxin or any excipient of Dysport; infection at the injection site(s); any current or planned treatment that interferes with neuromuscular function; pregnant or women not willing to use contraception. Location of spasticity: upper limb: elbow flexors, wrist flexors, finger flexors. For each participant, the investigators selected the most hypertonic muscle group (defined by Modified Ashworth Scale score) out of elbow flexors, wrist flexors and finger flexors, and gave an additional injection to 2 other muscle groups (including these groups + shoulder extensors).
Interventions	AbobotulinumtoxinA 500 U: 2 vials (1 of placebo and 1 of abobotulinumtoxinA 500 U) were each diluted with 2.5 mL saline and combined into a single injection of 5 mL solution. This was injected into target muscle group and at least 2 other muscle groups (guided by electrical stimulation to identify the correct location). AbobotulinumtoxinA 1000 U: same as above (except 2 vials of active compound were used). Placebo: same as above (except 2 vials of placebo were used).
Outcomes	Outcome assessed at: baseline, and 1, 4 and 12 weeks. Primary outcomes: spasticity/muscle tone: Tardieu Scale (at 4 weeks); safety assessments (adverse events). Secondary outcomes: upper limb function using the Disability Assessment Scale (4‐point scale); quality of life (subscores of the SF‐36 and the EQ‐5D). Length of follow‐up: 12 weeks.
Notes	The full study (Gracies 2015) included more than just participants with TBI, but the results for participants with TBI were presented separately in the conference abstract by (O'Dell 2015). However, these results did not distinguish between different dosages and reported results as if for a 2‐armed trial (abobotulinumtoxinA 550 U and abobotulinumtoxinA 1000 U vs placebo). This study also measured spasticity using the Modified Ashworth Scale, but we reported Tardieu Scale results given we prespecified this as our preferred measure. The authors also used the Physician Global Assessment scale for assessing the 'severity' of a condition. Given this is not a brain injury or rehabilitation‐specific measure, neither is it clear which functional domain this outcome fitted within, this outcome was not included in the review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"Patients were randomly allocated in a ratio of 1:1:1.... Computer‐generated randomisation lists were created by a sponsor statistician independent from the study..." Furthermore, "randomisation was stratified by botulinum‐toxin‐A treatment status at baseline only... irrespective of the centre of recruitment or of the cause of spastic paresis.... no rationale exists for stratification of patients by cause [stroke and traumatic brain injury]."
Allocation concealment (selection bias)	Low risk	"Computer‐generated randomisation lists were created by a sponsor statistician independent from the study and treatment numbers were assigned when patients entered the study with a 24‐h interactive response system from an external contract research organisation..."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"A double‐dummy technique was used to maintain masking of patients and investigators. A treatment pack contained two vials of abobotulinumtoxinA 500 U (1000 U group), one vial of abobotulinumtoxinA 500 U plus one vial of placebo (500 U group), or two vials of placebo (placebo group). The [treatment] packs were identical in appearance and the procedure for reconstitution in each group was identical."
Blinding of outcome assessment (detection bias) All outcomes	Low risk	"The [treatment] packs were identical in appearance and the procedure for reconstitution in each group was identical."
Incomplete outcome data (attrition bias)	Low risk	In the main study (of which the TBI participants formed a subgroup of < 10%, i.e. 23 of 243 participants) reported that > 94% of those randomised completed the study to 12‐week follow‐up and that those lost were relatively evenly spread between groups. Reasons for discontinuation were provided, and ITT methods for missing data appeared appropriate. In the subgroup reported in a conference abstract, it would appear that all participants with TBI were retained within the study.
Selective reporting (reporting bias)	Unclear risk	Study protocol was registered on clinicaltrials.gov (NCT01313299). Outcome data reported appeared in line with those prospectively stated; however, for the TBI subset of participants included in this review, outcome data for different doses of the active intervention were conflated and results were given in the form of percentages only.
Baseline Imbalances	Unclear risk	Baseline characteristics were described as "similar" between the 3 groups, but no specific reference was made to the those in the TBI subgroup, wherein the differences in years since traumatic event were larger than for those with stroke. It is reported that "a majority" (74%) of the TBI group had previously received botulinum toxin treatment, but it was not reported whether this differed between intervention groups and placebo.
Appropriate study design (cross‐over trial only)	Low risk	Not relevant, not a cross‐over trial.
Adequate washout period (cross‐over trial only)	Low risk	Not relevant, not a cross‐over trial.
Other bias	Unclear risk	Authors reported that both the "funder and the corresponding author were jointly involved in the study design, data gathering, data management, and statistical analysis. With the exception of the four authors (FC, BBDF, CV, and PP) who were employees of the funder, the funder had no role in the interpretation of the data or in the decision to submit the manuscript for publication. The funder funded editorial assistance provided during the writing of the manuscript. All authors had full access to all the data in the study and final responsibility for the decision to submit the paper for publication."