. 2019 Oct 8;2019(10):CD001408. doi: 10.1002/14651858.CD001408.pub2

Scholtes 2006.

Methods	Method of randomisation: computer‐generated random blocks of 4 stratified per centre Blinding: no blinding Intention‐to‐treat analysis: no Loss of follow‐up: 1 child from the control group dropped out at the parent's request Unit of analysis: child
Participants	Place: 4 centres in the Netherlands Period of study: patients recruited from October 2001 and March 2003 Number assigned: Scholtes 2006a and Scholtes 2007: 47 Van der Houwen 2011: 22 Number assessed: Scholtes 2006a and Scholtes 2007: 46 23 BoNT‐A group 23 control group Van der Houwen 2011: 22 12 BoNT‐A group 10 control group Inclusion criteria: Children with CP (spastic diplegia and hemiplegia) Aged 4 to 12 years Lower limb spasticity in 2 or more muscle groups interfering with mobility GMFCS levels I to IV Gait with persistent knee flexion in stance Ability to carry out instructions Knowledge of the Dutch language Ability to walk 6 strides successfully (only in Van der Houwen 2011) Exclusion criteria: BoNT‐A treatment in the preceding 16 weeks Orthopaedic surgery in the preceding 24 weeks Contraindications for BoNT‐A, general anaesthesia Orthopaedic deformities and severe fixed contractures Ataxia or dyskinesia Other problems affecting walking Age: BoNT‐A group (mean/SD): 8.1/2.3 Control group (mean/SD): 7.1/2.3 Gender: BoNT‐A group: 16 males; 7 females Control group: 16 males; 7 females Motor distribution: BoNT‐A group: 20 diplegia; 3 hemiplegia Control group: 22 diplegia; 1 hemiplegia GMFCS BoNT‐A group: 9 level I; 3 level II; 10 level III; 1 level IV; 0 level V Control group: 9 level I; 4 level II; 7 level III; 3 level IV; 0 level V
Interventions	BoNT‐A group: Single‐cycle multilevel BoNT‐A injections (onabotulinumtoxinA) 4 to 6 U/kg/muscle group). Maximum dose of 25 U/kg for children < 5 years and 30 U/kg for children ≧ 6 years. Muscle selection was based on gait analysis and clinical examination. Comprehensive rehabilitation. Each child was treated 3 to 5x/week for 12 weeks by a physiotherapist (45‐ to 60‐minute sessions). Serial casting was used if ankle dorsiflexion < 0° Stiff insoles or AFOs were used if required Control group: Usual physiotherapy (low intensity, 1 to 2 sessions of 30 to 60 minutes per week, some used orthoses) After 18 to 30 weeks, children in the control group were also treated with BoNT‐A injections following the same protocol as the intervention group
Outcomes	Length of follow‐up: Scholtes 2006a Follow‐up of 12 months BoNT‐A group: assessments at baseline, 6, 12, 24, and 48 weeks Control group: assessments every 6 weeks in the control phase. Assessments at baseline, 6, 12, 24, and 48 weeks in the intervention phase Scholtes 2007 Follow‐up of 6 months BoNT‐A group: assessments at baseline, 6, 12, and 24 weeks. Gait analysis performed only at baseline, 6 and 24 weeks. Control group: 2 assessments with a mean interval of 24.61 weeks (SD 5.7; range 18 to 30) Van der Houwen 2011 Follow‐up of 6 weeks Assessments at baseline and 6 weeks Primary outcomes: Scholtes 2006a Gross Motor Function Measure‐66 Scholtes 2007 Edinburgh visual Gait Analysis Interval Testing (GAIT) scale Van der Houwen 2011 Dynamic video electromyography Secondary outcomes: Scholtes 2006a Gross energy cost of walking (subgroup of 24 children) Parent self‐reported problem score Scholtes 2007 Range of motion Spasticity (even though it was not stated, the description matches the Tardieu Scale)
Notes	Comments: Since all children in this trial received a BoNT‐A injection in the end, it also included a before‐after type analysis for the entire cohort. For the purposes of this review, we only evaluated the comparisons between the intervention group and the control phase of the control group. Some of the outcomes reported on in this trial were not within the scope of this review and were not used (energy of walking, problem score, electromyography). Source of funding: supported by the Johanna Kinderfonds (grant no. 2000/0145); Prinses Beatrix Fonds (grant no. PGO01‐134), and Stichting Bio‐Kinderrevalidatie, the Netherlands. Study medication was self‐supported by the Department of Rehabilitation Medicine, VU University Medical Center. Conflicts of interest: the study authors declare no conflicts of interest
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Comment: computer‐generated sequence
Allocation concealment (selection bias)	High risk	Comment: not described. Likely no concealed allocation due to the nature of the interventions
Blinding of participants and personnel (performance bias)   All outcomes	High risk	Comment: no blinding
Blinding of outcome assessment (detection bias)   All outcomes	Unclear risk	Comment: the gait assessment was done by an independent researcher who had no knowledge of the group allocation
Incomplete outcome data (attrition bias)   All outcomes	Low risk	Comment: energy cost measures were available only for a subset of children. However, this outcome was not addressed in our review.
Selective reporting (reporting bias)	Unclear risk	Comment: study protocol not available. It appears that the relevant outcomes were addressed.
Other bias	Low risk	Comment: no other sources of bias identified