Repeated injection cycles with abobotulinumtoxinA, a botulinum toxin type A, are recommended in current clinical guidelines as a treatment option for adults with upper limb spastic paresis. However, the magnitude of the maximal therapeutic effect of repeated abobotulinumtoxinA treatment across different efficacy parameters and the number of injection cycles required to reach maximal effect remain to be elucidated. Here, we present a post hoc exploratory analysis of a randomized, double-blind, placebo-controlled trial (12-24 weeks; NCT01313299) and open-label extension study (up to 12 months; NCT0131331), in patients aged 18-80 years with hemiparesis for ≥6 months after stroke/traumatic brain injury. Two inferential methods were used to assess the changes in efficacy parameters after repeat abobotulinumtoxinA treatment cycles: Mixed Model Repeated Measures analysis and Non-Linear Random Coefficients analysis. Using the latter model, the expected maximal effect size (not placebo-controlled) and the number of treatment cycles to reach 90% of this maximal effect were estimated. Treatment responses in terms of passive and perceived parameters (i.e. modified Ashworth scale in primary target muscle group, disability assessment scale for principal target for treatment or limb position, and angle of catch at fast speed) were estimated to reach near-maximal effect in two to three cycles. Near-maximal treatment effect for active parameters (i.e. active range of motion against the resistance of extrinsic finger flexors and active function, assessed by the Modified Frenchay Scale) was estimated to be reached one to two cycles later. In contrast to most parameters, active function showed greater improvements at Week 12 (estimated maximal change from baseline-modified Frenchay Scale overall score: +0.8 (95% confidence interval, 0.6; 1.0) than at Week 4 (+0.6 [95% confidence interval, 0.4; 0.8]). Overall, the analyses suggest that repeated treatment cycles with abobotulinumtoxinA in patients chronically affected with upper limb spastic paresis allow them to relearn how to use the affected arm with now looser antagonists. Future studies should assess active parameters as primary outcome measures over repeated treatment cycles, and assess efficacy at the 12-week time-point of each cycle, as the benefits of abobotulinumtoxinA may be underestimated in the studies of insufficient duration. Abbreviated summary In this post hoc analysis of repeated abobotulinumtoxinA injection cycles in upper limb spastic paresis, Gracies et al. used statistical modelling to elucidate the maximal therapeutic effect of abobotulinumtoxinA. Notably, the number of injections required to reach this maximal effect was higher for active (e.g. active function) compared with passive (e.g. tone) parameters.

2nd Department of Neurology Comenius University Faculty of Medicine and University Hospital Bratislava Bratislava Slovak Republic

Brain Injury Rehabilitation Unit National Institute for Medical Rehabilitation Budapest Hungary

Delafont Statistics Alençon France

Department of Biomedical and Biotechnological Sciences University of Catania Catania Italy

Department of Neurology and Center of Clinical Neuroscience Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Ipsen Pharma Les Ulis France

Physical Medicine and Rehabilitation Unit A O U Policlinico Vittorio Emanuele Catania Italy

Service de médecine physique et réadaptation Hôpital Rangueil Toulouse France

UR 7377 BIOTN Université Paris Est Créteil Service de Rééducation Neurolocomotrice Hôpitaux Universitaires Henri Mondor Créteil France

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Baude M, Mardale V, Loche CM, Hutin E, Gracies JM, Bayle N. Intra- and inter-rater reliability of the Modified Frenchay Scale to measure active upper limb function in hemiparetic patients. Ann Phys Rehabil Med 2016; 59: e59–60.

Bayle N, Maisonobe P, Raymond R, Balcaitiene J, Gracies J-M. Composite active range of motion (CXA) and relationship with active function in upper and lower limb spastic paresis. Clin Rehabil 2020; 34: 803–11. PubMed PMC

Brashear A, Zafonte R, Corcoran M, Galvez-Jimenez N, Gracies JM, Gordon MF, et al.Inter- and intrarater reliability of the Ashworth Scale and the Disability Assessment Scale in patients with upper-limb poststroke spasticity. Arch Phys Med Rehabil 2002; 83: 1349–54. PubMed

Dashtipour K, Chen JJ, Walker HW, Lee MY. Systematic literature review of abobotulinumtoxinA in clinical trials for adult upper limb spasticity. Am J Phys Med Rehabil 2015; 94: 229–38. PubMed PMC

Delafont B, Carroll K, Vilain C, Pham E. Investigation of mixed model repeated measures analyses and non-linear random coefficient models in the context of long-term efficacy data. Pharm Stat 2018; 17: 515–26. PubMed

Francis HP, Wade DT, Turner-Stokes L, Kingswell RS, Dott CS, Coxon EA. Does reducing spasticity translate into functional benefit? An exploratory meta-analysis. J Neurol Neurosurg Psychiatry 2004; 75: 1547–51. PubMed PMC

Gordon MF, Brashear A, Elovic E, Kassicieh D, Marciniak C, Liu J, for the BOTOX Poststroke Spasticity Study Group, et al.Repeated dosing of botulinum toxin type A for upper limb spasticity following stroke. Neurology 2004; 63: 1971–3. PubMed

Gracies JM, Bayle N, Vinti M, Alkandari S, Vu P, Loche CM, et al.Five-step clinical assessment in spastic paresis. Eur J Phys Rehabil Med 2010; 46: 411–21. PubMed

Gracies JM, Brashear A, Jech R, McAllister P, Banach M, Valkovic P, et al.Safety and efficacy of abobotulinumtoxinA for hemiparesis in adults with upper limb spasticity after stroke or traumatic brain injury: a double-blind randomised controlled trial. Lancet Neurol 2015; 14: 992–1001. PubMed

Gracies JM, O’Dell M, Vecchio M, Hedera P, Kocer S, Rudzinska-Bar M, for the International AbobotulinumtoxinA Adult Upper Limb Spasticity Study Group, et al.Effects of repeated abobotulinumtoxinA injections in upper limb spasticity. Muscle Nerve 2018; 57: 245–54. PubMed PMC

Gracies JM, Yablon SA, Raghavan P, Barbano R, Brashear A, Simpson D. Article 10: relationship between active function and tone in a placebo-controlled study of botulinum neurotoxin vs tizanidine in upper limb spasticity. Arch Phys Med Rehabil 2009; 90: e5–6.

Pila O, Duret C, Gracies J-M, Francisco GE, Bayle N, Hutin É. Evolution of upper limb kinematics four years after subacute robot-assisted rehabilitation in stroke patients. Int J Neurosci 2018; 128: 1030–9. PubMed

Prakash A, Risser RC, Mallinckrodt CH. The impact of analytic method on interpretation of outcomes in longitudinal clinical trials. Int J Clin Pract 2008; 62: 1147–58. PubMed PMC

Royal College of Physicians. Spasticity in adults: management using botulinum toxin. National guidelines 2018. Available at:” https://www.rcplondon.ac.uk/guidelines-policy/spasticity-adults-management-using-botulinum-toxin (5 June 2018, accessed).

Sheean GL. Botulinum treatment of spasticity: why is it so difficult to show a functional benefit? Curr Opin Neurol 2001; 14: 771–6. PubMed

Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW, Gronseth GS, et al.Practice guideline update summary: botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2016; 86: 1818–26. PubMed PMC

World Health Organization. International classification of functioning, disability and health: ICF. Geneva: World Health Organization; 2001.