Botulinum toxin treatment of spasticity targeted to muscle endplates: an international, randomised, evaluator-blinded study comparing two different botulinum toxin injection strategies for the treatment of upper limb spasticity

Abstract

Objectives: The therapeutic effects of botulinum neurotoxin (BoNT) are well documented in upper limb spasticity. However, several factors may influence treatment efficacy, including targeting of neuromuscular junctions (NMJs). We examined whether NMJ-targeted BoNT injections were non-inferior, in terms of efficacy, to current injection practices.

Design: Open-label prospective evaluator-blinded study.

Setting: Conducted across 20 medical centres in Denmark, Finland, Norway and Sweden (24 September 2012 to 11 March 2015).

Participants: Aged ˃18 years with upper limb spasticity (Modified Ashworth Scale [MAS] score of 2 or 3) following stroke or traumatic brain injury, had received ≥2 consecutive BoNT-A treatment cycles (the latest of which was abobotulinumtoxinA [aboBoNT-A]) and needed BoNT-A retreatment (same modality as previous cycle). Patients requiring aboBoNT-A doses >800units were excluded. In total, 88 patients were randomised (intention-to-treat [ITT] population), most were male (n=58/88, 65.9%) and 54/88 (61.4%) completed the study (per protocol [PP] population).

Interventions: Randomisation (1:1) to receive a single dose of aboBoNT-A (≤800 U) according to either current clinical practice (300 U/mL) or as an NMJ-targeted injection (100 U/mL).

Primary outcome measure: Proportion of patients with a ≥1 level reduction from baseline in MAS score at week 4 post-injection (responders).

Results: In the ITT population, the proportion of responders at elbow flexors was 72.7% in the current practice group and 56.8% in the NMJ-targeted group (adjusted difference -0.1673 [95% CIs: -0.3630 to 0.0284]; p=0.0986). Similar results were observed in the PP population (69.0% vs 68.0%, respectively, adjusted difference 0.0707 [-0.1948 to 0.3362]; p=0.6052).

Conclusions: Owing to the limited number of participants, non-inferiority of NMJ-targeted injections could not be determined. However, there was no statistical difference between groups. Larger studies are needed confirm whether the two techniques offer comparable efficacy.

Trial registration number: NCT01682148.

Keywords: abobotulinumtoxina; bont; botulinum toxin; neuromuscular junctions; nmj zone.

Conflict of interest statement

Competing interests: The authors have, during the last 3 years, received educational support from the sponsor, Ipsen AB and/or served as consultants for the sponsor. The sponsor contributed to the design of the study; in the collection, analyses/interpretation of data; in the writing of the manuscript and in the decision to publish the results.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Study design. *If no routine BoNT-A treatment was given at visit 3, max 24 weeks poststudy injection. NMJ, neuromuscular junction.

Figure 2

Proportion (%) of responders at week 4 (≥1 level decrease in MAS from baseline). Adjusted difference of ratios for each population (95% CI): ITT: −0.1673 (–0.3630 to 0.0284) p=0.0986; PP: 0.0707 (–0.1948 to 0.3362) p=0.6052. Non-inferiority was not demonstrated. ITT, intention-to-treat; MAS, Modified Ashworth Scale; NMJ, neuromuscular junction; PP, per protocol.

Figure 3

Mean (SD) change in MAS in elbow flexors at week 4compared with baseline. ITT, intention-to-treat; MAS, Modified Ashworth Scale; NMJ, neuromuscular junction; PP, per protocol.