Abstract
Background: Resistance from antagonistic muscle groups might be a crucial factor reducing function in chronic hemiparesis. The resistance due to spastic co-contraction might be reduced by botulinum toxin injections. We assessed the effects of abobotulinumtoxinA injection in the upper limb muscles on muscle tone, spasticity, active movement, and function. Methods: In this randomised, placebo-controlled, double-blind study, we enrolled adults (aged 18-80 years) at least 6 months after stroke or brain trauma from 34 neurology or rehabilitation clinics in Europe and the USA. Eligible participants were randomly allocated in a 1:1:1 ratio with a computer-generated list to receive a single injection session of abobotulinumtoxinA 500 U or 1000 U or placebo into the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and into at least two additional muscle groups from the elbow, wrist, or finger flexors or shoulder extensors. Patients and investigators were masked to treatment allocation. The primary endpoint was the change in muscle tone (Modified Ashworth Scale [MAS]) in the PTMG from baseline to 4 weeks. Secondary endpoints were Physician Global Assessment (PGA) at week 4 and change from baseline to 4 weeks in the perceived function (Disability Assessment Scale [DAS]) in the principal target of treatment, selected by the patient together with physician from four functional domains (dressing, hygiene, limb position, and pain). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01313299. Findings: 243 patients were randomly allocated to placebo (n=81), abobotulinumtoxinA 500 U (n=81), or abobotulinumtoxinA 1000 U (n=81). Mean change in MAS score from baseline at week 4 in the PTMG was -0·3 (SD 0·6) in the placebo group (n=79), -1·2 (1·0) in the abobotulinumtoxinA 500 U group (n=80; difference -0·9, 95% CI -1·2 to -0·6; p<0·0001 vs placebo), and -1·4 (1·1) in the abobotulinumtoxinA 1000 U group (n=79; -1·1, -1·4 to -0·8; p<0·0001 vs placebo). Mean PGA score at week 4 was 0·6 (SD 1·0) in the placebo group (n=78), 1·4 (1·1) in the abobotulinumtoxinA 500 U group (n=80; p=0·0003 vs placebo), and 1·8 (1·1) in the abobotulinumtoxinA 1000 U group (n=78; p<0·0001 vs placebo). Mean change from baseline at week 4 in DAS score for the principal target of treatment was -0·5 (0·7) in the placebo group (n=79), -0·7 (0·8) in the abobotulinumtoxinA 500 U group (n=80; p=0·2560 vs placebo), and -0·7 (0·7) in the abobotulinumtoxinA 1000 U group (n=78; p=0·0772 vs placebo). Three serious adverse events occurred in each group and none were treatment related; two resulted in death (from pulmonary oedema in the placebo group and a pre-existing unspecified cardiovascular disorder in the abobotulinumtoxinA 500 U group). Adverse events that were thought to be treatment related occurred in two (2%), six (7%), and seven (9%) patients in the placebo, abobotulinumtoxinA 500 U, and abobotulinumtoxinA 1000 U groups, respectively. The most common treatment-related adverse event was mild muscle weakness. All adverse events were mild or moderate. Interpretation: AbobotulinumtoxinA at doses of 500 U or 1000 U injected into upper limb muscles provided tone reduction and clinical benefit in hemiparesis. Future research into the treatment of spastic paresis with botulinum toxin should use active movement and function as primary outcome measures.
| Original language | English (US) |
|---|---|
| Article number | 148 |
| Pages (from-to) | 992-1001 |
| Number of pages | 10 |
| Journal | The Lancet Neurology |
| Volume | 14 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2015 |
Funding
J-MG served as a consultant and received research grant support from Allergan, Ipsen, and Merz. AB served as a consultant for Concerta, Ipsen, and Allergan, and she has received research and salary support from the National Institute of Neurological Disorders and Stroke. AB was paid by the Wake Forest School of Medicine and the research funds go to the Wake Forest School of Medicine. MB has received training fees and meeting sponsorship from Ipsen and Merz. HW has received consultancy stipends from Merz and Ipsen. CM has received research grant support through her institution from Allergan, Ipsen, and Merz, and was on an advisory board for Ipsen but did not receive any compensation. TD served as a consultant for Allergan, Ipsen, and Merz. SK received training fees and meeting sponsorship from Ipsen, Merz, and Allergan. FG has received compensation from Ipsen for being an advisory board member and support from Allergan for consultancy, speaking engagements, and preceptorship. PM has received compensation for consulting, speakers' bureaus, and conducting clinical trials for Allergan, Ipsen, and Merz. RJ has received grants from the Czech Science Foundation, Czech Ministry of Health, Czech Ministry of Education, and Charles University, Prague and honorarium from Ipsen for consultations and lectures. SE has received grants from Ipsen. All non-Ipsen authors (J-MG, AB, RJ, PM, MB, PV, HW, CM, TD, AS, SK, SE, FG) also received compensation from Ipsen for conducting this clinical trial. BBDF, CV, and PP are employees or contractors of Ipsen, and FC is a former employee of Ipsen. The other authors declare no competing interests. The manuscript was written with editorial assistance from Martin Gilmour (ESP Bioscience, Crowthorne, UK), funded by Ipsen. The clinical research organisation responsible for the study was INC Research. We thank all the patients who participated in this study and their families; Pascale Cavillon (Ipsen) for study coordination; and the following research associates from study centres: G Stoquart and R Rak (both in Belgium), Y Angerova (Czech Republic), N Bayle and C M Loche (both in France), T Ialongo (Italy), A Botsina and A Korenko (both in Russia), J Benetin (Slovakia), M Pautler, C Dolezal, C McAllister, D Brown, G Kim, M D C Lichtenberger, A A Nmashie, R L Harvey, and Y Salem (all in the USA).
ASJC Scopus subject areas
- Clinical Neurology