AbobotulinumtoxinA Versus OnabotulinumtoxinA in Adults with Upper Limb Spasticity: A Randomized, Double-Blind, Crossover Study Protocol

Alberto Esquenazi, Ziyad Ayyoub, Monica Verduzco-Gutierrez, Pascal Maisonobe, James Otto, Atul T Patel, Alberto Esquenazi, Ziyad Ayyoub, Monica Verduzco-Gutierrez, Pascal Maisonobe, James Otto, Atul T Patel

Abstract

Introduction: The safety and efficacy of both abobotulinumtoxinA and onabotulinumtoxinA for upper limb spasticity are well established, but head-to-head comparisons are lacking.

Methods: DIRECTION is an international, randomized, double-blind, crossover study comparing the safety and efficacy of abobotulinumtoxinA with onabotulinumtoxinA in the management of upper limb spasticity at doses at or near maximum recommended in product labelling. Participants (18-75 years) will be randomized (1:1) to either one cycle of abobotulinumtoxinA (900U) followed by onabotulinumtoxinA (360U) or vice versa. To maintain blinding, a fixed volume (3.6 ml) will be injected into the target upper limb muscles (four wrist and finger flexors and biceps brachii). The second treatment cycle will begin at Week 12 if retreatment criteria are fulfilled, and if not, they will be reassessed every 4 weeks until they meet retreatment parameters.

Planned outcomes: The primary hypothesis is that there is comparable safety between products; non-inferiority will be tested based on treatment-emergent adverse event (TEAE) rates from injection to Week 12. A secondary hypothesis is that abobotulinumtoxinA has longer duration of effect than onabotulinumtoxinA. This hypothesis will be tested with secondary efficacy endpoints, including injection cycle duration, Modified Ashworth Scale, Disability Assessment Scale and Physician Global Assessment.

Trial registration: EudraCT ( http://eudract.ema.europa.eu ): 2021-000161-32 and Clinicaltrials.gov ( https://ichgcp.net/clinical-trials-registry/NCT04936542" title="See in ClinicalTrials.gov">NCT04936542. Overview of the study protocol by the principal investigator (MP4 185265 KB).

Keywords: AbobotulinumtoxinA; Botulinum toxin; Clinical trial; OnabotulinumtoxinA; Spasticity; Upper limb.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Study design. aboBoNT-A abobotulinumtoxinA, onaBoNT-A onabotulinumtoxinA, W week
Fig. 2
Fig. 2
Injection scheme. aboBoNT-A abobotulinumtoxinA, onaBoNT-A onabotulinumtoxinA

References

    1. Doan QV, Brashear A, Gillard PJ, Varon SF, Vandenburgh AM, Turkel CC, et al. Relationship between disability and health-related quality of life and caregiver burden in patients with upper limb poststroke spasticity. PM&R. 2012;4(1):4–10. doi: 10.1016/j.pmrj.2011.10.001.
    1. Royal College of Physicians (UK). Spasticity in adults: management using botulinum toxin. National guidelines 2018. . Last accessed Jul 2021.
    1. Simpson DM, Hallett M, Ashman EJ. Practice guideline update summary: Botulinum neurotoxin for the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. Neurology. 2016;86:1–9. doi: 10.1212/WNL.0000000000002560.
    1. Esquenazi A, Albanese A, Chancellor MB, Elovic E, Segal KR, Simpson DM, et al. Evidence-based review and assessment of botulinum neurotoxin for the treatment of adult spasticity in the upper motor neuron syndrome. Toxicon. 2013;67:115–128. doi: 10.1016/j.toxicon.2012.11.025.
    1. Bigalke H. Properties of pharmaceutical products of botulinum neurotoxins. In: Jankovic J, Albanese A, Atassi MZ, Dolly JO, Hallett M, Mayer NH, editors. Botulinum toxin: therapeutic clinical practice and science. Philadelphia: Saunders Elsevier; 2009. pp. 389–397.
    1. Hambleton P, Pickett AM. Potency equivalence of botulinum toxin preparations. J R Soc Med. 1994;87(11):719.
    1. 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(10):992–1001. doi: 10.1016/S1474-4422(15)00216-1.
    1. Gracies JM, O'Dell M, Vecchio M, Hedera P, Kocer S, Rudzinska-Bar M, et al. Effects of repeated abobotulinumtoxinA injections in upper limb spasticity. Muscle Nerve. 2018;57(2):245–254. doi: 10.1002/mus.25721.
    1. McCrory P, Turner-Stokes L, Baguley IJ, De Graaff S, Katrak P, Sandanam J, et al. Botulinum toxin A for treatment of upper limb spasticity following stroke: a multi-centre randomized placebo-controlled study of the effects on quality of life and other person-centred outcomes. J Rehabil Med. 2009;41(7):536–544. doi: 10.2340/16501977-0366.
    1. Rosales RL, Balcaitiene J, Berard H, Maisonobe P, Goh KJ, Kumthornthip W, et al. Early abobotulinumtoxina (Dysport) in post-stroke adult upper limb spasticity: ONTIME pilot study. Toxins. 2018;10(7):253. doi: 10.3390/toxins10070253.
    1. Brashear A, Gordon MF, Elovic E, Kassicieh VD, Marciniak C, Do M, et al. Intramuscular injection of botulinum toxin for the treatment of wrist and finger spasticity after a stroke. N Engl J Med. 2002;347(6):395–400. doi: 10.1056/NEJMoa011892.
    1. Simpson DM, Gracies JM, Yablon SA, Barbano R, Brashear A. Botulinum neurotoxin versus tizanidine in upper limb spasticity: a placebo-controlled study. J Neurol Neurosurg Psychiatry. 2009;80(4):380–385. doi: 10.1136/jnnp.2008.159657.
    1. Marciniak CM, Harvey RL, Gagnon CM, Duraski SA, Denby FA, McCarty S, et al. Does botulinum toxin type A decrease pain and lessen disability in hemiplegic survivors of stroke with shoulder pain and spasticity?: a randomized, double-blind, placebo-controlled trial. Am J Phys Med Rehabil. 2012;91(12):1007–1019. doi: 10.1097/PHM.0b013e31826ecb02.
    1. Turner-Stokes L, Jacinto J, Fheodoroff K, Brashear A, Maisonobe P, Lysandropoulos A, et al. Longitudinal goal attainment with integrated upper limb spasticity management including repeat injections of botulinum toxin A: findings from the prospective, observational upper limb international spasticity (ULIS-III) cohort study. J Rehabil Med. 2021;53(2):jrm00157. doi: 10.2340/16501977-2801.
    1. Grosset DG, Tyrrell EG, Grosset KA. Switch from abobotulinumtoxinA (Dysport) to incobotulinumtoxinA (Xeomin) botulinum toxin formulation: a review of 257 cases. J Rehabil Med. 2015;47(2):183–186. doi: 10.2340/16501977-1895.
    1. Dursun N, Akarsu M, Gokbel T, Akyuz M, Karacan C, Dursun E. Switching from onabotulinumtoxin-A to abobotulinumtoxin-A in children with cerebral palsy treated for spasticity: a retrospective safety and efficacy evaluation. J Rehabil Med. 2019;51(5):390–394. doi: 10.2340/16501977-2550.
    1. Jacinto J, Varriale P, Pain E, Lysandropoulos A, Esquenazi A. Patient perspectives on the therapeutic profile of botulinum neurotoxin type A in spasticity. Front Neurol. 2020;11:388. doi: 10.3389/fneur.2020.00388.
    1. Brin MF, James C, Maltman J. Botulinum toxin type A products are not interchangeable: a review of the evidence. Biologics. 2014;8:227–241.
    1. Zhang Y, Coulton K, Rosales R, Moore AP, Plested M. Do clinically equivalent dosing ratios exist between different formulations of botulinum toxin-A in the treatment of adult spasticity, dystonia, blepharospasm and hemifacial spasm—a systematic review. Toxicon. 2015;93S:S66. doi: 10.1016/j.toxicon.2014.11.214.
    1. Albanese A, Abbruzzese G, Dressler D, Duzynski W, Khatkova S, Marti MJ, et al. Practical guidance for CD management involving treatment of botulinum toxin: a consensus statement. J Neurol. 2015;262:2201–2213. doi: 10.1007/s00415-015-7703-x.
    1. Sampaio C, Costa J, Ferreira JJ. Clinical comparability of marketed formulations of botulinum toxin. Mov Disord. 2004;19(Suppl 8):S129–S136. doi: 10.1002/mds.20066.
    1. Wenzel R, Jones D, Borrego JA. Comparing two botulinum toxin type A formulations using manufacturers' product summaries. J Clin Pharm Ther. 2007;32(4):387–402. doi: 10.1111/j.1365-2710.2007.00835.x.
    1. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther. 1987;67(2):206–207. doi: 10.1093/ptj/67.2.206.
    1. Turner-Bowker D, Hogue SJ. Short Form 12 Health Survey (SF-12) In: Michalos AC, editor. Encyclopedia of quality of life and well-being research. Dordrecht: Springer Netherlands; 2014. pp. 5954–5957.
    1. Turner-Stokes L, Ashford SA, Jacinto J, Maisonobe P, Balcaitiene J, Fheodoroff K. Impact of integrated upper limb spasticity management including botulinum toxin A on patient-centred goal attainment: rationale and protocol for an international, prospective, longitudinal cohort study (ULIS-III) BMJ Open. 2016;123:S81.
    1. Hefter H, Jost WH, Reissig A, Zakine B, Bakheit AM, Wissel J. Classification of posture in poststroke upper limb spasticity: a potential decision tool for botulinum toxin A treatment? Int J Rehabil Res. 2012;35(3):227–233. doi: 10.1097/MRR.0b013e328353e3d4.
    1. Esquenazi A, Delgado MR, Hauser RA, Picaut P, Foster K, Lysandropoulos A, et al. Duration of Symptom relief between injections for abobotulinumtoxinA (Dysport®) in spastic paresis and cervical dystonia: comparison of evidence from clinical studies. Front Neurol. 2020;11:576117. doi: 10.3389/fneur.2020.576117.
    1. de Sainte-Marie D, Lysandropoulos A. Botulinum neurotoxins are used at low doses in the treatment of spasticity in clinical practice: results from a market research analysis. Toxicon. 2018;156:S22. doi: 10.1016/j.toxicon.2018.11.057.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe