Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study

Abstract

In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn-Tolosa-Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites.

Keywords: TremorTek®; Xeomin; botulinum toxin; clinical-decision support; incobotulinumtoxinA; kinematics; treatment planning; tremor; upper-limb essential tremor.

Conflict of interest statement

M.J. has received research grant support from and served as a consultant for AbbVie, Allergan, Boston Scientific, Ipsen, Medtronic, MDDT Inc., Merz Pharmaceuticals, and Teva, and is a shareholder of MDDT Inc. J.L. is an employee and shareholder of MDDT Inc. A.S., M.A., H.D. are employees of Merz Pharmaceuticals. R.C. has received research grant support from Medtronic Inc. and Merz Pharmaceuticals and has received personal fees from Allergan, and Merz Pharmaceuticals. F.I. has received research grant support from Allergan and Merz Pharmaceuticals and has served as a consultant for Allergan, Ipsen, and Merz Pharmaceuticals. C.B. has received research grant support from Allergan and Merz and has served as a consultant for Allergan, Ipsen, and Merz. D.H. has served as a consultant for Allergan and Merz. D.K. and S.F. have no conflicts of interest to disclose. O.S. is a former employee of Merz Pharmaceuticals. D.M.S. has received research grant support from, and served as a consultant for, Allergan, Ipsen, and Merz.

Figures

Figure 1

Patient disposition. a Multiple entries possible; b Serious adverse event of chest discomfort, not related to study medication.

Figure 2

FTM tremor rating and motor performance. (A) FTM tremor score (injected limb), mean changes from baseline (±SD) (FAS, observed cases), and (B) FTM motor performance score (injected limb), mean changes from baseline (±SD) (FAS, observed cases). * p < 0.05 for incobotulinumtoxinA versus placebo (ANCOVA). Lower scores indicate better results. ANCOVA, analysis of covariance; FAS, full analysis set; FTM, Fahn–Tolosa–Marin.

Figure 3

Kinematic tremor analysis. (A) Maximum angular tremor amplitude at the wrist (injected limb), mean change from baseline (FAS, observed cases, (deg)), and (B) maximum log-transformed accelerometric tremor amplitude at the hand (injected limb), mean change from baseline (±SD) (FAS, observed cases, (m/s2)). * p < 0.05 for incobotulinumtoxinA versus placebo (ANCOVA). Lower scores indicate better results. ANCOVA, analysis of covariance; deg, degrees of arc; FAS, full analysis set.

Figure 4

Maximum grip strength using hand-held dynamometers (injected limb) (safety evaluation set). * p < 0.05, 95% CI based on t-distribution for the difference between treatment groups.