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

Mandar Jog,Michael Althaus,Astrid Scheschonka,David King,Chris Boulias,Jack Lee,Douglas Hobson,Farooq Ismail,Robert Chen,Olivier Simon,David M Simpson,Hanna Dersch,Steven Frucht

doi:10.3390/toxins12120807

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.

Highlights

Essential tremor (ET), a common movement disorder affecting 4.6% of individuals ≥65 years of age [1], is characterized by uncontrollable trembling of the upper limbs [2]
The present study investigated thisexperienced promising approach was benefit reproducible under placebo-controlled conditions investigated whether this promising approach was reproducible under placebo-controlled conditions in in a multicenter setting, with the objective of assessing the efficacy and safety of a single, kinematic aplanned multicenter setting, with the objective of assessing the efficacy and safetywith of a single, kinematic planned intramuscular injection of incobotulinumtoxinA, compared placebo, in moderate-tointramuscular injection of incobotulinumtoxinA, compared with placebo, in moderate-to-marked marked ET of the upper limb
One patient in the incobotulinumtoxinA group was lost to follow-up, one patient in the placebo group withdrew from the study due to a treatment-emergent adverse event and one patient in the placebo group withdrew from the study due to a treatment-emergent adverse (TEAE) considered unrelated to treatment (Figure 1)

Summary

Introduction

Essential tremor (ET), a common movement disorder affecting 4.6% of individuals ≥65 years of age [1], is characterized by uncontrollable trembling of the upper limbs [2]. Other areas, including the head, face, jaw, and vocal cords, can be affected [2,3,4]. ET can significantly impair activities of daily living (ADL) [3,5]. Treatment is based on severity and impact on the quality of life [5]. Propranolol and primidone, the most commonly used therapies, reduce tremor amplitude by ~50% [2].

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Discussion

Conclusion