A Phase 2 Proof-of-Concept, Randomized, Placebo-Controlled Trial of CX-8998 in Essential Tremor

Abstract

Background: Available essential tremor (ET) therapies have limitations.

Objectives: The objective of this study was to evaluate CX-8998, a selective T-type calcium channel modulator, in essential tremor.

Methods: Patients 18-75 years old with moderate to severe essential tremor were randomized 1:1 to receive CX-8998 (titrated to 10 mg twice daily) or placebo. The primary end point was change from baseline to day 28 in The Essential Tremor Rating Assessment Scale performance subscale scored by independent blinded video raters. Secondary outcomes included in-person blinded investigator rating of The Essential Tremor Rating Assessment Scale performance subscale, The Essential Tremor Rating Assessment Scale activities of daily living subscale, and Kinesia ONE accelerometry.

Results: The video-rated The Essential Tremor Rating Assessment Scale performance subscale was not different for CX-8998 (n = 39) versus placebo (n = 44; P = 0.696). CX-8998 improved investigator-rated The Essential Tremor Rating Assessment Scale performance subscale (P = 0.017) and The Essential Tremor Rating Assessment Scale activities of daily living (P = 0.049) but not Kinesia ONE (P = 0.421). Adverse events with CX-8998 included dizziness (21%), headache (8%), euphoric mood (6%), and insomnia (6%).

Conclusions: The primary efficacy end point was not met; however, CX-8998 improved some assessments of essential tremor, supporting further clinical investigation. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Keywords: CX-8998; T-CALM; T-Type calcium channel modulator; essential tremor; phase 2 trial.

FIG. 1

(A) Change from baseline to days 15 and 28 in TETRAS‐PS, as scored by independent video raters (primary efficacy end point). (B) Change from baseline to days 15 and 28 in TETRAS‐PS, as scored by investigators. (C) Change from baseline to days 15 and 28 in TETRAS‐ADL. (D) Change from baseline to days 15 and 28 in TETRAS total score. (E) Percentage of patients rated as minimally/much/very much improved on the CGI‐I on day 28. (F) Percentage of patients rated as minimally/much/very much improved on the PGIC on day 28. To facilitate comparisons, the CGI‐I and PGIC responses were mapped to values from −3 to 3 (from worst outcome to best outcome). The full analysis set was used in all analyses. P values shown in B–D are nominal. For more details, see Tables [Link], [Link], and S4. CGI‐I, Clinical Global Impression of Improvement; LS, least squares; PGIC, Patient Global Impression of Change; TETRAS, The Essential Tremor Rating Assessment Scale; TETRAS‐PS, The Essential Tremor Rating Assessment Scale performance subscale; TETRAS‐ADL, The Essential Tremor Rating Assessment Scale activities of daily living subscale.