Objective: We will study CX-8998, a selective Cav3 antagonist with safety data in 194 patients,  in the treatment of ET. Few large controlled ET trials were conducted prior to 2006 and the optimal study design is debated. The rationale for primary efficacy endpoint and study design in tremor is presented here.

Background: Essential tremor (ET) is a common movement disorder with a large unmet medical need:  50% of patients report lack of efficacy from 1st-line therapies and 1/3 who respond discontinue due to side-effects. Animal and human studies suggest that Cav3 antagonism is a potential therapeutic target for tremor reduction. Existing Cav3 modulators have limited potency, selectivity, and pharmacokinetics.

Methods: We reviewed ET studies performed since 2005. We compared published and unpublished clinimetric data for the Fahn-Tolosa-Marín tremor rating scale (FTM) and the ET Rating Assessment Scale (TETRAS), with emphasis on acceptability, reliability, validity and responsiveness to change. We considered the pros and cons of parallel vs crossover study designs.

Results: While FTM has been widely used in clinical ET studies, it has a ceiling effect for patients with moderate-severe limb tremor as grade 4 tremor is any tremor with amplitude > 4 cm. FTM rates rest tremor, which is uncommon in ET and often misdiagnosed. In contrast, in TETRAS, grade 4 limb tremor is > 20 cm; TETRAS does not rate rest tremor. Upper extremity tremor (a principal concern of most patients) predominates the TETRA -PS (performance score). TETRAS correlates strongly with FTM, ADL, and transducer measures of tremor, and TETRAS has outstanding inter- and intra-rater reliability, even with untrained raters. Based on repeated measures of 9 ET patients, the minimum change in the TETRAS-PS is < 8 points, corresponding to a mean 44% reduction in amplitude. A crossover design has operational and sample size benefits, but a parallel design has less dropout risk, reduced total patient weeks, no carryover effect risk, and enhanced blinding. A sample size of 34 subjects was computed at a minimum of 90% power to detect an 8-point reduction in the TETRAS performance subscale, assuming standard deviation 10 and alpha 0.05.

Conclusions: A double-blind placebo-controlled parallel design with ≈34 patients per arm, using the TETRAS-PS as the primary efficacy measure, is optimal for evaluating therapies such as CX-8998.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/tetras-applicability-and-study-design-in-randomized-placebo-controlled-clinical-trial-of-cav3-modulation-for-essential-tremor-patients/