Abstract
Background: Essential tremor (ET) is a common, progressive neurological syndrome with bilateral upper-limb dysfunction of at least 3-year duration, with or without tremor in other body locations. This disorder has a negative impact on daily function and quality of life. A single oral therapy has been approved by FDA for ET. Off-label pharmacotherapies have inadequate efficacy and poor tolerability with high rates of patient dissatisfaction and discontinuation. Safe and efficacious pharmacotherapies are urgently needed to decrease tremor and improve daily living. T-CALM (Tremor-CAv3 modulation) protocol is designed to assess safety and efficacy of CX-8998, a selective modulator of the T-type calcium channel, for ET therapy.Methods/Design: T-CALM is a phase 2, proof of concept, randomized, double-blind, placebo-controlled trial. Titrated doses of CX-8998 to 10 mg BID or placebo will be administered for 28 days to moderate to severe ET patients who are inadequately treated with existing therapies. The primary endpoint will be change from baseline to day 28 of The Essential Tremor Rating Assessment Performance Subscale (TETRAS-PS). Secondary efficacy endpoints for clinician and patient perception of daily function will include TETRAS Activity of Daily Living (ADL), Quality of Life in Essential Tremor Questionnaire (QUEST), Clinical Global Impression-Improvement (CGI-I), Patient Global Impression of Change (PGIC), and Goal Attainment Scale (GAS). Kinesia One, Kinesia 360, and iMotor will biometrically evaluate motor function and tremor amplitude. Safety will be assessed by adverse events, physical and neurological exams and laboratory tests. Sample size of 43 patients per group is estimated to have 90% power to detect a 5.5-point difference between CX-8998 and placebo for TETRAS-PS. Efficacy analyses will be performed with covariance (ANCOVA) and 2-sided test at 0.05 significance level.Discussion: T-CALM has a unique design with physician rating scales, patient-focused questionnaires and scales and objective motor measurements to assess clinically meaningful and congruent efficacy. Patient perception of ET debilitation and therapy with CX-8998 will be key findings. Overall goal of T-CALM is generation of safety and efficacy data to support a go, no-go decision to further develop CX-8998 for ET. Design of T-CALM may guide future clinical studies of ET pharmacotherapies.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03101241
Highlights
BackgroundEssential tremor (ET) is described as a progressive neurological disorder that elicits involuntary rhythmic trembling of the hands, head, larynx, legs or trunk
To meticulously evaluate the presence of ET, a comprehensive medical history and neurologic examination are recommended
If the T-CALM proof of concept trial demonstrates that CX-8998 is effective with a favorable safety and tolerability profile, late stage clinical development will be undertaken and potentially support regulatory approval as a novel, selective, durable, and potent ET pharmacotherapy
Summary
Essential tremor (ET) is described as a progressive neurological disorder that elicits involuntary rhythmic trembling of the hands, head, larynx, legs or trunk. In addition to standard of care, there is a definitive need for novel, durably effective ET pharmacotherapies with minimal side effects that have a beneficial impact on amplitude of tremor and activities of daily living and other functional outcomes This goal can be achieved with additional research for more clinically meaningful therapeutic targets and a better understanding of ET pathophysiology and clinical and genetic heterogeneity. If the T-CALM proof of concept trial demonstrates that CX-8998 is effective with a favorable safety and tolerability profile, late stage clinical development will be undertaken and potentially support regulatory approval as a novel, selective, durable, and potent ET pharmacotherapy. The T-CALM study may generate meaningful guidelines for design, patient selection, and relevant and convergent efficacy endpoints for future clinical trials of novel ET pharmacotherapies. An optional additional component of the main T-CALM study is the T-CALM digital substudy that will evaluate the feasibility of three different digital monitoring platforms for accurate quantification of changes in motor function in ET patients
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