Challenges in the Design and Conduct of Therapeutic Trials in Channel Disorders

Abstract

Summary: Neurologic channelopathies are rare, inherited paroxysmal disorders of muscle (e.g., the periodic paralyses and nondystrophic myotonias) and brain (e.g., episodic ataxias, idiopathic epilepsies, and familial hemiplegic migraine). Mutation is necessary but not sufficient for phenotypic expression and there are no simple phenotype-genotype relationships. Attacks may be spontaneous or triggered, with affected individuals often asymptomatic and neurologically normal between attacks. Performance of daily activities may be affected by the unpredictable nature; often late-onset degenerative changes cause permanent disability; for example, muscle atrophy and fixed weakness in periodic paralysis and cerebellar atrophy and progressive ataxia in the episodic ataxias. Currently, the natural history of these disorders is being defined. Clearly, the established methodologies for randomized controlled clinical trials are not feasible for rare diseases and innovative trial design is essential. There is a requirement for clinically relevant outcome measures for episodic disorders. Increasing our knowledge of the pathophysiology will help in targeting and designing rational therapeutic approaches. We will use the current understanding of the neurological channelopathies to illustrate some of the opportunities, challenges, and strategies in bringing safe and effective treatments to patients. There are reasons for optimism that new partnerships between clinical investigators, government, patient advocacy groups, and industry will prevent symptoms and progression of the neurological channelopathies.

Clinical research for rare disease: Opportunities, challenges, and solutions

“…It is clear that careful consideration needs to be made regarding those assumptions to identify the study design that best fits the research question. [25-27]…”

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol

“…In Europe, 30 million patients (6 to 8% of the population) have a rare disease [ 1 ]. International regulatory authorities such as the Food and Drug Administration (FDA) and European Medical Agency (EMA) accept that it is unreasonable to demand the standard level of evidence (level 1) of multiple Randomized Controlled Trials (RCTs) in building an evidence-base for treatment of rare diseases [ 2 - 4 ]. The ability to conduct RCTs in rare diseases is hampered by low numbers of patients and large clinical heterogeneity.…”

Treatment of Neuromuscular Channelopathies: Current Concepts and Future Prospects

“…A detailed discussion of the pathophysiology of neuromuscular channelopathies is beyond the scope of this review, and the reader is directed to several more detailed reviews on the subject [1][2][3][4] and a recent review on clinical trial design in neurologic channelopathies. 5 …”