Designing Clinical Trials for Dystonia

Abstract

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

Ranking of Dystonia Severity by Pairwise Video Comparison

“…Specifically in the case of dystonia, the perceived stigma, affective symptoms, and pain have an impact in addition to the perceived effect of treatment and other sociodemographic factors . Consequently, current guidelines recommend consideration of these nonmotor aspects in the setting of treatment goals and the use of hrQoL instruments as secondary outcome measures to assess treatment efficacy . Although clearly our study was not designed to make inferences on the determinants of hrQoL in dystonia, our observations fit previously defined factors, given the high ratings in the CDQ‐24 stigma subscale and the association of VAS pain ratings with CDQ‐24 in our cohort.…”

Primary results from the Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE)

“…In CD PROBE, the mean change in TWSTRS Total score from baseline to final visit was 12.1, which is 30.9% lower than the baseline score (median change from baseline to final visit is 14.0, a 35.9% reduction). The CDIP-58 also has no defined MID [10], but the changes from baseline to peak effect for each subscale in CD PROBE were comparable to or better than those in a smaller clinical trial [19].…”

“…There is no defined minimal important difference (MID) for TWSTRS [10], but BoNT trials have defined a responder as a subject with a decrease in the TWSTRS Total score of ≥ 30% and/or ≥ 10 points [21,25]. In CD PROBE, the mean change in TWSTRS Total score from baseline to final visit was 12.1, which is 30.9% lower than the baseline score (median change from baseline to final visit is 14.0, a 35.9% reduction).…”

“…Furthermore, placebo-controlled trials are usually short-term and are not suitable to determine long-term efficacy and safety. Observational studies are designed to address such concerns, and if designed to collect data in a pre-specified fashion, may provide important insight into the effects of medical treatments on disease state [10,11].…”

Editorial: Neurotherapeutics of Movement Disorders

“…Payami and Factor [9] provide a perspective on the impact of such practices using adenosine A2a antagonists as an example. Finally, Galpern et al [10] provide a perspective on certain principles and components of the clinical trial design process from exploratory safety and tolerability studies to phase III randomized, double-blind, placebo-controlled efficacy trials. While they focus on dystonia, the article provides important information that can be useful in developing trials for any movement disorder.…”