Enhanced Bulbar Function in Amyotrophic Lateral Sclerosis: The Nuedexta Treatment Trial

Abstract

The goal of this randomized, blinded, crossover clinical trial was to determine whether Nuedexta (dextromethorphan and quinidine) enhanced speech, swallowing, and salivation in patients with ALS. Sixty patients with amyotrophic lateral sclerosis (ALS) received either Nuedexta or placebo for 28 to 30 days, followed by a 10 to 15-day washout period. Subsequently, patients were switched to the opposite treatment arm for the remaining days of the trial. The primary endpoint was a reduction in the self-report Center for Neurologic Study Bulbar Function Scale (CNS-BFS) score. The rater-administered ALS Functional Rating Scale Revised was the principal secondary endpoint. The CNS-BFS score improved with active treatment, decreasing from a mean of 59.3 in the placebo arm of the trial to 53.5 during the drug-treatment arm (p < 0.001). Each of the individual domains of bulbar function interrogated by the CNS-BFS responded to treatment with Nuedexta as follows: salivation: 15.8 versus 14.3 (p = 0.004); speech: 24.6 versus 22.2 (p = 0.003); swallowing: 18.9 versus 17.1 (p = 0.009). Similarly, the bulbar component of the ALS Functional Rating Scale Revised improved with active treatment (p = 0.003), although the drug did not affect the motor and respiratory components of this scale. This study is unique for several reasons. Firstly, it was driven by patient reports of improved speech and swallowing while taking Nuedexta for control of emotional lability. Secondly, the study was conducted over a short duration (70 days), and thirdly, a self-report scale was selected as the principle outcome measure. Considering the importance of bulbar functions, these results, if confirmed, point to an additional use of Nuedexta as an adjunct to the management of ALS.Electronic supplementary materialThe online version of this article (doi:10.1007/s13311-016-0508-5) contains supplementary material, which is available to authorized users.

Additional evidence for a therapeutic effect of dextromethorphan/quinidine on bulbar motor function in patients with amyotrophic lateral sclerosis: A quantitative speech analysis

“…Our prior work has also demonstrated the poor diagnostic accuracy of clinician‐based detection of early bulbar involvement with a false‐positive rate as high as 39% . Our expectation for detecting significant clinical effects on speech in the current study, however, was low because the subgroup of participants studied had, by chance, less severe bulbar dysfunction at baseline than many of the participants in the parent trial and as a group were less responsive to DM/Q treatment . These mixed findings between clinical and quantitative endpoints underscore the ongoing challenges with choosing endpoints for clinical trials that target bulbar motor functions such as speech and swallowing.…”

“…A full list of the inclusion/exclusion criteria applied in the DM/Q clinical trial is provided in the report by Smith et al . .…”

“…Participants were deemed ineligible for inclusion if they showed evidence of cognitive impairment, had previously used DM/Q or if use of DM/Q was medically contraindicated. A full list of the inclusion/exclusion criteria applied in the DM/Q clinical trial is provided in the report by Smith et al [5].…”

“…timed swallowing, chewing and speech tasks). The absence of improvement in these measures requires further inquiry because: (i) the evidence for a therapeutic effect will be strengthened if the perceived benefits are observed to translate into objective gains in bulbar motor performance; and (ii) although expert consensus regarding best practices for assessment of bulbar function is currently lacking [10], recent research has identified computer-based measures of speech that are more responsive to bulbar motor involvement than the objective speech measures [11][12][13] used in the DM/Q study [5]. The latter point is particularly germane to this report because it raises the possibility that relative nonresponders in the original trial, i.e.…”

Assessment of bulbar function in amyotrophic lateral sclerosis: validation of a self‐report scale (Center for Neurologic Study Bulbar Function Scale)

“…Historically, ALS trials have emphasized survival. On a background of failed trials, Nuedexta has been shown to improve speech and swallowing in a double-blind treatment trial [15]. The endpoint of this Phase 2 study was a self-report scale [Center for Neurologic Study Bulbar Function Scale (CNS-BFS)] that proved to be more sensitive to a treatment effect than commonly used measures, such as timed speech and swallowing.…”