A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment.

BACKGROUND: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. OBJECTIVE: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. METHODS: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). RESULTS: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). CONCLUSION: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Where the BOLD signal goes when alpha EEG leaves.

Previous studies using simultaneous EEG and fMRI recordings have yielded discrepant results regarding the topography of brain activity in relation to spontaneous power fluctuations in the alpha band of the EEG during eyes-closed rest. Here, we explore several possible explanations for this discrepancy by re-analyzing in detail our previously reported data. Using single subject analyses as a starting point, we found that alpha power decreases are associated with fMRI signal increases that mostly follow two distinct patterns: either 'visual' areas in the occipital lobe or 'attentional' areas in the frontal and parietal lobe. On examination of the EEG spectra corresponding to these two fMRI patterns, we found greater relative theta power in sessions yielding the 'visual' fMRI pattern during alpha desynchronization and greater relative beta power in sessions yielding the 'attentional' fMRI pattern. The few sessions that fell into neither pattern featured the overall lowest theta and highest beta power. We conclude that the pattern of brain activation observed during spontaneous power reduction in the alpha band depends on the general level of brain activity as indexed over a broader spectral range in the EEG. Finally, we relate these findings to the concepts of 'resting state' and 'default mode' and discuss how - as for sleep - EEG-based criteria might be used for staging brain activity during wakefulness.

Quantitative functional MR imaging of the visual cortex at 1.5 T as a function of luminance contrast in healthy volunteers and patients with multiple sclerosis.

BACKGROUND AND PURPOSE: In patients with multiple sclerosis (MS), a few preliminary functional MR (fMR) imaging studies of the visual cortex reveal information about magnitude differences between healthy individuals and patients with MS at only a single luminance level. We therefore investigated whether varying luminance contrast levels can help uncover subtle changes in fMR imaging characteristics of the visual cortex in healthy volunteers and patients with MS. METHODS: Blood oxygenation level-dependent fMR imaging signal changes in the primary visual cortex were examined as a function of luminance contrast at 1.5 T in 10 healthy volunteers and nine patients with MS. Ten axial sections through the calcarine fissure were obtained with an echo-planar T2*-weighted imaging sequence (4000/54/1 [TR/TE/excitation]; field of view, 220 mm; voxel size, 1.72 x 1.72 x 5 mm). The imaging series consisted of an alternating 20-second rest epoch (black screen) with a 20-second activation epoch (flickering checkerboard) repeated six times. Each imaging series used a graded increase of eight luminance contrast levels. A paired t test between rest and activation images was used to analyze significant (P <.001) contiguous voxels in the region of interest (primary visual cortex). RESULTS: A progressive increase in fMR imaging activation across all luminance contrast levels in healthy controls and patients with MS was shown. The patients with MS had a significantly lower magnitude in the number of fMR imaging activated voxels at all luminance contrast levels (P <.001). A statistically significant increase in fMR imaging activation (activation threshold) was seen at the second luminance contrast level in controls and at the seventh level in patients with MS. CONCLUSION: Quantifiable changes in blood oxygenation level-dependent signal and a progressive increase in activated voxels within the primary visual cortex with increasing luminance contrast were demonstrated at 1.5 T in controls. The patients with MS showed a significant decrease in the number of activated voxels and an increase in activation threshold compared with healthy controls.