A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

Abstract

At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Inhibitory system overstimulation plays a role in the pathogenesis of neuromuscular and neurological diseases: a novel hypothesis

“…For example, in two trials gabapentin increased the rate of disease progression in patients with ALS 55 . A similar effect was reported in patients with ALS who received the GABAergic compound topiramate 56 . GABAergic action can also explain the more rapid disease progression of ALS in clinical trials in which patients received the antibiotic minocycline 57 , which has GABAergic activity 58 .…”

Assessment of Motor Units in Neuromuscular Disease

“…Hand-held dynamometry (HHD) using grip strength to assess voluntary isometric strength has been developed for practical use and was superior to an ALS score and manual scores [19]. HHD was used in the 2 recent large international phase II-III ALS clinical trials [20,21], as well as other recent smaller studies [22], with HHD inferior to the revised ALS functional rating scale-revised (ALSFRS-R) but better than vital capacity [23]. The methodology for HHD and manual testing has become standardized but nonlinear decline in muscle strength due to collateral reinnervation, the use of muscles such as finger flexion (which is relatively preserved in ALS), and the wide variability in normal muscle strength (whereby the strength of the manual tester can influence the result), are potential limitations of the muscle strength testing methods.…”

“…The statistical MUNE method was used in the unsuccessful multicenter creatine study, and it became clear that the method was limited as it does not account for motor unit variability as seen as advanced disease [95]. Other methods of motor unit assessment have been used in single trials of memantine [96], but methods of assessing motor units were not used in 2 recent, large international phase IIb multicenter studies [20,21], nor other recent exploratory phase II studies [22,97,98]. The discussion of MUNE at recent meetings has been limited; for example, MUNIX was the only method discussed at the recent International ALS/Motor Neurone Disease Symposium in December 2015 [99].…”

Electrical impedance myography to assess outcome in amyotrophic lateral sclerosis clinical trials

“…While recent trials have failed to demonstrate benefit of a variety of therapeutic interventions, including celecoxib, topiramate, creatine (Cudkowicz et al, 2003;Shefner et al, 2004;Cudkowicz et al, 2006), advances in basic science are leading to a proliferation of new agents that will require clinical evaluation. A significant problem in clinical trial design is that large numbers of patients must be studied for long time periods for modest therapeutic benefit to be appreciated, making the design of phase II proof-of-concept trials challenging.…”

“…A significant problem in clinical trial design is that large numbers of patients must be studied for long time periods for modest therapeutic benefit to be appreciated, making the design of phase II proof-of-concept trials challenging. For example, the study of topiramate in ALS required 288 patients to be studied over a one-year period in order to obtain a 80% power to detect a slowing of disease progression of 35% (Cudkowicz et al, 2003).…”