Damian McNamara

August 06, 2019

A potassium channel blocker that was approved by the US Food and Drug Administration nearly a decade ago to improve walking in adults with multiple sclerosis (MS) may also increase information-processing speed (IPS) in this patient population, new research suggests.

In a randomized controlled trial, participants who took 10 mg of slow-release dalfampridine (Ampyra, Acorda) twice daily for 12 weeks experienced an average improvement of 9.9 points on the Symbol Digit Modalities Test (SMDT). Patients who took placebo experienced an average improvement of 5.2 points.

This translates to a moderate effect size, the researchers note.

“An option for treatment of cognitive impairment is now available for people with MS,” Laura De Giglio, PhD, MS Center Sant’Andrea Hospital, Department of Human Neuroscience, Sapienza University of Rome, Italy, told Medscape Medical News.

“Clinicians should test patients for the presence of deficit of information processing speed and initiate treatment with dalfampridine if the deficit is present,” De Giglio added.

The findings were published online July 22 in Neurology.

No Consensus
Previous observational research and randomized controlled studies have explored changes in cognition associated with dalfampridine for patients with MS. However, the results were conflicting, and the primary endpoints did not include neuropsychological performance.

For a more definitive answer, De Giglio and colleagues randomly assigned 80 adults with MS to receive dalfampridine and 40 patients to receive placebo.

They enrolled the 74 women and 46 men at regional MS centers in Rome between February 2015 and June 2016. The mean age of the participants was 48 years, and the mean duration of disease was 16 years.

At baseline, all participants had SMDT scores below the 10th percentile, reflecting relatively slow information-processing speeds.

The difference between groups in the primary outcome, change in SMDT score at 12 weeks, was statistically significant in favor of treatment (P = .0018).

The investigators also calculated a SMDT z score to gauge outcomes in comparison with a normative mean.

They report that the average change from baseline was 0.8 (95% confidence interval [CI], 0.6 – 1.0) for patients treated with dalfampridine and 0.3 (95% CI, −0.0 to 0.5) for those who took placebo (P = .0013).

Treatment with dalfampridine also was superior to placebo in terms of the proportion of participants who achieved an improvement of 4 points or more in raw score on the SDMT (86% vs 60%, respectively; P = .0029).

In addition, by 12 weeks, SMDT scores improved at least 20% among a greater proportion of the treatment group (76% vs 45%; P = .0012).

Interestingly, after the 4-week washout period, the between-group differences in SDMT scores were no longer significant.

“Suitable Treatment”
The investigators also explored multiple secondary endpoints. They confirm that dalfampridine had a positive effect on IPS and working memory, but they were unable to show an effect on other cognitive domains.

There was a significant improvement in cognitive fatigue with dalfampridine compared with placebo. Mean improvement on the Modified Fatigue Impact Scale (MFIS) total score was −7.84 with dalfampridine (95% CI, −11.7 to −3.9), vs −0.2 (95% CI, −4.6 to 4.9) with placebo (P = .0085).

The findings “suggest that the drug should also be considered as suitable treatment for this disabling and common symptom of MS,” the researchers write.

The majority of adverse events (AEs) were mild, they note. AEs observed more frequently in the dalfampridine group included postural instability, insomnia, and dizziness.

“The adverse events that we observed are in line with the safety profile of the drug that has already been reported,” De Giglio said.

Risks for AEs should “always be evaluated” on an individual basis, she added.

“We suggest that in many patients, the benefits may outweigh the risks of adverse events,” she said.

Some participants discontinued the study because of AEs. In the treatment group, these included three patients who experienced postural instability and one patient who experienced a focal seizure. One participant in the placebo group fell because of postural instability.

In the future, the investigators plan to explore factors that predict drug response to better understand patients who could benefit from the therapy, De Giglio said.

In addition, “more studies are necessary to test long-term effects of dalfampridine on cognitive outcomes,” she said.

Real-Life Benefits
In addition to the primary IPS outcomes, improvements in patient-reported cognitive fatigue are a potential advantage, James F. Sumowski, PhD, Icahn School of Medicine at Mount Sinai in New York City, and Nils Muhlert, PhD, Division of Neuroscience and Experimental Psychology, University of Manchester, United Kingdom, note in an accompanying editorial.

“Although this MFIS subscale is termed ‘cognitive fatigue,’ the actual questions may better reflect treatment-related reductions in patient-reported cognitive difficulties — for example, less alert, trouble concentrating, difficulty organizing thoughts — which suggests real-life benefits,” they write.

They note that clinicians as well as patients with MS “will likely be enthusiastic” about this drug as a potential treatment for slowed processing speed.

“We must recognize, however, that there is no panacea for MS-related cognitive deficits, and that dalfampridine may not work for every patient,” the editorialists note.

“While more work is needed, current evidence for dalfampridine as a potential component of comprehensive treatment and prevention of cognitive decline is surely positive and welcome news for patients, clinicians, and caregivers,” they add.

The study was initiated by the investigators and was supported Biogen. De Giglio received consulting fees and travel grants from Biogen. Other study authors’ relevant financial relationships are listed in the original article. Sumoski has consulted with or performed advisory work for Biogen Idec. Muhlert has disclosed no relevant financial relationships.

Neurology. Published online July 22, 2019. Abstract, Editorial

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