Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial

Abstract

Background: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg.

Methods: Patients were randomized to double-blind treatment with twice-daily dalfampridine-ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25-Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test.

Results: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean ± SE): 0.443 ± 0.042 ft/s versus 0.303 ± 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported.

Conclusions: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed.

Figure 1.

Patient disposition Safety was analyzed for all patients who took at least one dose of double-blind treatment, and the analyzed population for efficacy analysis represents a modified intention-to-treat population that included all randomized patients who took at least one dose of double-blind treatment and who had baseline and at least one postbaseline assessment of the Timed 25-Foot Walk. ER, extended release.

Figure 2.

Primary efficacy endpoint: change from baseline in walking speed 3 to 4 hours after administration of the last dose at visit 3 (4 weeks) The timing of the Timed 25-Foot Walk evaluation was designed to correspond approximately to the peak steady-state plasma concentration of dalfampridine. ER, extended release.

Figure 3.

Change from baseline at 4 weeks (visit 3) for the key secondary endpoints of (A) walking speed at time of minimum steady-state plasma concentration and (B) 12-item Multiple Sclerosis Walking Scale (MSWS-12) score ER, extended release.

Figure 4.

Post hoc analysis of walking speed using all Timed 25-Foot Walk (T25FW) assessments before treatment (screening and visit 1) as baseline and all on-treatment T25FW assessments (visits 2 and 3; 2 and 4 weeks, respectively) as the on-drug value A, Mean change from baseline; B, mean percentage change from baseline. ER, extended release.

Figure 5.

Post hoc analysis of (A) proportion of patients achieving at least 20% improvement in average walking speed and (B) change from baseline in 12-item Multiple Sclerosis Walking Scale (MSWS-12) score in patients achieving at least 20% improvement in average walking speed ER, extended release.

Figure 6.

Change from baseline in walking distance at 2 weeks assessed using the 6-Minute Walk test ER, extended release.