PMID- 26565077 OWN - NLM STAT- MEDLINE DCOM- 20160805 LR - 20220318 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 37 IP - 12 DP - 2015 Dec 1 TI - Effects of Dalfampridine Extended-release Tablets on 6-minute Walk Distance in Patients With Multiple Sclerosis: A Post Hoc Analysis of a Double-blind, Placebo-controlled Trial. PG - 2780-7 LID - S0149-2918(15)01175-3 [pii] LID - 10.1016/j.clinthera.2015.10.014 [doi] AB - PURPOSE: Dalfampridine extended-release (ER) tablets 10 mg BID have been approved for use in improving walking in people with multiple sclerosis (MS). This subgroup analysis evaluated the effects of dalfampridine ER 5 and 10 mg BID on distance walked, as assessed using the 6-minute walk (6MW) test. METHODS: This analysis of data from a randomized, placebo-controlled, double-blind study (N = 430) included only the 153 patients with 6MW data available. Participants (aged 18-70 years) were randomly assigned in a 1:1:1 ratio to receive dalfampridine ER 5 or 10 mg or placebo, BID for 4 weeks. The 6MW was used for assessing walking distance at baseline and 2 weeks after the start of treatment at the 26 study sites that were able to perform this test. Participants were administered the 12-item MS Walking Scale (MSWS-12), a patient-reported measure of the impact of MS on walking. Post hoc outcomes included the percentages of patients who achieved an increase from baseline in 6MW distance of >/=20% and who achieved a minimal clinically important difference (MCID) from baseline in 6MW distance, defined as >/=+55 m. Changes from baseline in walking speed (MSWS-12) were compared, stratified by subgroup that achieved >/=20% versus <20% improvement on the 6MW. The correlation between change in walking speed over time and subgroup (by change in distance walked) was evaluated. The tolerability of dalfampridine was assessed based on the prevalence of treatment-emergent adverse events (TEAEs). FINDINGS: In the post hoc analysis, the percentage of patients with an improvement in 6MW distance that met or exceeded the MCID was significantly greater with dalfampridine ER 10 mg BID relative to placebo (37.3% vs 12.2%; nominal P = 0.004). Similarly, the percentage with an improvement in 6MW distance of >/=20% was significantly greater with dalfampridine 10 mg BID relative to placebo (45.1% vs 14.3%; nominal P < 0.001). Regardless of treatment allocation, improvement in MSWS-12 was significantly greater in the subgroup that achieved a >/=20% improvement on the 6MW compared with the subgroup with <20% improvement (mean changes, -15.5 vs -7.2; nominal P = 0.041). The prevalences and types of TEAEs were consistent with those reported in previous studies. IMPLICATIONS: Based on the MCID for 6MW, the use of dalfampridine ER 10 mg BID but not 5 mg BID was associated with statistically significant and clinically meaningful improvements in walking relative to placebo. The correlation between improvement on MSWS-12 and the 20% increase in 6MW distance suggests that an improvement on MSWS-12 is clinically relevant. These results, although highlighting a lack of efficacy of dalfampridine ER 5 mg BID, suggest that the 10-mg BID dose is effective for improving walking speed, as observed on short timed-walk tests, and for increasing distance walked over longer timed-walk periods. ClinicalTrials.gov identifier: NCT01328379. CI - Copyright (c) 2015 The Authors. Published by Elsevier Inc. All rights reserved. FAU - Applebee, Angela AU - Applebee A AD - MS Center of Northern New England, Fletcher Allen Hospital/University of Vermont, Burlington, Vermont. Electronic address: angela.applebee@vtmednet.org. FAU - Goodman, Andrew D AU - Goodman AD AD - Department of Neurology, University of Rochester Medical Center, Rochester, New York. FAU - Mayadev, Angeli S AU - Mayadev AS AD - Multiple Sclerosis Center, Swedish Neuroscience Institute, Seattle, Washington. FAU - Bethoux, Francois AU - Bethoux F AD - Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio. FAU - Goldman, Myla D AU - Goldman MD AD - Department of Neurology, University of Virginia, Charlottesville, Virginia. FAU - Klingler, Michael AU - Klingler M AD - Acorda Therapeutics, Inc, Ardsley, New York. FAU - Blight, Andrew R AU - Blight AR AD - Acorda Therapeutics, Inc, Ardsley, New York. FAU - Carrazana, Enrique J AU - Carrazana EJ AD - Acorda Therapeutics, Inc, Ardsley, New York. LA - eng SI - ClinicalTrials.gov/NCT01328379 PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20151110 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Delayed-Action Preparations) RN - 0 (Tablets) RN - BH3B64OKL9 (4-Aminopyridine) SB - IM MH - 4-Aminopyridine/*administration & dosage/pharmacology/*therapeutic use MH - Adolescent MH - Adult MH - Aged MH - Delayed-Action Preparations/administration & dosage/pharmacology/therapeutic use MH - Exercise Test/drug effects MH - Humans MH - Middle Aged MH - Multiple Sclerosis/*drug therapy MH - Tablets MH - Walking/*physiology MH - Young Adult OTO - NOTNLM OT - 4-aminopyridine OT - 6-minute walk test OT - ambulation OT - dalfampridine OT - multiple sclerosis OT - subgroup analysis EDAT- 2015/11/14 06:00 MHDA- 2016/08/06 06:00 CRDT- 2015/11/14 06:00 PHST- 2015/09/02 00:00 [received] PHST- 2015/10/07 00:00 [revised] PHST- 2015/10/15 00:00 [accepted] PHST- 2015/11/14 06:00 [entrez] PHST- 2015/11/14 06:00 [pubmed] PHST- 2016/08/06 06:00 [medline] AID - S0149-2918(15)01175-3 [pii] AID - 10.1016/j.clinthera.2015.10.014 [doi] PST - ppublish SO - Clin Ther. 2015 Dec 1;37(12):2780-7. doi: 10.1016/j.clinthera.2015.10.014. Epub 2015 Nov 10.