Dalfampridine Extended Release Research Articles

Randomized, Placebo-controlled Crossover Study of Dalfampridine Extended-release in Transverse Myelitis.

BackgroundDalfampridine has the potential to be effective in patients with transverse myelitis (TM) as this rare disorder shares some clinical and pathogenic similarities with multiple sclerosis.MethodsThis is a randomized, double-blind, placebo-controlled crossover study of dalfampridine extended-release (D-ER, Ampyra®). Sixteen adult study participants with monophasic TM confirmed by MRI were enrolled if their baseline timed 25-foot walking speed was between 5 and 60 seconds. Participants were randomized to receive 10 mg twice-daily doses of either D-ER or placebo control for eight weeks, then crossed over to the second arm of placebo or dalfampridine for eight weeks. The primary outcome measure was the timed 25-foot walk.ResultsOf 16 enrolled participants, three withdrew and 13 completed the trial. Among the 13 completers, nine individuals showed an average timed walk that was faster in the D-ER arm compared to the placebo arm, but only four participants met the stricter statistical threshold to be classified as a responder. Analyses of secondary clinical outcome measures including strength, balance assessments, spasticity, and Expanded Disability Status Scale (EDSS) score showed trends toward improvement with D-ER.ConclusionsD-ER may be beneficial in TM to improve walking speed and other neurological functions.

Inpatient Admissions and Costs Associated with Persistent Use of Dalfampridine Extended-Release in Multiple Sclerosis: A Claims Database Analysis.

While the clinical benefits of dalfampridine extended-release (D-ER) have been established in patients with multiple sclerosis (MS) through multiple clinical trials, there is limited real-world data on D-ER use, in particular the persistent use of D-ER, and associated acute care resource utilization and costs. To examine the real-world association of D-ER use and inpatient admissions and costs among patients with MS. This study was a retrospective observational claims analysis of the MarketScan database (April 2009-March 2014). Eligible patients consisted of adult enrollees aged 18-64 years who had (a) 12 months of continuous private plan enrollment preceding (baseline) and following (follow-up) the first D-ER claim; (b) ≥ 2 MS diagnosis codes with ≥ 1 during the baseline period; (c) ≥ 2 consecutive D-ER claims; and (d) no alternate gait-impairing etiologies during the baseline and follow-up periods. Patients were separated into 2 D-ER cohorts in the main analysis: persistent (≥ 360 days of D-ER supply) and nonpersistent (< 360 days of supply) users. Sensitivity analyses were conducted, examining additional breakdowns of days of supply within the nonpersistent cohort. Inpatient admissions (all-cause and MS-related) and health care expenditures were calculated and compared between the cohorts during follow-up using Wilcoxon rank-sum and chi-square tests. Regression models were conducted, controlling for age, sex, MS relapses, comorbidities, disease-modifying therapy use, and other baseline factors, including inpatient admissions and costs. Of 1,598 eligible patients, 719 (45.0%) were persistent D-ER users, and 879 (55.0%) were nonpersistent D-ER users. The 2 cohorts had similar demographic and clinical characteristics, with mean (SD) ages of 51.0 (8.4) and 50.6 (8.6) years and were 71.3% and 66.6% female, respectively. Compared with nonpersistent D-ER use, persistent D-ER use was associated with lower odds of all-cause inpatient admissions (OR = 0.58, P = 0.010) and MS-related inpatient admissions (OR = 0.50, P = 0.004). Persistent use was also associated with lower inpatient expenditures for all-cause admissions ($669 vs. $1,515, P = 0.002) and MS-related admissions ($388 vs. $891, P = 0.008). Persistent D-ER use was associated with significantly lower rates of all-cause and MS-related inpatient admissions and costs. Funding for this research and medical writing assistance was provided by Acorda Therapeutics. The study sponsor was involved in all stages of the study research and manuscript preparation. Guo and Niyazov were employees of Acorda Therapeutics at the time of this study and may own stock/stock options. Wu, Macaulay, Terasawa, and Schmerold are employees of Analysis Group, which received consultancy fees from Acorda Therapeutics for this project. Krieger was a consultant for Acorda Therapeutics for this project and has the following additional financial interests to report: consulting/advisory board work with Bayer, Biogen, EMD Serono, Novartis, Genentech, Genzyme, and Teva. Study concept and design were contributed by Guo, Niyazov, Macaulay, and Wu. Macaulay, Terasawa, Schmerold, and Wu helped prepare the data, and data interpretation was performed by Krieger, Guo, Niyazov, and Macaulay, along with Terasawa and Wu. The manuscript was written by Terasawa and Schmerold, along with Macaulay, and revised by all the authors. A portion of the current research was presented in poster format at the 2106 American Academy of Neurology Annual Meeting, which took place in Vancouver, BC, Canada, on April 15-21, 2016.

Dalfampridine in Parkinson's disease related gait dysfunction: A randomized double blind trial

BackgroundDisease-related gait dysfunction causes extensive disability for persons with Parkinson's disease (PD), with no effective therapies currently available. The potassium channel blocker dalfampridine has been used in multiple neurological conditions and improves walking in persons with multiple sclerosis. ObjectivesWe aimed to evaluate the effect of dalfampridine extended release (D-ER) 10mg tablets twice daily on different domains of walking in participants with PD. MethodsTwenty-two participants with PD and gait dysfunction were randomized to receive D-ER 10mg twice daily or placebo for 4weeks in a crossover design with a 2-week washout period. The primary outcomes were change in the gait velocity and stride length. ResultsAt 4weeks, gait velocity was not significantly different between D-ER (0.89m/s±0.33) and placebo (0.93m/s±0.27) conditions. The stride length was also similar between conditions: 0.96m±0.38 for D-ER versus 1.06m±0.33 for placebo. D-ER was generally well tolerated with the most frequent side effects being dizziness, nausea and balance problems. ConclusionsD-ER is well tolerated in PD patients, however it did not show significant benefit for gait impairment.

Safety, Tolerability, and Sensorimotor Effects of Extended-release Dalfampridine in Adults With Cerebral Palsy: A Pilot Study

PurposeThe goal of this study was to evaluate the safety and tolerability of dalfampridine extended release (D-ER) in a pilot study of adults with cerebral palsy (CP) and limited ambulatory ability, and to explore drug effects on sensorimotor function. MethodsAn initial double-blind, single-dose crossover study was performed in 11 individuals randomized 1:1 to receive D-ER (10 mg) or placebo, followed by a 2-day washout period and the opposite treatment, with evaluation for safety and tolerability. A twice daily dosing, double-blind, placebo-controlled, crossover study was then performed. Participants were randomized in a 1:1 ratio to 1 of 2 sequences: 1 week of D-ER (10 mg BID) or placebo, followed by a 1-week washout and 1 week of the opposite treatment. Key inclusion criteria were age 18 to 70 years, body mass index 18.0 to 30.0 kg/m2, diagnosis of CP, and ability to perform all study procedures. Key exclusion criteria were severe CP, moderate or severe renal impairment, history of nonfebrile seizures, and prior dalfampridine use. Primary outcomes were safety profile and tolerability. Exploratory functional outcomes comprised changes in upper and lower extremity sensorimotor function (grip and pinch strength tests), manual dexterity (Box and Block Tests), and walking speed (Timed 25-Foot Walk). The most pronounced measured functional deficit in each individual was defined as the exploratory primary functional end point. Full crossover data were analyzed by using a mixed effects model. FindingsAmong the 24 total participants who were randomized to treatment and completed the twice daily dosing phase study, their mean age was 38.6 years (range, 20–62 years), 54% were women, and 83% had spastic CP. Adverse events were consistent with previous D-ER trials, most commonly headache (13% D-ER, 4% placebo), fatigue (13% D-ER, 0% placebo), insomnia (8% D-ER, 4% placebo), diarrhea (4% D-ER, 4% placebo), and nausea (4% D-ER, 4% placebo). The mixed model analysis of full crossover data identified no significant difference between D-ER and placebo in the primary functional analysis (the most pronounced deficit; P = 0.70) or in the secondary analyses (hand strength [P = 0.48], manual dexterity [P = 0.13], or walking speed [P = 0.42]). ImplicationsIn this preliminary study of adults with CP, a BID dose of 10-mg D-ER was generally safe and well tolerated. The exploratory functional assessments for upper and lower sensorimotor deficits did not establish that the study population was markedly responsive to D-ER relative to placebo. These findings do not provide the proof-of-concept that would support further evaluation of D-ER as a potential intervention to improve function in adults with CP. ClinicalTrials.gov identifier: NCT01468350.

A Randomized Crossover Trial of Dalfampridine Extended Release for Effect on Ambulatory Activity in People with Multiple Sclerosis

Dalfampridine extended release (D-ER) is indicated to improve walking in people with multiple sclerosis (MS) as demonstrated by an increase in walking speed. This study assessed the effects of D-ER on accelerometer-based measures in people with MS, including intensity of walking and total amount of walking during daily activities. In this double-blind placebo-controlled crossover study, people with MS-related walking difficulty were randomized (1:1) to receive 4 weeks of D-ER 10 mg twice daily and 4 weeks of placebo in either order separated by a 2-week washout. Participants wore accelerometers for 7 days at baseline and week 3 of each on-drug period. The primary outcome was the peak activity index (PAI), defined as the most intense 30 individual minutes of the day (strides per minute). Secondary outcomes included daily step count, 6-Minute Walk Test (6MWT), Timed Up and Go (TUG) test, and patient-reported outcomes. A mixed-effects repeated-measures statistical model was used. Forty-three participants were randomized (mean Expanded Disability Status Scale score, 5.17). Least squares mean (standard error) change from baseline on the PAI was 0.6 (0.54) strides/min on D-ER and 0.3 (0.55) strides/min on placebo and in daily step count was 148.7 (222.4) on D-ER and 128.0 (225.4) on placebo. Other accelerometer-based measures and the 6MWT showed no significant differences between D-ER and placebo. The TUG test (P = .042) favored D-ER. There were no serious adverse events. Dalfampridine did not show an effect on accelerometer-measured ambulatory activity in people with MS-related walking difficulty. More work is needed to confirm these results.

Treatment patterns and health care resource utilization associated with dalfampridine extended release in multiple sclerosis: a retrospective claims database analysis.

BackgroundAlthough previous studies have demonstrated the clinical benefits of dalfampridine extended release (D-ER) tablets in patients with multiple sclerosis (MS), there are limited real-world data on D-ER utilization and associated outcomes in patients with MS.PurposeThe objective of this study was to evaluate treatment patterns, budget impact, and health care resource utilization (HRU) associated with D-ER use in a real-world setting.MethodsA retrospective claims database analysis was conducted using the HealthCore Integrated Research DatabaseSM. Adherence (measured by medication possession ratio, or [MPR]) and persistence (measured by days between initial D-ER claim and discontinuation or end of follow-up) were evaluated over 1-year follow-up. Budget impact was calculated as cost per member per month (PMPM) over the available follow-up period. D-ER and control cohorts were propensity-score matched on baseline demographics, comorbidities, and MS-related resource utilization to compare walking-impairment-related HRU over follow-up.ResultsOf the 2,138 MS patients identified, 1,200 were not treated with D-ER (control) and 938 were treated with D-ER. Patients were aged 51 years on average and 74% female. Approximately 82.6% of D-ER patients were adherent (MPR >80%). The estimated budget impact range of D-ER was $0.014–$0.026 PMPM. Propensity-score-matched D-ER and controls yielded 479 patients in each cohort. Postmatching comparison showed that the D-ER cohort was associated with fewer physician (21.5% vs 62.4%, P<0.0001) and other outpatient visits (22.8% vs 51.4%, P<0.0001) over the 12-month follow-up. Changes in HRU from follow-up to baseline were lower in the D-ER cohort for metrics including walking-impairment-related hospitalizations and emergency department visits.ConclusionThe majority of D-ER patients were adherent to treatment. D-ER utilization was associated with fewer walking-impairment-related physician and outpatient visits, with lower HRU increase over time. The budget impact of D-ER was low.

Changes in Cognitive Processing Speed, Mood, and Fatigue in an Observational Study of Persons With Multiple Sclerosis Treated With Dalfampridine-ER.

Multiple sclerosis (MS) is a degenerative neurological condition that results in impairments in multiple domains including cognition, fatigue, and mood. Dalfampridine-extended release (D-ER) has been approved to improve walking in persons with MS. It is plausible that D-ER could improve cognition, fatigue, and mood through the same mechanisms. We aim to examine effects of D-ER on cognition, depression, mood, and fatigue and to describe how these associations differ among those with and without D-ER related improvements in walking speed. Patients with MS at the Mandell Center who were newly prescribed D-ER as part of their standard MS care were invited to participate in this observational pre-post study. Thirty-nine participants with MS were observed for 14 weeks; 31 remained on D-ER for 14 weeks or longer. Of these, 28 were then subdivided based on walk responder status. Cognition was assessed using the SDMT; depression was measured with the CESD. Self-reported cognition, mood, and fatigue were also measured using subscales of the Performance Scales (PS). Among those on drug through 14 weeks, there was significant improvement in the SDMT (P < 0.001) and the PS Fatigue score (P = 0.04). Among those who discontinued drug before 14 weeks, PS Cognition and PS Mood scores significantly improved (P = 0.02). Timed walk responders had significant improvements in SDMT (P < 0.001) and PS Fatigue (P = 0.046) from baseline to week 14. Among timed walk nonresponders, none of the measures significantly changed. Dalfampridine-extended release may improve cognition and fatigue in persons with MS, especially among timed walk responders.

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

PurposeDalfampridine 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. MethodsThis 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). FindingsIn 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. ImplicationsBased 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.

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

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. 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. 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. 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.

Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial

Background: Mobility impairment is a common disability in MS and negatively impacts patients’ lives. Objective: Evaluate the effect of prolonged-release (PR) fampridine (extended-release dalfampridine in the United States) on self-assessed walking disability, dynamic/static balance and safety in patients with MS. Methods: MOBILE was a randomised, double-blind, exploratory, placebo-controlled trial. Patients with progressive/relapsing-remitting MS and Expanded Disability Status Scale score of 4.0–7.0 were treated with PR-fampridine or placebo twice daily for 24 weeks. Efficacy endpoints included change from baseline in the 12-item MS Walking Scale (MSWS-12), Timed Up and Go (TUG) test and Berg Balance Scale (BBS). Results: 132 patients were randomised at 24 sites in six countries. PR-fampridine therapy resulted in greater median improvements from baseline in MSWS-12 score, TUG speed and BBS total score versus placebo over 24 weeks. A higher proportion of patients receiving PR-fampridine versus placebo experienced significant improvements at MSWS-12 improvement thresholds ⩾7 (p = 0.0275), ⩾8 (p = 0.0153) and ⩾9 points (p = 0.0088) and TUG speed thresholds ⩾10% (p = 0.0021) and ⩾15% (p = 0.0262). PR-fampridine was well tolerated. Conclusions: PR-fampridine therapy resulted in early and sustained improvements in broad measures of walking and balance over six months.

Assessment of confirmed urinary tract infection in patients treated with dalfampridine for multiple sclerosis

Urinary tract infections (UTIs) were reported frequently with dalfampridine extended-release (dalfampridine-ER) 10 mg relative to placebo in previous multiple sclerosis (MS) studies. The objective of this study was to determine whether dalfampridine-ER is associated with increased incidence of confirmed UTIs in MS patients. This post hoc analysis used UTI data from a study comparing the 4-week safety and efficacy of 5 mg (n = 144) and 10 mg (n = 142) twice-daily dalfampridine-ER versus placebo (n = 143). To confirm UTIs, three clinical assessments were used: standard urinalysis (leukocytes > 5/high-power field); urine culture (≥ 100,000 and ≥ 10,000 colony-forming units [CFUs]/mL) for those who reported UTIs as adverse events (AEs) or had positive urinalysis; and UTI symptomatology. Fisher’s exact test assessed statistical significance. The proportion of patients who reported UTIs as AEs in the placebo and dalfampridine-ER 5 mg and 10 mg groups were 5.6%, 6.3%, and 9.9%, respectively. In comparison, those with laboratory-confirmed UTIs were lower: ≥ 100,000 CFUs/mL: 4.2%, 2.8%, and 2.8%; and ≥ 10,000 CFUs/mL: 4.2%, 3.5%, and 4.9%, respectively (no significant statistical difference across treatments). The proportion of patients with confirmed UTI was similar between dalfampridine-ER and placebo, thus suggesting that the treatment does not increase the risk of UTIs.

Dalfampridine in chronic sensorimotor deficits after ischemic stroke: A proof of concept study.

To evaluate the safety and tolerability of dalfampridine extended release (D-ER) in participants with chronic post-ischemic stroke deficits, and to assess for potential drug activity on sensorimotor function. Using a double-blind, placebo-controlled, cross-over design, participants were randomized to placebo/D-ER or D-ER/placebo sequences and given D-ER 10 mg or placebo twice daily. Key inclusion criteria were: ischemic stroke ≥ 6 months, Fugl-Meyer Assessment lower extremity motor score ≤ 28, ability to complete Timed 25-Foot Walk (T25FW). The primary outcome was safety and tolerability. The key exploratory measure was walking speed (T25FW). Other assessments were: Box and Block, and Grip and Pinch tests; Functional Independence Measure. Full-crossover data were analyzed using mixed-effects model. A total of 83 participants were randomized: 70 completed and 13 discontinued the study. Adverse events were consistent with previous D-ER trials; no new safety signals were observed. Four participants experienced serious adverse events: 3 seizures (1 placebo, 2 D-ER), 1 was secondary to intentional overdose. Most common treatment-emergent adverse events were: dizziness, nausea, arthralgia and fatigue. Mixed-effects analysis showed an effect for D-ER vs. placebo in improving walking speed (0.21 vs. 0.10 ft/s; p = 0.027). D-ER was generally well tolerated in participants with chronic stroke deficits. Potential drug activity on lower extremity sensorimotor function, with an improvement in walking speed, was seen.

Prescriber utilization of dalfampridine extended release tablets in multiple sclerosis: a retrospective pharmacy and medical claims analysis.

PurposeThis study aimed to characterize the prescribing of dalfampridine extended release (D-ER) 10 mg tablet treatment in people with multiple sclerosis (MS).MethodsA retrospective cohort study was performed using Medco pharmacy and medical claims. Medical claims were used to identify MS patients with more than one prescription for D-ER with 1 year of prior continuous enrollment (n=704). These patients were matched 2:1 on age, sex, and health insurance source with a comparison group of MS patients who were treatment naïve for D-ER (n=1,403). Categorical data were analyzed by χ2 test; ordinal data by Wilcoxon rank sum test; and continuous data by Student’s t-test.ResultsMost patients were women aged 45–64 years. In the year preceding D-ER initiation, the prevalence of seizure and renal impairment was numerically lower in the D-ER cohort relative to those who were D-ER naïve (seizure: 3.1% versus 4.7%, respectively; renal impairment: 4.3% versus 5.1%, respectively); however, prescriptions for antiepileptic drugs in the two cohorts were comparable. In the year preceding treatment initiation, 62% of the D-ER cohort was prescribed MS-specific disease-modifying therapies relative to 45% who were D-ER naïve.ConclusionSeizure and renal impairment rates among D-ER-naïve patients were consistent with published literature, yet rates among those prescribed D-ER during the year preceding treatment initiation were slightly lower than rates among D-ER-naïve patients. Given that D-ER is contraindicated in patients with history of seizure or moderate or severe renal impairment, lower rates may indicate that risk-minimization strategies contributed to the lower prevalence.

Positive neurologic phenomena with initiation of dalfampridine for multiple sclerosis

ObjectiveReview cases of positive neurologic phenomena initiated or worsened with dalfampridine in patients with multiple sclerosis. BackgroundOral, extended release dalfampridine (4-aminopyridine or 4-AP) is a potassium-channel blocker approved for the treatment of gait impairment in multiple sclerosis (MS). The enhanced conduction along demyelinated axons promoted by dalfampridine could potentially lead to development of positive neurologic phenomena. MethodsWe reviewed the medical records of patients who were started on dalfampridine for activation of positive sensory or motor symptoms. ResultsFour of 76 patients (5.3%) developed positive sensory symptoms within one month of starting dalfampridine; one additional patient had new-onset seizure. Cessation of dalfampridine was insufficient to resolve symptoms in two patients with recurrent trigeminal neuralgia. ConclusionsInitiation of dalfampridine may be associated with initiation or recurrence of positive sensory symptoms in patients with multiple sclerosis. The increased axonal conduction from potassium channel blockade may contribute to this exacerbation of positive sensory phenomena.

Effects of 5mg and 10mg Dalfampridine Extended Release Tablets on 6-Minute Walk Distance in People with Multiple Sclerosis: A Subgroup Analysis of a Double-Blind, Placebo-Controlled Trial (S01.007)

Effects of 5mg and 10mg Dalfampridine Extended Release Tablets on 6-Minute Walk Distance in People with Multiple Sclerosis: A Subgroup Analysis of a Double-Blind, Placebo-Controlled Trial (S01.007)

Changes in Gait, Walking, and Balance Parameters after Withdrawal and Re-Initiation of Dalfampridine Extended Release Tablets in Patients with Multiple Sclerosis: Results from the STEADY Study (P04.103)

Changes in Gait, Walking, and Balance Parameters after Withdrawal and Re-Initiation of Dalfampridine Extended Release Tablets in Patients with Multiple Sclerosis: Results from the STEADY Study (P04.103)

Safety and Efficacy of 5mg and 10mg Dalfampridine Extended Release Tablets in Patients with Multiple Sclerosis: First Results from a Double-Blind, Placebo-Controlled Trial (P04.096)

Safety and Efficacy of 5mg and 10mg Dalfampridine Extended Release Tablets in Patients with Multiple Sclerosis: First Results from a Double-Blind, Placebo-Controlled Trial (P04.096)

PND50 Estimation of the Effect of Dalfampridine Extended Release on Health Utility in Patients With Multiple Sclerosis Using Two Equations for Mapping the MSWS-12 to the EQ-5D

PND50 Estimation of the Effect of Dalfampridine Extended Release on Health Utility in Patients With Multiple Sclerosis Using Two Equations for Mapping the MSWS-12 to the EQ-5D

Extended-release dalfampridine in the management of multiple-sclerosis-related walking impairment

Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that causes neurological impairment in young adults. As part of the disease, ambulation remains one of the most disabling features of multiple sclerosis. Extended-release dalfampridine is a long-acting form of 4-aminopyridine that has been shown in two phase III trials to increase ambulation speed in a subset of patients with multiple sclerosis (timed walk responders). The primary endpoint of these studies was 'responder status', analyzing difference in the proportion of timed walk responders between extended-release dalfampridine and placebo groups. Extended-release dalfampridine exerts its effects by inhibiting voltage-activated K(+) channels and has been previously demonstrated to improve action potential propagation in demyelinated nerve fibers in vitro. Side effects of extended-release dalfampridine include increased urinary tract infections, insomnia, headache, asthenia, dizziness, back pain, and paresthesias. Rare seizure events are also reported on the approved dose of 10 mg every 12 h. In this review we will summarize the results of key phase II and phase III trials of extended-release dalfampridine, its safety, and potential use in patients with multiple sclerosis.

Impact of extended-release dalfampridine on walking ability in patients with multiple sclerosis.

Dalfampridine extended release (ER) 10 mg is an oral tablet form of the potassium (K+) channel-blocking compounded dalfampridine, also known as fampridine, and chemically 4-aminopyridine or 4-AP, which received regulatory approval in the United States for the treatment of walking in patients with multiple sclerosis (MS) in January 2010. Two pivotal Phase 3 clinical trials demonstrated significant improvements in walking in patients with the four primary forms of MS following administration of dalfampridine ER tablets 10 mg twice daily. The drug is thought to act by restoring conduction in focally demyelinated axons and by enhancing neurotransmission, thereby leading to improved neurological function. This review describes how dalfampridine represents a new pharmacotherapeutic approach to the clinical management of mobility impairment. It describes the mechanism of action and chemistry of dalfampridine ER, its pharmacokinetics, tolerability, and side effects, and the outcomes of multicenter trials showing its efficacy in improving walking speed. Clinician and patient global assessments, as well as patient self-assessment of the impact of MS on their gait disability, confirm clinically relevant benefit from the therapy. Patients tolerate the drug well and their improvement in terms of household and community ambulation, inferred from analysis of pooled data from several studies, is likely to translate into benefits in the performance of instrumental activities of daily living and a reduction in the neuropsychiatric burden of disease.