Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials.

BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS). OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT). METHODS: Patients received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW. RESULTS: We had 269 patients enter MS-F203EXT and 154 patients complete it; for a maximum exposure of 5 years. We had 214 patients enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders. CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

A pooled analysis of two phase 3 clinical trials of dalfampridine in patients with multiple sclerosis.

BACKGROUND: Two phase 3 clinical trials demonstrated that dalfampridine extended-release 10-mg tablets (D-ER), twice daily, significantly improved walking relative to placebo in patients with multiple sclerosis (MS). The objective of this study was to evaluate the efficacy and safety of D-ER in patients with MS using pooled data from the two phase 3 trials. METHODS: Data were pooled from the two trials, and D-ER was compared with placebo for timed-walk responder rate, changes in walking speed, and the 12-item Multiple Sclerosis Walking Scale (MSWS-12). Response rates were evaluated with respect to demographic and clinical characteristics. RESULTS: D-ER had a significantly higher proportion of timed-walk responders relative to placebo (37.6% vs. 8.9%; P < .0001). The responder rate was independent of age, gender, race, body-mass index, type of MS, duration of MS, baseline Expanded Disability Status Scale score, baseline walking speed, and concomitant use of immunomodulatory therapies. Significant improvements were observed in walking speed and in MSWS-12 score for the pooled D-ER group compared with placebo. The safety profile was consistent with the individual studies; no new safety or tolerability concerns were identified. CONCLUSIONS: D-ER demonstrated efficacy for the improvement of walking in patients with MS; response was independent of demographic and clinical characteristics.

A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.

OBJECTIVE: A previous phase 3 study showed significant improvement in walking ability in multiple sclerosis (MS) patients treated with oral, extended-release dalfampridine (4-aminopyridine) 10mg twice daily. The current study was designed to confirm efficacy and further define safety and pharmacodynamics. METHODS: This was a 39-center, double-blind trial in patients with definite MS of any course type. Participants were randomized to 9 weeks of treatment with dalfampridine (10mg twice daily; n = 120) or placebo (n = 119). Response was defined as consistent improvement on the Timed 25-Foot Walk, with percentage of timed walk responders (TWRs) in each treatment group as the primary outcome. The last on-treatment visit provided data from 8 to 12 hours postdose, to examine maintenance of effect. RESULTS: One patient from each group was excluded from the modified Intention to Treat population. The proportion of TWRs was higher in the dalfampridine group (51/119 or 42.9%) compared to the placebo group (11/118 or 9.3%, p < 0.0001). The average improvement in walking speed among dalfampridine-treated TWRs during the 8-week efficacy evaluation period was 24.7% from baseline (95% confidence interval, 21.0-28.4%); the mean improvement at the last on-treatment visit was 25.7%, showing maintenance of effect over the interdosing period. There were no new safety findings. INTERPRETATION: This interventional study provides class 1 evidence that dalfampridine extended-release tablets produce clinically meaningful improvement in walking ability in a subset of people with MS, with the effect maintained between doses.

Current and future directions in MS management: key considerations for managed care pharmacists.

BACKGROUND: The management paradigm for multiple sclerosis (MS) continues to evolve and is shifting toward earlier diagnosis, differentiation of patients with varying clinical prognoses, and earlier initiation of treatment in selected individuals. Based on surveys conducted at the 2008 annual conference of the Academy of Managed Care Pharmacy (AMCP) and at regional meetings held in 2009, several topics were identified for which pharmacists indicated a need for new and updated information. OBJECTIVE: To review (a) recent insights into the pathophysiology underlying MS, (b) the improvements in identification of patients with a clinically isolated syndrome (CIS) who will progress to clinically definite MS (CDMS), (c) the current role of magnetic resonance imaging (MRI) and other technologies in the diagnosis and ongoing management of MS, (d) the optimal time to initiate treatment in patients with CIS or MS, and (e) the potential utility of new and emerging therapies in MS management. METHODS: The medical education company PRIME conducted an educational needs assessment regarding knowledge of recent developments and future directions in MS management at a symposium held at the Academy of Managed Care Pharmacy Educational Conference in Kansas City, Missouri, on October 17, 2008. This was augmented by an ongoing educational needs assessment initiative that involved a national series of regional dinner meetings for managed care pharmacists on the topic of MS in the first 3 quarters of 2009. Collectively, these needs assessments were designed to determine educational gaps that existed after participants attended the symposia on MS, in an effort to plan a follow-up enduring educational activity that addressed those gaps. Measures of learners' post-program intent were collected, as well as specific topic areas recommended for a follow-up activity. SUMMARY: Advances have been made in the understanding of CIS subtypes and refinement of MS diagnostic criteria. Early initiation of treatment in patients with a CIS has been shown to prolong the time to progression to CDMS, delay the development of disability, and may also decrease longterm health care costs. In addition, a number of novel therapies for patients with MS are in late stages of clinical development, including several oral medications that are of particular interest to managed care pharmacists. These will provide potentially attractive treatment alternatives for patients with MS, who currently must choose from a selection of injectable drugs.

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.

BACKGROUND: Clinical studies suggested that fampridine (4-aminopyridine) improves motor function in people with multiple sclerosis. This phase III study assessed efficacy and safety of oral, sustained-release fampridine in people with ambulatory deficits due to multiple sclerosis. METHODS: We undertook a randomised, multicentre, double-blind, controlled phase III trial. We randomly assigned 301 patients with any type of multiple sclerosis to 14 weeks of treatment with either fampridine (10 mg twice daily; n=229) or placebo (n=72), using a computer-generated sequence stratified by centre. We used consistent improvement on timed 25-foot walk to define response, with proportion of timed walk responders in each treatment group as the primary outcome. We used the 12-item multiple sclerosis walking scale to validate the clinical significance of the response criterion. Efficacy analyses were based on a modified intention-to-treat population (n=296), which included all patients with any post-treatment efficacy data. The study is registered with ClinicalTrials.gov, number NCT00127530. FINDINGS: The proportion of timed walk responders was higher in the fampridine group (78/224 or 35%) than in the placebo group (6/72 or 8%; p<0.0001). Improvement in walking speed in fampridine-treated timed walk responders, which was maintained throughout the treatment period, was 25.2% (95% CI 21.5% to 28.8%) and 4.7% (1.0% to 8.4%) in the placebo group. Timed walk responders showed greater improvement in 12-item multiple sclerosis walking scale scores (-6.84, 95% CI -9.65 to -4.02) than timed walk non-responders (0.05, -1.48 to 1.57; p=0.0002). Safety data were consistent with previous studies. INTERPRETATION: Fampridine improved walking ability in some people with multiple sclerosis. This improvement was associated with a reduction of patients' reported ambulatory disability, and is a clinically meaningful therapeutic benefit.

The symptomatic management of multiple sclerosis.

The management of multiple sclerosis (MS) revolves around disease management, symptom management, and person management. Of these, symptom management takes up the bulk of the time of the practicing physician. Some symptoms are easily managed whereas others are more difficult. Decisions have often to be made on whether to treat or to wait and watch. This article discusses the varied symptoms of MS and the approaches to management, which involves rehabilitation, pharmacological treatments, and surgical procedures. The skilled physician managing MS should be familiar with the multiple approaches to improving the quality of life of those with MS. After the diagnosis has been established and the decisions regarding treatment approaches have been made, the talk in a typical office appointment for MS usually turns to symptom management. Thus, the majority of management decisions made by the clinician revolve around that important topic. It is symptom management that will determine quality of life for those with MS, It is the basis for improving function, and, up until twenty years ago, it was the only basis for treating MS. Now, however, we can approach treatment by disease management, symptom management, and person management. The MS specialist must be well versed in all three areas.

Symptoms and physical activity behavior in individuals with multiple sclerosis.

We examined overall and specific symptoms as correlates of physical activity in individuals with multiple sclerosis (MS). Participants (N = 133) completed questionnaires that measured overall symptoms; and specific symptoms of depression, pain, and fatigue; difficulty walking; and physical activity. Initial analyses indicated that higher levels of overall symptoms (r = -.50), fatigue (r = -.26), and difficulty walking (r = -.46) were associated with lower levels of physical activity. Path analysis demonstrated that higher levels of overall symptoms were directly and indirectly associated with lower levels of physical activity; the indirect pathway involved difficulty walking (gamma beta = -.17). Such findings indicate that walking difficulty may partially explain the negative relationship between overall symptoms and physical activity behavior in MS.

Pharmacologic options for the management of multiple sclerosis symptoms.

Multiple sclerosis (MS) is a disease with a wide-ranging impact on physical functioning. Although pharmacotherapy plays an indispensable role in the management of MS symptoms, optimal disease management requires a multidisciplinary approach that combines medication, rehabilitation, and patient education. Successful control of symptoms is critical to quality of life for MS patients. Immunomodulating drugs provide a means of controlling the underlying disease process, but they are not a cure. This places responsibility on health care providers to control a patient's MS-related symptoms to limit disability and delay impairment in the activities of daily living. Owing to the importance of symptom control, comprehensive patient evaluations should be performed at regular intervals to determine the extent of neurological damage and disease progression and to address changing patient needs. The goal of interventions should be not only to treat the primary and secondary symptoms of MS but also to provide access to the psychosocial support that will help MS patients and their families continue to cope as disease status changes.