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Keith C. Hayes - One of the best experts on this subject based on the ideXlab platform.
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Fampridine-SR for multiple sclerosis and spinal cord injury.
Expert review of neurotherapeutics, 2007Co-Authors: Keith C. HayesAbstract:Fampridine-SR is a sustained-release tablet form of the K+ channel-blocking compound 4-aminopyridine that has been shown to restore conduction in focally demyelinated axons, to enhance synaptic transmission in many types of neurons and to potentiate muscle contraction. The present review describes the mechanism of action and chemistry of Fampridine-SR, its pharmacokinetics and safety, and the outcomes of clinical trials of its safety and efficacy for enhancing neuromuscular function in patients with multiple sclerosis or spinal cord injury. Randomized clinical trials completed to date indicate that this form of K+ channel blockade may be useful for the improvement of walking ability in patients with multiple sclerosis.
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Pharmacokinetics and Safety of Multiple Oral Doses of Sustained-Release 4-Aminopyridine (Fampridine-SR) in Subjects With Chronic, Incomplete Spinal Cord Injury
Archives of physical medicine and rehabilitation, 2004Co-Authors: Keith C. Hayes, Patrick J. Potter, Mitchell A. Katz, Andrew R. Blight, Jane T Hsieh, Ron CohenAbstract:Abstract Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil 2004;85:29–34. Objective To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). Design Open-label. Setting Clinical research unit in Ontario. Participants Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). Intervention Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily, each for 1wk). Main outcome measures Steady-state pharmacokinetic parameters: maximum observed plasma concentration (C max ), minimum observed plasma concentration (C min ), average observed plasma concentration (C av ), area under the plasma concentration-time curve from 0 to 12 hours (AUC 0–12 ), time to C max (t max ), plasma half-life (t 1/2 ), apparent volume of distribution (V d /F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. Results Mean steady-state C max , C min , C av , and AUC 0–12 increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50mg twice daily. Fampridine-SR had a mean t max of 2.2 to 3.0 hours and a mean t 1/2 of 5.7 to 6.9 hours. Mean V d /F (415.4–528.0L) and Cl/F (51.4–57.7L/h) were independent of dosage, as were mean t max and t 1/2 across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. Conclusion In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twice-daily manner. Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily.
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Pharmacokinetic studies of single and multiple oral doses of Fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.
Clinical neuropharmacology, 2003Co-Authors: Keith C. Hayes, Patrick J. Potter, Robert R. Hansebout, Joanne M. Bugaresti, Jane T. C. Hsieh, Sera Nicosia, Mitchell A. Katz, Andrew R. Blight, Ronald A. CohenAbstract:Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered Fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of Fampridine (Fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of Fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using Fampridine-SR in patients with chronic SCI are currently underway.
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Randomized Double-Blind Crossover Trial of Fampridine-SR (Sustained Release 4-Aminopyridine) in Patients With Incomplete Spinal Cord Injury
Journal of neurotrauma, 1998Co-Authors: Patrick J. Potter, Keith C. Hayes, Jane T. C. Hsieh, J. L. Segal, S. R. Brunnemann, Gail A. Delaney, D. S. Tierney, D. MasonAbstract:A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral Fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received Fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of Fampridine-SR over placebo on patient satisfaction (McNemar's test, p 2 < 0.05) and quality of life scores (p 2 < 0.01). Sensory scores (p 1 < 0.01), including both pin prick (p 1 = 0.059) and light touch (p 1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p 1 < 0.01) all yielded evidence of benefit of Fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p 2 < 0.05) reduced when patients received Fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use Fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of Fampridine-SR in SCI patients.
Andrew R. Blight - One of the best experts on this subject based on the ideXlab platform.
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assessment of clinically meaningful improvements in self reported walking ability in participants with multiple sclerosis results from the randomized double blind phase iii enhance trial of prolonged release Fampridine
CNS Drugs, 2019Co-Authors: Jeremy Hobart, Michael Linnebank, Tjalf Ziemssen, Andrew R. Blight, Raymond Hupperts, R Farrell, Peter Feys, Andrew D Goodman, Veronica Englishby, Manjit McneillAbstract:Walking impairment is a hallmark of multiple sclerosis (MS). It affects > 90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-Fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-Fampridine from the perspective of the individual with MS warrants full and detailed examination. The objective of this study was to evaluate whether PR-Fampridine has a clinically meaningful effect on self-reported walking ability in walking-impaired participants with MS. ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-Fampridine 10 mg twice daily in walking-impaired individuals age 18–70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0–7.0 at screening. Participants were stratified by EDSS score (≤ 6.0 or 6.5–7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefined threshold for clinically meaningful improvement (≥ 8 points) over 24 weeks. Secondary endpoints included the proportion with ≥ 15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. In total, 636 participants with MS were randomized (PR-Fampridine, n = 317; placebo, n = 319; modified intention-to-treat sample: PR-Fampridine, n = 315; placebo, n = 318). At baseline in the PR-Fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0–7.0] and 5.5 [4.0–7.0], mean [range] MSWS-12 scores were 63.6 [0–100] and 65.4 [0–100], and mean [range] TUG speed was 0.38 [0.0–1.0] and 0.38 [0.0–1.2] feet/s, respectively. A significantly higher percentage of PR-Fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confidence interval 1.15–2.26]; p = 0.006). For PR-Fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p < 0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-Fampridine group than placebo group (difference ≥ 3%) by Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term were urinary tract infection and insomnia. There were no seizures reported. PR-Fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in self-reported walking and functional ability in walking-disabled participants with MS. NCT02219932.
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two phase 3 multicenter randomized placebo controlled clinical trials of Fampridine sr for treatment of spasticity in chronic spinal cord injury
Spinal Cord, 2014Co-Authors: Diana D Cardenas, Patrick J. Potter, Ron Cohen, John F Ditunno, Virginia Graziani, Amie Mclain, Daniel P Lammertse, M S Alexander, Andrew R. BlightAbstract:Two randomized, double-blind, placebo-controlled trials. To evaluate the efficacy and safety of Fampridine sustained-release tablets (Fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI). United States and Canada. Patients with incomplete chronic SCI were randomized to twice daily Fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician’s Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women). The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were −0.15 (placebo) and −0.19 (Fampridine-SR) in the first study, and −0.16 (placebo) and −0.28 (Fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments. Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI.
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sustained release oral Fampridine in multiple sclerosis a randomised double blind controlled trial
The Lancet, 2009Co-Authors: Andrew D Goodman, Ron Cohen, Theodore R Brown, Lauren B Krupp, Randall T Schapiro, Steven R Schwid, Lawrence Marinucci, Andrew R. BlightAbstract:Summary 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 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. Funding Acorda Therapeutics Inc.
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Steady-state pharmacokinetics and tolerability of orally administered Fampridine sustained-release 10-mg tablets in patients with multiple sclerosis: a 2-week, open-label, follow-up study.
Clinical therapeutics, 2009Co-Authors: Timothy Vollmer, Andrew R. Blight, Herbert R. HenneyAbstract:Abstract Background: Fampridine sustained release (SR) has generally been well tolerated in clinical studies in patients with multiple sclerosis (MS) at doses ≤20 mg/d. The pharmacokinetics of single escalating doses of Fampridine SR (5, 10, 15, and 20 mg) were evaluated in a companion study. Objectives: The primary objective of this study, which followed on from the single-dose pharmacokinetic study, was to assess the steady-state pharmacokinetics of Fampridine in patients with MS over 2 weeks of oral administration of open-label Fampridine SR 20 mg BID. Tolerability was also evaluated. Methods: The dose of Fampridine SR was titrated upward to twice-daily administration over days 1 and 2, with 20 mg given in the morning and 10 mg in the evening. From days 3 to 14, patients received Fampridine SR 20 mg BID (total daily dose, 40 mg). Fampridine pharmacokinetic parameters were determined on days 1, 8, and 15. The parameters of interest included C max , T max , C min , AUC, and apparent t ½ These parameters were compared with those from the single-dose study. Tolerability was assessed based on adverse events, physical examinations, vital signs, laboratory tests, and ECGs. Results: Twenty-one white patients who participated in the single-dose study were enrolled in the steadystate study (52.4% female; mean [SD] age, 45.1 [7.4] years; weight range, 54–87 kg). Fampridine pharmacokinetic parameters on day 1 were consistent with those obtained in the single-dose study. The T max did not differ significantly between day 1, day 8, day 15, and the single-dose study (range, 3.25–3.78 hours). C max values on days 8 and 15 (66.7 and 62.6 ng/mL, respectively) were significantly higher than those on day 1 (48.6 ng/mL) and in the singledose study (50.5 ng/mL) (all, P max /C min did not differ significantly between day 1 and the single-dose study (2.44 and 2.43, respectively) or between days 8 and 15 (2.90 and 2.88, respectively); however, the single-dose and day-1 values differed significantly from the day-8 and day-15 values (P ≤ 0.001). There were no significant differences with respect to any other pharmacokinetic parameters. One hundred adverse events were reported by 21 patients. With the exception of 1 case of severe nausea, all adverse events were of mild to moderate severity. Thirty-five events reported by 14 subjects were considered treatment related. Dizziness was the most common treatment-related adverse event, with 11 episodes reported by 8 patients. No clinically significant changes were found in clinical laboratory values, vital signs, or physical examination findings from baseline to the last visit, and there were no clinically significant changes in QTc intervals (Bazett's correction). Conclusions: In these patients with MS, the steady-state pharmacokinetic profile of Fampridine SR 20 mg BID administered for 2 weeks appeared to support the use of twice-daily dosing in this population. This dosage was generally well tolerated.
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Dose comparison trial of sustained-release Fampridine in multiple sclerosis
Neurology, 2008Co-Authors: Andrew D Goodman, Ron Cohen, Theodore R Brown, Lauren B Krupp, Randall T Schapiro, Steven R Schwid, Lawrence Marinucci, Jeffrey A. Cohen, Andrew R. BlightAbstract:Objective: To examine the efficacy and safety of three different doses of sustained-release Fampridine in people with multiple sclerosis (MS). Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive Fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. Results: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo ( p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more “consistent responders” in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. Conclusions: This phase 2 study suggests that a subgroup of patients, when treated with Fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.
Patrick J. Potter - One of the best experts on this subject based on the ideXlab platform.
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two phase 3 multicenter randomized placebo controlled clinical trials of Fampridine sr for treatment of spasticity in chronic spinal cord injury
Spinal Cord, 2014Co-Authors: Diana D Cardenas, Patrick J. Potter, Ron Cohen, John F Ditunno, Virginia Graziani, Amie Mclain, Daniel P Lammertse, M S Alexander, Andrew R. BlightAbstract:Two randomized, double-blind, placebo-controlled trials. To evaluate the efficacy and safety of Fampridine sustained-release tablets (Fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI). United States and Canada. Patients with incomplete chronic SCI were randomized to twice daily Fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician’s Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women). The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were −0.15 (placebo) and −0.19 (Fampridine-SR) in the first study, and −0.16 (placebo) and −0.28 (Fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments. Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI.
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Pharmacokinetics and Safety of Multiple Oral Doses of Sustained-Release 4-Aminopyridine (Fampridine-SR) in Subjects With Chronic, Incomplete Spinal Cord Injury
Archives of physical medicine and rehabilitation, 2004Co-Authors: Keith C. Hayes, Patrick J. Potter, Mitchell A. Katz, Andrew R. Blight, Jane T Hsieh, Ron CohenAbstract:Abstract Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil 2004;85:29–34. Objective To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). Design Open-label. Setting Clinical research unit in Ontario. Participants Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). Intervention Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily, each for 1wk). Main outcome measures Steady-state pharmacokinetic parameters: maximum observed plasma concentration (C max ), minimum observed plasma concentration (C min ), average observed plasma concentration (C av ), area under the plasma concentration-time curve from 0 to 12 hours (AUC 0–12 ), time to C max (t max ), plasma half-life (t 1/2 ), apparent volume of distribution (V d /F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. Results Mean steady-state C max , C min , C av , and AUC 0–12 increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50mg twice daily. Fampridine-SR had a mean t max of 2.2 to 3.0 hours and a mean t 1/2 of 5.7 to 6.9 hours. Mean V d /F (415.4–528.0L) and Cl/F (51.4–57.7L/h) were independent of dosage, as were mean t max and t 1/2 across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. Conclusion In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twice-daily manner. Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily.
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Pharmacokinetic studies of single and multiple oral doses of Fampridine-SR (sustained-release 4-aminopyridine) in patients with chronic spinal cord injury.
Clinical neuropharmacology, 2003Co-Authors: Keith C. Hayes, Patrick J. Potter, Robert R. Hansebout, Joanne M. Bugaresti, Jane T. C. Hsieh, Sera Nicosia, Mitchell A. Katz, Andrew R. Blight, Ronald A. CohenAbstract:Fampridine (4-aminopyridine) is a potassium channel blocking agent that restores conduction in demyelinated axons and improves neurologic function in patients with chronic spinal cord injury (SCI). Based on the pharmacokinetic profile of orally administered Fampridine, multiple daily doses (4 or more) would need to be taken to sustain its therapeutic effects. Two studies were conducted to determine the pharmacokinetics and safety profile of an oral, sustained-release (SR) formulation of Fampridine (Fampridine-SR, 10-25 mg) administered as a single dose (n = 14) and twice daily for 1 week (n = 16) in patients with chronic, incomplete SCI. Mean plasma concentrations and area under the plasma concentration-time curve were proportional to the dose administered, whereas other pharmacokinetic parameters were independent of dose. Fampridine-SR was absorbed slowly (peak plasma concentration shortly after dosing, 2.6-3.7 hours) and eliminated (plasma half-life, 5.6-7.6 hours), and reached steady state after 4 days of twice-daily administration. Fampridine-SR was well tolerated, with only mild to moderate adverse events reported, and no serious adverse events. The extended plasma half-life of Fampridine-SR allows convenient twice-daily dosing. Clinical trials designed to assess neurologic and functional improvement using Fampridine-SR in patients with chronic SCI are currently underway.
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Randomized Double-Blind Crossover Trial of Fampridine-SR (Sustained Release 4-Aminopyridine) in Patients With Incomplete Spinal Cord Injury
Journal of neurotrauma, 1998Co-Authors: Patrick J. Potter, Keith C. Hayes, Jane T. C. Hsieh, J. L. Segal, S. R. Brunnemann, Gail A. Delaney, D. S. Tierney, D. MasonAbstract:A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral Fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received Fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of Fampridine-SR over placebo on patient satisfaction (McNemar's test, p 2 < 0.05) and quality of life scores (p 2 < 0.01). Sensory scores (p 1 < 0.01), including both pin prick (p 1 = 0.059) and light touch (p 1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p 1 < 0.01) all yielded evidence of benefit of Fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p 2 < 0.05) reduced when patients received Fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use Fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of Fampridine-SR in SCI patients.
Ron Cohen - One of the best experts on this subject based on the ideXlab platform.
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two phase 3 multicenter randomized placebo controlled clinical trials of Fampridine sr for treatment of spasticity in chronic spinal cord injury
Spinal Cord, 2014Co-Authors: Diana D Cardenas, Patrick J. Potter, Ron Cohen, John F Ditunno, Virginia Graziani, Amie Mclain, Daniel P Lammertse, M S Alexander, Andrew R. BlightAbstract:Two randomized, double-blind, placebo-controlled trials. To evaluate the efficacy and safety of Fampridine sustained-release tablets (Fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI). United States and Canada. Patients with incomplete chronic SCI were randomized to twice daily Fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician’s Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women). The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were −0.15 (placebo) and −0.19 (Fampridine-SR) in the first study, and −0.16 (placebo) and −0.28 (Fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments. Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI.
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sustained release oral Fampridine in multiple sclerosis a randomised double blind controlled trial
The Lancet, 2009Co-Authors: Andrew D Goodman, Ron Cohen, Theodore R Brown, Lauren B Krupp, Randall T Schapiro, Steven R Schwid, Lawrence Marinucci, Andrew R. BlightAbstract:Summary 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 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. Funding Acorda Therapeutics Inc.
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Dose comparison trial of sustained-release Fampridine in multiple sclerosis
Neurology, 2008Co-Authors: Andrew D Goodman, Ron Cohen, Theodore R Brown, Lauren B Krupp, Randall T Schapiro, Steven R Schwid, Lawrence Marinucci, Jeffrey A. Cohen, Andrew R. BlightAbstract:Objective: To examine the efficacy and safety of three different doses of sustained-release Fampridine in people with multiple sclerosis (MS). Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study recruited 206 participants at 24 centers in the United States and Canada. After a single-blind, 2-week placebo run-in, participants were randomly assigned to receive Fampridine (10, 15, or 20 mg twice daily) or placebo for 15 weeks. The primary efficacy variable was percent change in walking speed based on the timed 25-foot walk. Results: Trends for increased walking speed were consistent across dose groups vs placebo, but not significant, on the prospective analysis. An increase from baseline in lower extremity strength during the 12-week stable-dose period was seen in the groups receiving 10- and 15-mg doses, compared with placebo ( p = 0.018 and 0.003). There were no significant changes in other secondary assessments. Post hoc analysis revealed subsets of participants in each dose group with walking speeds during the treatment period that were consistently faster than during the nontreatment period. There were significantly more “consistent responders” in the drug-treated groups than in the placebo group (36.7% compared with 8.5%). Consistent responders showed significantly greater improvement in self-assessed ambulation on the 12-Item MS Walking Scale than did nonresponders. Fampridine was generally well tolerated. Severe and serious adverse events were more frequent at the highest dose. Conclusions: This phase 2 study suggests that a subgroup of patients, when treated with Fampridine, experiences a clinically relevant improvement in walking ability, which is sustained for at least 14 weeks.
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Pharmacokinetics and Safety of Multiple Oral Doses of Sustained-Release 4-Aminopyridine (Fampridine-SR) in Subjects With Chronic, Incomplete Spinal Cord Injury
Archives of physical medicine and rehabilitation, 2004Co-Authors: Keith C. Hayes, Patrick J. Potter, Mitchell A. Katz, Andrew R. Blight, Jane T Hsieh, Ron CohenAbstract:Abstract Hayes KC, Potter PJ, Hsieh JT, Katz MA, Blight AR, Cohen R. Pharmacokinetics and safety of multiple oral doses of sustained-release 4-aminopyridine (Fampridine-SR) in subjects with chronic, incomplete spinal cord injury. Arch Phys Med Rehabil 2004;85:29–34. Objective To examine the pharmacokinetics and safety of sustained-release 4-aminopyridine (Fampridine-SR), a potassium channel blocker, in subjects with chronic, incomplete spinal cord injury (SCI). Design Open-label. Setting Clinical research unit in Ontario. Participants Sixteen neurologically stable subjects with chronic, incomplete SCI (American Spinal Injury Association Impairment Scale grade B, C, or D). Intervention Oral administration of Fampridine-SR (25, 30, 35, 40, 50, 60mg twice daily, each for 1wk). Main outcome measures Steady-state pharmacokinetic parameters: maximum observed plasma concentration (C max ), minimum observed plasma concentration (C min ), average observed plasma concentration (C av ), area under the plasma concentration-time curve from 0 to 12 hours (AUC 0–12 ), time to C max (t max ), plasma half-life (t 1/2 ), apparent volume of distribution (V d /F), and apparent total clearance (Cl/F). Safety assessments: physical examinations, vital sign measurements, clinical laboratory tests, electrocardiogram recordings, and adverse events. Results Mean steady-state C max , C min , C av , and AUC 0–12 increased over the entire Fampridine-SR dosage range and were dosage dependent up to 50mg twice daily. Fampridine-SR had a mean t max of 2.2 to 3.0 hours and a mean t 1/2 of 5.7 to 6.9 hours. Mean V d /F (415.4–528.0L) and Cl/F (51.4–57.7L/h) were independent of dosage, as were mean t max and t 1/2 across dosages. Adverse events were mild or moderate and were not dosage related. During the entire study period (17wk), dizziness was the most frequently reported adverse event, followed by urinary tract infection, paresthesia, ataxia, and insomnia. Conclusion In subjects with chronic, incomplete SCI, Fampridine-SR was slowly absorbed and eliminated, which will allow Fampridine-SR to be administered in a convenient twice-daily manner. Fampridine-SR was well tolerated at dosages from 25 to 60mg twice daily.
D. Mason - One of the best experts on this subject based on the ideXlab platform.
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Randomized Double-Blind Crossover Trial of Fampridine-SR (Sustained Release 4-Aminopyridine) in Patients With Incomplete Spinal Cord Injury
Journal of neurotrauma, 1998Co-Authors: Patrick J. Potter, Keith C. Hayes, Jane T. C. Hsieh, J. L. Segal, S. R. Brunnemann, Gail A. Delaney, D. S. Tierney, D. MasonAbstract:A randomized double-blind dose-titration crossover trial of the safety and efficacy of oral Fampridine-SR (sustained release 4-aminopyridine) was conducted on spinal cord injured (SCI) patients at two centers. Twenty-six patients (n = 26) with incomplete lesions completed the trial. These patients all had chronic (>2 years) and stable neurological deficits. They received Fampridine-SR 12.5 and 17.5 mg b.i.d. over a 2-week treatment period, followed by a 1-week washout and 2 weeks of placebo, or vice versa. Patients reported significant benefit of Fampridine-SR over placebo on patient satisfaction (McNemar's test, p 2 < 0.05) and quality of life scores (p 2 < 0.01). Sensory scores (p 1 < 0.01), including both pin prick (p 1 = 0.059) and light touch (p 1 = 0.058), and motor scores (adjusted to reflect only paretic segments) (p 1 < 0.01) all yielded evidence of benefit of Fampridine-SR over placebo. The Ashworth scale of spasticity was significantly (p 2 < 0.05) reduced when patients received Fampridine-SR. There were no statistically significant benefits of the drug on measures of pain or bowel, bladder and sexual function, or functional independence. Side effects of lightheadedness and nausea were transient and trivial relative to efficacy, and approximately 30% of patients reported a wish to continue to use Fampridine-SR. The clinical benefits most likely derive from the K+ channel blocking action of the drug. Potassium channel blockade enhances axonal conduction across demyelinated internodes and enhances neuroneuronal and neuromuscular transmission in preserved axons. These results provide the first evidence of therapeutic benefit of Fampridine-SR in SCI patients.
