Sustained-Release Fampridine for Symptomatic Treatment of Multiple Sclerosis

2008 ◽  
Vol 42 (10) ◽  
pp. 1458-1465 ◽  
Author(s):  
Anne R Korenke ◽  
Michael P Rivey ◽  
Douglas R Allington
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Adverse Events ◽  
Sustained Release ◽  
English Language ◽  
Walking Speed ◽  
Data Extraction ◽  
Walking Ability ◽  
Phase 3 ◽  
Safety And Efficacy

Objective: To review the pharmacology, pharmacokinetics, clinical trials, and adverse effects of sustained-release (SR) fampridine in patients with multiple sclerosis (MS). Data Sources: An English-language human data search was done using PubMed/MEDLINE (1966-August 2008) to retrieve relevant material using the search terms fampridine-SR, 4-aminopyridine. and multiple sclerosis. References of selected articles and information from the drug developer were used to further identify pertinent trials. Study Selection and Data Extraction: Article selection was based primarily on studies that evaluated the pharmacokinetics, safety, and efficacy of fampridine-SR in patients with MS. Relevant meeting abstracts were also included as part of the analysis. Data Synthesis: Fampridine-SR is a sustained-release, orally administered potassium-channel blocker acting in the central nervous system to enhance conduction in demyelinated axons Several small trials have evaluated the safety and efficacy of fampridine-SR in patients with MS to improve their walking ability. Data from a recent large Phase 3 trial indicated that walking speed improved in 42.9% of patients with MS who were treated with fampridine-SR compared with 9.3% of those who received placebo (p < 0.001), Treatment-related adverse events associated with the use of fampridine-SR include dizziness, insomnia, nausea, and paresthesia. More severe adverse events, such as seizure, have occurred in patients receiving doses higher than those currently recommended. Conclusions: Positive results from 2 Phase 3 clinical trials have put fampridine-SR on the path toward approval as a medication for improving walking speed and tower extremity strength in patients with MS.

scholarly journals A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment

2021 ◽  
pp. 135245852110353
Author(s):  
Jeffrey A Cohen ◽  
Michelle H Cameron ◽  
Myla D Goldman ◽  
Andrew D Goodman ◽  
Aaron E Miller ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Extended Release ◽  
Walking Speed ◽  
Testing Procedure ◽  
Double Blind Study ◽  
Phase 3 ◽  
Timed Up And Go ◽  
Double Blind ◽  
Meaningful Improvement

Background: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. Objective: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. Methods: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). Results: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). Conclusion: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

scholarly journals A Pooled Analysis of Two Phase 3 Clinical Trials of Dalfampridine in Patients with Multiple Sclerosis

2014 ◽  
Vol 16 (3) ◽  
pp. 153-160 ◽  
Author(s):  
Andrew D. Goodman ◽  
Theodore R. Brown ◽  
Randall T. Schapiro ◽  
Michael Klingler ◽  
Ron Cohen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Clinical Characteristics ◽  
Walking Speed ◽  
Pooled Analysis ◽  
Responder Rate ◽  
Phase 3 ◽  
Two Phase ◽  
Pooled Data ◽  
The Individual

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 &lt; .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.

scholarly journals 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

2015 ◽  
Vol 21 (10) ◽  
pp. 1322-1331 ◽  
Author(s):  
Andrew D Goodman ◽  
Francois Bethoux ◽  
Theodore R Brown ◽  
Randall T Schapiro ◽  
Ron Cohen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Walking Speed ◽  
Prolonged Release ◽  
Open Label ◽  
Phase 3 ◽  
Two Phase ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Maximum Exposure

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.

Levoleucovorin as Replacement for Leucovorin in Cancer Treatment

2012 ◽  
Vol 46 (10) ◽  
pp. 1349-1357 ◽  
Author(s):  
Victor Tuan Giam Chuang ◽  
Manabu Suno
Keyword(s):  
Clinical Trials ◽  
Cancer Treatment ◽  
Clinical Studies ◽  
English Language ◽  
Antitumor Agents ◽  
Data Extraction ◽  
Phase 1 ◽  
Phase 3 ◽  
Medline Search ◽  
Reasonable Alternative

Objective: To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin. Data Sources: A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms I-LV. levoleucovorin, d,I-LV, leucovorin, folinic acid, tolinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials. Study Selection and Data Extraction: Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed. Data Synthesis: From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents. Conclusions: The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.

Ezogabine: An Evaluation of Its Efficacy and Safety as Adjunctive Therapy for Partial-Onset Seizures in Adults

2012 ◽  
Vol 46 (10) ◽  
pp. 1358-1367 ◽  
Author(s):  
Mikiko Yamada ◽  
Timothy E Welty
Keyword(s):  
Clinical Trials ◽  
Clinical Studies ◽  
English Language ◽  
De Novo ◽  
Phase 1 ◽  
Published Data ◽  
Partial Seizures ◽  
Phase 3 ◽  
Safety And Efficacy

Objective: To evaluate the safety, efficacy, pharmacokinetics, pharmacodynamic properties, and clinical application of ezogabine (retigabine. INN), an antiepileptic drug approved in 2011. Data Sources: Published data from in vitro, animal, and clinical studies were obtained from PubMed and CINAHL searches, from January 1980 to March 31, 2012. Other relevant data regarding the safety and efficacy of ezogabine were obtained from the Food and Drug Administration and the European Medication Agency Web sites. Study Selection and Data Extraction: Selected articles were prospective in vitro, animal, and controlled clinical studies of ezogabine. Non-English-language articles were excluded. Data Synthesis: In vitro and animal studies show that ezogabine activates voltage-gated potassium channels, leading to reduction of seizure frequency by inhibiting hyperexcitability activity in the central nervous system. Additionally, ezogabine enhances γ-aminobutyric acid (GABA) activity and de novo GABA synthesis. Eight clinical studies of ezogabine have been published, 5 being Phase 1 clinical trials in healthy subjects and 3 being Phase 3 clinical trials in patients with pharmacoresistant partial-onset seizures. Phase 3 clinical trials demonstrated the safety and efficacy of ezogabine in patients with partial-onset seizures. Conclusions: Clinical trials have shown that ezogabine is efficacious as an adjunctive agent in patients with pharmacoresistant partial seizures. Careful monitoring of drug interactions and adverse reactions is necessary. While ezogabine is efficacious (or partial seizures, its precise role in the management of patients with epilepsy is yet to be determined.

scholarly journals Dalfampridine: Review of its Efficacy in Improving Gait in Patients with Multiple Sclerosis

2011 ◽  
Vol 3 ◽  
pp. JCNSD.S4868 ◽  
Author(s):  
M.A. Sahraian ◽  
A.H. Maghzi ◽  
M. Etemadifar ◽  
A. Minagar
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Clinical Trials ◽  
Nervous System ◽  
Channel Blocker ◽  
Symptomatic Treatment ◽  
Walking Ability ◽  
Human Central Nervous System ◽  
Safety And Efficacy ◽  
Immune Mediated

Multiple sclerosis (MS) is a progressive immune-mediated neurodegenerative disease of human central nervous system (CNS), which causes irreversible disability in young adults. The cause and cure for MS remain unknown. Pathophysiology of MS includes two arms: inflammatory demyelination and neurodegeneration. The inflammatory demyelination of MS which is mainly promoted by a massive activation of the immune system against putative CNS antigen(s) leads to loss of oligodendrocyte/myelin complex which slows down or halts impulse conduction in denuded axons. Practically, loss of myelin significantly reduces signal conduction along the demyelinated axons through alterations in the distribution of axonal ion channels. Dalfampridine (4-aminopyridine or 4-AP) is an oral potassium channel blocker, which was recently approved by FDA for symptomatic treatment of MS. Dalfampridine, which acts at the central and peripheral nervous systems, enhances conduction in demyelinated axons and improves walking ability of MS patients. A number of clinical trials have evaluated the safety and efficacy of fampridine in MS patients with the degree of gait improvement as the main outcome. The objective of this manuscript is to provide an overview of the pharmacology, pharmacokinetics, clinical trials, side effects and interactions of dalfampridine used in treatment of MS patients.

Treatment Options for Rheumatoid Arthritis: Celecoxib, Leflunomide, Etanercept, and Infliximab

2000 ◽  
Vol 34 (6) ◽  
pp. 743-760 ◽  
Author(s):  
Brigitte T Luong ◽  
Barbara S Chong ◽  
Dionne M Lowder
Keyword(s):  
Rheumatoid Arthritis ◽  
English Language ◽  
Data Extraction ◽  
Treatment Options ◽  
Nonsteroidal Antiinflammatory Drugs ◽  
Antiinflammatory Drugs ◽  
Safety And Efficacy ◽  
Medline Search ◽  
Pertinent Data

OBJECTIVE: To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). DATA SOURCES: A MEDLINE search (1966–January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. STUDY SELECTION: All controlled and uncontrolled trials were reviewed. DATA EXTRACTION: Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. DATA SYNTHESIS: Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. CONCLUSIONS: Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

Leukotriene-Receptor Antagonists and 5-Lipoxygenase Inhibitors in Asthma

1993 ◽  
Vol 27 (7-8) ◽  
pp. 898-903 ◽  
Author(s):  
Julie S. Larsen ◽  
Edward P. Acosta
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Data Extraction ◽  
Background Information ◽  
Receptor Antagonists ◽  
Lipoxygenase Inhibitors ◽  
Medline Search ◽  
Leukotriene Receptor Antagonists ◽  
Patient Tolerance ◽  
Leukotriene Receptor

OBJECTIVE: To familiarize readers with a potentially new class of compounds for treating asthma. Background information on leukotrienes is provided in addition to an indepth review of pertinent clinical trials. DATA SOURCES: Information was obtained from controlled clinical trials, abstracts, and review articles identified through a MEDLINE search of English-language articles. STUDY SELECTION: Emphasis was placed on early clinical trials that showed some benefit with these compounds as well as more recent studies using newer agents that produced more promising results. DATA EXTRACTION: Information regarding leukotriene biochemistry was extracted from basic science research and data from human studies were evaluated by the authors according to patient selection, study design, methodology, and therapeutic response. DATA SYNTHESIS: Leukotrienes have a pathophysiologic role in asthma. Two distinct but pharmacologically similar classes of leukotriene inhibitors are currently being clinically evaluated. These are leukotriene receptor antagonists and 5-lipoxygenase inhibitors. Early clinical trials with these agents yielded unfavorable results primarily because of lack of drug potency and selectivity, poor patient tolerance, and possibly the route of administration. Subsequent studies with more potent and selective agents have further implicated leukotrienes as biochemical mediators in asthma and, consequently, have shown promising clinical outcomes with respect to pulmonary function testing and patient tolerance. CONCLUSIONS: Advancements in the pathogenesis of asthma are beginning to define a role for the leukotrienes. Although more studies are needed to assess the efficacy of leukotriene inhibitors, recent clinical trials using leukotriene-receptor antagonists and 5-lipoxygenase inhibitors indicate a potential for the expansion of therapeutic regimens currently used in the treatment of asthma.

Ticlopidine and Antiplatelet Therapy

1993 ◽  
Vol 27 (9) ◽  
pp. 1090-1098 ◽  
Author(s):  
Patricia Flores-Runk ◽  
Ralph H. Raasch
Keyword(s):  
Clinical Trials ◽  
English Language ◽  
Data Extraction ◽  
Artery Bypass ◽  
Antiplatelet Agent ◽  
Antiplatelet Agents ◽  
Graft Patency ◽  
Diabetic Microangiopathy ◽  
Severe Reaction ◽  
English Language Journal

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of ticlopidine. Comparisons with other antiplatelet agents are presented, with an emphasis on efficacy, and a recommendation is provided regarding ticlopidine's place in therapy. DATA SOURCES: A MEDLINE literature retrieval of English-language journal articles from 1987 to January 1993 and references identified from bibliographies of review articles and clinical trials. STUDY SELECTION: Randomized, blind, controlled studies of ticlopidine and other antiplatelet agents were preferentially selected. DATA EXTRACTION: Clinical trials were reviewed in terms of study design, efficacy results, and toxicity. DATA SYNTHESIS: Ticlopidine is a new antiplatelet agent with a distinct mechanism of action. In the largest trial of the drug for the prevention of stroke, it was found to be more effective than aspirin in reducing the risk of stroke or death. Clinical trials have also shown ticlopidine to decrease the rate of vascular death and myocardial infarction in patients with unstable angina, and to maintain venous graft patency after coronary artery bypass grafting. The use of ticlopidine in diabetic microangiopathy and peripheral vascular disease appears promising, but further studies are needed. Adverse reactions most commonly reported with ticlopidine are gastrointestinal complaints; the most severe reaction is transient neutropenia, which is seen in approximately 2.3 percent of patients and is severe in nearly 1 percent. CONCLUSIONS: Ticlopidine is a reasonable alternative for use in preventing stroke among patients unable to take aspirin or those who do not benefit from aspirin therapy. Its use as first-line therapy is limited by its high cost and the occurrence of hematologic adverse effects.

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