XenoPort and GlaxoSmithKline Report Positive Top-Line Results of Second Phase 3 Restless Legs Syndrome Trial for XP13512/GSK1838262
21 January 2008
Study Highlights Safety and Efficacy of XP13512 in Primary Restless Legs Syndrome Patients Treated for Nine Months
XenoPort, Inc. and GlaxoSmithKline today announced positive top-line results from a placebo-controlled Phase 3 clinical trial designed to evaluate the potential of XP13512 (GSK1838262) to maintain efficacy over the course of nine months in patients with moderate-to-severe primary Restless Legs Syndrome, or RLS. Data from this randomized withdrawal trial showed that XP13512 was generally well-tolerated and that there was a statistically significant difference between the percentage of patients treated with XP13512 and placebo who met a pre-specified relapse criteria during the randomized phase of the study.
"The results of this study strengthen our belief that XP13512 has the potential to be a safe and effective treatment for primary RLS. Our first placebo-controlled Phase 3 efficacy trial of XP13512, with results announced in April 2007, demonstrated statistically significant benefits of XP13512 in treating RLS symptoms over 12 weeks. We are encouraged by the results of this new placebo-controlled Phase 3 clinical trial, which demonstrated that XP13512 was effective and generally well-tolerated when administered to primary RLS patients for nine months," said Ronald W. Barrett, Ph.D., chief executive officer of XenoPort.
"This study is an important next step in moving toward the submission of the NDA for XP13512, a potential new treatment for patients with primary RLS. XenoPort and GSK are committed to continuing research in this important area where there is still significant unmet medical need," said Atul Pande, M.D., senior vice president, GlaxoSmithKline Neurosciences Medicines Development Center.
This multi-center, randomized, placebo-controlled clinical trial enrolled 327 patients diagnosed with moderate-to-severe primary RLS. In the first phase of the trial, all patients were administered 1200 mg of XP13512, taken at approximately 5:00 p.m., for 24 weeks. Patients were assessed to determine treatment response at the end of this single-blind phase of the clinical trial. Responders were defined as those patients who met three criteria: a decrease in total International RLS (IRLS) rating scale score of six or more points compared to baseline score, a decrease in IRLS score to less than 15 and an assessment of "much improved" or "very much improved" on the Investigator Clinical Global Impression of Improvement (CGI-I). Responders were required to have been stable on 1200 mg of XP13512 for at least the last month of the 24-week treatment period.
After completing the single-blind phase, responders entered the 12-week, randomized, double-blind phase of the clinical trial. Patients randomized to the placebo group received 600 mg of XP13512 for two weeks and then received placebo for an additional ten weeks. Patients randomized to the XP13512 treatment group continued to receive 1200 mg of XP13512 for the entire 12-week, double-blind period.
The primary endpoint of the trial was the proportion of RLS patients who "relapsed," or had their RLS symptoms worsen, during the 12-week, double-blind treatment period. Patients were considered to have "relapsed" if either or both of the following occurred: 1) the patient withdrew from the clinical trial due to lack of efficacy; and/or 2) there were two consecutive study visits in which (a) the patient's IRLS score worsened by at least six points compared to the IRLS score at the point of randomization; (b) the patient achieved an IRLS score of at least 15; and (c) the patient received an assessment of "much worse" or "very much worse" as compared to the condition of the patient at the point of randomization using an Investigator Clinical Global Impression of Change (CGI-C).
Clinical Trial Results
Three hundred twenty seven patients were enrolled in the study, and 221 patients completed the 24-week, single-blind portion of the clinical trial, of which 194 (88%) met the responder criteria and were randomized to double-blind treatment.
Analysis of the primary endpoint indicated that treatment with XP13512 resulted in a statistically significant lower proportion of relapses compared to placebo during the double-blind treatment period (23% placebo compared to 9% XP13512; p= 0.0158).
During the single-blind phase of the trial, 13% and 4% of XP13512-treated patients withdrew from the clinical trial due to adverse events or lack of efficacy, respectively. The most commonly reported adverse events during the single-blind phase of the clinical trial were somnolence (30%) and dizziness (22%), which were generally mild or moderate in intensity and transient in nature.
During the double-blind phase, 0% and 3% of XP13512- and placebo-treated patients, respectively, withdrew from the trial due to adverse events. The incidence of somnolence and dizziness in XP13512-treated patients during the double-blind portion of the trial were 3% and 2%, respectively.
During the trial, there was one death that was determined to be unrelated to XP13512 treatment. There were five other serious adverse events, only one of which was judged as possibly related to XP13512 treatment.
"We are encouraged that XP13512 treatment was associated with a statistically significant difference from placebo in this randomized withdrawal study, particularly in light of the stringent criteria for relapse used in this clinical trial," added Dr. Barrett. "We are also pleased with the tolerability profile of XP13512 in this nine-month study. We look forward to reporting the top-line results of the final 12-week Phase 3 efficacy study of XP13512 in RLS patients later this quarter and the expected filing of the NDA for RLS treatment in the third quarter of this year by GSK."
XP13512 is a patented, new chemical entity that is designed to improve upon the clinical utility of gabapentin by taking advantage of high-capacity transport mechanisms in the gastrointestinal tract to improve absorption.
According to the National Institutes of Health, up to 12 million people in the U.S. are afflicted with RLS across a range of severity from mild to severe. The syndrome is characterized by disturbing, unpleasant and sometimes painful sensations in the legs that result in a compelling urge to move. The discomfort is often temporarily relieved by movement. Because symptoms typically occur at night, RLS patients often suffer from sleep disruption. RLS symptoms can be debilitating - published data suggest that RLS can have an impact on quality of life equivalent to, or worse than, major chronic medical disorders such as diabetes and osteoarthritis.
Source: XenoPort, Inc. and GlaxoSmithKline (21/01/08)
Treatment: CCSVI both IJV ballooned 09/2010, No DMDs, Tysabri on hold after 24 Infusions, after LDN, ABX Wheldon Regime for 1 year.