A randomized, double-blind, placebo-controlled, crossover study of XP13512/GSK1838262 in the treatment of patients with primary restless legs syndrome

Stanford University Center of Excellence for Sleep Disorders, Stanford, CA 94305-5730, USA.
Sleep (Impact Factor: 4.59). 03/2009; 32(2):159-68.
Source: PubMed


To evaluate the efficacy and tolerability of XP13512/ GSK1838262, an investigational nondopaminergic agent for the treatment of moderate-to-severe primary restless legs syndrome (RLS).
Randomized, double-blind, placebo-controlled, crossover trial.
Nine US clinical sites.
Thirty-eight treatment-naive subjects with RLS (mean +/- SD age 50.1 +/- 13.2 years).
XP13512 1800 mg/day followed by placebo or placebo followed by XP13512 1800 mg/day for 14 days, with a 7-day washout between treatment periods.
The primary endpoint was mean change from baseline International RLS Study Group rating scale (IRLS) total score on Day 14, analyzed using analysis of variance with sequence, period, and treatment as fixed effects and subjects within sequence as a random effect. XP13512 significantly reduced IRLS total score on Day 14 compared with placebo (mean +/- SD: XP13512 -12.1 +/-6.5, placebo -1.9 +/- 6.3; P < 0.0001). Polysomnographic data showed that XP13512 significantly improved sleep architecture on Day 14 compared with placebo (mean +/- SD change from baseline sleep time [minutes]: stage 1: XP13512 -9.8 +/- 23.9, placebo 0.4 +/-23.2; adjusted P<0.0054, nominal P<0.0001; stage 3/4 (slow-wave sleep): XP13512 22.8 +/- 40.8, placebo 1.4 +/- 34.3; adjusted P=0.0092, nominal P=0.0002). The most frequently reported adverse events were somnolence (XP13512 30.6%, placebo 2.8%) and dizziness (XP13512 27.8%, placebo 5.6%).
XP13512 1800 mg/day significantly reduced RLS symptoms, improved sleep, and was generally well tolerated in subjects with moderate-to-severe primary RLS across 14 days of treatment.

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    • "Kushida and colleagues51 conducted a phase 2, randomized, double-blind crossover comparison of gabapentin enacarbil 1800 mg daily (600 mg at 5 pm, 1200 mg at bedtime) versus placebo. Subjects were naïve to RLS treatment, and there was a 7-day wash-out period between each of the 14-day phases. "
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    ABSTRACT: The FDA approved gabapentin enacarbil in 2011 as the first non-dopaminergic agent for the treatment of restless legs syndrome (RLS) symptoms. Although gabapentin enacarbil is a pro-drug of gabapentin, its pharmacokinetics differ. Absorption of gabapentin enacarbil is more predictable, and inter-patient variability in bioavailability is lower than that of gabapentin. Studies have demonstrated superiority of gabapentin enacarbil compared to placebo. Comparisons to currently available RLS treatments are lacking, but clinical trials demonstrate comparable improvement in RLS symptoms to the dopamine agonists ropinirole and pramipexole, which are usually considered first-line therapy for daily RLS symptoms. Gabapentin enacarbil was well tolerated in clinical trials. The role of the drug in RLS treatment remains undefined, although it will likely be used as an alternative for refractory RLS when other treatments have failed. Additionally, gabapentin enacarbil may be recommended for patients with daily RLS symptoms that are less intense or are associated with pain as an alternative to dopamine agonists.
    09/2012; 4:147-56. DOI:10.4137/JCNSD.S9107
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    • "The last two studies are both 52-week open-label studies using gabapentin enacarbil 1200 mg/day. The first is an extension study undertaken by Ellenbogen et al.55 Participants (n = 573) were enrolled from several prior gabapentin enacarbil studies.52–54 They consumed the study drug at 5 pm with food. "
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    ABSTRACT: Gabapentin enacarbil XR is a new extended-release formulation which attempts to overcome the reduced efficacy of shorter-acting gabapentin, with sustained delivery over a 24-hour period. It is a gabapentin prodrug which is efficiently and rapidly converted to gabapentin during active transport throughout the length of the intestine via high-capacity monocarboxylate type 1 nutrient transporters unlike its predecessor, which is absorbed via low-capacity transporters largely confined to the upper intestinal region. Its lack of saturable absorption allows for dose-proportional absorption and hence increased bioavailability. Several clinical trials addressing its efficacy in moderate to severe restless legs syndrome (RLS) demonstrate improvements in the International RLS Rating Scale after a 2-week to 3-month period. Open-label studies of 52 weeks' duration showed maintenance of symptom reduction with once-daily administration of the extended-release formulation. The most commonly reported treatment-emergent adverse effects were somnolence and dizziness. Although the incidence of emergent adverse effects is high, it is comparable with that of gabapentin. No studies thus far have documented augmentation as an issue, unlike that observed with most dopaminergic agents. In addition, both dopamine precursors and agonists have not been shown to increase slow wave sleep or improve overall sleep architecture consistently despite improvement in the periodic leg movement index, in contrast with gabapentin enacarbil. Presently, gabapentin enacarbil has not been approved by the Therapeutic Goods Administration or Medsafe for use in RLS. The cost of this medication may also be a potential barrier for many patients. Future comparative efficacy studies with gabapentin, first-line dopaminergic agents, rotigotine, being the other once daily RLS medication, and pregabalin, the structural analog of gabapentin, will be necessary.
    Therapeutics and Clinical Risk Management 05/2012; 8:201-8. DOI:10.2147/TCRM.S24436 · 1.47 Impact Factor
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    • "tramadol, tilidine and codeine) but their use over the long-term could be problematic due to addiction issues [8]. Alpha-2-delta ligands (pregabalin, gabapentin and gabapentin enacarbil) are currently being examined in clinical trials and might constitute a promising alternative if their efficacy is confirmed in long-term trials [45,46]. "
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    ABSTRACT: Restless legs syndrome (RLS) is a neurological disorder with a lifetime prevalence of 3-10%. in European studies. However, the diagnosis of RLS in primary care remains low and mistreatment is common. The current article reports on the considerations of RLS diagnosis and management that were made during a European Restless Legs Syndrome Study Group (EURLSSG)-sponsored task force consisting of experts and primary care practitioners. The task force sought to develop a better understanding of barriers to diagnosis in primary care practice and overcome these barriers with diagnostic and treatment algorithms. The barriers to diagnosis identified by the task force include the presentation of symptoms, the language used to describe them, the actual term "restless legs syndrome" and difficulties in the differential diagnosis of RLS. The EURLSSG task force reached a consensus and agreed on the diagnostic and treatment algorithms published here.
    BMC Neurology 02/2011; 11(1):28. DOI:10.1186/1471-2377-11-28 · 2.04 Impact Factor
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