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

TWO TO 3 PERCENT OF THE US POPULATION EXPERIENCE CLINICALLY RELEVANT SYMPTOMS OF PRIMARY RESTLESS LEGS SYNDROME (RLS) SEVERE enough to warrant treatment.1–3 Patients with RLS report difficulty falling asleep and exhibit abnormal sleep architecture,1,4 with a clinically significant decrease in sleep efficiency due to their symptoms. Consequently, RLS often impacts patients' daytime functioning and is a major source of morbidity and lost productivity.5 Dopaminergic agents provide important benefits for many RLS patients.5–7 However, neither ropinirole nor pramipexole has demonstrated efficacy in improving sleep architecture (eg, the time or percentage of total sleep time spent in slow wave sleep is either unchanged or reduced in these studies).6–8 Up to 30% of patients with RLS report symptoms that worsen with long-term dopaminergic treatment (augmentation).9,10 Recurrence of early-morning RLS symptoms, or rebound, may occur with short-term dopamine agonist treatment. Early clinical studies suggested that gabapentin, approved in the United States for the treatment of postherpetic neuralgia11–13 and partial seizures,13–15 is effective in improving RLS symptoms.16–20 Gabapentin has also been shown to reduce the frequency of periodic leg movements (PLMs)21–23 and to improve sleep23 in patients with RLS. However, gabapentin is not approved for the treatment of RLS and has inherent pharmacokinetic deficiencies that may limit effectiveness. Plasma exposure to gabapentin is highly variable due to saturation of its absorption pathway in the upper intestine24 and gabapentin requires frequent dosing due to its short plasma half-life. XP13512/GSK1838262 was developed to overcome the pharmacokinetic deficiencies of gabapentin.25 XP13512 is absorbed by high-capacity nutrient transporters throughout the gastrointestinal tract and is rapidly and extensively converted by nonspecific esterases to gabapentin. The pharmacokinetics of XP13512 provide dose-proportional gabapentin exposure. XP13512 is formulated as an extended-release tablet that allows for reduced dosing frequency.26 This study explored the efficacy and tolerability of XP13512 in subjects with moderate-to-severe primary RLS. An 1800 mg/day dose was chosen to produce maximum gabapentin levels of approximately 6–12 μg/mL in the late evening and night.26 Exploratory secondary analyses examined the effects of XP13512 on sleep quality and sleep architecture.