A randomized, double-blind, placebo-controlled, dose-response study to assess the pharmacokinetics, efficacy, and safety of gabapentin enacarbil in subjects with restless legs syndrome.

OBJECTIVE: The objective of this study was to determine steady-state gabapentin exposures and corresponding relief of symptoms and safety profile produced by 4 dose levels of gabapentin enacarbil (GEn) in subjects with restless legs syndrome (RLS). METHODS: Subjects with RLS (n = 217) were randomized to receive once-daily, orally administered GEn 600 (n = 48), 1200 (n = 45), 1800 (n = 38), or 2400 mg (n = 45) or placebo (n = 41) in this 12-week, double-blind, multicenter study (NCT01332305). Clinic visits were at screening, baseline, and weeks 1, 2, 3, 4, 6, 8, 10, and 12; plasma gabapentin concentrations were measured by a validated liquid chromatography-mass spectrometry/mass spectrometry method at weeks 4 and 12. RESULTS: Exposure to gabapentin was proportional to GEn dose. Time to maximum plasma concentration was 7 to 9 hours, and elimination half-life was ~6 hours. The mean reduction from baseline to week 12 in International Restless Legs Syndrome Rating Scale total score and proportions of subjects with "much improved"/"very much improved" Clinical Global Impression-Improvement scores (investigator and patient ratings) ranged from -12.9 to -13.9 for GEn treatment groups versus -9.3 for placebo. The 2 most commonly reported adverse events were somnolence and dizziness. CONCLUSIONS: Gabapentin exposure was approximately proportional to GEn dose. Efficacy data showed that a once-daily dose of GEn 600 to 2400 mg provides greater relief of RLS symptoms than placebo; GEn was generally well tolerated with an adverse event profile consistent with gabapentin.

Clinical predictors of glycosylated hemoglobin response to thiazolidinedione therapy.

BACKGROUND: The aim of this investigation was to assess clinical predictors of the glycosylated hemoglobin (HbA1C) response after the addition of a thiazolidinedione (TZD) to a biguanide, a sulfonylurea, or both in subjects with type 2 diabetes. METHODS: Chart review (n = 68 physicians) was used to identify consecutive subjects started on a TZD. Qualifying subjects had been treated with pioglitazone (> or = 4 mg/day) or rosiglitazone (> or = 30 mg/day) for > or = 12 weeks. Clinical characteristics and HbA1C responses were assessed for the purpose of creating an initial predictive response model (Study 1). A separate sample from a managed care database was used to independently validate the model (Study 2). RESULTS: Data were collected from 4085 subjects (1365 in Study 1; 2720 in Study 2). In Study 1, baseline HbA1C was 8.2 +/- 0.1%. Forty-five percent (611 of 1365) and 55% (754 of 1365) were prescribed pioglitazone and rosiglitazone, respectively. In multivariate regression, baseline HbA1C (beta = -0.693%), age (beta = -0.006%), and use of multiple agents at baseline (referent = single agent, beta = 0.189%) were significant (P < 0.05) predictors, explaining 49% of the variance in HbA1C response in Study 1 and 44% of the variance in HbA1C response in the Study 2 sample. The model showed no material evidence of bias across the range of baseline HbA1C values. CONCLUSIONS: These results suggest that readily available clinical information, particularly baseline HbA1C, explains a substantial proportion of the variance in the response to TZD therapy.