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Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

ABSTRACT: BACKGROUND:Dopamine agonists (DAs) are a first-line therapy for moderate-to-severe restless legs syndrome (RLS), but these treatments may lead to complications, such as augmentation and impulse control disorders, requiring switching to another therapeutic class. Here we assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with moderate-to-severe primary RLS, with or without prior DA exposure. METHODS:Data from 3 trials were pooled. Patients were identified as DA-naive or DA-exposed, based on prior treatment with ropinirole, pramipexole, rotigotine, or pergolide mesylate, and the dopamine precursor levodopa. Details on prior treatment duration and dose were unavailable. Patients with a history of augmentation were excluded. Within DA-naive/DA-exposed patients we investigated the co-primary end points from the pivotal trials: mean change from baseline to week 12 in International RLS (IRLS) Rating Scale total score and proportion of responders ("much"/"very much" improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety was also assessed. RESULTS:671 patients were randomized (DA-naive: placebo, n?=?194; GEn 600 mg, n?=?131; GEn 1200 mg, n?=?214; DA-exposed: placebo, n?=?50; GEn 600 mg, n?=?30; GEn 1200 mg, n?=?52). Across treatment arms, no significant differences between DA-naive and DA-exposed subgroups in IRLS Rating Scale total score change from baseline at any visit were seen, except week 1 in the placebo group (-6.1 DA-naive vs -3.4 DA-exposed, P?=?.020). No significant differences in the odds of CGI-I response at week 12 between DA-naive vs DA-exposed patients in any treatment group were seen; however, with placebo there was a nonsignificant trend toward fewer responders among DA-exposed (34.0%) vs DA-naive (44.3%) patients. Both GEn doses significantly improved the IRLS Rating Scale total score change from baseline and CGI-I response vs placebo, regardless of prior DA exposure. The most common treatment-emergent adverse events were dizziness and somnolence. CONCLUSIONS:Prior DA exposure had no significant effect on efficacy or tolerability of GEn (600 or 1200 mg) in this pooled analysis of adults with moderate-to-severe primary RLS. These data support the use of GEn in DA-exposed and DA-naive patients. TRIAL REGISTRATION:ClinicalTrials.gov NCT00298623, NCT00365352, and NCT01332305.

SUBMITTER: Ondo WG

PROVIDER: S-EPMC4711039 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

Ondo William G WG Hermanowicz Neal N Borreguero Diego García DG Jaros Mark J MJ Kim Richard R Shang Gwendoline G

Journal of clinical movement disorders 20150330

<h4>Background</h4>Dopamine agonists (DAs) are a first-line therapy for moderate-to-severe restless legs syndrome (RLS), but these treatments may lead to complications, such as augmentation and impulse control disorders, requiring switching to another therapeutic class. Here we assess efficacy and tolerability of gabapentin enacarbil (GEn) in adults with moderate-to-severe primary RLS, with or without prior DA exposure.<h4>Methods</h4>Data from 3 trials were pooled. Patients were identified as D ...[more]

PMID: 26788345

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Project description:To assess maintenance of efficacy and tolerability of gabapentin enacarbil in patients with moderate to severe primary restless legs syndrome (RLS).This study (conducted April 18, 2006, to November 14, 2007) comprised a 24-week, single-blind (SB) treatment phase (gabapentin enacarbil, 1200 mg) followed by a 12-week randomized, double-blind (DB) phase. Responders from the SB phase (patients with improvements on the International Restless Legs Scale [IRLS] and investigator-rated Clinical Global Impression-Improvement scale at week 24 and stable while taking a gabapentin enacarbil dose of 1200 mg for at least 1 month before randomization) were randomized to gabapentin enacarbil, 1200 mg, or placebo once daily at 5 pm with food. The primary end point was the proportion of patients experiencing relapse (worse scores on the IRLS and investigator-rated Clinical Global Impression of Change scale on 2 consecutive visits at least 1 week apart or withdrawal because of lack of efficacy) during the DB phase.A total of 221 of 327 patients completed the SB phase, 194 (96 in the gabapentin enacarbil group and 98 in the placebo group) were randomized to DB treatment, and 168 (84 in the gabapentin enacarbil group and 84 in the placebo group) completed the DB phase. A significantly smaller proportion of patients treated with gabapentin enacarbil (9/96 [9%]) experienced relapse compared with the placebo-treated patients (22/97 [23%]) (odds ratio, 0.353; 95% confidence interval, 0.2-0.8; P=.02). Somnolence and dizziness were the most common adverse events. One death occurred (unintentional choking during the SB phase) and was judged as being unrelated to the study drug. No clinically relevant changes were observed in laboratory values, in vital signs, or on electrocardiograms.Gabapentin enacarbil, 1200 mg, maintained improvements in RLS symptoms compared with placebo and showed long-term tolerability in adults with moderate to severe primary RLS for up to 9 months of treatment.

Project description:To evaluate the efficacy and tolerability of gabapentin enacarbil (GEn) 1200 mg or 600 mg compared with placebo in subjects with moderate-to-severe primary restless legs syndrome (RLS).This 12-week, multicenter, double-blind, placebo-controlled study randomized subjects (1:1:1) to GEn 1200 mg, 600 mg, or placebo. Co-primary endpoints: mean change from baseline in International Restless Legs Scale (IRLS) total score and proportion of responders (rated as "very much" or "much" improved) on the investigator-rated Clinical Global Impression-Improvement scale (CGI-I) at Week 12 LOCF for GEn 1200 mg compared with placebo. Secondary endpoints included GEn 600 mg compared with placebo on the IRLS and CGI-I at Week 12 LOCF and subjective measures for sleep. Safety and tolerability assessments included adverse events.325 subjects were randomized (GEn 1200 mg = 113; 600 mg = 115; placebo = 97). GEn 1200 mg significantly improved mean [SD] IRLS total score at Week 12 LOCF (baseline: 23.2 [5.32]; Week 12: 10.2 [8.03]) compared with placebo (baseline: 23.8 [4.58]; Week 12: 14.0 [7.87]; adjusted mean treatment difference [AMTD]: -3.5; p = 0.0015), and significantly more GEn 1200 mg-treated (77.5%) than placebo-treated (44.8%) subjects were CGI-I responders (p < 0.0001). Similar significant results were observed with GEn 600 mg for IRLS (AMTD: -4.3; p < 0.0001) and CGI-I (72.8% compared with 44.8%; p < 0.0001). GEn also significantly improved sleep outcomes (Post-Sleep Questionnaire, Pittsburgh Sleep Diary and Medical Outcomes Sleep Scale) compared with placebo. The most commonly reported adverse events were somnolence (GEn 1200 mg = 18.0%; 600 mg = 21.7%; placebo = 2.1%) and dizziness (GEn 1200 mg = 24.3%; 600 mg = 10.4%; placebo = 5.2%). Dizziness increased with increased dose and led to discontinuation in 2 subjects (GEn 1200 mg, n = 1; GEn 600 mg, n = 1). Somnolence led to discontinuation in 3 subjects (GEn 600 mg).GEn 1200 mg and 600 mg significantly improve RLS symptoms and sleep disturbance compared with placebo and are generally well tolerated.

Project description:Restless Legs Syndrome is very common in hemodialysis patients however there are no comparative studies assessing the effectiveness of a non-pharmacological treatment to a classical treatment on parameters related to syndromes' severity and quality of life.In this randomized, partially double blind, placebo controlled trial, thirty two hemodialysis patients with restless legs syndrome were randomly assigned into three groups: 1) the exercise training group (N = 16), 2) the dopamine agonists group (ropinirole 0.25 mg/d) (N = 8) and 3) the placebo group (N = 8). The intervention programs lasted 6 months. Restless Legs Syndrome severity was assessed using the international severity scale, physical performance by a battery of tests, muscle size and composition by computed tomography, body composition by Dual Energy X Ray Absorptiometry, while depression score, sleep quality, daily sleepiness and quality of life were assessed through questionnaires.Exercise training and dopamine agonists were effective in reducing syndrome's symptoms by 46% (P = 0.009) and 54% (P = 0.001) respectively. Within group changes revealed that both approaches significantly improved quality of life (P < 0.05), however, only the dopamine agonists significantly improved sleep quality (P = 0.009). Within group changes showed a tendency for lean body mass improvements with dopamine agonists, this reached statistical significance only with the exercise training (P = 0.014), which also reduced fat infiltration in muscles (P = 0.044) and improved physical performance (P > 0.05) in various tests. Between group changes detect significant improvements with both exercise and dopamine agonists in depression score (P = 0.003), while only the dopamine agonist treatment was able to significantly improve sleep quality, compared to exercise and placebo (P = 0.016).A 6-month exercise training regime was as effective as a 6-month low dosage dopamine agonist treatment in reducing restless legs syndrome symptoms and improving depression score in uremic patients. Further research is needed in order to show whether a combination treatment could be more beneficial for the amelioration of RLS.NCT00942253.

Dataset Information

Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

Publications

Effect of prior exposure to dopamine agonists on treatment with gabapentin enacarbil in adults with moderate-to-severe primary restless legs syndrome: pooled analyses from 3 randomized trials.

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