Cardiac repolarization with Gabapentin enacarbil in a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.

BACKGROUND: Gabapentin enacarbil (GEn) is a prodrug of gabapentin and is approved in the United States in adults for the management of postherpetic neuralgia and in the United States and Japan for the treatment of moderate-to-severe primary restless legs syndrome. OBJECTIVE: This study examined the lack of effect of GEn on cardiac repolarization in accordance with International Conference on Harmonisation E14 guidance. METHODS: This was a randomized, double-blind, double-dummy, placebo- and active- controlled, crossover study in healthy adults (age range, 18-50 years). Study participants received the following in randomized order with a minimum 7-day washout period between treatments: placebo at 0 hours and GEn 1200 mg at 2 hours (GEn 1200 mg group), placebo at 0 hours and GEn 6000 mg at 2 hours (GEn 6000 mg group), placebo at 0 and 2 hours (placebo group), moxifloxacin 400 mg (active control group) at 0 hours, and placebo at 2 hours (moxifloxacin group). Dose offsetting permitted moxifloxacin to be administered in the fasted state and GEn to be administered in the fed state. Assessments included continuous ECG monitoring, pharmacokinetic parameters, and safety and tolerability profiles. The primary end point was the change from baseline in the Fridericia corrected QT interval, at each time point, for the GEn 6000 mg and placebo groups. RESULTS: Of 52 adults enrolled (mean [SD] age, 30.8 [8.55] years; 50% women), 44 adults (85%) completed the study. Forty-nine adults received GEn 1200 mg, 47 received GEn 6000 mg, 48 received placebo, and 47 received moxifloxacin. The highest estimated (upper limit of the 95% CI) model-adjusted difference in mean change from baseline in the Fridericia corrected QT interval between GEn and placebo was 3.55 (5.66) msec for 1200 mg and 1.20 (3.32) msec for 6000 mg. Assay sensitivity was confirmed with moxifloxacin 400 mg. The geometric mean (%CV) Cmax (between-subject coefficient of variation) was 7.49 (21.2) µg/mL for GEn 1200 mg, 32.46 (23.9) µg/mL for GEn 6000 mg, and 2.08 (24.5) µg/mL for moxifloxacin 400 mg. The most frequently reported adverse events with GEn 6000 mg were dizziness (30%), feeling drunk (26%), nausea (15%), headache (13%), and vomiting (13%). CONCLUSION: Single doses of GEn, up to 6000 mg, had no effect on cardiac repolarization in this thorough-QT study and are unlikely to cause clinically relevant QT prolongation in clinical use. Assay sensitivity was confirmed with moxifloxacin as an active control. ClinicalTrials.gov identifier: NCT01516372.

Randomized, double-blind, placebo-controlled, phase II trial of gabapentin enacarbil for migraine prophylaxis.

OBJECTIVE: The objective of this article is to evaluate the efficacy and safety of gabapentin enacarbil (GEn) for migraine prophylaxis. METHODS: In this randomized, double-blind, parallel-group study, patients with International Headache Society-defined migraine who met criteria suggesting the need for prophylactic therapy were randomized 2:1:2:2:1 to one of the following five groups, designated according to target daily dose of study medication during the 20-week treatment period: placebo, GEn 1200 mg, GEn 1800 mg, GEn 2400 mg, or GEn 3000 mg. RESULTS: The intent-to-treat population included 523 patients (n = 128 placebo, n = 66 GEn 1200 mg, n = 134 GEn 1800 mg, n = 133 GEn 2400 mg, n = 62 GEn 3000 mg). No statistically significant difference between active treatment (the average of 1800 mg and 2400 mg treatment groups) and placebo was found for change from baseline in the number of migraine headache days during the last four weeks of treatment prior to taper (the primary endpoint). Results of analyses of the primary endpoint using the per protocol population, analyses using imputation methods different from those of the primary analysis, and nonparametric analyses were consistent with the primary analysis in showing no difference between active treatment and placebo. The pattern of results was similar for the secondary efficacy endpoints. Pharmacokinetic data demonstrate that patients had adequate estimated exposure to GEn. The adverse event profile of GEn was consistent with that in previous studies. CONCLUSION: GEn did not significantly differ from placebo for migraine headache prophylaxis. A high placebo effect should be considered when interpreting these results.

Safety and efficacy of ezogabine (retigabine) in adults with refractory partial-onset seizures: Interim results from two ongoing open-label studies.

Interim results of two open-label extension studies assessed ezogabine/retigabine safety and tolerability for partial-onset seizures. At data cutoff, 336 (60%) patients received ≥ 12 months' open-label ezogabine/retigabine. The most common TEAEs included dizziness (22%), somnolence (19%), headache (14%), and fatigue (10%). Change in seizure frequency from baseline (median reduction, 53%) and responder rate (52.5%) was maintained in patients remaining on ezogabine/retigabine. Continuous 6-month and 12-month seizure-free rates for ezogabine/retigabine exposures ≥ 12 months were 13.1% and 7.1%, respectively.

Lack of efficacy of the selective iNOS inhibitor GW274150 in prophylaxis of migraine headache.

INTRODUCTION: This study investigated the efficacy and tolerability of the highly selective iNOS inhibitor GW274150 in prophylaxis of migraine headache. SUBJECTS AND METHODS: The study was conducted in two parts, each comprising a 4-week baseline period, a 12-week, double-blind, parallel-group treatment period, and a 4-week follow-up period. The study had an adaptive design in that findings of Part 1 of the study were used to inform the conduct of Part 2. Following an interim analysis at the end of Part 1, the trial could be stopped for futility or continued in Part 2 to study the full-dose response or to increase sample size in case initial assumptions had been violated. The primary end-point in both parts of the study was the probability of the occurrence of a migraine headache day during the baseline period and the treatment period. RESULTS: In Part 1, adult male and female patients with migraine received GW274150 60 mg (n = 37), 120 mg (n = 37), or placebo (n = 38) once daily for 12 weeks. In Part 2, female patients with migraine received GW274150 60 mg (n= 160) or placebo (n = 154) once daily for 12 weeks. GW274150 was no more effective than placebo for the primary efficacy end-point or any secondary efficacy end-point in Part 1 or Part 2. GW274150 was generally well tolerated. CONCLUSIONS: GW274150 at doses predicted to inhibit iNOS >80% did not differ from placebo in the prophylaxis of migraine. The results do not support a role of iNOS inhibition in migraine prevention.

Oral sumatriptan for the acute treatment of probable migraine: first randomized, controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of sumatriptan tablets in adults who meet International Headache Society (IHS) criteria for probable migraine but who do not meet IHS criteria for migraine with or without aura. BACKGROUND: Headaches with some but not all of the features of migraine meet criteria for probable migraine, a form of migraine recognized by the IHS. Probable migraine attacks are also prevalent and frequently underdiagnosed. METHODS: This was a randomized, multicenter, double-blind, placebo-controlled, parallel-group study. Adults (18 to 65 years) with a 1-year history of headaches that met 2004 IHS criteria for probable migraine without aura (same operational definition as 1988 IHS migrainous disorder) were eligible for enrollment. All patients were triptan- and ergot-naïve and had never been diagnosed with migraine. Patients were randomized in a 1:1:1:1 fashion to receive sumatriptan 25, 50, or 100 mg conventional tablets or matching placebo and were instructed to treat a single moderate or severe probable migraine attack. A post hoc analysis was conducted to evaluate the population of patients who achieved headache relief sustained throughout the immediate posttreatment period. Patients who reported relief within 2 hours and subsequently lost headache relief within 4 hours were considered nonresponders. RESULTS: At 2 hours, more patients treated with sumatriptan achieved headache relief, the primary efficacy measure, compared with placebo, but differences only approached statistical significance for 100 mg (P= .053). The 2-hour headache relief rate in the sumatriptan 25 or 50 mg groups was not significantly different than placebo. The time to use of rescue was significantly shorter in the placebo group compared with the sumatriptan 100 mg group (P= .002). The time to use of rescue in the sumatriptan 25 or 50 mg groups was not significantly different than placebo. More patients treated with placebo (22%) lost headache relief within 4 hours compared with patients treated with sumatriptan 25 mg (17%), 50 mg (14%), or 100 mg (7%). A post hoc analysis demonstrated that at 2 hours, headache relief sustained through 4 hours (S 0-4 hours) was achieved in 44%, 49%, and 57% of patients treated with sumatriptan 25, 50, and 100 mg, respectively, compared with 34% of patients treated with placebo (P < .05 for sumatriptan 50 and 100 mg vs. placebo). All doses of sumatriptan were well tolerated and no serious adverse events were reported. CONCLUSION: These results suggest that oral sumatriptan may be effective and is well tolerated for the acute treatment of probable migraine without aura, however, the difference between sumatriptan and placebo was not statistically significant for the a priori defined primary endpoint.