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William G. Ondo - One of the best experts on this subject based on the ideXlab platform.

  • Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management.
    Practical neurology, 2017
    Co-Authors: Subhashie Wijemanne, William G. Ondo
    Abstract:

    Restless legs syndrome (RLS) is a chronic neurological disorder that interferes with rest and sleep. It has a wide spectrum of symptom severity, and treatment is started when symptoms become bothersome. Dopamine agonists and calcium channel apha-2-delta antagonists (Gabapentin, Gabapentin Enacarbil and pregabalin) are first-line treatments; calcium channel alpha-2-deltas are preferred over dopamine agonists because they give less augmentation, a condition with symptom onset earlier in the day and intensification of RLS symptoms. Dopamine agonists can still be used as first-line therapy, but the dose should be kept as low as possible. Iron supplements are started when the serum ferritin concentration is ≤75 µg/L, or if the transferrin saturation is less than 20%. For severe or resistant RLS, a combined treatment approach can be effective. Augmentation can be very challenging to treat and lacks evidenced-based guidelines.

  • practice guideline summary treatment of restless legs syndrome in adults report of the guideline development dissemination and implementation subcommittee of the american academy of neurology
    Neurology, 2016
    Co-Authors: John W. Winkelman, William G. Ondo, Melissa J Armstrong, Richard P Allen, Ray K Chaudhuri, Claudia Trenkwalder, Phyllis C Zee, Gary S Gronseth, David Gloss, Theresa A Zesiewicz
    Abstract:

    Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and Gabapentin Enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or Gabapentin Enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C).

  • Efficacy of Gabapentin Enacarbil in adult patients with severe primary restless legs syndrome.
    Sleep medicine, 2015
    Co-Authors: Daniel O. Lee, William G. Ondo, Mark J. Jaros, Richard Kim, Diego Garcia-borreguero, Alon Y. Avidan, Mark Buchfuhrer, Mansoor Ahmed, Ryan Hays, Gwendoline Shang
    Abstract:

    Abstract Aim Assess efficacy and tolerability of Gabapentin Enacarbil (GEn) in adults with severe primary restless legs syndrome (RLS). Methods We pooled data from three 12-week, double-blind, placebo-controlled, randomized trials (NCT00298623, NCT00365352, NCT01332305) across GEn 600-mg, GEn 1200-mg, and placebo treatment groups for severe primary RLS (baseline International Restless Legs Scale (IRLS) total score ≥24). Co-primary end points at week 12 were mean change from baseline in IRLS total score and proportion of responders ("much"/very much" improved) on the investigator-rated Clinical Global Impression – Improvement (CGI-I) Scale. Outcomes for individual IRLS items (eg, sleep, mood, quality of life, pain, safety) were assessed. Results A total of 309 patients had severe primary RLS (placebo, n  = 110; GEn 600 mg, n  = 80; GEn 1200 mg, n  = 119). GEn 600 mg and 1200 mg significantly improved least-squares mean IRLS total scores versus placebo at week 12 (placebo, −12.3; GEn 600 mg, −16.3; GEn 1200 mg, −18.0; treatment difference vs. placebo, both p  0.01). Significantly more patients with severe primary RLS treated with GEn 600 mg (64%) and 1200 mg (74%) were CGI-I responders at week 12 versus placebo (42%; p  0.01 for both GEn doses). Both GEn doses led to significant improvements in the other outcomes explored versus placebo at week 12. The most frequent treatment-emergent adverse events (TEAEs) were somnolence (GEn, 21–24%; placebo, 3%) and dizziness (GEn, 14–19%; placebo, 3%). Conclusions GEn (600 mg or 1200 mg) once daily significantly improved RLS symptoms and consequences of these symptoms in severe primary RLS. The most frequent TEAEs were somnolence and dizziness.

  • 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.
    Journal of clinical movement disorders, 2015
    Co-Authors: William G. Ondo, Mark J. Jaros, Richard Kim, Neal Hermanowicz, Diego García Borreguero, Gwendoline Shang
    Abstract:

    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. 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. 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. 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. ClinicalTrials.gov NCT00298623 , NCT00365352 , and NCT01332305

  • 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
    Journal of Clinical Movement Disorders, 2015
    Co-Authors: William G. Ondo, Mark J. Jaros, Richard Kim, Neal Hermanowicz, Diego García Borreguero, Gwendoline Shang
    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

Kenneth C Cundy - One of the best experts on this subject based on the ideXlab platform.

  • Population Pharmacokinetics and Pharmacodynamics of Gabapentin After Administration of Gabapentin Enacarbil
    The Journal of Clinical Pharmacology, 2013
    Co-Authors: Juthamas Sukbuntherng, James Tovera, Marie-liesse Lassauzet, Kenneth C Cundy
    Abstract:

    Gabapentin Enacarbil (GEn) is an actively transported prodrug of Gabapentin that provides sustained dose-proportional exposure to Gabapentin and predictable bioavailability. Gabapentin Enacarbil is approved by the US Food and Drug Administration for the treatment of moderate-to-severe primary restless legs syndrome (RLS) in adults. Using plasma Gabapentin concentration data obtained after administration of GEn in 12 phase 1 to 3 GEn studies in healthy adults or patients with RLS (dose range, 300-2400 mg/d), a population pharmacokinetic (PK) model was developed by nonlinear mixed-effect modeling using NONMEM. Data were similar in subjects with and without RLS. Population PK-pharmacodynamic (PD) models were evaluated using Gabapentin exposure and change from baseline in investigator- or patient-rated Clinical Global Impression of Improvement (CGI-I) or International Restless Legs Scale (IRLS) total score. Potential PK-PD models for sleep outcomes and safety parameters were also explored. The CGI-I response increased with increasing GEn dose, whereas the IRLS total score was similar at all exposures tested. Early adverse events of dizziness or somnolence/sedation were more frequent for GEn 600 mg than higher doses; however, this is confounded by the fact that all subjects received the 600-mg dose for 3 days prior to titration to higher dosages.

  • Evaluation of Gabapentin Enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults.
    Clinical therapeutics, 2012
    Co-Authors: Dan Chen, Ritu Lal, Katie Zomorodi, Harisha Atluri, Wendy Luo, James Tovera, Daniel Bonzo, Kenneth C Cundy
    Abstract:

    Abstract Background Gabapentin Enacarbil, a transported prodrug of Gabapentin, was recently approved by the US Food and Drug Administration for the treatment of moderate to severe restless legs syndrome. Objective As part of the overall safety evaluation of Gabapentin Enacarbil, the present definitive QT/QTc study was conducted to assess the effects of Gabapentin Enacarbil on cardiac repolarization in accordance with the International Conference on Harmonization E14 guidance. Methods This randomized, double-blind, placebo- and active-controlled, crossover study enrolled 54 healthy adults. Subjects were randomly assigned to receive a single oral dose of Gabapentin Enacarbil 1200, 6000 mg, moxifloxacin 400 mg (active control), and placebo in a randomized sequence, with treatment periods separated by a 7-day washout. Blood samples were collected for pharmacokinetic analysis, and continuous ECG measurements were recorded using a Holter monitor. The primary end point was the time-matched difference in individualized baseline-adjusted QTc (ddQTcIb) between Gabapentin Enacarbil and placebo. General tolerability was also monitored. Results Of the 54 subjects enrolled in the study (mean [SD] age, 29.2 [10.1]; 42.6% female; mean body mass index, 25.8 [3.0]), 48 (88.9%) completed the study, and 6 were discontinued prematurely after having received ≥1 dose of study medication. Thus, the numbers of patients in the safety population were: Gabapentin Enacarbil 1200 mg, 50; Gabapentin Enacarbil 6000 mg, 50; moxifloxacin, 50; and placebo, 51. The maximum ddQTcIb values were 0.7 msec (upper 95% confidence limit [CL], 3.0) with Gabapentin Enacarbil 1200 mg; 1.3 msec (upper CL, 3.6) with Gabapentin Enacarbil 6000 mg; and 7.4 msec (lower CL, 5.1) with moxifloxacin. A QT–concentration relationship was reported with moxifloxacin. Gabapentin exposures were dose-proportional with Gabapentin Enacarbil doses of 1200 and 6000 mg. The most commonly reported adverse events with Gabapentin Enacarbil 6000 mg were dizziness and somnolence (60.0% and 54.0%, respectively). Conclusion In this population of healthy adults, Gabapentin Enacarbil at doses of 1200 and 6000 mg was not associated with QT prolongation and was generally well-tolerated.

  • Clinical pharmacokinetics of Gabapentin after administration of Gabapentin Enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study.
    Clinical therapeutics, 2011
    Co-Authors: Ritu Lal, Robin L. Blumenthal, Juthamas Sukbuntherng, Dan Chen, Wendy Luo, Kenneth C Cundy
    Abstract:

    Abstract Background Gabapentin Enacarbil, a transported acyloxyalkylcarbamate prodrug of Gabapentin, provides predictable and dose-proportional Gabapentin exposure (AUC). Gabapentin is cleared via renal excretion, and its elimination is proportional to creatinine clearance (CrCL); CrCL can, therefore, be used as a predictor of Gabapentin renal clearance. Gabapentin produced from hydrolysis of Gabapentin Enacarbil is also eliminated via the renal clearance pathway. It was, therefore, anticipated that the pharmacokinetics of Gabapentin derived from Gabapentin Enacarbil would also be affected by renal function. Objective The objective of this study was to describe a population pharmacokinetic analysis of Gabapentin Enacarbil in patients with varying degrees of renal function, using data from an open-label study of Gabapentin Enacarbil in patients with renal impairment (XenoPort, Inc. protocol XP066), to determine whether dosage adjustments are necessary in patients with renal impairment. Methods Men and women >18 years of age with a body mass index ≤34 kg/m 2 and who were, in general, healthy with the exception of renal impairment were enrolled All patients received a single 600-mg Gabapentin Enacarbil extended-release tablet under fed conditions. After dosing, plasma, urine, and dialysate samples were analyzed. Safety profile evaluations included adverse events, vital signs, ECGs, and laboratory values. Pharmacokinetic data were compared with those from Phase I–III studies in subjects with normal renal function to evaluate the relationship between Gabapentin oral clearance (CL/F) and CrCL. Results Fifteen patients (11 men and 4 women) were enrolled. One patient had moderate renal impairment (CrCL 30–59 mL/min), 7 patients had severe renal impairment (CrCL 2 . Mean maximum plasma Gabapentin concentration was 5.77 μg/mL in patients with moderate and severe renal impairment, and 5.59 μg/mL in patients with end-stage renal disease who were undergoing hemodialysis. Based on the population pharmacokinetic analysis, Gabapentin CL/F after administration of Gabapentin Enacarbil was proportionally related to CrCL, with an approximately 1.6-fold decrease in CL/F for every 2-fold decrease in CrCL. The most frequent adverse event was dizziness (4 of 15 patients). Other adverse events that were assessed as possibly or probably related to treatment were defecation urgency, extremity pain, feeling of relaxation, and muscle weakness; each occurred in 1 patient only. All events were mild or moderate and resolved without sequelae. Conclusions The data suggest that dosage adjustment for Gabapentin Enacarbil is necessary in patients with impaired renal function. Gabapentin Enacarbil, 600 mg, seemed to be well tolerated in this small selected population.

  • Efficacy of Gabapentin Enacarbil vs placebo in patients with postherpetic neuralgia and a pharmacokinetic comparison with oral Gabapentin.
    Pain Medicine, 2011
    Co-Authors: Miroslav Backonja, Daniel M. Canafax, Kenneth C Cundy
    Abstract:

    Background. The efficacy of Gabapentin in some patients with postherpetic neuralgia (PHN) may be limited by suboptimal drug exposure from unpredictable and saturable absorption. Gabapentin Enacarbil (GEn) was designed for absorption by high-capacity transporters expressed throughout the intestine and undergoes rapid postabsorption hydrolysis to Gabapentin. GEn extended-release tablets provide sustained, dose-proportional Gabapentin exposure. This study assessed the efficacy of GEn vs placebo and compared the pharmacokinetics of Gabapentin after oral dosing of GEn or Gabapentin in patients with PHN. Methods. In this double-blind, randomized study, 115 patients with PHN completed a 7-day baseline period and 11-day Gabapentin run-in period. Eligible patients were randomized and 101 received double-blind GEn 1,200 mg (624 mg-equivalents Gabapentin) ( n = 47) or placebo ( n = 54), twice daily for 14 days. We evaluated patient-reported pain, sleep, mood, global improvement, and adverse events, plus Gabapentin pharmacokinetics. Results. The improvement in mean weekly pain scores from baseline to the end of treatment (primary endpoint) was significantly greater for GEn (−2.1) vs placebo (−1.2), P = 0.0321. Significant improvements from GEn vs placebo were also seen in sleep, mood, and patient global assessment ( P < 0.05). With a 31% lower daily dose of Gabapentin equivalents, GEn tablets provided a significant increase in average steady state Gabapentin concentrations vs Gabapentin capsules in the same patients ( n = 42; P = 0.0050). Conclusions. GEn was effective in providing PHN pain relief, improved Gabapentin exposure compared with Gabapentin capsules, and was generally safe and well tolerated in patients with PHN.

  • NEUROPATHIC PAIN SECTION Original Research Articles Efficacy of Gabapentin Enacarbil vs Placebo in Patients with Postherpetic Neuralgia and a Pharmacokinetic Comparison with Oral Gabapentin
    2011
    Co-Authors: Miroslav Backonja, Daniel M. Canafax, Kenneth C Cundy
    Abstract:

    Background. The efficacy of Gabapentin in some patients with postherpetic neuralgia (PHN) may be limited by suboptimal drug exposure from unpredict- able and saturable absorption. Gabapentin Enacarbil (GEn) was designed for absorption by high-capacity transporters expressed throughout the intestine and undergoes rapid postabsorption hydrolysis to gaba- pentin. GEn extended-release tablets provide sus- tained, dose-proportional Gabapentin exposure. This study assessed the efficacy of GEn vs placebo and compared the pharmacokinetics of Gabapentin after oral dosing of GEn or Gabapentin in patients with PHN. Methods. In this double-blind, randomized study, 115 patients with PHN completed a 7-day baseline period and 11-day Gabapentin run-in period. Eligible patients were randomized and 101 received double- blindGEn1,200 mg(624 mg-equivalentsGabapentin) (n = 47) or placebo (n = 54), twice daily for 14 days. We evaluated patient-reported pain, sleep, mood, global improvement, and adverse events, plus gaba- pentin pharmacokinetics. Results. The improvement in mean weekly pain scores from baseline to the end of treatment (primary endpoint) was significantly greater for GEn (-2.1) vs placebo (-1.2), P = 0.0321. Significant improvements from GEn vs placebo were also seen in sleep, mood, and patient global assessment (P < 0.05). With a 31% lower daily dose of gabapen- tin equivalents, GEn tablets provided a significant increase in average steady state Gabapentin con- centrations vs Gabapentin capsules in the same patients (n = 42; P = 0.0050). Conclusions. GEn was effective in providing PHN painrelief,improvedGabapentinexposurecompared with Gabapentin capsules, and was generally safe and well tolerated in patients with PHN.

Ronald W. Barrett - One of the best experts on this subject based on the ideXlab platform.

  • Dose Response of Gabapentin Enacarbil versus Placebo in Subjects with Moderate-to-Severe Primary Restless Legs Syndrome
    CNS Drugs, 2012
    Co-Authors: Susan A. Meter, Sarah T. Kavanagh, Samantha Warren, Ronald W. Barrett
    Abstract:

    Background : The efficacy and tolerability of Gabapentin Enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg. Objective : The objective of this study was to evaluate key efficacy and safety outcomes in subjects with RLS treated with once-daily Gabapentin Enacarbil 600 mg, 1200 mg, 1800 mg and 2400 mg, providing supportive evidence of the efficacy of Gabapentin Enacarbil 600 mg compared with higher doses and placebo. Study design : Integrated post hoc analysis of three 12-week, randomized, double-blind, placebo-controlled trials in subjects with RLS. Setting : The three studies were carried out at multiple centres in the US. Patients : In total, 760 subjects were included in the pooled analysis (placebo, n = 245; Gabapentin Enacarbil 600 mg, n= 163; Gabapentin Enacarbil 1200 mg, n = 269; Gabapentin Enacarbil 1800mg, n = 38; Gabapentin Enacarbil 2400 mg, n = 45). Intervention : In all studies, Gabapentin Enacarbil or placebo was administered once daily at approximately 5 p.m. with food. Gabapentin Enacarbil was initiated at a dose of 600 mg with subsequent titration in 600 mg increments every 3 days up to the randomized dose. Main outcome measure : The efficacy endpoints analysed for the purpose of this integrated analysis were change from baseline in International Restless Legs Scale (IRLS) total score and the proportion of responders (subjects rated as ‘much’ or ‘very much’ improved) on the investigator-rated Clinical Global Impression-Improvement (CGI-I) scale. Safety endpoints assessed were the incidence of treatment-emergent adverse events (AEs) and serious AEs. Results : Gabapentin Enacarbil 600 mg significantly improved IRLS total score compared with placebo (adjusted mean [standard error] change in IRLS total score from baseline to week 12 last observation carried forward: −13.6 [0.71] vs −9.3 [0.55]; adjusted mean treatment difference: −4.3; 95% CI −6.01, −2.52; p < 0.0001). A significantly higher proportion of subjects was rated as responders on the investigator-rated CGI-I scale with Gabapentin Enacarbil 600 mg compared with placebo (70.2% vs 42.2%; adjusted odds ratio 3.1; 95% CI 1.96, 4.89; p < 0.0001). Similar treatment benefits were seen with both efficacy endpoints for the three higher doses. The AEs reported most frequently were somnolence and dizziness; there was a dose-response relationship to these AEs. No new or unexpected safety issues were identified by this integrated analysis. Conclusion : The lowest dose of Gabapentin Enacarbil evaluated (600 mg) significantly improved RLS symptoms compared with placebo. The safety profile was consistent with that described previously in the literature.

  • Dose response of Gabapentin Enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies.
    CNS drugs, 2012
    Co-Authors: Susan Vanmeter, Samantha Warren, Sarah Kavanagh, Ronald W. Barrett
    Abstract:

    Background: The efficacy and tolerability of Gabapentin Enacarbil (Horizant®; GlaxoSmithKline, Brentford, UK) has been demonstrated in several restless legs syndrome (RLS) phase II and phase III clinical studies at various doses from 600 mg to 2400 mg.

  • A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Tolerability of Gabapentin Enacarbil in Subjects with Restless Legs Syndrome
    Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 2011
    Co-Authors: Daniel O. Lee, Ronald B. Ziman, A. Thomas Perkins, J. Steven Poceta, Arthur S. Walters, Ronald W. Barrett
    Abstract:

    Study Objective: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 (R...

  • Long-term maintenance treatment of restless legs syndrome with Gabapentin Enacarbil: a randomized controlled study.
    Mayo Clinic proceedings, 2010
    Co-Authors: Richard K. Bogan, Clete A. Kushida, Michel A. Cramer Bornemann, Pierre V. Trân, Ronald W. Barrett
    Abstract:

    OBJECTIVE To assess maintenance of efficacy and tolerability of Gabapentin Enacarbil in patients with moderate to severe primary restless legs syndrome (RLS). PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

  • Gabapentin Enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial.
    Clinical neuropharmacology, 2009
    Co-Authors: Arthur S. Walters, Daniel M. Canafax, Clete A. Kushida, William G. Ondo, Aaron Ellenbogen, Philip M. Becker, Ronald W. Barrett
    Abstract:

    Objectives: Assess the efficacy and tolerability of Gabapentin Enacarbil (GEn), a transported prodrug of Gabapentin with improved Gabapentin exposure, in adults with moderate-to-severe primary restless legs syndrome. Methods: This 14-day, double-blind, randomized, controlled trial of GEn at 1200 or 600 mg or placebo taken once daily, evaluated the mean change from baseline International Restless Legs Scale (IRLS) total score at end of treatment (day 14: primary comparison, GEn at 1200 mg vs placebo). Secondary end points included Clinical Global Impression—Improvement scale outcomes at day 14. Results: Ninety-five subjects were randomized (GEn: 1200 mg, n = 33 and 600 mg, n = 29; placebo, n = 33); 2 subjects (GEn at 1200 mg) withdrew because of adverse events. At day 14, the mean (SD) change from baseline IRLS total score was significantly greater with GEn at 1200 mg (-16.1 [7.93]) compared with placebo (—8.9 [7.72]; adjusted mean treatment difference, -7.2; P < 0.0001). Investigator-rated Clinical Global Impression-Improvement scale responses also significantly favored GEn at 1200 mg compared with placebo (P < 0.0001). The mean (SD) change from baseline IRLS total score with GEn at 600 mg at day 14 was -9.1 (5.95), similar to placebo. The most commonly reported treatment-emergent adverse events were somnolence (GEn: 1200 mg, 36% and 600 mg, 14%; placebo, 15%) and dizziness (GEn: 1200 mg, 18% and 600 mg, 14%; placebo, 3%), most of which were rated mild or moderate in intensity. Conclusions: Gabapentin Enacarbil at 1200 mg significantly improved restless legs syndrome symptoms compared with placebo. Efficacy outcomes for GEn at 600 mg were similar to placebo. Both GEn doses were generally well tolerated.

Gwendoline Shang - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-Sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials
    Clinical therapeutics, 2016
    Co-Authors: Mansoor Ahmed, Mark J. Jaros, Richard Kim, J. Steven Poceta, Ryan Hays, Gwendoline Shang
    Abstract:

    Abstract Purpose Few studies have investigated restless legs syndrome (RLS) treatment effects on individual International RLS Study Group Rating Scale (IRLS) items. We assessed the effects of Gabapentin Enacarbil (GEn) on individual IRLS items and their correlation with sleep disturbances in adults with moderate-to-severe primary RLS. Methods Data were pooled from the randomized, double-blind, placebo-controlled, 12-week studies of XP052, XP053, and XP081 for adults who received GEn (600 or 1200 mg) or placebo once daily. Adults had primary RLS, IRLS total score ≥15, and RLS symptoms >15 days during the month before screening and for ≥4 of the 7 consecutive evenings at baseline. End points included mean change from baseline to week 12 in individual IRLS and post-sleep questionnaire (PSQ) items. For IRLS items, least squares mean treatment differences were calculated from a mixed model for repeated measures. For PSQ items, Cochran–Mantel–Haenszel row mean scores tests with integer scoring were used. Correlations between IRLS and PSQ items were assessed by Spearman's rank coefficients. Safety profile outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. Findings The modified intent-to-treat population included 671 patients (GEn 600 mg=161; GEn 1200 mg=266; placebo=244). GEn significantly improved mean [SE] differences versus placebo for all IRLS items at week 12, including severity of sleep disturbance (GEn 600 mg, −0.4 [0.10]; GEn 1200 mg, −0.4 [0.09]), daytime tiredness (−0.4 [0.09]; −0.4 [0.08]), RLS severity (−0.4 [0.10]; −0.3 [0.08]), impact on daily affairs (−0.3 [0.07]; −0.3 [0.07]), and mood disturbance (−0.2 [0.07]; −0.3 [0.06]); all P P P Implications GEn significantly improved individual IRLS items and sleep disturbance versus placebo. Correlations between IRLS and PSQ items were moderate to strong. This was not a formal meta-analysis and was not powered to compare the GEn doses. Nevertheless, our study finds that the benefits of GEn extend to individual IRLS items and supports the importance of sleep quality in RLS treatment. ClinicalTrials.gov identifiers: NCT00298623, NCT00365352, and NCT01332305.

  • The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials
    CNS Drugs, 2016
    Co-Authors: Neal Hermanowicz, Aaron Ellenbogen, Mark J. Jaros, Gwendoline Shang, Gordon Irving, Mark Buchfuhrer, Richard Kim
    Abstract:

    Background Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life. Objectives The aim of this study was to assess the effects of Gabapentin Enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults. Methods Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)–pain response were examined. Results The modified intention-to-treat population included 671 adults (placebo, n  = 244; GEn 600 mg, n  = 161; GEn 1200 mg, n  = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 ( p  

  • The Effect of Gabapentin Enacarbil on Quality of Life and Mood Outcomes in a Pooled Population of Adult Patients with Moderate-to-Severe Primary Restless Legs Syndrome
    CNS drugs, 2016
    Co-Authors: Alon Y. Avidan, Mark J. Jaros, Gwendoline Shang, Daniel Lee, Margaret Park, Richard Kim
    Abstract:

    Objective The aim was to assess Gabapentin Enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS).

  • The Effect of Gabapentin Enacarbil on Quality of Life and Mood Outcomes in a Pooled Population of Adult Patients with Moderate-to-Severe Primary Restless Legs Syndrome
    CNS Drugs, 2016
    Co-Authors: Alon Y. Avidan, Mark J. Jaros, Gwendoline Shang, Daniel Lee, Margaret Park, Richard Kim
    Abstract:

    Objective The aim was to assess Gabapentin Enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS). Methods Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied. Results The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n  = 204; GEn 600 mg, n  = 114; GEn 1200 mg, n  = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p  

  • Impact of Data Imputation Methodology on Pain Assessment over 24 Hours in a Randomized, Placebo-Controlled Study of Gabapentin Enacarbil in Patients with Neuropathic Pain Associated with Postherpetic Neuralgia
    Pain medicine (Malden Mass.), 2016
    Co-Authors: Anne Calkins, Jeff Gudin, Barry E. Gidal, Mark J. Jaros, Richard Kim, Gwendoline Shang
    Abstract:

    Objective. To assess the impact of Gabapentin Enacarbil on primary and secondary pain endpoints using three data imputation methodologies in a randomized phase II study of adult patients with postherpetic neuralgia. Methods. The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. Secondary endpoints (daytime/nighttime average pain intensity score, daytime/nighttime current pain intensity score, and daytime/nighttime worst pain intensity score) were based on daily electronic diary assessments. Comparisons of each Gabapentin Enacarbil dose with placebo were performed using three different statistical methodologies: last observation carried forward, baseline observation carried forward, and mixed-effect model for repeated measures. Results. Of the 376 randomized patients, 371 were in the intent-to-treat population (Gabapentin Enacarbil 1,200 mg, 107; 2,400 mg, 82; 3,600 mg, 87; placebo, 95). For mean 24-hour average pain intensity score, there were statistically significant improvements from baseline to end of maintenance treatment for all Gabapentin Enacarbil groups vs placebo using the three analysis methods. Significant improvements were also observed for all secondary endpoints with Gabapentin Enacarbil 1,200 mg using the three analysis methods. Most secondary endpoints also showed improvements following treatment with Gabapentin Enacarbil 2,400 mg or 3,600 mg compared with placebo. Conclusions. Gabapentin Enacarbil (1,200 mg, 2,400 mg, and 3,600 mg) was effective and well tolerated in patients with postherpetic neuralgia compared with placebo, as confirmed by three different and robust statistical methodologies.

Richard Kim - One of the best experts on this subject based on the ideXlab platform.

  • Effect of Gabapentin Enacarbil on Individual Items of the International Restless Legs Study Group Rating Scale and Post-Sleep Questionnaire in Adults with Moderate-to-Severe Primary Restless Legs Syndrome: Pooled Analysis of 3 Randomized Trials
    Clinical therapeutics, 2016
    Co-Authors: Mansoor Ahmed, Mark J. Jaros, Richard Kim, J. Steven Poceta, Ryan Hays, Gwendoline Shang
    Abstract:

    Abstract Purpose Few studies have investigated restless legs syndrome (RLS) treatment effects on individual International RLS Study Group Rating Scale (IRLS) items. We assessed the effects of Gabapentin Enacarbil (GEn) on individual IRLS items and their correlation with sleep disturbances in adults with moderate-to-severe primary RLS. Methods Data were pooled from the randomized, double-blind, placebo-controlled, 12-week studies of XP052, XP053, and XP081 for adults who received GEn (600 or 1200 mg) or placebo once daily. Adults had primary RLS, IRLS total score ≥15, and RLS symptoms >15 days during the month before screening and for ≥4 of the 7 consecutive evenings at baseline. End points included mean change from baseline to week 12 in individual IRLS and post-sleep questionnaire (PSQ) items. For IRLS items, least squares mean treatment differences were calculated from a mixed model for repeated measures. For PSQ items, Cochran–Mantel–Haenszel row mean scores tests with integer scoring were used. Correlations between IRLS and PSQ items were assessed by Spearman's rank coefficients. Safety profile outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. Findings The modified intent-to-treat population included 671 patients (GEn 600 mg=161; GEn 1200 mg=266; placebo=244). GEn significantly improved mean [SE] differences versus placebo for all IRLS items at week 12, including severity of sleep disturbance (GEn 600 mg, −0.4 [0.10]; GEn 1200 mg, −0.4 [0.09]), daytime tiredness (−0.4 [0.09]; −0.4 [0.08]), RLS severity (−0.4 [0.10]; −0.3 [0.08]), impact on daily affairs (−0.3 [0.07]; −0.3 [0.07]), and mood disturbance (−0.2 [0.07]; −0.3 [0.06]); all P P P Implications GEn significantly improved individual IRLS items and sleep disturbance versus placebo. Correlations between IRLS and PSQ items were moderate to strong. This was not a formal meta-analysis and was not powered to compare the GEn doses. Nevertheless, our study finds that the benefits of GEn extend to individual IRLS items and supports the importance of sleep quality in RLS treatment. ClinicalTrials.gov identifiers: NCT00298623, NCT00365352, and NCT01332305.

  • The Effect of Gabapentin Enacarbil on Pain Associated with Moderate-to-Severe Primary Restless Legs Syndrome in Adults: Pooled Analyses from Three Randomized Controlled Trials
    CNS Drugs, 2016
    Co-Authors: Neal Hermanowicz, Aaron Ellenbogen, Mark J. Jaros, Gwendoline Shang, Gordon Irving, Mark Buchfuhrer, Richard Kim
    Abstract:

    Background Adults with moderate-to-severe primary restless legs syndrome (RLS) often experience painful dysesthesias, which may lead to impaired quality of life. Objectives The aim of this study was to assess the effects of Gabapentin Enacarbil (GEn) on pain associated with moderate-to-severe primary RLS in adults. Methods Data were pooled from three double-blind, randomized, placebo-controlled, 12-week trials (NCT00298623, NCT00365352, NCT01332305) for adults receiving GEn or placebo once daily. Change in average daily RLS pain score and a combined International Restless Legs Scale (IRLS)–pain response were examined. Results The modified intention-to-treat population included 671 adults (placebo, n  = 244; GEn 600 mg, n  = 161; GEn 1200 mg, n  = 266). Both GEn doses significantly improved average daily RLS pain score at week 12 ( p  

  • The Effect of Gabapentin Enacarbil on Quality of Life and Mood Outcomes in a Pooled Population of Adult Patients with Moderate-to-Severe Primary Restless Legs Syndrome
    CNS drugs, 2016
    Co-Authors: Alon Y. Avidan, Mark J. Jaros, Gwendoline Shang, Daniel Lee, Margaret Park, Richard Kim
    Abstract:

    Objective The aim was to assess Gabapentin Enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS).

  • The Effect of Gabapentin Enacarbil on Quality of Life and Mood Outcomes in a Pooled Population of Adult Patients with Moderate-to-Severe Primary Restless Legs Syndrome
    CNS Drugs, 2016
    Co-Authors: Alon Y. Avidan, Mark J. Jaros, Gwendoline Shang, Daniel Lee, Margaret Park, Richard Kim
    Abstract:

    Objective The aim was to assess Gabapentin Enacarbil (GEn) treatment effects on quality of life (QOL) and mood in adults with moderate-to-severe primary restless legs syndrome (RLS). Methods Data were pooled from three placebo-controlled, randomized, double-blind, 12-week trials for adults receiving GEn (600 mg or 1200 mg) or placebo once daily. QOL was assessed with the RLS QOL questionnaire in two studies. Mood was examined with the Profile of Mood States Brief Form (POMS-B), and as an exploratory analysis with International Restless Legs Scale (IRLS) item 9 (daily affairs) and item 10 (mood disturbance) across all three studies. Mood and QOL were secondary endpoints in the individual clinical trials. No adjustments for multiplicity were applied. Results The QOL analysis modified intent-to-treat (MITT) population included 541 adults (placebo, n  = 204; GEn 600 mg, n  = 114; GEn 1200 mg, n  = 223). Both GEn doses significantly improved QOL versus placebo (week 12; p  

  • Impact of Data Imputation Methodology on Pain Assessment over 24 Hours in a Randomized, Placebo-Controlled Study of Gabapentin Enacarbil in Patients with Neuropathic Pain Associated with Postherpetic Neuralgia
    Pain medicine (Malden Mass.), 2016
    Co-Authors: Anne Calkins, Jeff Gudin, Barry E. Gidal, Mark J. Jaros, Richard Kim, Gwendoline Shang
    Abstract:

    Objective. To assess the impact of Gabapentin Enacarbil on primary and secondary pain endpoints using three data imputation methodologies in a randomized phase II study of adult patients with postherpetic neuralgia. Methods. The primary endpoint was change from baseline to end of maintenance treatment in mean 24-hour average pain intensity score. Secondary endpoints (daytime/nighttime average pain intensity score, daytime/nighttime current pain intensity score, and daytime/nighttime worst pain intensity score) were based on daily electronic diary assessments. Comparisons of each Gabapentin Enacarbil dose with placebo were performed using three different statistical methodologies: last observation carried forward, baseline observation carried forward, and mixed-effect model for repeated measures. Results. Of the 376 randomized patients, 371 were in the intent-to-treat population (Gabapentin Enacarbil 1,200 mg, 107; 2,400 mg, 82; 3,600 mg, 87; placebo, 95). For mean 24-hour average pain intensity score, there were statistically significant improvements from baseline to end of maintenance treatment for all Gabapentin Enacarbil groups vs placebo using the three analysis methods. Significant improvements were also observed for all secondary endpoints with Gabapentin Enacarbil 1,200 mg using the three analysis methods. Most secondary endpoints also showed improvements following treatment with Gabapentin Enacarbil 2,400 mg or 3,600 mg compared with placebo. Conclusions. Gabapentin Enacarbil (1,200 mg, 2,400 mg, and 3,600 mg) was effective and well tolerated in patients with postherpetic neuralgia compared with placebo, as confirmed by three different and robust statistical methodologies.