David Hebert

Adjunctive lacosamide for partial-onset seizures : Efficacy and safety results from a randomized controlled trial

Purpose:  To evaluate the efficacy and safety of lacosamide (200 and 400 mg/day) when added to one to three concomitant antiepileptic drugs (AEDs) in patients with uncontrolled partial‐onset seizures.

Lacosamide as adjunctive therapy for partial‐onset seizures: A randomized controlled trial

Purpose:  To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial‐onset seizures taking one to three concomitant antiepileptic drugs (AEDs).

A Pooled Analysis of Lacosamide Clinical Trial Data Grouped by Mechanism of Action of Concomitant Antiepileptic Drugs

AbstractBackground: Lacosamide, a new antiepileptic drug (AED) with a different pharmacological action that enhances sodium channel slow inactivation, is approved for the adjunctive treatment of partial-onset seizures in adults. Previous analyses of pooled phase II/III trials have demonstrated that lacosamide provides additional efficacy when added to a broad range of AEDs. Objective: To further evaluate the efficacy and safety of lacosamide by grouping patients based upon the sodium channel-blocking properties of their concomitant AEDs. Study Design:Post hoc exploratory analyses were performed on pooled data in which patients were grouped based upon inclusion or non-inclusion of at least one ‘traditional’ sodium channel-blocking AED (defined as carbamazepine, lamotrigine, oxcarbazepine and phenytoin derivatives) as part of their concomitant AED regimen. Setting: Data pooled from previously conducted phase II/III clinical trials of lacosamide. Patients: Adult patients with partial-onset seizures with or without secondary generalization (N = 1308). Intervention: Four- to six-week Titration Phase followed by 12-week maintenance treatment with adjunctive lacosamide (Vimpat®) [200, 400 or 600 mg/day] or placebo. Main Outcome Measure: Efficacy variables included change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase. The proportion of patients experiencing a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate) was also assessed. Safety parameters assessed were treatment-emergent adverse events (TEAEs) and discontinuation due to TEAEs. Additional safety assessments were changes in ECG and laboratory parameters as well as vital signs (including bodyweight). Results: Of 1308 patients in the pooled phase II/III population, the majority (82%) were using at least one ‘traditional’ sodium channel-blocking concomitant AED. In this subgroup of patients, adjunctive lacosamide showed significant reductions in seizure frequency (p<0.01, all dosages) and significantly greater 50% and 75% responder rates (p < 0.01 for 400 mg/day; p < 0.01 [50% responder rate] and p<0.05 [75% responder rate] for 600 mg/day) compared with placebo; these effects were similar to the results seen in the pooled phase II/III population. TEAEs and discontinuations due to TEAEs in this subgroup were dose related and similar to the pooled phase II/III population. In the remaining subgroup of patients, i.e. those not taking ‘traditional’ sodium channel-blocking AEDs as part of their concomitant AED regimen (n = 231; 18%), a pronounced, dose-related seizure reduction was observed with lacosamide (p<0.01, 400 and 600mg/day for median percent seizure reduction and 50% or 75% responder rates). Also in this group, incidences of TEAEs were low, and discontinuations due to TEAEs did not appear to increase with dose. Analyses of ECG, laboratory and vital signs (including bodyweight) assessments did not identify abnormalities in either subgroup that were outside of the known safety profile of lacosamide observed in the pooled phase II/III population. Conclusion: In this post hoc exploratory analysis, adjunctive lacosamide demonstrated significant seizure reduction over placebo regardless of the inclusion of ‘traditional’ sodium channel blockers in the concomitant AED regimen. Future prospective studies evaluating single AED combinations (e.g. lacosamide plus one other drug) are needed to better evaluate the potential for additive or synergistic effects of lacosamide in combination with AEDs not considered ‘traditional’ sodium channel blockers.

Socioenvironmental influences on children's fruit, juice and vegetable consumption as reported by parents: reliability and validity of measures.

OBJECTIVE To pilot test theory-based questionnaires to measure socioenvironmental influences on childrens fruit, juice and vegetable (FJV) consumption as reported by parents. DESIGN Cross-sectional. SETTING Parents of fourth to sixth grade students completed socioenvironmental questionnaires. The students completed food records (FRs) for 2 days in the classroom. SUBJECTS Interviews were completed by 109 parents (17% African-American, 32% Hispanic-American and 51 Euro-American). RESULTS Student mean daily FJV intake was 2.1 servings. Principal components analyses revealed subscales measuring positive and negative parenting practices; self-efficacy for modelling and planning/encouraging FJV consumption, and making FJV available; encouraging, consequences and discouraging food socialization practices; negative home, cost and canned/frozen food barriers; meal planning; child shopping; mother food preparation; and child lunch and dinner FJV preparation practices. Internal consistencies were adequate to high. Negative parent practices and negative home FJV barriers were significantly negatively correlated with child FJV consumption variables. Planning/encouraging self-efficacy was positively associated with fruit consumption, and child dinner FJV preparation was significantly negatively correlated with child juice consumption. CONCLUSIONS These questionnaires may provide important insights about the relationship between parent-reported socioenvironmental influences and childrens FJV consumption. Future work should test these questionnaires with larger groups of parents and youths, with more reliable estimates of usual FJV intake, e.g. 7-day food records, to obtain a detailed understanding of how parents influence what children eat. Tests of models of relationships among these variables are warranted, but should control for possible confounding variables, e.g. socioeconomic status, gender of the child, etc.

Lacosamide: pharmacology, mechanisms of action and pooled efficacy and safety data in partial-onset seizures

Lacosamide is an antiepileptic drug approved in the USA and Europe as adjunctive therapy for partial-onset seizures. Studies suggest that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels and possibly interacts with collapsin response mediator protein-2. The efficacy of lacosamide has been shown in animal models of epilepsy and Phase II/III clinical trials. Pharmacokinetic studies show that it is renally excreted, minimally bound to plasma proteins and has no known clinically relevant drug–drug interactions. Clinical trials show that lacosamide is well tolerated; the most common adverse events were dizziness, nausea and vomiting. In a Phase II/III pooled analysis, lacosamide 200 and 400 mg/day significantly reduced partial-onset seizure frequency and improved the 50% responder rate compared with placebo.

Examining the Clinical Utility of Lacosamide Pooled Analyses of Three Phase II/III Clinical Trials

AbstractBackground: Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool. Objective: To provide insight into the clinical utility of lacosamide by performing a priori-defined and post hoc analyses on a large, pooled patient population. Study Design: Pooled data from three randomized, double-blind, multicentre, placebo-controlled phase II/III trials. Patients: Adult patients with partial-onset seizures with or without secondary generalization (N = 1294). Intervention: Four- to six-week titration followed by 12-week maintenance treatment with lacosamide (Vimpat®) 200, 400 or 600mg/day or placebo. Main Outcome Measure:A priori- defined primary efficacy variables for the pooled analysis were change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase; a priori-defined secondary efficacy variables were the proportion of patients achieving a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate), the proportion of Maintenance Phase completers remaining seizure free throughout the entire Maintenance Phase and the percentage of seizure-free days during the Maintenance Phase for patients entering the Maintenance Phase. The pooled analyses of the change in seizure frequency, and 50% and 75% responder rates were performed with an intent-to-treat (ITT) approach, including all patients receiving at least one dose of trial medication and having at least one post-baseline efficacy assessment. Similar analyses of the two primary efficacy variables and 75% responder rates were also performed using a modified ITT population (ITTm) that included ITT patients who entered the Maintenance Phase. Additional post hoc efficacy analyses were an evaluation of onset of efficacy and assessment of efficacy in patients grouped by prior surgical history and individual concomitant AED use. In addition, pharmacokinetic-pharmacodynamic modelling was performed, and safety data were assessed. Results: In this pooled analysis of 1294 difficult-to-treat patients, all three dosages of lacosamide (200, 400 and 600 mg/day) showed a significant improvement compared with placebo for median percent seizure reduction (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day), as well as for 50% responder rate (ITT and ITTm; p <0.05 for 200 mg/day, p<0.001 for 400 and 600 mg/day). Evaluation of 75% responder rate in the phase II/III pooled population showed that a significantly higher proportion of patients randomized to lacosamide 400 or 600 mg/day achieved a ≥75% reduction in seizure frequency compared with placebo (ITT and ITTm; p < 0.001); statistical significance was not observed for lacosamide 200 mg/day (ITT and ITTm). A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%). The mean change from baseline in the percentage of seizure-free days in patients entering the Maintenance Phase for the phase II/III pool was 8.0%, 11.6% and 14.7% with lacosamide 200 (p =0.077), 400 (p<0.001) and 600 (p<0.001) mg/day groups, respectively, compared with 6.1% in the placebo group.The onset of efficacy relative to placebo was evident by the first week of treatment with lacosamide. Efficacy was similar in lacosamide-treated patients reporting prior surgical intervention for epilepsy compared to lacosamidetreated patients with no prior surgical intervention. Lacosamide showed a reduction in seizures, regardless of the concomitant AEDs used. The preferred pharmacokinetic-pharmacodynamic model (Emax) supported the therapeutic dose range of lacosamide, and no additional safety concerns were identified in the phase II/III pooled analysis. Conclusions: Results of these a priori-defined and post hoc pooled data analyses from phase II/III trials demonstrate that lacosamide effectively reduces seizures in patients at all three dosages evaluated with an early onset of efficacy, regardless of patient surgical history and concomitant AED regimen.

Pilot Study of the Validity and Reliability of Brief Fruit, Juice and Vegetable Screeners among Inner City African-American Boys and 17 to 20 Year Old Adults

OBJECTIVE Compare the validity and reliability of a one-week fruit, juice and vegetable (FJV) food frequency questionnaire (FFQ) that does not require averaging in response categories and one-week food recognition form (FRF) against three to four 24-hour dietary recalls (24hdr) among mostly African-American boys and 17 to 20 year-old adults for possible use in subsequent intervention studies. DESIGN In Study One, the FFQ was administered to 40 boys in four Boy Scout (BS) troops on two occasions separated by two weeks. The FRF was administered to 36 boys in four other BS troops after school on six school days, covering seven consecutive days. All these boys completed four 24hdr, including one Sunday. In Study Two, 56 17 to 20 year-old adults completed the FFQ during telephone interviews on two occasions two weeks apart. In between, they completed three 24hdr by telephone interview on one weekend and two weekdays. SUBJECTS/SETTING Participants in Study One were members of eight urban BS troops, and in Study Two were high school (HS) seniors and recent HS graduates. BS data were collected at times scheduled for troop meetings or immediately after school. The young adult group completed telephone interviews in the evenings and on weekends. MAIN MEASURES This research compared a FJV FFQ and a FJV FRF (incorporating the same 24 foods) against three to four 24hdr conducted using NDS software from the University of Minnesota. STATISTICAL ANALYSES PERFORMED Descriptive statistics, intraclass correlations, Spearman correlations, corrections for attenuation. RESULTS The first FFQ provided substantially higher mean consumption estimates for both groups. The FFQ had moderate reliability across assessments and moderate validity coefficients for fruit and total FJV combined for the BS sample. The FRF had higher validity coefficients for juice. The FFQ had moderate reliability and poor validity among the young adult group. Correction for measurement error in the 24hdr substantially increased validity coefficients to high levels for BS fruit and total FJV and to moderate levels for the HS groups, with some exceptions. APPLICATIONS/CONCLUSIONS FFQ more validly assessed fruit and combined FJV consumption for the nine to 14 year-old BS but overestimated mean values. FRF means were closer to those of the 24hdr and were more valid for assessing juice consumption. The FFQ had moderate validity among the young adult group but overestimated consumption. Further research is needed on simpler methods of reporting diet in these age groups.

Development of lacosamide for the treatment of partial-onset seizures

Lacosamide is an antiepileptic drug (AED) available in multiple formulations that was first approved in 2008 as adjunctive therapy for partial‐onset seizures (POS) in adults. Unlike traditional sodium channel blockers affecting fast inactivation, lacosamide selectively enhances sodium channel slow inactivation. This mechanism of action results in stabilization of hyperexcitable neuronal membranes, inhibition of neuronal firing, and reduction in long‐term channel availability without affecting physiological function. Lacosamide has a well‐characterized and favorable pharmacokinetic profile, including a fast absorption rate, minimal or no interaction with cytochrome P‐450 izoenzymes, and a low potential for drug–drug interactions. Lacosamide clinical development included three placebo‐controlled, double‐blind, randomized trials conducted in more than 1300 patients, each demonstrating safety and efficacy of lacosamide compared to placebo as adjunctive therapy for adults with POS. The clinical use of lacosamide may broaden, pending results of trials evaluating its use as monotherapy for POS in adults, as treatment for epilepsy in pediatric subjects, and as adjunctive treatment for uncontrolled primary generalized tonic–clonic seizures in those with idiopathic generalized epilepsy.

Efficacy of lacosamide by focal seizure subtype

The purpose of this post hoc exploratory analysis was to determine the effects of the antiepileptic drug, lacosamide, on focal (partial-onset) seizure subtypes. Patient data from the three lacosamide pivotal trials were grouped and pooled by focal seizure subtype at Baseline: simple partial seizures (SPS), complex partial seizures (CPS), and secondarily generalized partial seizures (SGPS). Both efficacy outcomes (median percent change from Baseline to Maintenance Phase in seizure frequency per 28 days and the proportion of patients experiencing at least a 50% reduction in seizures) were evaluated by lacosamide dose (200, 400, or 600 mg/day) compared to placebo for each seizure subtype. An additional analysis was performed to determine whether a shift from more severe focal seizure subtypes to less severe occurred upon treatment with lacosamide. In patients with CPS or SGPS at Baseline, lacosamide 400 mg/day (maximum recommended daily dose) and 600 mg/day reduced the frequency of CPS and SGPS compared to placebo. Likewise, a proportion of patients with CPS and SGPS at Baseline experienced at least a 50% reduction in the frequency of CPS and SGPS (≥50% responder rate) in the lacosamide 400 and 600 mg/day groups compared with placebo. For both outcomes, numerically greatest responses were observed in the lacosamide 600 mg/day group among patients with SGPS at Baseline. In patients with SPS at Baseline, no difference between placebo and lacosamide was observed for either efficacy outcome. An additional exploratory analysis suggests that in patients with SPS at Baseline, CPS and SGPS may have been shifted to less severe SPS upon treatment with lacosamide. The results of these exploratory analyses revealed reductions in CPS and SGPS frequency with adjunctive lacosamide. Reduction in CPS and SGPS may confound assessment of SPS since the CPS or SGPS may possibly change to SPS by effective treatment.

Meal, Location, and Day of Week Influence Fruit and Vegetable Intake Among 9-14 Year Old Boys

Abstract This study investigated the relationship among meal (breakfast, lunch, supper, snack), location (home, school, eating out, other), and day of week (weekday, weekend day) on fruit and vegetable (FV 89% African-American, 8% Hispanic). Participants completed up to four 24-hour food recalls conducted after school over a 2-week period by trained staff using the computerized Nutrient Data System of the University of Minnesota. Servings of fruit, juice, and vegetables were hand-coded according to the Food Guide Pyramid serving sizes. Mixed model analyses were conducted using both the actual fruit, juice, and vegetable servings, and with dichotomized data, where 1=ate FV vegetables were selected in 45% of home lunches. About 60% of dinners at home and eaten out included vegetables. Between 45% and 50% of lunch and dinner vegetables eaten out were hi-fat vegetables; only 8-20% of home and school meals included hi-fat vegetables. There were significant differences in F&V intake by meal and day of week. Juice was selected at 50% of weekday breakfasts, but only 30% of weekend breakfasts, and at less than 10% of other meals. Fruit was consumed at 36% of weekday lunch meals and at 20% of weekend snacks, but at less than 10% of other meals. Interventions to improve F&V intake must target F&V differently by meal, location, and day.