Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Barcs, Gábor; Walker, Elizabeth; Elger, Christian E.; Scaramelli, A.; Stefan, H.; Sturm, Y.; Moore, Alan; Flesch, G.; Kramer, Lynn D.; D’Souza, Joseph

doi:10.1111/j.1499-1654.2000.001597.x

Cited by 197 publications

(45 citation statements)

References 6 publications

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“…Combining AEDs based on their mechanism of action can also provide a rational approach to the challenge 1, 3. While the potential for enhanced neurotoxicity when combining two sodium channel‐blocking AEDs was observed over 40 years ago, evidence for enhanced efficacy with specific combinations remains inconsistent 4, 5, 6…”

Section: Introductionmentioning

confidence: 99%

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

et al. 2016

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ObjectiveTo assess prospectively the effectiveness of lacosamide (LCM) added to levetiracetam (LEV) after down‐titration of a concomitant sodium channel blocker (SCB) among patients with focal epilepsy not adequately controlled on LEV and SCB.MethodsIn this open‐label trial, LCM was initiated at 100 mg/day and up‐titrated to 200‐600 mg/day over 9 weeks; SCB down‐titration started when LCM dose reached 200 mg/day. Patients remained on stable LCM/LEV doses for 12 weeks’ maintenance (21‐week treatment period). The primary outcome was retention rate on LCM.ResultsDue to recruitment challenges, fewer than the planned 300 patients participated in the trial, resulting in the trial being underpowered. Overall, 120 patients (mean age 39.7 years) started and 93 completed the trial. The most frequently used SCBs were lamotrigine (39.2%), carbamazepine (30.8%) and oxcarbazepine (27.5%). Eighty‐four patients adhered to protocol and discontinued their SCB after cross‐titration, but there was insufficient evidence for 36 patients. Retention rate was 73.3% (88/120) for all patients and 83.3% (70/84) for those with evidence of SCB discontinuation. Seizure freedom for patients completing maintenance was 14.0% (13/93). Discontinuation due to adverse events (6.7%) and lack of efficacy (3.3%) occurred primarily during cross‐titration. Most frequently reported adverse events during treatment were dizziness (23.3%), headache (15.0%) and fatigue (8.3%).ConclusionsIn patients with uncontrolled seizures on LEV/SCB, the LCM/LEV combination appeared to be effective and well tolerated. A cross‐titration schedule—flexible LCM up‐titration, concomitant SCB down‐titration and stable background LEV—could present a feasible and practical approach to initiating LCM while minimizing pharmacodynamic interactions with a SCB.

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Section: Introductionmentioning

confidence: 99%

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

et al. 2016

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“…A multinational double‐blind placebo‐controlled study [ P rospective R andomized Study of O xcarbazepine XR in Subjects with Partial Epilepsy, Refractory (PROSPER); ClinicalTrials.gov identifier: NCT00772603] demonstrated the efficacy of once‐daily SPN‐804 administered as adjunctive therapy at fixed dosages (1200 and 2400 mg QD) in adults with refractory partial‐onset seizures 6. Consistent with the more favorable plasma concentration–time profile of SPN‐804 vs OXC‐IR, discontinuations due to adverse events (AEs) with SPN‐804 were threefold to fivefold lower in the PROSPER study than in a similarly designed study of OXC‐IR 600 and 1200 mg BID 5. Double‐blind, randomized, controlled, fixed‐dose trials such as PROSPER provide critical efficacy and safety information that informs regulatory approval.…”

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confidence: 76%

“…Oxcarbazepine retains the efficacy of CBZ 3 but has more favorable metabolic, pharmacokinetic, tolerability, and safety profiles 4. However, the usefulness of immediate‐release OXC (OXC‐IR) can often be compromised by poor tolerability, particularly at higher dosages (i.e., ≥1200 mg/day) 5.…”

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confidence: 99%

Long‐term efficacy and safety of adjunctive extended‐release oxcarbazepine (Oxtellar XR ^® ) in adults with partial‐onset seizures

et al. 2015

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ObjectiveTo evaluate long‐term outcomes of adjunctive therapy with SPN‐804 (Oxtellar XR®, Supernus Pharmaceuticals), an extended‐release tablet formulation of oxcarbazepine (OXC), in adults with refractory partial‐onset seizures.MethodsAfter completing a 16‐week double‐blind, placebo‐controlled trial of SPN‐804 at fixed dosages (1200 or 2400 mg QD), patients entering this open‐label extension study were converted in blinded fashion to 1200 mg QD SPN‐804 as a target starting dose for long‐term treatment. Patients were followed for 1 year, during which SPN‐804 dosages could be adjusted up to 2400 mg/day according to clinical response.ResultsOf 214 patients, 84% completed 1‐year open‐label treatment. Median maintenance SPN‐804 dosage was 1200 mg; <10% of patients required 2400 mg. Median 28‐day seizure frequency reduction from baseline was 59%; seizure frequency was reduced ≥50% in 58% of patients; 11% were seizure free ≥6 months; and 5% were seizure free ≥1 year. SPN‐804 was discontinued due to adverse events in 5% (n = 10). Incidences of each of the most common adverse events (dizziness, headache, diplopia, nausea, vomiting, balance disorder, blurred vision) were ≤15% during 1‐year follow‐up and occurred most frequently in patients previously naïve to SPN‐804. No new safety signals, no clinically significant changes in health status, and no deaths attributable to SPN‐804 were observed.ConclusionSPN‐804 administered once daily for 1 year was effective as adjunctive therapy in improving seizure control and maintaining therapeutic response in adults with refractory partial‐onset seizures. With dosage flexibility, SPN‐804 was well tolerated.

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“…4). 70 Although there are some justifications for applying a LOCF analysis (mainly to obtain an estimate of efficacy not confounded by other variables such as failure to tolerate the treatment), every clinician will agree that a much more meaningful estimate of treatment effects is represented by the number of responders who were able to complete the trial.…”

Section: Randomized Controlled Trialsmentioning

confidence: 99%

“…Responder rates (proportion of patients with >50% decrease in seizure frequency compared with baseline) and rates of premature discontinuation from the trial in a placebo‐controlled adjunctive‐therapy trial of oxcarbazepine ( OXC ) in a total of 694 patients with focal seizures 70. For oxcarbazepine‐treated groups, most premature discontinuations were due to adverse events.…”

Section: Randomized Controlled Trialsmentioning

confidence: 99%

Not all that glitters is gold: A guide to the critical interpretation of drug trials in epilepsy

Perucca

Wiebe

2016

Epilepsia Open

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SummaryClinical trials represent the best source of evidence on which to base treatment decisions. For such evidence to be utilized meaningfully, however, it is essential that results are interpreted correctly. This requires a good understanding of strengths and weaknesses of the adopted design, the clinical relevance of the outcome measures, and the many factors that could affect such outcomes. As a general rule, uncontrolled studies tend to provide misleading evidence as a result of the impact of confounders such as regression to the mean, patient‐related bias, and observer bias. On the other hand, although randomized controlled trials (RCTs) are qualitatively superior, aspects of their execution may still decrease their validity. Bias and decreased validity in RCTs may occur by chance alone (for example, treatment groups may not necessarily be balanced for important variables despite randomization) or because of specific features of the trial design. In the case of industry‐driven studies, bias often influences the outcome in favor of the sponsor's product. Factors that need to be carefully scrutinized include (1) the purpose for which the trial is conducted; (2) potential bias due to unblinding or lack of blinding; (3) the appropriateness of the control group; (4) the power of the study in detecting clinically relevant differences; (5) the extent to which eligibility criteria could affect outcomes and be representative of routine clinical practice; (6) whether the treatments being compared are used optimally in terms of dosing, duration of treatment, and other variables; (7) the appropriateness of the statistical comparisons; (8) the clinical relevance of the outcome measures and whether all key outcome information is reported (for example, responder rates in completers); and (9) potential bias in the way results are presented and discussed. This article discusses each of these aspects and illustrates the discussion with examples taken from published antiepileptic drug trials.

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Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Cited by 197 publications

References 6 publications

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

Long‐term efficacy and safety of adjunctive extended‐release oxcarbazepine (Oxtellar XR ^® ) in adults with partial‐onset seizures

Not all that glitters is gold: A guide to the critical interpretation of drug trials in epilepsy

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Oxcarbazepine Placebo‐Controlled, Dose‐Ranging Trial in Refractory Partial Epilepsy

Cited by 197 publications

References 6 publications

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

Lacosamide and sodium channel-blocking antiepileptic drug cross-titration against levetiracetam background therapy

Long‐term efficacy and safety of adjunctive extended‐release oxcarbazepine (Oxtellar XR ® ) in adults with partial‐onset seizures

Not all that glitters is gold: A guide to the critical interpretation of drug trials in epilepsy

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Product

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Long‐term efficacy and safety of adjunctive extended‐release oxcarbazepine (Oxtellar XR ^® ) in adults with partial‐onset seizures