Faculty Bibliography

PURPOSE: Monotherapy approvals have been difficult to obtain from the U.S. Food and Drug Administration (FDA), and have almost all been achieved using a trial design entitled 'withdrawal to monotherapy' in treatment-resistant patients, which employs a so-called 'pseudo-placebo' as a comparator arm. The authors submitted a white paper to the FDA advocating use of a virtual placebo historical control as an alternative to pseudo-placebo. Such an approach reduces patient risk that would result from exposure to pseudo-placebo. In this article, we present the data submitted to the FDA to justify a historical control. METHODS: We analyzed individual patient data from eight previously completed withdrawal to monotherapy studies, which we determined had similar design. All studies employed percent meeting predetermined exit criteria (denoting worsening of seizure control) as the outcome measure. Kaplan-Meier estimates of the percent exiting were calculated at 112 days. RESULTS: The percent meeting exit criteria were uniformly high, ranging from 74.9-95.9%. The eight studies appear to meet the criteria set forth for use of historical control. The estimate of the combined percent exit based on the noniterative mixed-effects model is 85.1%, with a lower bound of the 95% prediction interval of 65.3%, and 72.2% for an 80% prediction interval. CONCLUSION: There is justification for proposing that these data can serve as a historical control for future monotherapy studies, obviating the need for a placebo/pseudo-placebo arm in trials intended to demonstrate the efficacy of approved drugs as monotherapy in treatment-resistant patients

OBJECTIVE: To explore efficacy and safety/tolerability of adjunctive brivaracetam (BRV), a novel, high-affinity synaptic vesicle protein 2A ligand, which also inhibits neuronal voltage-dependent sodium channels, in patients with refractory partial-onset seizures (POS). METHODS: This was an exploratory, phase IIb, double-blind, randomized, parallel-group, placebo-controlled, dose-ranging study in patients 16-65 years with epilepsy experiencing > or =4 POS during 4-week baseline despite 1-2 concomitant antiepileptic drugs. Patients were randomized (1:1:1:1) to placebo, BRV 5 mg/day (BRV5), BRV 20 mg/day (BRV20), or BRV 50 mg/day (BRV50), administered BID without uptitration during a 7-week treatment period. Primary efficacy endpoint was POS frequency/week during the treatment period relative to placebo. RESULTS: A total of 208 patients constituted the intention-to-treat population; 197 completed the study. Estimated percentage reductions over placebo in POS frequency/week were 9.8% (BRV5; p = 0.240), 14.9% (BRV20; p = 0.062), and 22.1% (BRV50; p = 0.004). Median percent reductions from baseline in POS frequency/week were 21.7% (placebo), 29.9% (BRV5; p = 0.086), 42.6% (BRV20; p = 0.014), and 53.1% (BRV50; p < 0.001); > or =50% responder rates were 16.7% (placebo), 32.0% (BRV5; p = 0.047), 44.2% (BRV20; p = 0.002), and 55.8% (BRV50; p < 0.001); seizure freedom rates (POS) during the 7-week treatment period were 1.9% (placebo), 8.0% (BRV5; p = 0.193), 7.7% (BRV20; p = 0.193), and 7.7% (BRV50; p = 0.201). BRV was well-tolerated. Most adverse events were mild to moderate and occurred with similar incidence in placebo and BRV groups, and discontinuations due to treatment-emergent adverse events were infrequent (placebo 3.7%; BRV 2.6%). CONCLUSIONS: This interventional study provides preliminary Class I evidence that adjunctive BRV was efficacious and well-tolerated in patients aged 16-65 years with POS

Comparative effectiveness research (CER) is the study of the relative effects of treatments to determine which will be most likely to improve overall health for a specific condition. This area has received a great deal of political focus, and substantial funding for CER is included in the American Reinvestment and Recovery Act of 2009. The results of CER are intended to inform evidence-based guidelines and to improve the quality and effectiveness of medical care. In the absence of such research, guidelines often depend on consensus to rank available therapies. We believe that an increase in CER would clearly enhance evidence-based guidelines. However, the research must be performed and analyzed with great care to avoid reaching unhelpful, or even harmful, conclusions. Specifically, individual patient characteristics must be taken into account, study endpoints must approximate the most important patient outcomes, therapies must be used optimally within the studies, and the most relevant therapies for a given indication must be included for comparison. CER that is not performed or interpreted correctly could have the potential to affect negatively our choices of therapies. The neurology community must help inform the process of CER to ensure the highest-quality research, which in turn will result in the most valid outcomes

To improve patient care and facilitate clinical research, the International League Against Epilepsy (ILAE) appointed a Task Force to formulate a consensus definition of drug resistant epilepsy. The overall framework of the definition has two 'hierarchical' levels: Level 1 provides a general scheme to categorize response to each therapeutic intervention, including a minimum dataset of knowledge about the intervention that would be needed; Level 2 provides a core definition of drug resistant epilepsy using a set of essential criteria based on the categorization of response (from Level 1) to trials of antiepileptic drugs. It is proposed as a testable hypothesis that drug resistant epilepsy is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. This definition can be further refined when new evidence emerges. The rationale behind the definition and the principles governing its proper use are discussed, and examples to illustrate its application in clinical practice are provided

There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain

PURPOSE: We report a multicenter, double-blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization-related epilepsy. METHODS: Participants were adults with medically refractory partial seizures, including secondarily generalized seizures. Half received stimulation and half no stimulation during a 3-month blinded phase; then all received unblinded stimulation. RESULTS: One hundred ten participants were randomized. Baseline monthly median seizure frequency was 19.5. In the last month of the blinded phase the stimulated group had a 29% greater reduction in seizures compared with the control group, as estimated by a generalized estimating equations (GEE) model (p = 0.002). Unadjusted median declines at the end of the blinded phase were 14.5% in the control group and 40.4% in the stimulated group. Complex partial and 'most severe' seizures were significantly reduced by stimulation. By 2 years, there was a 56% median percent reduction in seizure frequency; 54% of patients had a seizure reduction of at least 50%, and 14 patients were seizure-free for at least 6 months. Five deaths occurred and none were from implantation or stimulation. No participant had symptomatic hemorrhage or brain infection. Two participants had acute, transient stimulation-associated seizures. Cognition and mood showed no group differences, but participants in the stimulated group were more likely to report depression or memory problems as adverse events. DISCUSSION: Bilateral stimulation of the anterior nuclei of the thalamus reduces seizures. Benefit persisted for 2 years of study. Complication rates were modest. Deep brain stimulation of the anterior thalamus is useful for some people with medically refractory partial and secondarily generalized seizures

Epilepsy and pregnancy registries have been operational for more than 10 years, have accrued considerable experience, and collected an impressive amount of data. As findings have been published, it has become important to understand how observations from the different registries are comparable, especially since their methodologies differ somewhat. In September 2008, representatives of the UK Epilepsy and Pregnancy Register, the North American AED Pregnancy Registry (NAAPR), and the European and International Registry of Antiepileptic Drugs in Pregnancy (EURAP) met for a workshop. Their objectives were to exchange information on their methodologies and to discuss areas where harmonization might be possible. This report summarizes these discussions