Epilepsy Clinical Trials Research Articles

Validation of the Seizure-Related Impact Assessment Scale (SERIAS): a study protocol

IntroductionThis study aims to validate the Seizure-Related Impact Assessment Scale (SERIAS). This novel patient-reported outcome measure (PROM) compares the ‘trade-off’ between seizures and treatment-related adverse effects, and measures epilepsy disability...

The adaptation of the desirability of outcome ranking for interventional clinical trials in epilepsy: A novel consumer-led outcome measure.

Interventional clinical trials in epilepsy are typically designed and powered to detect a change in seizure frequency as the primary endpoint, with little consideration given to other benefits or harms of the therapy, or impacts on common epilepsy comorbidities. Desirability of outcome ranking (DOOR) is a novel methodology for evaluating benefits and harms associated with introduction of a new treatment. Multiple outcomes are combined and the resulting combinations are ranked according to their desirability. Herein we describe the adaptation of DOOR for use in therapy trials in epilepsy. Consumers with epilepsy were presented with a selection of measures typically included in epilepsy trials and asked to rank their importance in terms of a desirable outcome and to identify interactions between different seizure control levels and other measures. Seizure control, adverse events, and psychiatric comorbidities were identified as most important, and combinations of these outcomes were ranked to form epilepsy-DOOR. A separate consumer discussion group verified the appropriateness and accuracy of the ranking. The resultant epilepsy-DOOR includes 60 possible outcomes, representing high granularity for the assessment of future interventions. It demonstrates the importance of consumer involvement in trial design and presents an alternative to seizure frequency for evaluating new treatments for epilepsy.

Appropriate selection of participants for clinical trials in epilepsy

Appropriate selection of participants for clinical trials in epilepsy

Reasons for ineligibility for clinical trials of patients with medication-resistant epilepsy.

Selection criteria for clinical trials for medication-resistant epilepsy are used to limit variability and to ensure safety. However, it has become more challenging to recruit subjects for trials. This study investigated the impact of each inclusion and exclusion criterion on medication-resistant epilepsy clinical trial recruitment at a large academic epilepsy center. We retrospectively identified all patients with medication-resistant focal or generalized onset epilepsy who attended an outpatient clinic over a consecutive 3-month period. We assessed each patient's eligibility for trials with commonly required inclusion and exclusion criteria to evaluate the proportion of eligible patients and the most common reasons for exclusion. Among 212 patients with medication-resistant epilepsy, 144 and 28 patients met the criteria for focal or generalized onset epilepsy, respectively. Overall, 9.4% (n = 20) patients were eligible for trials (19 focal onset and one generalized onset). Most patients were excluded from the study due to insufficient seizure frequency (58% of focal onset, 55% of generalized onset). A small proportion of patients with medication-resistant epilepsy were eligible for trials based on common selection criteria. These eligible patients may not be representative of the general population of patients with medication-resistant epilepsy. Insufficient seizure frequency was the most common reason for exclusion.

EEG parameters as endpoints in epilepsy clinical trials - An expert panel opinion paper

IntroductionThe lack of ideal measurement of treatment efficacy is a well acknowledged problem in the epilepsy community, both in clinical care and clinical trials. Whilst still the current gold-standard, self-reported seizure frequency significantly underestimates the true number of seizures and does not account for any other at least equally important outcome parameters, such as neurodevelopment and cognition. With the rise of disease modifying treatments, the need for more reliable endpoints in practice and clinical trials becomes more pressing. In this paper we assembled an expert panel to discuss the nature of these needs, current limitations, and obstacles based on a survey amongst these experts who were queried about the most important issues regarding the use of electroencephalography (EEG) parameters as endpoints in clinical drug and device development. MethodsA structured survey was sent to a group of experts in the design and conduct of epilepsy trials in adults and children. This was followed by a virtual in-person meeting discussing the results of the trial and identifying a list of most important issues. ResultsSix clinical trialists and 5 individuals from pharmaceutical companies returned the survey containing 14 questions, and 8 clinical trialists and 10 pharma-representatives attended the meeting. Three main issues were identified (1) lack of accuracy of seizure diaries due to nocturnal seizures, subtle motor seizures, impairment of consciousness and lack of awareness of the seizure by the patient (2) inter-rater variability of EEG assessment (3) lack of standardization regarding definition(s) of seizures (clinical and electrographic), EEG recording methods and EEG data management. Recommended solutions included (1) validation of EEG parameters as biomarkers and use of wearables (2) development of a manual that describes EEG rating criteria, protocol for validation by > 1 central reader and use of a resolution of disagreements reporting template (3) standardization of EEG recording, data management and reporting. Discussion & conclusionCurrent developments in research and technology seem promising to advance the use of EEG parameters as potential endpoints and offer partial solutions to the current needs. However, continuous, focused and collaborative efforts of all stakeholders (academia, industry and regulatory agencies) are needed to formulate guidelines, validate emerging technologies and approve them for use in trials. It is the intent of this opinion “position paper” to stimulate those efforts.

Ensuring the Continuity of Data Collection in a Focal Epilepsy Clinical Trial During the COVID-19 Pandemic (P2-8.007)

Ensuring the Continuity of Data Collection in a Focal Epilepsy Clinical Trial During the COVID-19 Pandemic (P2-8.007)

Analysis of Deep Brain Stimulation Lead Targeting in the Stimulation of Anterior Nucleus of the Thalamus for Epilepsy Clinical Trial.

BACKGROUNDDeep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an effective therapy for patients with drug-resistant focal epilepsy. Best practices for surgical targeting of the ANT can be refined as new information becomes available regarding effective stimulation sites.OBJECTIVETo conduct a retrospective analysis of the relationship between outcomes (seizure reduction during year 1) and DBS lead locations in subjects from the SANTÉ pivotal trial (Stimulation of ANT for Epilepsy) based upon recent clinical findings.METHODSPostoperative images from SANTÉ subjects (n = 101) were evaluated with respect to lead trajectory relative to defined anatomic landmarks. A qualitative scoring system was used to rate each lead placement for proximity to an identified target region above the junction of the mammillothalamic tract with the ANT. Each subject was assigned a bilateral lead placement score, and these scores were then compared to clinical outcomes.RESULTSApproximately 70% of subjects had “good” bilateral lead placements based upon location with respect to the defined target. These subjects had a much higher probability of being a clinical responder (>50% seizure reduction) than those with scores reflecting suboptimal lead placements (43.5% vs 21.9%, P < .05).CONCLUSIONConsistent with experience from more established DBS indications, our findings and other recent reports suggest that there may be specific sites within the ANT that are associated with superior clinical outcomes. It will be important to continue to evaluate these relationships and the evolution of other clinical practices (eg, programming) to further optimize this therapy.

Breaking the Seizure Randomness Myth: Evidence for a Recurring Ebb and Flow of Seizure Risk on the Continuum of Time.

Seizure Cycles in Focal Epilepsy Leguia MG, Andrzejak RG, Rummel C, et al. JAMA Neurol. 2021;78(4):454-463. doi:10.1001/jamaneurol.2020.5370. PMID: 33555292; PMCID: PMC7871210.Importance:Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown.Objective:To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years.Design, Setting, and Participants:This retrospective cohort study analyzed data from continuous intracranial electroencephalography (cEEG) and seizure diaries collected between January 19, 2004, and May 18, 2018, with durations up to 10 years. A total of 222 adults with medically refractory focal epilepsy were selected from 256 total participants in a clinical trial of an implanted responsive neurostimulation device. Selection was based on availability of cEEG and/or self-reports of disabling seizures.Exposures:Anti-seizure medications and responsive neurostimulation, based on clinical indications.Main Outcomes and Measures:Measures involved (1) self-reported daily seizure counts, (2) cEEG-based hourly counts of electrographic seizures, and (3) detections of interictal epileptiform activity (IEA), which fluctuates in daily (circadian) and multiday (Multidien) cycles. Outcomes involved descriptive characteristics of cycles of IEA and seizures: (1) prevalence, defined as the percentage of patients with a given type of seizure cycle; (2) strength, defined as the degree of consistency with which seizures occur at certain phases of an underlying cycle, measured as the phase-locking value (PLV); and (3) seizure chronotypes, defined as patterns in seizure timing evident at the group level.Results:Of the 222 participants, 112 (50%) were male, and the median age was 35 years (range, 18-66 years). The prevalence of circannual (approximately 1 year) seizure cycles was 12% (24 of 194), the prevalence of multidien (approximately weekly to approximately monthly) seizure cycles was 60% (112 of 186), and the prevalence of circadian (approximately 24 hours) seizure cycles was 89% (76 of 85). Strengths of circadian (mean [SD] PLV, 0.34 [0.18]) and multidien (mean [SD] PLV, 0.34 [0.17]) seizure cycles were comparable, whereas circannual seizure cycles were weaker (mean [SD] PLV, 0.17 [0.10]). Across individuals, circadian seizure cycles showed 5 peaks: morning, mid-afternoon, evening, early night, and late night. Multidien cycles of IEA showed peak periodicities centered around 7, 15, 20, and 30 days. Independent of multidien period length, self-reported, and electrographic seizures consistently occurred during the days-long rising phase of multidien cycles of IEA.Conclusions and Relevance:Findings in this large cohort establish the high prevalence of plural seizure cycles and help explain the natural variability in seizure timing. The results have the potential to inform the scheduling of diagnostic studies, the delivery of time-varying therapies, and the design of clinical trials in epilepsy.

Use of an electronic seizure diary in a randomized, controlled trial of natalizumab in adult participants with drug-resistant focal epilepsy

ObjectiveTo analyze electronic diary (e-diary) use in a phase 2, randomized, controlled clinical trial (OPUS; NCT03283371) of natalizumab in adult participants with drug-resistant focal epilepsy. MethodsWe developed an e-diary, which incorporated an episodic seizure diary and a daily diary reminder, for use as the primary source to record participants’ daily seizure activity in the OPUS phase 2 clinical trial. Participants and/or their designated caregivers made e-diary entries by selecting seizure descriptions generated in the participants’ and/or caregivers’ own words at the time of screening. Seizures and seizure-free days were reported for the current day and for up to 5 and 4 retrospective days, respectively. A record of seizure symptoms entered within the prior 5-day period was displayed on accessing the diary. Changes were not permitted in the e-diary once a seizure record was saved unless a data change request was made. A paper backup diary was available. ResultsE-diary entries (N = 15,176) from the 6-week baseline period and subsequent 24-week placebo-controlled period were analyzed for 66 adults who were randomized and dosed in the OPUS trial. The overall e-diary compliance, defined as the total number of days with any entry out of the total number of days in the baseline and placebo-controlled periods for all participants combined, was 83.6%. Caregivers made 190 (1.3%) e-diary entries. Day-of-event e-diary entries totaled 11,248 (74.1%). At least one paper backup diary was used by 36 (54.5%) participants. SignificanceOur data highlight that good e-diary compliance can be achieved across participants in randomized clinical trials in adult focal epilepsy. In addition to identifying and addressing any barriers that may prevent a minority of participants from achieving good e-diary compliance, consideration of e-diary elements, such as recall period and reporting of seizure-free days, will facilitate the most accurate data capture in epilepsy clinical trials.

Seizure Cycles in Focal Epilepsy

Focal epilepsy is characterized by the cyclical recurrence of seizures, but, to our knowledge, the prevalence and patterns of seizure cycles are unknown. To establish the prevalence, strength, and temporal patterns of seizure cycles over timescales of hours to years. This retrospective cohort study analyzed data from continuous intracranial electroencephalography (cEEG) and seizure diaries collected between January 19, 2004, and May 18, 2018, with durations up to 10 years. A total of 222 adults with medically refractory focal epilepsy were selected from 256 total participants in a clinical trial of an implanted responsive neurostimulation device. Selection was based on availability of cEEG and/or self-reports of disabling seizures. Antiseizure medications and responsive neurostimulation, based on clinical indications. Measures involved (1) self-reported daily seizure counts, (2) cEEG-based hourly counts of electrographic seizures, and (3) detections of interictal epileptiform activity (IEA), which fluctuates in daily (circadian) and multiday (multidien) cycles. Outcomes involved descriptive characteristics of cycles of IEA and seizures: (1) prevalence, defined as the percentage of patients with a given type of seizure cycle; (2) strength, defined as the degree of consistency with which seizures occur at certain phases of an underlying cycle, measured as the phase-locking value (PLV); and (3) seizure chronotypes, defined as patterns in seizure timing evident at the group level. Of the 222 participants, 112 (50%) were male, and the median age was 35 years (range, 18-66 years). The prevalence of circannual (approximately 1 year) seizure cycles was 12% (24 of 194), the prevalence of multidien (approximately weekly to approximately monthly) seizure cycles was 60% (112 of 186), and the prevalence of circadian (approximately 24 hours) seizure cycles was 89% (76 of 85). Strengths of circadian (mean [SD] PLV, 0.34 [0.18]) and multidien (mean [SD] PLV, 0.34 [0.17]) seizure cycles were comparable, whereas circannual seizure cycles were weaker (mean [SD] PLV, 0.17 [0.10]). Across individuals, circadian seizure cycles showed 5 peaks: morning, mid-afternoon, evening, early night, and late night. Multidien cycles of IEA showed peak periodicities centered around 7, 15, 20, and 30 days. Independent of multidien period length, self-reported and electrographic seizures consistently occurred during the days-long rising phase of multidien cycles of IEA. Findings in this large cohort establish the high prevalence of plural seizure cycles and help explain the natural variability in seizure timing. The results have the potential to inform the scheduling of diagnostic studies, the delivery of time-varying therapies, and the design of clinical trials in epilepsy.

Changing characteristics of epilepsy interventional clinical trials over the last decade: Clinicaltrials.Gov registry

IntroductionEpilepsy affects about 1% of the world’s population (over 50 million). Of these, one-third have refractory or medication-resistant epilepsy. This group of people drives the development and testing of new interventions for epilepsy. To better address the needs of people with epilepsy, the characteristics of clinical trials, as well as the gaps in the population of interest, need to be evaluated. MethodsWe searched the www.ClinicalTrials.gov database using the keywords “seizure” or “epilepsy” between 9/1/2008−9/1/2018 and filtering for Interventional Clinical trials. The data were categorized by three equal time intervals (tertiles), and evaluated by type of intervention (behavioral, diet, device, drug, other), primary purpose (treatment, diagnosis, prevention, or basic science), gender, age, phase (Phase1 to Phase 4 trials), length and status of the study, enrollment/recruitment/randomization, location, blinding status, assignment group (single/parallel/crossover/factorial/sequential), and funding. We focused on drugs and devices and used a binary logistic regression model to analyze the role of time, length of study, funding, location, randomization, and age. ResultsWe found 359 epilepsy clinical trials; of these, 245 (68.2%) clinical trials involved drugs, and 55 (15.3%) were device trials. Over the three tertiles, the percentage of device trials increased while medication trials decreased. Device:drug trial odds ratios increased six times by the third tertile. Also, the results showed that clinical trials for drugs and devices occurred more in adults than children. Industry funding decreased 20% over time. The US contribution to clinical research was stable, but device trials were more likely to occur outside of the US. ConclusionDrugs constitute the substantial fields of interventional trials in epilepsy but decreased in proportion over the last decade, while the presence of the device trials steadily increased. Device trials focused on treatment and diagnosis of seizures and have been more invested in non-US countries.

A robust Bayesian mixed effects approach for zero inflated and highly skewed longitudinal count data emanating from the zero inflated discrete Weibull distribution.

This article proposes a Bayesian mixed effects zero inflated discrete Weibull (ZIDW) regression model for zero inflated and highly skewed longitudinal count data, as an alternative to mixed effects regression models that are based on the negative binomial, zero inflated negative binomial, and conventional discrete Weibull (DW) distributions. The mixed effects ZIDW regression model is an extension of a recently introduced model based on the DW distribution and uses the log-link function to specify the relationship between the linear predictors and the median counts. The ZIDW approach offers a more robust characteristic of central tendency, compared to the mean count, when there is skewness in the data. A matrix generalized half-t (MGH-t) prior distribution is specified for the random effects covariance matrix as an alternative to the widely used Wishart prior distribution. The methodology is applied to a longitudinal dataset from an epilepsy clinical trial. In a data contamination simulation study, we show that the mixed effect ZIDW regression model is more robust than the competing mixed effects regression models when the data contain excess zeros or outliers. The performance of the ZIDW regression model is also assessed in a simulation study under the specification of, respectively, the MGH-t and Wishart prior distributions for the random effects covariance matrix. It turns out that the highest posterior density intervals under the MGH-t prior for the fixed effects maintain nominal coverage when the true variability between random slopes over time is small, whereas those under the Wishart prior are generally conservative.

Bridging the childhood epilepsy treatment gap in northern Nigeria (BRIDGE): Rationale and design of pre-clinical trial studies.

Epilepsy is the most common serious childhood neurological disorder. In the low- and middle-income countries (LMICs) of Africa, children with epilepsy suffer increased morbidity and mortality compared to their counterparts in high-income countries, and the majority do not receive treatment - the childhood epilepsy treatment gap. Reports of the childhood epilepsy treatment gap in Africa are likely underestimates; most surveys do not include several common childhood seizure types, including most types of non-convulsive epilepsy. Efforts to scale up childhood epilepsy care services in the LMICs of Africa must contend with a shortage of physicians and diagnostic technology [e.g., electroencephalograms (EEGs)]. One pragmatic solution is to integrate epilepsy care into primary care by task-shifting to community health extension workers. The aims of this project (BRIDGE) are to: 1) train, develop, and pilot task-shifted epilepsy care teams; 2) develop and pilot innovative childhood epilepsy screening and diagnostic paradigms adapted to the local Hausa language/culture in Kano, northern Nigeria; and, 3) quantify and map the childhood epilepsy treatment gap, using geographic information systems (GIS), to target limited resources to areas of greatest need. Task-shifted teams will diagnose and manage childhood epilepsy using an innovative epilepsy screening tools and diagnostic and management paradigms in environments with limited EEG access. If validated and demonstrated efficacious in clinical trials, this project can be taken to scale across broader areas of west Africa's LMICs that share language and culture. BRIDGE has the potential to enhance access to basic childhood epilepsy care and establish the foundation for childhood epilepsy clinical trials in west Africa.

Characteristics of Interventional Epilepsy Clinical Trials During the Last Decade (P3.5-004)

Characteristics of Interventional Epilepsy Clinical Trials During the Last Decade (P3.5-004)

Behavioral interventions in epilepsy.

Behavioral intervention describes multiple modalities of treatments which are of increasing interest in epilepsy. This review addresses recent behavioral clinical trials in epilepsy including cognitive behavioral therapy (CBT), mindfulness, progressive muscle relaxation (PMR), and self-management. Results and conclusions from updated Cochrane reviews and the recent International League Against Epilepsy Psychology task force are presented. Two recent large randomized controlled trials (mindfulness and progressive muscle relaxation) reported improved seizure frequency with behavioral treatments. In both studies, participants in both the active and the attentional control arms showed significant seizure reduction, whereas quality of life and stress reduction were better noted in the active arms. Additional behavioral modalities have reported improved seizure control including yoga, bio/neurofeedback, and music therapy.Significant improvements in multiple quality of life, cognitive domains, and medication adherence have been reported from randomized and open label trials of cognitive behavioral therapy, and self-management programs. Multiple promising self-management programs have been recently reported, often utilizing the power of web-based apps, and digitally delivered group therapy. In 2018, the International League Against Epilepsy Psychology task force recommended that 'psychological interventions should be incorporated into comprehensive epilepsy care.' Behavioral treatments are successful and likely underutilized in the treatment of epilepsy. Given the challenge of conducting randomized clinical trials of behavioral therapy, much remains to be studied. However, for motivated and interested patients, appropriately chosen behavioral therapies appear to be important adjuncts to standard therapy. The timing is currently optimal to take best advantage of smartphone apps and web-based delivery systems, both for research and therapeutic purposes.

Generation and On-Demand Initiation of Acute Ictal Activity in Rodent and Human Tissue.

Controlling seizures remains a challenging issue for the medical community. To make progress, researchers need a way to extensively study seizure dynamics and investigate its underlying mechanisms. Acute seizure models are convenient, offer the ability to perform electrophysiological recordings, and can generate a large volume of electrographic seizure-like (ictal) events. The promising findings from acute seizure models can then be advanced to chronic epilepsy models and clinical trials. Thus, studying seizures in acute models that faithfully replicate the electrographic and dynamical signatures of a clinical seizure will be essential for making clinically relevant findings. Studying ictal events in acute seizure models prepared from human tissue is also important for making findings that are clinically relevant. The key focus in this paper is on the cortical 4-AP model due to its versatility in generating ictal events in both in vivo and in vitro studies, as well as in both mouse and human tissue. The methods in this paper will also describe an alternative method of seizure induction using the Zero-Mg2+ model and provide a detailed overview of the advantages and limitations of the epileptiform-like activity generated in the different acute seizure models. Moreover, by taking advantage of commercially available optogenetic mouse strains, a brief (30 ms) light pulse can be used to trigger an ictal event identical to those occurring spontaneously. Similarly, 30 - 100 ms puffs of neurotransmitters (Gamma-Amino Butyric Acid or glutamate) can be applied to the human tissue to trigger ictal events that are identical to those occurring spontaneously. The ability to trigger ictal events on-demand in acute seizure models offers the newfound ability to observe the exact sequence of events that underlie seizure initiation dynamics and efficiently evaluate potential anti-seizure therapies.

Alternative Trial Methodology in Pediatric Epilepsy Clinical Trials - Time to “Nth” Seizure Analysis in Children with Partial Onset Seizures Treated With Pregabalin (S53.002)

Alternative Trial Methodology in Pediatric Epilepsy Clinical Trials - Time to “Nth” Seizure Analysis in Children with Partial Onset Seizures Treated With Pregabalin (S53.002)

Do neurologists around the world agree when diagnosing epilepsy? – Results of an international EpiNet study

ObjectivePrevious studies have shown moderate agreement between physicians when diagnosing epilepsy, but have included small numbers. The EpiNet study group was established to undertake multicentre clinical trials in epilepsy. Before commencing trials, we wanted to determine levels of agreement between physicians from different countries and different health systems when diagnosing epilepsy, specific seizure types and etiologies. Methods30 Case scenarios describing six children and 24 adults with paroxysmal events (21 epileptic seizures, nine non-epileptic attacks) were presented to physicians with an interest in epilepsy. Physicians were asked how likely was a diagnosis of epilepsy; if seizures were generalised or focal; and the likely etiology. For 23 cases, clinical information was presented in Step 1, and investigations in Step 2. Results189 Participants from 36 countries completed the 30 cases. Levels of agreement were determined for 154 participants who provided details regarding their clinical experience. There was substantial agreement for diagnosis of epilepsy (kappa=0.61); agreement was fair to moderate for seizure type(s) (kappa=0.40) and etiology (kappa=0.41). For 23 cases with two steps, agreement increased from step 1 to step 2 for diagnosis of epilepsy (kappa 0.56–0.70), seizure type(s) (kappa 0.38–0.52), and etiology (kappa 0.38–0.47). Agreement was better for 53 epileptologists (diagnosis of epilepsy, kappa=0.66) than 56 neurologists with a special interest in epilepsy (kappa=0.58). Levels of agreement differed slightly between physicians practicing in different parts of the world, between child and adult neurologists, and according to one’s experience with epilepsy. ConclusionAlthough there is substantial agreement when epileptologists diagnose epilepsy, there is less agreement for diagnoses of seizure types and etiology. Further education of physicians regarding semiology of different seizure types is required. Differences in approach to diagnosis, both between physicians and between countries, could impact negatively on clinical trials of anti-epileptic drugs.

A multi-dataset time-reversal approach to clinical trial placebo response and the relationship to natural variability in epilepsy

PurposeClinical epilepsy drug trials have been measuring increasingly high placebo response rates, up to 40%. This study was designed to examine the relationship between the natural variability in epilepsy, and the placebo response seen in trials. We tested the hypothesis that ‘reversing' trial direction, with the baseline period as the treatment observation phase, would reveal effects of natural variability. MethodClinical trial simulations were run with time running forward and in reverse. Data sources were: SeizureTracker.com (patient reported diaries), a randomized sham-controlled TMS trial, and chronically implanted intracranial EEG electrodes. Outcomes were 50%-responder rates (RR50) and median percentage change (MPC). ResultsThe RR50 results showed evidence that temporal reversal does not prevent large responder rates across datasets. The MPC results negative in the TMS dataset, and positive in the other two. ConclusionsTypical RR50s of clinical trials can be reproduced using the natural variability of epilepsy as a substrate across multiple datasets. Therefore, the placebo response in epilepsy clinical trials may be attributable almost entirely to this variability, rather than the “placebo effect”.

Reducing placebo exposure in trials: Considerations from the Research Roundtable in Epilepsy.

The randomized controlled trial is the unequivocal gold standard for demonstrating clinical efficacy and safety of investigational therapies. Recently there have been concerns raised about prolonged exposure to placebo and ineffective therapy during the course of an add-on regulatory trial for new antiepileptic drug approval (typically ∼6 months in duration), due to the potential risks of continued uncontrolled epilepsy for that period. The first meeting of the Research Roundtable in Epilepsy on May 19-20, 2016, focused on "Reducing placebo exposure in epilepsy clinical trials," with a goal of considering new designs for epilepsy regulatory trials that may be added to the overall development plan to make it, as a whole, safer for participants while still providing rigorous evidence of effect. This topic was motivated in part by data from a meta-analysis showing a 3- to 5-fold increased rate of sudden unexpected death in epilepsy in participants randomized to placebo or ineffective doses of new antiepileptic drugs. The meeting agenda included rationale and discussion of different trial designs, including active-control add-on trials, placebo add-on to background therapy with adjustment, time to event designs, adaptive designs, platform trials with pooled placebo control, a pharmacokinetic/pharmacodynamic approach to reducing placebo exposure, and shorter trials when drug tolerance has been ruled out. The merits and limitations of each design were discussed and are reviewed here.