Navigating the Maze: Seizure Management and Epilepsy Clinical Trials

Epilepsy is a chronic neurological disorder characterized by recurrent unprovoked seizures. It affects approximately 50 million people worldwide, making it one of the most common neurological disorders, especially in low- and middle-income countries (with an estimated 80% of cases concentrated in those areas). [1] While epilepsy is a common neurological disorder, seizure disorders are highly variable and individual seizure disorders may be quite rare.

Seizure management has seen transformative advancements in recent years, including new and innovative therapies as well as effective applications of precision medicine and advanced monitoring technologies. Despite these advancements, clinical trials for epilepsy still face enduring challenges. [2] Tackling these obstacles is crucial to improving awareness of epilepsy and enhancing the lives of those living with the condition. 

Let’s examine these hurdles in epilepsy clinical trials and explore promising solutions.

Challenges in epilepsy clinical trials

The challenges in epilepsy clinical trials encompass methodological, diagnostic, and accessibility aspects.

1. Seizure variability and monitoring complexity

Seizures are inherently unpredictable and vary widely in frequency, type, and severity. This variability complicates the establishment of consistent baselines and makes it challenging to measure the true efficacy of treatments. Traditionally, paper diaries have been adopted to monitor in between-visits manifestations. These self-reports, often completed in a calendar format, use coding systems that are prone to reporting errors, inaccuracies if not captured on time, and false positives. The resulting inconsistencies limit the reliability of trial data and potentially hinder progress.

2. High placebo response rates 

It may be surprising, but placebo response rates in epilepsy clinical trials are abnormally high, often ranging between 15-40%, influenced by factors such as trial design and the interaction between participants and clinical staff. [3] These responses are driven by the psychological and contextual effects of participating in trials, creating challenges in distinguishing true treatment effects from placebo effects. Especially in difficult to treat seizure disorders, particularly those affecting children, there may be great hope and expectations in joining a clinical trial which increases the likelihood of there being a significant placebo response. Consequently, researchers often require larger sample sizes and robust methodologies, including placebo response mitigation training to ensure reliable results, which likely increases both the cost and the time necessary to complete a trial. To enhance the chances of detecting the signal of efficacy over the many noise sources in a study, there must be attention to detail in the setup and performance throughout the study.

3. Impact of cognitive and psychiatric comorbidities

Cognitive impairments and psychiatric comorbidities such as depression and anxiety are highly prevalent in people with epilepsy and can also be present in the parents/caregivers in pediatric populations, creating an additional set of factors. These factors can influence trial outcomes and the overall patient experience. Measuring these cognitive and mental health dimensions alongside seizure activity introduces additional complexity. Researchers need comprehensive endpoints that address not just seizure control but also cognitive and quality-of-life impacts.

4. Recruitment and retention challenges

Recruiting participants for epilepsy trials is a persistent challenge. Fear of stigma, the burden of participation, and concerns about potential side effects deter many eligible individuals. Retention rates can also be low, as participants often find clinical trial protocols demanding or intrusive, especially if they involve frequent hospital visits or extensive monitoring. Efforts must be made to reduce potential burdens on study participants including study partners (e.g. parents/caregivers) to better ensure compliance with the demands of the study and retention in the study. Another clear challenge for recruitment comes from the potential rarity of the seizure disorder of interest. Having the right network of epileptologists with interested patients/families is key to successful recruitment.

5. Regulatory and ethical hurdles

Epilepsy trials often involve vulnerable populations, including children and those with severe forms of epilepsy. Designing studies that meet ethical and regulatory standards while balancing participant safety with scientific rigor adds another layer of complexity. For both ethical and practical reasons, most trials of anti-convulsants will begin as add-on studies which means that maintenance drug monitoring is important in making sure that non-compliance with those medications do not interfere with the outcome of the study.

Addressing challenges through innovation

Enhanced seizure tracking in between visits: the role of electronic patient diaries (eDiaries)

The introduction of wearable devices and mobile apps has improved seizure detection and monitoring. Signant Health, in collaboration with The Epilepsy Study Consortium Inc., has developed an electronic diary (eDiary) suitable to capture reliable data in real-time, reducing bias in data collection.

Importantly, the solution offers the flexibility to customize details captured for each episode, ensuring that all necessary information needed for the study (e.g. seizure frequency, seizure duration, category of seizure) – and only necessary information – is recorded, which facilitates patient/diary-keeper participation/compliance while generating a high-quality data set for regulatory submissions. Beyond supporting better data sets, the eDiary empowers patients by offering more insights into their own condition, potentially promoting better self-management. 

Targeted placebo minimization training

Programs like Signant's placebo response minimization training aim to address the high placebo response rates in epilepsy trials. These initiatives standardize staff-study participant interactions and foster neutral communication to avoid inadvertently amplifying placebo effects. Participants and their study partners are educated about realistic treatment expectations, aligning their perceptions with clinical goals and improving the reliability of outcomes.

Integration of cognitive assessment tools

Cognitive function is increasingly recognized as a critical endpoint in epilepsy trials. Epileptic seizures trigger neuronal death through multiple pathophysiological mechanisms, with particularly devastating effects in vulnerable brain regions such as the hippocampus, amygdala, and temporal cortex. The extent of this neuronal loss directly contributes to cognitive deterioration across multiple domains, including working and episodic memory, executive function, attention and information processing speed. Research demonstrated that cognitive decline severity correlates strongly with both seizure frequency and epilepsy duration, creating a progressive impairment pattern that significantly impacts patients' quality of life. 

Tools like Signant's computerized cognitive assessment solution, CDR System, offer sensitive, standardized measurements of cognitive changes over time. These systems ensure consistent test conditions across diverse trial sites, accommodate repeated assessments, and eliminate errors associated with traditional methods. By addressing cognitive outcomes alongside seizure activity, these tools provide a more comprehensive evaluation of treatment efficacy or side effects. [4,5]

Conclusion and future directions 

Addressing the challenges in epilepsy clinical trials is not just about advancing treatments but also about improving overall awareness and care for those affected. To increase participation in clinical trials, public awareness efforts and reducing stigma around epilepsy should be encouraged. To enhance data quality and better understand treatment effects on patients, patient-centered outcomes, including eDiaries and cognitive batteries, should be incorporated into clinical trials. This approach places the patient voice at the center while creating pathways for successful new treatments.

About the authors

Pascal Goetghebeur is an experienced CNS pharmacologist and behavioral scientist specializing in psychiatry and neurodegeneration. At Signant Health, he serves as Clinical Principal for Cognition, Science & Medicine in the Digital Health Sciences division, focusing on the role of cognition in drug development and managing the clinical aspect of Signant’s proprietary cognitive assessment battery.

Lewis M. Fredane, MD, is the Clinical Vice President at Signant Health, serving as the Therapeutic Area Leader for neurology. He oversees Signant’s eCOA, Rater Training, and Quality Assurance in this field. Previously, Dr. Fredane was a practicing neurologist and clinical assistant professor at Drexel University College of Medicine. He has experience in pharmaceutical drug development with companies like Sanofi/Genzyme and Meda Pharmaceuticals and has worked with CRO Omnicare Clinical Research. 

Manuela Bossi, PhD is Associate Director, Digital Health Sciences at Signant Health, where she provides scientific expertise across various therapeutic areas. She earned her PhD from University College London, gaining extensive experience in clinical research and the development of digital treatments for a childhood condition. Over years at Signant, Dr. Bossi has supported commercial, product and operational teams, particularly in clinical trials for epilepsy/seizure disorders, oncology, immunology and dermatology. Along these, she has played a key role in the design and development of complex eDiaries.

References
[1] https://www.who.int/news-room/fact-sheets/detail/epilepsy

[2] Ghosh, S., Sinha, J. K., Ghosh, S., Sharma, H., Bhaskar, R., & Narayanan, K. B. (2023). A Comprehensive Review of Emerging Trends and Innovative Therapies in Epilepsy Management. Brain Sciences, 13(9), 1305. https://doi.org/10.3390/brainsci13091305

[3] Kerr WT, Suprun M, Kok N, Reddy AS, McFarlane KN, Kwan P, Somerville E, Bagiella E, French JA. Factors associated with placebo response rate in randomized controlled trials of antiseizure medications for focal epilepsy. Epilepsia. 2025 Feb;66(2):407-416. doi: 10.1111/epi.18197. Epub 2024 Dec 21. PMID: 39707877; PMCID: PMC11827720.

[4] Wesnes KA, Edgar C, Dean ADP, Wroe SJ (2009). The cognitive and psychomotor effects of remacemide and carbamazepine in newly diagnosed epilepsy. Epilepsy and Behaviour. 14: 522-528.  doi: 10.1016/j.yebeh.2008.11.012. Epub 2008 Dec 25.

[5] Meador KJ, Yang H, Piña-Garza JE, Laurenza A, Kumar D,  Wesnes KA (2016). Cognitive effects of adjunctive perampanel for partial-onset seizures: a randomized trial. Epilepsia 2016 Feb;57(2):243-51  doi: 10.1111/epi.13279