EPILEPSY · White paper
Epilepsy Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About epilepsy — and why its trials are hard
Epilepsy is a common neurological disorder defined by an enduring predisposition to recurrent, unprovoked seizures, classified broadly as focal or generalized. Its causes span genetic, structural, metabolic, infectious, and unknown etiologies, and it carries substantial cognitive, psychiatric, and social burden plus risks such as status epilepticus and sudden unexpected death in epilepsy (SUDEP). Diagnosis integrates clinical history with EEG and MRI, and ICD-11 (code 8A61) provides a more granular, etiology-aware framework. Treatment centers on anti-seizure medications (ASMs): more than 25 are approved, from older agents (carbamazepine, valproate) to modern drugs (levetiracetam, lamotrigine, lacosamide, brivaracetam, cenobamate) and the cannabidiol Epidiolex for specific developmental epilepsies. Roughly a third of patients remain drug-resistant, sustaining demand for novel mechanisms. Trials are challenged by strong placebo responses, seizure-diary inaccuracy, inter-individual variability, and difficulty blinding device or surgical interventions. Percent reduction in seizure frequency and the 50% responder rate remain the regulatory backbone endpoints.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Levetiracetam (Keppra) | 1999 | Adjunctive then monotherapy for focal and generalized seizures | Pivotal add-on focal-seizure trials | SV2A modulation; significant reduction in seizure frequency and higher 50% responder rates vs placebo; broad tolerability | |
| Lamotrigine (Lamictal) | 1994 | Broad-spectrum therapy for focal and generalized seizures | Pivotal adjunctive and monotherapy trials | Sodium-channel blockade / glutamate inhibition; effective across seizure types with favorable cognitive profile | |
| Lacosamide (Vimpat) | 2008 | Adjunctive and monotherapy for focal (partial-onset) seizures | SP667 / SP754 pivotal focal-seizure trials | Enhances slow inactivation of sodium channels; significant seizure-frequency reduction vs placebo | |
| Brivaracetam (Briviact) | 2016 | Adjunctive/monotherapy for focal-onset seizures | N01252 / N01253 / N01358 pivotal trials | High-affinity SV2A ligand; significant reduction in focal seizure frequency vs placebo | |
| Cannabidiol (Epidiolex) | 2018 | Lennox-Gastaut and Dravet syndromes (later tuberous sclerosis complex) | GWPCARE pivotal trials | First plant-derived cannabinoid approved; significant reduction in drop/convulsive seizure frequency vs placebo | |
| Cenobamate (Xcopri) | 2019 | Adjunctive therapy for focal-onset seizures in adults | C013 / C017 pivotal trials | Dual sodium-current and GABA-A modulation; high 50% responder rates and notable seizure-freedom rates in refractory focal epilepsy |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in epilepsy development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Talampanel — Adjunctive epilepsy program (NCT00868361) | Trial terminated; development for epilepsy discontinued | AMPA antagonist; halted partly due to poor recruitment (fast/slow acetylators) and limited development viability |
| Retigabine (ezogabine) — RESTORE program; post-approval program (e.g., NCT01668654) | Approved (Potiga/Trobalt, 2011) then withdrawn from market in 2017 | Kv7 potassium-channel opener; blue skin/retinal pigmentation and declining use led manufacturer withdrawal; pediatric clinical hold cited |
| Ganaxolone (early adult focal program) — 1042-0603 adjunctive focal epilepsy (NCT01963208 and extension NCT02519439) | Missed primary endpoint in the double-blind adult focal study; extension discontinued | Neuroactive steroid; adult focal-seizure efficacy not demonstrated (later approved for CDKL5 deficiency disorder in a different program) |
Choosing the right endpoint
Primary endpoints that matter in epilepsy trials
- Percent change in seizure frequency — Median reduction from baseline vs placebo; primary regulatory efficacy measure for adjunctive ASM trials
- 50% responder rate — Proportion achieving >=50% reduction in seizure frequency; standard co-primary/key secondary endpoint
- Seizure freedom — Complete cessation over a defined period; meaningful but unattainable for many, especially drug-resistant patients
- Quality of life / neuropsychiatric outcomes — QOLIE and mood/cognition measures capturing burden beyond seizure counts
- Seizure diary reliability — Accuracy of patient/caregiver reporting limits all frequency endpoints; wearable and video-EEG tools aim to reduce bias
How iNGENū runs epilepsy trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
The full white paper: approved-product analyses, pivotal endpoints and trial-design strategy. Open-access · no sign-in.
Frequently asked questions
Epilepsy clinical trials — FAQs
How many anti-seizure medications are available and how are new ones proven?
Why is drug-resistant epilepsy still a major unmet need?
What makes epilepsy trials difficult to run?
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