Cenobamate Efficacy in Individuals With Autoimmune Epilepsy (CENSUS)

Evaluation of the Efficacy and Safety of Cenobamate in Individuals With Autoimmune Epilepsy: a Real-world Study

Over the last decades, multiple neuronal autoantibodies directed against intracellular or cell-surface antigens have been identified in association with epilepsy and encephalopathy. In some patients with immune-mediated brain disorders, seizures persist and become chronic despite treatment with antiseizure medications (ASMs) and immunotherapy. This condition is particularly common in patients with antibodies against glutamic acid decarboxylase 65 (GAD65) or onconeural antigens (e.g., Hu, Ma2, and CRMP5/CV2). The persistence of seizures despite immunotherapy suggests the development of a sustained epileptogenic predisposition, consistent with the current conceptual definition of epilepsy.

Cenobamate (CNB) is a recently approved antiseizure medication for the treatment of focal-onset seizures, with or without secondary generalization, in adults whose epilepsy remains uncontrolled despite prior treatment with at least two ASMs. CNB has demonstrated broad antiseizure efficacy, likely due to its dual mechanism of action: inhibition of the persistent component of voltage-gated sodium currents and positive allosteric modulation of GABAA receptors through a non-benzodiazepine mechanism.

Recent retrospective data suggest that CNB may be effective in patients with anti-GAD65 autoimmune encephalitis, potentially compensating for impaired GABAergic neurotransmission associated with these antibodies. Other studies have also suggested that GABA-enhancing ASMs, such as benzodiazepines and barbiturates, may be beneficial in anti-GABAAR encephalitis, whereas sodium channel blockers may be effective in LGI1/CASPR2 antibody-associated encephalitis by reducing repetitive neuronal firing through interactions with voltage-gated sodium channels.

The primary objective of this study is to determine the proportion of patients achieving a ≥50% reduction in seizure frequency during the 24 weeks following initiation of cenobamate compared with baseline seizure frequency.

Secondary objectives include:

evaluating the proportion of patients achieving ≥75% and 100% seizure reduction,

assessing the safety and tolerability of cenobamate by documenting the frequency and severity of adverse events,

analyzing the impact of CNB treatment on quality of life using validated scales such as the Clinical Global Impression (CGI) and the Hospital Anxiety and Depression Scale (HADS),

exploring treatment efficacy according to the specific autoantibody subtype associated with autoimmune epilepsy.

Study Overview

• Status: Enrolling by invitation
• Conditions: Autoimmune Epilepsy

Detailed Description

In recent decades, multiple neuronal autoantibodies directed against cell-surface or intracellular antigens associated with epilepsy and/or encephalopathy have been discovered [2]. Some patients with immune-mediated brain diseases experience seizures that become chronic and are resistant to both antiseizure medications (ASMs) and immunotherapy. This occurs more frequently in patients with antibodies directed against glutamic acid decarboxylase 65 (GAD65) and against onconeural proteins (e.g., Hu, Ma2, collapsing response mediator protein 5/CV2). In this context, the persistence of seizures despite immunotherapy suggests a lasting predisposition, consistent with the current conceptual definition of epilepsy [4].

Cenobamate (CNB) is an antiseizure medication (ASM) recently approved for the treatment of focal-onset seizures, with or without secondary generalization, in adult patients with epilepsy inadequately controlled despite a history of treatment with at least two ASMs [5].

CNB has demonstrated broad-spectrum efficacy, exerting its antiseizure effect through a dual mechanism of action. In addition to inhibiting the persistent component of voltage-gated sodium currents, CNB also acts as a non-benzodiazepine positive allosteric modulator of GABAA channels [6].

The efficacy of CNB in the treatment of patients with anti-GAD65 encephalitis has been suggested by a recent retrospective study, hypothetically compensating for the deficit in GABAergic neurotransmission observed in autoimmune encephalitis associated with anti-GAD65 antibodies [7].

Furthermore, other studies have indicated that ASMs that enhance GABA transmission, such as benzodiazepines and barbiturates, may be beneficial in patients with anti-GABAAR encephalitis, whereas sodium channel blockers have demonstrated efficacy in the treatment of LGI1/CASPR2 antibody-associated encephalitis, reducing repetitive neuronal firing through interaction with voltage-gated sodium channels [8].

Primary objective:

To determine the percentage of patients achieving a ≥50% reduction in seizure frequency during the 24 weeks following initiation of cenobamate treatment compared with the pre-treatment baseline.

Secondary objectives:

• To evaluate the proportion of patients achieving a ≥75% and 100% reduction in seizure frequency compared with baseline.
• To evaluate the safety and tolerability of CNB by documenting the frequency and severity of adverse events.
• To analyze the impact of CNB treatment on patients' quality of life using validated scales such as the Clinical Global Impression (CGI) and the Hospital Anxiety and Depression Scale (HADS).
• To examine the efficacy of CNB according to the specific type of antibody associated with autoimmune epilepsy.

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

Study Locations

• Italy
  • Lazio
    • Rome, Lazio, Italy, 00168
      • UOC di Neurologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study population will include adult patients (>18 years) who provide written informed consent and have a diagnosis of autoimmune epilepsy according to the ILAE 2017 criteria. Eligible participants must have been on a stable treatment regimen with immunotherapy and antiseizure medications (ASMs) for at least 3 months prior to initiating cenobamate (CNB).

Patients will be excluded if they have a familial short QT syndrome, known hypersensitivity to CNB or any excipients, or a history of severe adverse drug reactions, including DRESS or Stevens-Johnson syndrome. Additional exclusion criteria include inability to read and write in Italian, as well as pregnancy or breastfeeding.

Description

Inclusion Criteria:

• Age >18 years.
• Signed informed consent.
• Diagnosis of autoimmune epilepsy according to the ILAE 2017 criteria.
• Stable treatment regimen with immunotherapy and antiseizure medications (ASMs) during the 3 months preceding the initiation of CNB treatment.

Exclusion Criteria:

• Diagnosis of familial short QT syndrome.
• Hypersensitivity to CNB or any of its excipients.
• History of severe adverse drug reactions, including DRESS and Stevens-Johnson syndrome.
• Inability to read and write in Italian.
• Pregnant or breastfeeding patients

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
patients treated with Cenobamate (CNB); Patients affected by confirmed autoimmune epilepsy undergoing treatment with cenobamate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure frequency at week 24	Proportion of patients achieving a ≥50% reduction in seizure frequency at 24 weeks compared with the pre-treatment baseline.	"From therapy-start to week 24 of treatment"

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizure frequency at week 24	Proportion of patients achieving a ≥75% reduction in monthly seizure frequency compared with the pre-treatment baseline over 24 weeks.	From therapy start to week 24 of treatment
Seizure frequency at week 24	Description: Proportion of patients achieving a ≥90% reduction in monthly seizure frequency compared with the pre-treatment baseline over 24 weeks.	From therapy start to week 24 of treatment
Seizure frequency at week 24	Proportion of patients achieving a 100% reduction in monthly seizure frequency compared with the pre-treatment baseline over 24 weeks.	From therapy start to week 24 of treatment
Safety assessment	Description of the frequency and severity of adverse events	From enrollment to the end of the observation period (Aug 2027)
Overall functioning, at week 24	Assessment of the overall functioning in patients undergoing treatment with CNB using the Clinical Global Impression (CGI) evaluated at baseline and at 24 weeks after treatment	From therapy start to week 24
Mood disorders assessment	Assessment of anxiety, and depression before and after 24 weeks of CNB treatment using the Hospital Anxiety and Depression Scale (HADS), evaluated at baseline and at 24 weeks after treatment initiation.	from baseline (therapy-start) to week 24

Collaborators and Investigators

• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Collaborators: Aziende Chimiche Riunite Angelini Francesco S.p.A
• Investigators: Principal Investigator: Paolo Calabresi, Fondazione Policlinico Universitario A. Gemelli, IRCCS

Publications and helpful links

General Publications

• Husari KS, Dubey D. Autoimmune Epilepsy. Neurotherapeutics. 2019 Jul;16(3):685-702. doi: 10.1007/s13311-019-00750-3.
• Beghi E. The Epidemiology of Epilepsy. Neuroepidemiology. 2020;54(2):185-191. doi: 10.1159/000503831. Epub 2019 Dec 18.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2026
• Primary Completion (Estimated): August 1, 2027
• Study Completion (Estimated): August 1, 2027

Study Registration Dates

• First Submitted: March 11, 2026
• First Submitted That Met QC Criteria: March 11, 2026
• First Posted (Actual): March 16, 2026

Study Record Updates

• Last Update Posted (Actual): March 16, 2026
• Last Update Submitted That Met QC Criteria: March 11, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: epilepsy; autoimmune epilepsy; cenobamate
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy
• Other Study ID Numbers: CENSUS_ID 7735; 153(A)IM24351 (Other Grant/Funding Number: Angelini Pharma S.p.A.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No