COMparison Between Anakinra and Tocilizumab in NORSE - "COMBAT-NORSE" (COMBAT-NORSE)

May 8, 2026 updated by: Lawrence Hirsch, Yale University

Comparing the Effects of Anakinra and Tocilizumab on Outcomes in Patients With New-Onset Refractory Status Epilepticus

The goal of this clinical trial is to find out whether two existing medications-anakinra and tocilizumab-can effectively treat a rare and life-threatening brain condition called NORSE (New-Onset Refractory Status Epilepticus). NORSE causes continuous seizures in previously healthy children and adults and does not respond to standard treatments. It often leads to long-term disability or death.

Doctors currently use anakinra and tocilizumab as second-line treatments when first-line therapies fail, but there is no clear evidence showing which drug works better or when it should be given. This study aims to answer those questions.

The study will enroll patients across 33 hospitals in the United States, Canada, Europe, and Asia.

It includes two groups:

  1. Randomized Cohort Patients will be randomly assigned to receive either anakinra or tocilizumab within the first 7 days of their illness. Only patients whose doctors were already planning to use one of these medications as part of standard care will be eligible for randomization. Researchers will monitor their recovery and compare outcomes between the two treatments.
  2. Observational Cohort Patients who cannot be randomized-usually because they were diagnosed too late-will still be followed to study how the timing of treatment affects recovery.

Participants will:

  • Receive one of the two medications (depending on their group assignment).
  • Take part in follow-up assessments over the course of one year, including medical evaluations and surveys. Some participants may be followed annually beyond one year.
  • Optionally participate in a 60-minute interview to share their or their caregiver's experience with NORSE.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Estimated)

438

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age 2 and older.
  • In their usual state of health prior to their onset of SE.

  • Presenting with NORSE as defined in the consensus criteria:

    1. Refractory SE (failed 2 appropriately used anti-seizure medications) in a patient without active epilepsy or other pre-existing relevant neurological disorder and without an acute or active structural, toxic, or metabolic cause found in the first 72 hours.
    2. Includes patients with any RSE, not just super-refractory SE.

    3. Includes patients who ultimately are discovered to have a known etiology (infectious, autoimmune, genetic, etc.), as well as those who remain cryptogenic.

      • Additional Inclusion Criteria for the Randomized Arm:
  • Anakinra and/or tocilizumab are being planned or considered as part of standard clinical care.
  • The onset of SE was in the prior 7 days at the time of enrollment.

Exclusion Criteria:

  • Any acute or active systemic medical illness such as metastatic cancer, renal failure, hepatic failure, poorly controlled diabetes, etc., in the opinion of the investigators. If this is unclear, the study PI Dr. Hirsch will determine if this criterion is met.

Additional Exclusion Criteria for the Randomized Control Cohort:

  • Contraindication to either anakinra or tocilizumab as listed in the prescribing information:

    1. Known hypersensitivity to E. Coli-derived proteins, anakinra, tocilizumab, or any component of the products
    2. Active serious infection at the time of initiation
    3. Concomitant use of TNF blocking agents; absolute neutrophil count < 2000; platelet count < 100,000 per mm³; or ALT or AST > 1.5 X the upper limit of normal
    4. Elevated risk of GI perforation.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Randomized Controlled Trial (RCT) Cohort
A randomized controlled cohort (RCT) of anakinra vs. tocilizumab (targeted immunotherapies) started up to and including 7 days after the onset of status epilepticus (SE)
Drug: Anakinra

SOC will be followed , Suggested Dose:

10 mg/kg/day IV, divided into 4 daily doses (q6h) Maximum dose: 400 mg/day

Drug: Tocilizumab

SOC will be followed,

Suggested Dose:

If <30 kg: 12 mg/kg IV once every 2 weeks If ≥30 kg: 8 mg/kg IV once every 2 weeks Maximum dose: 800 mg per dose
Other: Observational Cohort
An observational cohort enrolling patients with acute cryptogenic NORSE who cannot be randomized or who are identified too late to be randomized by the end of day 7 .
Other: Standard medical treatment
For patients who could not be randomized by day 7, standard clinical care will be followed and patients will be followed prospectively and observationally.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Glasgow Outcome Scale - Extended (GOS-E)
Time Frame: 12 months
The Glasgow Outcome Scale - Extended (GOS-E) is an 8-point scale used to measure global functional outcome. Participants are scored into one of the 8 categories: 1. Death, 2. Vegetative State, 3. Lower Severe Disability, 4. Upper Severe Disability, 5. Lower Moderate Disability, 6. Upper Moderate Disability, 7. Lower Good Recovery, 8. Upper Good Recovery.
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to resolution of status epilepticus (SE)
Time Frame: 24 hours off anesthetic drips
Time (days) until discontinuation of anesthetic drips for 24h for the treatment of SE with no return of SE on EEG
24 hours off anesthetic drips
Hospital length of stay
Time Frame: 12 months
Mean number of days during hospitalization from admission to discharge
12 months
Mortality
Time Frame: up to 12 months
Mortality, number of participants
up to 12 months
Number of serious adverse events attributed to anakinra or tocilizumab
Time Frame: From hospitalization to 1 month after stopping treatment, up to 12 months
Number of serious adverse events attributed to anakinra or tocilizumab
From hospitalization to 1 month after stopping treatment, up to 12 months
Number of participants Post-NORSE epilepsy
Time Frame: 12 months
Number of participants with any unprovoked seizures after hospital discharge
12 months
Number of participants with Treatment success
Time Frame: 12 months
Combined measure of lack of need for another immunomodulator after the study drug was begun, plus good outcome at 1 year (GOS-E of 5-8) (Yes/No)
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Yale University

Collaborators

Patient-Centered Outcomes Research Institute

Investigators

  • Principal Investigator: Lawrence Hirsch, MD, Yale University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 1, 2026

Primary Completion (Estimated)

March 31, 2030

Study Completion (Estimated)

September 30, 2030

Study Registration Dates

First Submitted

November 21, 2025

First Submitted That Met QC Criteria

December 3, 2025

First Posted (Actual)

December 15, 2025

Study Record Updates

Last Update Posted (Actual)

May 12, 2026

Last Update Submitted That Met QC Criteria

May 8, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2000041289
  • RD-2024C2-39648 (Other Grant/Funding Number: PCORI)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Making the Full Data Package available to enable other researchers (including PCORI) to use it to re-analyze the data or for independent (i.e., novel) research analyses.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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