COMparison Between Anakinra and Tocilizumab in NORSE - "COMBAT-NORSE"
COMBAT-NORSE
Comparing the Effects of Anakinra and Tocilizumab on Outcomes in Patients With New-Onset Refractory Status Epilepticus
2 other identifiers
interventional
438
7 countries
33
Brief Summary
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:
- 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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P50-P75 for phase_3
Started Mar 2026
Longer than P75 for phase_3
33 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
November 21, 2025
CompletedFirst Posted
Study publicly available on registry
December 15, 2025
CompletedStudy Start
First participant enrolled
March 1, 2026
CompletedPrimary Completion
Last participant's last visit for primary outcome
March 31, 2030
ExpectedStudy Completion
Last participant's last visit for all outcomes
September 30, 2030
December 15, 2025
December 1, 2025
4.1 years
November 21, 2025
December 3, 2025
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Glasgow Outcome Scale - Extended (GOS-E)
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 Outcomes (6)
Time to resolution of status epilepticus (SE)
24 hours off anesthetic drips
Hospital length of stay
12 months
Mortality
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
12 months
- +1 more secondary outcomes
Study Arms (2)
Randomized Controlled Trial (RCT) Cohort
ACTIVE COMPARATORA randomized controlled cohort (RCT) of anakinra vs. tocilizumab (targeted immunotherapies) started up to and including 7 days after the onset of status epilepticus (SE)
Observational Cohort
OTHERAn 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 .
Interventions
SOC will be followed , Suggested Dose: 10 mg/kg/day IV, divided into 4 daily doses (q6h) Maximum dose: 400 mg/day
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
For patients who could not be randomized by day 7, standard clinical care will be followed and patients will be followed prospectively and observationally.
Eligibility Criteria
You may qualify if:
- 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:
- 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.
- Includes patients with any RSE, not just super-refractory SE.
- Includes patients who ultimately are discovered to have a known etiology (infectious, autoimmune, genetic, etc.), as well as those who remain cryptogenic.
- 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.
You may not qualify if:
- 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.
- Contraindication to either anakinra or tocilizumab as listed in the prescribing information:
- Known hypersensitivity to E. Coli-derived proteins, anakinra, tocilizumab, or any component of the products
- Active serious infection at the time of initiation
- 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
- Elevated risk of GI perforation.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Yale Universitylead
- Patient-Centered Outcomes Research Institutecollaborator
Study Sites (33)
Barrow Institute
Phoenix, Arizona, 85013, United States
Children's Hospital Colorado
Aurora, Colorado, 80045, United States
Yale New Haven Hospital
New Haven, Connecticut, 06520, United States
Children's National (DC)
Washington D.C., District of Columbia, 20010, United States
University of Florida
Gainesville, Florida, 32611, United States
University of Chicago
Chicago, Illinois, 60637, United States
Northwestern University
Evanston, Illinois, 60208, United States
Mass General (MGH)
Boston, Massachusetts, 02114, United States
Beth Israel Deaconess
Boston, Massachusetts, 02215, United States
Boston Children's Hospital
Boston, Massachusetts, 02215, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
University of Nebraska
Lincoln, Nebraska, 68588, United States
New York University
New York, New York, 10012, United States
Columbia University
New York, New York, 10027, United States
Mount Sinai (NY)
New York, New York, 10029, United States
University of Cincinnati
Cincinnati, Ohio, 45221, United States
Cleveland Clinic
Cleveland, Ohio, 44195, United States
Oregon Health and Science University
Portland, Oregon, 97239, United States
Children's Hospital Philadelphia (CHOP)
Philadelphia, Pennsylvania, 19104, United States
University of Pennsylvania
Philadelphia, Pennsylvania, 19104, United States
UT Southwestern Medical Center
Dallas, Texas, 75390, United States
Baylor/Texas Children's
Houston, Texas, 77030, United States
Seattle Children's Hospital
Seattle, Washington, 98105, United States
University of Wisconsin
Madison, Wisconsin, 53706, United States
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226, United States
Western University
London, Canada
Hospital for Sick Children
Toronto, Canada
Salpêtrière
Paris, France
University of Modena
Modena, Italy
Seoul National University Hospital
Seoul, South Korea
Karolinska Institute
Stockholm, Sweden
Great Ormond Street Hospital
London, United Kingdom
King's College
London, United Kingdom
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Lawrence Hirsch, MD
Yale University
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 3
- Allocation
- RANDOMIZED
- Masking
- SINGLE
- Who Masked
- OUTCOMES ASSESSOR
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor of Neurology
Study Record Dates
First Submitted
November 21, 2025
First Posted
December 15, 2025
Study Start
March 1, 2026
Primary Completion (Estimated)
March 31, 2030
Study Completion (Estimated)
September 30, 2030
Last Updated
December 15, 2025
Record last verified: 2025-12
Data Sharing
- IPD Sharing
- Will share
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.