New Onset Refractory Status EpilepticusPhase 3COMBAT-NORSENCT07281027
COMparison Between Anakinra and Tocilizumab in NORSE - "COMBAT-NORSE"
A Phase 3 study testing Anakinra, Tocilizumab and Standard medical treatment in people with New Onset Refractory Status Epilepticus and New-Onset Refractory Status Epilepticus, run by Yale University at 33 sites in 7 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 2 years and older
- Conditions the study is for
- New Onset Refractory Status Epilepticus, New-Onset Refractory Status Epilepticus, Febrile Infection-Related Epilepsy Syndrome (FIRES)
- What is being tested?
- Anakinra, Tocilizumab and Standard medical treatment
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 438 participants
- Where
- 33 sitesin 7 countries
- Study dates
- 1 Dec 2026to 30 Sep 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 2 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Show all 9Show fewer
- 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.
Who cannot join
- 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:
- 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.
Trial locations and contacts
33 sites in 7 countries. Contact the study team or a site near you to ask about taking part.
33 sites in 7 countries
United States25 sites
Children's Hospital Colorado
Aurora, Colorado, 80045
Krista Eschbach, krista.eschbach@childrenscolorado.org
Mass General (MGH)
Boston, Massachusetts, 02114
Sahar Zafar, sfzafar@mgh.harvard.edu
Beth Israel Deaconess
Boston, Massachusetts, 02215
Brandon Westover, bwestove@bidmc.harvard.edu
Boston Children's Hospital
Boston, Massachusetts, 02215
Coral Stredny, coral.stredny@childrens.harvard.edu
University of Chicago
Chicago, Illinois, 60637
Hiba Haider, hibahaider@uchicago.edu
University of Cincinnati
Cincinnati, Ohio, 45221
Brandon Foreman, foremabo@ucmail.uc.edu
Cleveland Clinic
Cleveland, Ohio, 44195
Vineet Punia, puniav@ccf.org
UT Southwestern Medical Center
Dallas, Texas, 75390
Rana Said, rana.said@utsouthwestern.edu
Northwestern University
Evanston, Illinois, 60208
Stephen vanHaerents, svanhaer@nm.org
University of Florida
Gainesville, Florida, 32611
Carolina Maciel, carolina.maciel@neurology.ufl.edu
Baylor/Texas Children's
Houston, Texas, 77030
Yichen Lai, ylai@bcm.edu
University of Nebraska
Lincoln, Nebraska, 68588
Olga Taraschenko, olha.taraschenko@unmc.edu
University of Wisconsin
Madison, Wisconsin, 53706
Aaron Struck, struck@neurology.wisc.edu
Medical College of Wisconsin
Milwaukee, Wisconsin, 53226
Raquel Farias-Moeller, rfarias@mcw.edu
Yale New Haven Hospital
New Haven, Connecticut, 06520
Lawrence Hirsch, lawrence.hirsch@yale.edu
New York University
New York, New York, 10012
Claude Steriade, claude.steriade@nyulangone.org
Columbia University
New York, New York, 10027
Jan Claassen, jc1439@mail.cumc.columbia.edu
Mount Sinai (NY)
New York, New York, 10029
Ji Yeoun Yoo, jiyeoun.yoo@mssm.edu
Children's Hospital Philadelphia (CHOP)
Philadelphia, Pennsylvania, 19104
Danielle Decampo, decampod@chop.edu
University of Pennsylvania
Philadelphia, Pennsylvania, 19104
Catherine Kulick, catherine.kulick@pennmedicine.upenn.edu
Barrow Institute
Phoenix, Arizona, 85013
Susan Herman, susan.herman@commonspirit.org
Oregon Health and Science University
Portland, Oregon, 97239
Marissa Kellogg, kellogma@ohsu.edu
Mayo Clinic
Rochester, Minnesota, 55905
Kelsey Smith, smith.kelsey@mayo.edu
Seattle Children's Hospital
Seattle, Washington, 98105
Mark Wainwright, mark.wainwright@seattlechildrens.org
Children's National (DC)
Washington D.C., District of Columbia, 20010
Elizabeth Wells, ewells@childrensnational.org
Canada2 sites
Western University
London
Teneille Gofton, teneille.gofton@lhsc.on.ca
Hospital for Sick Children
Toronto
Cecil Hahn, cecil.hahn@sickkids.ca
United Kingdom2 sites
Great Ormond Street Hospital
London
Marios Kaliakatsos, marios.kaliakatsos@gosh.nhs.uk
King's College
London
Laura Mantoan, laura.mantoan@kcl.ac.uk
Italy1 site
University of Modena
Modena
Stefano Meletti, stefano.meletti@unimore.it
South Korea1 site
Seoul National University Hospital
Seoul
Soon-Tae Lee, staelee@snu.ac.kr
Sweden1 site
Karolinska Institute
Stockholm
Ronny Wickstrom, ronny.wickstrom@ki.se
About this study
Official title: 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.
Read more
The study will enroll patients across 33 hospitals in the United States, Canada, Europe, and Asia.
It includes two groups:
- 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.
- 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.
- Conditions
- New Onset Refractory Status Epilepticus, New-Onset Refractory Status Epilepticus, Febrile Infection-Related Epilepsy Syndrome (FIRES)
- Being tested
- Anakinra, Tocilizumab, Standard medical treatment
- Keywords
- refractory status epilepticus, NORSE, FIRES, anakinra, tocilizumab
- Medical subject headings
- Status Epilepticus
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AnakinraDrug
SOC will be followed , Suggested Dose:
10 mg/kg/day IV, divided into 4 daily doses (q6h) Maximum dose: 400 mg/day
TocilizumabDrug
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
Standard medical treatmentOther
For patients who could not be randomized by day 7, standard clinical care will be followed and patients will be followed prospectively and observationally.
| Study group | Role | What they receive |
|---|---|---|
| Randomized Controlled Trial (RCT) Cohort | Active comparator | 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) Receives: Drug: Anakinra; Drug: Tocilizumab |
| Observational Cohort | Other | 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 . Receives: Other: Standard medical treatment |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 months
Secondary outcomes (6)
Time to resolution of status epilepticus (SE)
Time (days) until discontinuation of anesthetic drips for 24h for the treatment of SE with no return of SE on EEG
Measured: 24 hours off anesthetic drips
Hospital length of stay
Mean number of days during hospitalization from admission to discharge
Measured: 12 months
Mortality
Mortality, number of participants
Measured: up to 12 months
Number of serious adverse events attributed to anakinra or tocilizumab
Number of serious adverse events attributed to anakinra or tocilizumab
Measured: From hospitalization to 1 month after stopping treatment, up to 12 months
Number of participants Post-NORSE epilepsy
Number of participants with any unprovoked seizures after hospital discharge
Measured: 12 months
Number of participants with Treatment success
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)
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Dec 2025
- Study start1 Dec 2026 (estimated)
- Primary completion31 Mar 2030 (estimated)
- Study completion30 Sep 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for New Onset Refractory Status EpilepticusStudies of the same condition, open and under way.
- More trials run by Yale UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 438 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Yale University
- Sponsor type
- University, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Responsible party
- Principal investigator, Lawrence Hirsch, Yale University
- Investigators
- Lawrence Hirsch, MD, Principal investigator, Yale University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07281027
- Sponsor's protocol ID
- 2000041289
- Other IDs
- RD-2024C2-39648
- Acronym
- COMBAT-NORSE
- Status last verified
- May 2026
- First submitted
- 21 Nov 2025
- Last updated
- 19 Aug 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: 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.
Study at a glance
From the registry record, last updated by the sponsor on 19 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparing the Effects of Anakinra and Tocilizumab on Outcomes in Patients With New-Onset Refractory Status Epilepticus
- ClinicalTrials.gov ID
- NCT07281027
- Acronym / sponsor ID
- COMBAT-NORSE / 2000041289
- Conditions
- New Onset Refractory Status Epilepticus, New-Onset Refractory Status Epilepticus, Febrile Infection-Related Epilepsy Syndrome (FIRES)
- Keywords
- refractory status epilepticus, NORSE, FIRES, anakinra, tocilizumab
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 438 participants (estimated)
- Lead sponsor
- Yale UniversityUniversity, hospital or other
- Collaborators
- Patient-Centered Outcomes Research Institute
- Study start
- 1 Dec 2026 (estimated)
- Primary completion
- 31 Mar 2030 (estimated)
- Study completion
- 30 Sep 2030 (estimated)
- First posted
- 15 Dec 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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:
- 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.
- 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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Randomized Controlled Trial (RCT) Cohort | Active comparator | Drug: Anakinra, Drug: TocilizumabA 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 | Other | Other: Standard medical treatmentAn 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 . |
Who may qualify
- Ages
- 2 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (9 listed)
- 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:
- 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.
Key exclusion criteria (7 listed)
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| AnakinraSOC will be followed , Suggested Dose: 10 mg/kg/day IV, divided into 4 daily doses (q6h) Maximum dose: 400 mg/day | Drug | Randomized Controlled Trial (RCT) Cohort |
| TocilizumabSOC 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 | Drug | Randomized Controlled Trial (RCT) Cohort |
| Standard medical treatmentFor patients who could not be randomized by day 7, standard clinical care will be followed and patients will be followed prospectively and observationally. | Other | Observational Cohort |
Primary outcome
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.
6 secondary outcomes
Time to resolution of status epilepticus (SE)
Time frame: 24 hours off anesthetic drips
Hospital length of stay
Time frame: 12 months
Mortality
Time frame: 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 participants Post-NORSE epilepsy
Time frame: 12 months
Number of participants with Treatment success
Time frame: 12 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Aug 2026.
- Individual participant dataSharing planned: Yes. 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.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Lawrence Hirsch, MD principal investigator
Yale University
33 sites in 7 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Anakinra, Tocilizumab and Standard medical treatment in people with New Onset Refractory Status Epilepticus and New-Onset Refractory Status Epilepticus, run by Yale University at 33 sites in 7 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 19 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 33 sites in United States, Canada, United Kingdom, France, Italy and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Camalene Chrysostoum (2037375851, camalene.chrysostoum@yale.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Glasgow Outcome Scale - Extended (GOS-E) (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 19 Aug 2026.