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

Yale University

Status and phase: Begins enrollment this month; Phase 3

Conditions: New-Onset Refractory Status Epilepticus; New Onset Refractory Status Epilepticus; Febrile Infection-Related Epilepsy Syndrome (FIRES)

Treatments: Other: Standard medical treatment; Drug: Tocilizumab; Drug: Anakinra

Study type: Interventional

Funder types: Other

Identifiers

NCT07281027

RD-2024C2-39648 (Other Grant/Funding Number)

2000041289

Details and patient eligibility

About

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.

Enrollment: 438 estimated patients

Sex: All

Ages: 2+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

---

438 participants in 2 patient groups

Randomized Controlled Trial (RCT) Cohort

Active Comparator group

Description:

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)

Treatment:

Drug: Tocilizumab

Drug: Anakinra

Observational Cohort

Other group

Description:

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 .

Treatment:

Other: Standard medical treatment