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

Official title

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

Overview

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.

Interventions

• 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 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.

Primary outcome measures

• Glasgow Outcome Scale - Extended (GOS-E) [Time frame: 12 months]

Secondary outcome measures (6)

• 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]

Eligibility criteria

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:

• 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.

• 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:

• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Treatment

Study locations

United States · 25 centers

• Barrow Institute — Phoenix
• Children's Hospital Colorado — Aurora
• Yale New Haven Hospital — New Haven
• Children's National (DC) — Washington D.C.
• University of Florida — Gainesville
• University of Chicago — Chicago
• Northwestern University — Evanston
• Mass General (MGH) — Boston
• … and 17 more centers

Canada · 2 centers

• Western University — London
• Hospital for Sick Children — Toronto

United Kingdom · 2 centers

• Great Ormond Street Hospital — London
• King's College — London

France · 1 center

• Salpêtrière — Paris

Italy · 1 center

• University of Modena — Modena

South Korea · 1 center

• Seoul National University Hospital — Seoul

Sweden · 1 center

• Karolinska Institute — Stockholm

Identifiers

NCT: NCT07281027 · 2000041289 · RD-2024C2-39648

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗