Targeted Hypothermia Versus Targeted Normothermia After Convulsive Refractory Status Epilepticus

NCT07383779 | Not Yet Recruiting Phase 3 DMC

• 2 other identifiers: P21/14 _ HYBERNATUS_II2023-A01518-37
• Study Type: interventional
• Target: 466
• Locations: 1 country
• Sites: 20

Brief Summary

The HYBERNATUS-II study is a phase-III, open-label, randomized controlled trial in patients with convulsive refractory SE receiving mechanical ventilation. Patients are allocated at random to either early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. This trial is a superiority multicentric trial and patients will be randomized in a 1:1 ratio using an electronic Cas Report Form. Before any examination or intervention related to the study may be carried out, the investigator must obtain the freely given, informed and written consent of the participant, or of his/her substitute decision maker (family member, close relative or legal representative) where applicable. However, eligible subjects are unconscious and inherently not able to consent. Two situations of inclusion are therefore envisaged: \- In case a substitute decision maker is present or contactable: a freely given, informed and written consent of the substitute decision maker will be performed. \- In case a substitute decision maker is not present or contactable in the inclusion time frame, the patient may be included through a process of differed consent. Substitute decision maker will be informed as soon as possible and a freely given, informed and written pursuit consent will be performed. In all cases, the patient will have to confirm his participation to the study through a freely given, informed and written pursuit consent as soon as their condition allows it. If the patient is under curatorship, the pursuit consent may be given based on his or her own decision. If the patient is under guardianship, the written guardian's consent will also be required. Individuals liable to participate in studies stipulated in line 1° of article L. 1121-1 of the Code de la Santé Publique (French Public Health Code) benefit from a preliminary medical examination adapted to the study. Patients will be included after informed consent as soon as possible once they satisfied all eligibility criteria. The inclusion window is until 3.5 hours (210 minutes) after convulsive SE onset. Consecutive eligible patients will be included and randomly allocated in a 1:1 ratio to one of the two procedure groups. Randomization and concealment will be ensured by using a secure, computer-generated, interactive, response system accessible via the Internet available at each study centre 24H/24. Randomization list will be prepared by an independent statistician who will not be in charge of the analysis. Randomization lists will be generated by a dedicated computer program, with randomly varying sized blocks, and stratified as follows: according to sites, previous history of epilepsy \[yes or not\], and results of brain imaging \[Abnormal Brain Imaging or not\]. Each investigator will be able to access the randomization site using a personal password. Randomization will be carried out after checking of the inclusion criteria and the absence of exclusion criteria and after obtaining a written and informed consent or according to the emergency procedure by the principal investigator or a physician representing the investigator before the person is enrolled in the study of each centre involved in the study. Each patient will be assigned a unique identification number. An inclusion confirmation will be sent by email to the investigator specifying the allocated procedure arm. Patients will be randomly allocated to one of the two study procedure groups. The two groups will differ only in the administration of early targeted hypothermia for 24 hours or targeted normothermia at the acute phase of ICU management. All other treatment will be standardized in the two groups. Targeted Hypothermia group : Implementation of allocation arm is started within 30 min after randomization.The objective is to lower the core body temperature to 33°C \[32-34°C\] rapidly after randomization then to maintain this temperature for 24 hours. The management in the targeted hypothermia group will include the following. Targeted normothermia group. Implementation of allocation arm is started within 30 min after randomization. The objective of the control group is to ensure normothermia 37° \[36.5-37.5°C\] for 72 hours after randomization. Antipyretic treatments will be given in case of a core temperature higher than 37.8°C. In case of failure, cooling with a surface non-invasive loop-feedback TTM device associating pads directly adhering to the patient's skin (Artic Sun TM provided by the study, similar in all participating centers) will be initiated with a target temperature of 37° \[36.5-37.5°C\]. No active warming will be provided for patients in the normothermia group who had a spontaneous body temperature below 36.5°C. Patients included in the study will be followed until the 90th day after inclusion. The duration of the participation will therefore be 3 months for each patient.

Conditions

Convulsive Refractory Status Epilepticus; Status Epilepticus

Outcome Measures

Primary Outcomes (2)

• To evaluate the efficacy of TH 33°C [32-34°C] for 24 hours in improving the 90-day neurological outcome

  Percentage of patients who reached the level \[5-8\] of the GOS-E scale \[scale range 1-8, 8 best score\] in each group at day 90

  90 days

• Decreasing post-randomization progression to electrographic SE at day-1 in patients with RSE

  Percentage of patients experiencing progression to electrographic SE (from 1 to 25 hours after randomization)

  1 day

Secondary Outcomes (16)

• To assess the efficacy of TH on reducing the burden of drugs

  1 day

• To assess the efficacy of TH on reducing the burden of seizures on day 1

  1 day

• To assess the efficacy of TH reducing the burden of seizures on day 2 and 3

  2 and 3 days

• To assess the tolerance of the intervention (pneumonia)

  7 days

• To assess the tolerance of the intervention (other infections)

  7 days

Study Arms (2)

Targeted Hypothermia

EXPERIMENTAL

Targeted temperature management in hypothermia at 33°C \[32-34°C\] for 24 hours, then progressive rewarming to normothermia 37°C \[36.5-37.5°C\] up to 72 hours after convulsive refractory SE onset

Device: Targeted Hypothermia

Targeted normothermia

NO INTERVENTION

Targeted normothermia 37°C \[36.5-37.5°C\] for 72 hours after convulsive refractory SE onset

Interventions

Targeted Hypothermia DEVICE

The objective is to lower the core body temperature to 33°C \[32-34°C\] rapidly after randomization then to maintain this temperature for 24 hours. The management in the targeted hypothermia group will include the following: * Sedation with Propofol maintenance infusion at a rate of 2-5 mg/kg/h * Hypothermia induction and maintenance using a non-invasive loop-feedback TTM device associating pads directly adhering to the patient's skin (Artic Sun TM provided by the study, similar in all participating centers). * Shivering will be assessed using the Bedside Shivering Assessment Scale (BSAS) (Appendix 14) with a tiered approach and avoiding continuous neuromuscular blockade use. * After 24 h of targeted hypothermia, rewarming will be standardized at a slow rate of 0.3°C per hour; if used, CisPropofol is progressively decreased (20% every 4 hours) to the lowest dose needed to ensure tolerance of the endotracheal tube

Targeted Hypothermia

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 and 65 years \[18-65 years\]
• Continued motor seizure activity lasting more than 5 minutes, or two or more motor seizures without a return to baseline level of consciousness in the interval at least 5 minutes after the first seizure
• Refractory to two recommended antiseizure medications (benzodiazepine and "classic" antiseizure drug)
• Receiving mechanical ventilation
• Time from seizure onset no longer than 3.5 hours (210 min)
• Consent to participate (patient's relative or emergent consent)

You may not qualify if:

• Estimated pre-morbid GOS-E score \< 5
• Preexisting ultimately fatal comorbidity \< 1 year
• Patients unlikely to survive for the next 24 hours
• Need for emergent surgery or interventional neuroradiology for bleeding embolization (neurosurgery or other precluding therapeutic hypothermia)
• Postanoxic status epilepticus
• Traumatic Brain Injury with an acute bleeding on Computed Tomographic (CT) scan or Magnetic Resonance Imaging (MRI) of the brain
• Bacterial meningitis as a cause of convulsive SE
• Cryoglobulinemia, sickle cell disease, serum cold agglutinins comorbidities
• Pregnancy
• Absence of coverage by the French/European statutory healthcare insurance system

Sponsors & Collaborators

• Versailles Hospital: lead

Study Sites (20)

Hôpital Ambroise Paré

Boulogne-Billancourt, France

Location

CHU Brest

Brest, France

Location

CH Simone Veil

Cannes, France

Location

Hôpital Louis Mourier

Colombes, France

Location

CH Sud Francilien

Corbeil-Essonnes, France

Location

CHU Dijon

Dijon, France

Location

CH Versailles

Le Chesnay, France

Location

CH Le Mans

Le Mans, France

Location

Hôpital de la Croix-Rousse

Lyon, France

Location

Hôpital Edouard Herriot

Lyon, France

Location

CH Melun-Sénart

Melun, France

Location

CH Annecy Genevois

Metz-Tessy, France

Location

CHU Nantes

Nantes, France

Location

CHR Orléans

Orléans, France

Location

GH Paris Saint-Joseph

Paris, France

Location

Hôpital COCHIN

Paris, France

Location

CHU Rennes

Rennes, France

Location

Hôpital Hautepierre

Strasbourg, France

Location

Hôpital Foch

Suresnes, France

Location

CHITS Toulon

Toulon, France

Location

Related Publications (4)

• Legriel S. Hypothermia as a treatment in status epilepticus: A narrative review. Epilepsy Behav. 2019 Dec;101(Pt B):106298. doi: 10.1016/j.yebeh.2019.04.051. Epub 2019 May 24.

  PMID: 31133509 BACKGROUND

• Legriel S. Hypothermia as an adjuvant treatment in paediatric refractory or super-refractory status epilepticus. Dev Med Child Neurol. 2020 Sep;62(9):1017-1023. doi: 10.1111/dmcn.14562. Epub 2020 May 15.

  PMID: 32412660 BACKGROUND

• Legriel S, Fontaine C, Jacq G. The value of hypothermia as a neuroprotective and antiepileptic strategy in patients with status epilepticus: an update of the literature. Expert Rev Neurother. 2025 Jan;25(1):57-66. doi: 10.1080/14737175.2024.2432869. Epub 2024 Nov 24.

  PMID: 39582132 BACKGROUND

• Legriel S, Lemiale V, Schenck M, Chelly J, Laurent V, Daviaud F, Srairi M, Hamdi A, Geri G, Rossignol T, Hilly-Ginoux J, Boisrame-Helms J, Louart B, Malissin I, Mongardon N, Planquette B, Thirion M, Merceron S, Canet E, Pico F, Tran-Dinh YR, Bedos JP, Azoulay E, Resche-Rigon M, Cariou A; HYBERNATUS Study Group. Hypothermia for Neuroprotection in Convulsive Status Epilepticus. N Engl J Med. 2016 Dec 22;375(25):2457-2467. doi: 10.1056/NEJMoa1608193.

  PMID: 28002714 BACKGROUND

MeSH Terms

Conditions

Status Epilepticus

Interventions

Hypothermia, Induced

Condition Hierarchy (Ancestors)

Seizures; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cryotherapy; Therapeutics

Central Study Contacts

Charlotte LETERME

CONTACT

0139239779; cleterme@ght78sud.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Discharged patients will receive a centralized phone call interview by an independent assessor blinded of allocation arms at 90 days after randomization to assess GOS-E status (multiple primary outcome). Continuous EEG recordings will be posteriori reviewed by an adjudication committee, composed of three independent neurophysiologist blinded of allocation arms, for identification of patients with progression to electrographic SE (multiple primary outcome).
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Investigator Coordinator

Model Details: Intervention group : Targeted temperature management in hypothermia at 33°C \[32-34°C\] for 24 hours, then progressive rewarming to normothermia 37°C \[36.5-37.5°C\] up to 72 hours after convulsive refractory SE onset Comparator group : Targeted normothermia 37°C \[36.5-37.5°C\] for 72 hours after convulsive refractory SE onset

Study Record Dates

• First Submitted: December 5, 2025
• First Posted: February 3, 2026
• Study Start: March 1, 2026
• Primary Completion (Estimated): June 1, 2029
• Study Completion (Estimated): June 1, 2029
• Last Updated: February 10, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (20)