Status EpilepticusSUPER-CATNCT05756621
Dual Anti-glutamate Therapy in Super-refractory Status Epilepticus After Cardiac Arrest
An observational study of Status Epilepticus and Cardiac Arrest, run by University of Milano Bicocca at 10 sites in Italy.
Trial summary
Status epilepticus (SE) is found in 20-30% of patients in coma after cardiac arrest, is often refractory to medical therapy and is considered a negative prognostic factor. Intensity and duration of treatment of refractory and super-refractory post-anoxic SE pose the ethical dilemma between futility of treatments and… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Status Epilepticus, Cardiac Arrest
- What is being tested?
- Ketamine and Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel
- Type of treatment
- Pill or oral medicine, Injection or infusion
- How many people
- 84 participants
- Where
- 10 sitesItaly
- Study dates
- 15 Jan 2022to 31 Dec 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Patients with super-refractory status epilepticus after cardiac arrest, admitted to the Intensive Care Unit, with continuous EEG monitoring, presence of first-line favorable prognostic indicators (pupillary reflexes and N20 cortical responses bilaterally; absence of periodic EEG pattern). Outcomes will be also analyzed for the following pre-defined population: "Patients with favorable prognostic indicators": patients presenting 5 or more of the following: 1) presence of a pupillary reflex bilaterally; (2) presence of corneal reflex bilaterally; (3) presence of N20 cortical response bilaterally; (4) NSE <68 ng/mL at 24-72 hours from ACC; (5) absence of periodic EEG patterns (GPDs); (6) absence of severe anoxic brain damage on neuroimaging
Who may be able to join
- age ≥ 18 years
- patients in coma after cardio-circulatory arrest (CCA) admitted to the Intensive Care Unit and treated with target temperature management (TTM) for the first 24 hours
- initiation of continuous electroencephalographic (cEEG) monitoring within 24-36 hours of CCA
- diagnosis of super-refractory status epilepticus, relapsed after the first cycle of anesthetics (lasting > 24 hours) and antiepileptic therapy, defined according to the international Salzburg criteria9
- presence of pupillary reflex present bilaterally
- presence of N20 cortical response present bilaterally
Who cannot join
- EEG with periodic pattern (generalized periodic discharges; GPDs)
- status epilepticus resolved after the first cycle of anesthetics + antiepileptics
- pregnant women
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
Italy10 sites
Ospedale Centrale di Bolzano
Bolzano, BZ
ASST Spedali Civili Brescia
Brescia, BS
Ospedale G. Brotzu
Cagliari, CA
Ospedale M. Bufalini
Cesena, FC
AOU Careggi
Florence, FI
Azienda Ospedaliero-Universitaria di Modena
Modena, MO
Fondazione IRCCS San Gerardo dei Tintori Monza
Monza, MB, 20900
Azienda Ospedaliero-Universitaria di Parma
Parma, PR
Ospedale Santa Chiara Trento
Trento, TN
Azienda Ospedaliero-Universitaria Integrata di Verona
Verona, VR
About this study
Official title: SUPER-refractory Status Epilepticus After Cardiac Arrest: a Multicenter, Retrospective, Cohort Study of Dual Anti-glutamate Therapy With Ketamine and Perampanel
Status epilepticus (SE) is found in 20-30% of patients in coma after cardiac arrest, is often refractory to medical therapy and is considered a negative prognostic factor. Intensity and duration of treatment of refractory and super-refractory post-anoxic SE pose the ethical dilemma between futility of treatments and, conversely, their premature suspension. A recent study by the Epilepsy Center of the San Gerardo Hospital has shown that patients with super-refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome in more than 40% of cases, if treated with intensive and protracted therapy.
However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A combined anti-glutamatergic therapy with ketamine (anti-NMDA receptor) and perampanel (anti-AMPA receptor), aimed at counteracting the excitotoxicity linked to global cerebral ischemia, could be particularly effective in the treatment of super-refractory SE with post-anoxic etiology. Preliminary results in the first 26 patients treated in the Coordinating Center of the project indicate that this therapy appears safe and highly effective (80% SE resolution, 40% good neurological outcome).
The aim of the SUPER-CAT study is to investigate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with post-anoxic super-refractory status epilepticus, compared to other therapies, using a multi-centre, retrospective, cohort study design.
Read the detailed description
Status epilepticus (SE) is found in 20-30% of patients in a coma after cardiac arrest, is frequently refractory to medical therapy and is usually considered a poor prognostic factor. The intensity and duration of treatment for post-anoxic refractory and super-refractory SE remains a highly controversial issue, posing the ethical dilemma between futility and premature discontinuation of care.
Although the TELSTAR randomized clinical trial demonstrated the futility of aggressive treatment in post-anoxic patients with generalized periodic pattern, the question remains open about the benefit of aggressive therapy in post-anoxic patients with SE properly defined according to the Salzburg criteria.
The latest guidelines of the European Resuscitation Council recommend the use of electroencephalogram (EEG) both for the neurological prognosis and for the diagnosis of post-cardiac arrest epileptic seizures, define the highly malignant EEG patterns (which do not include status epilepticus; while generalized periodic pattern and suppressed background are included) and recommend treatment of seizures with first-line antiepileptic therapy (levetiracetam or valproate), while there are no recommendations regarding second-line antiepileptic therapy. The same guidelines recommend a multi-modal approach, using different indicators (brainstem reflexes, somatosensory evoked potentials, EEG patterns, neuron-specific enolase [NSE] levels and neuroimaging) to arrive at the formulation of the neurological prognosis. A favorable neurological outcome is present in <15% of post-anoxic SE cases after moderate intensity treatment.
A recent study by the Epilepsy Center of the San Gerardo Hospital ASST Monza on a prospective cohort of 166 consecutive patients with cardiac arrest showed that patients with refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome (CPC 1-2) in > 40% of cases, if treated aggressively and prolonged with second-line anti-epileptic and anesthetic therapy.
However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A pilot study of the Epilepsy Center of the San Gerardo ASST Monza hospital has shown an efficacy of 75% of anti-glutamatergic therapy with oral load of perampanel (anti-AMPA receptor), combined with different types of anesthetics (including ketamine, anti -NMDA receptor), in 8 patients with super-refractory post-anoxic SE. All patients included in this series presented the main favorable prognostic indicators (presence of brainstem reflexes, presence of N20 cortical evoked potentials, absence of generalized periodic pattern) and in 60% of cases (5 out of 8 cases) a neuroimaging with mild anoxic damage. The clinical outcome was favorable, with the achievement of functional independence in 50% of cases (4 cases out of 8) after 3 months.
A dual anti-glutamatergic therapy, performed by combining ketamine and perampanel could contrast in a particularly effective way the excitotoxicity linked to the global cerebral ischemia, favoring the resolution of the super-refractory SE and improving the global outcome of the post-cardiac arrest patient. Preliminary results in the first 26 post-anoxic super-refractory SE patients treated in the project Coordinating Center indicate that a dual anti-glutamatergic therapy with ketamine and perampanel appears highly effective (81% SE resolution; 41% good neurological outcome after 6 months) and without significant side effects. The selection of these patients was made on the basis of the multi-modal prognostic indicators described above, in accordance with the current guidelines on neurological prognosis.
The aim of the SUPER-CAT study is to evaluate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with super-refractory SE of post-anoxic aetiology, compared to other therapies, using a multi-centre, retrospective, cohort study design.
The study will be conducted thanks to the collaboration of the Intensive Care and Resuscitation Units and the Epilepsy Centers of 9 Italian hospitals, with the epidemiological-statistical coordination of the Mario Negri Institute for Pharmacological Research in Milan.
Patients with super-refractory status epilepticus after in-hospital or out-of-hospital cardio-circulatory arrest will be enrolled.
The results of the study will allow to compare the feasibility, efficacy and safety of dual anti-glutamate therapy with ketamine and perampanel in super-refractory post-anoxic SE compared to other anti-epileptic and anesthetic therapies used in normal clinical practice. If clinically relevant, these results will lay the foundations for the development of a subsequent randomized clinical trial.
The study has a retrospective observational design, therefore no interventions or modifications in conventional diagnostic and therapeutic procedures will be carried out.
- Conditions
- Status Epilepticus, Cardiac Arrest
- Being tested
- Ketamine, Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel
- Keywords
- super-refractory, prognostic indicators, perampanel, ketamine
- Medical subject headings
- Status Epilepticus, Heart Arrest
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
KetamineDrug
Also called Perampanel
"Dual anti-glutamatergic therapy" (DUAL) intervention group: patients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of "ketamine pattern") + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual reduction according to clinical evolution.
Any anti-epileptic and anesthetic therapy, excluding Ketamine and PerampanelDrug
Also called Levetiracetam, Valproate, Phenytoin, Lacosamide, Topiramate, Propofol, Midazolam, Thiopental
Any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs Ketamine and Perampanel
| Study group | Role | What they receive |
|---|---|---|
| Dual anti-glutamate therapy (DUAL) | Patients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of "ketamine pattern") + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual dose reduction according to clinical evolution. Receives: Drug: Ketamine | |
| Control (OTHERS) | Patients who received any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs ketamine and perampanel. Receives: Drug: Any anti-epileptic and anesthetic therapy, excluding Ketamine and Perampanel |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of patients with resolution of status epilepticus
Number of patients with resolution of status epilepticus, not followed by relapse and without the use of additional antiepileptic drugs, evaluated over the entire period of stay in the Intensive Care Unit, in the two groups DUAL versus OTHERS
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Secondary outcomes (8)
Number of patients with with time-locked resolution of status epilepticus
Number of patients with with resolution of status epilepticus 5 days after the start of therapy, not followed by relapse and without the use of additional antiepileptic drugs (only in the DUAL group)
Measured: first 5 days after start of therapy
Number of patients with early favorable neurological outcome
Number of patients with early favorable neurological outcome, defined as the patient's awakening (up to "command execution") during the stay in the Intensive Care Unit
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with favorable long-term neurological outcome
Number of patients with favorable long-term neurological outcome, defined by a modified Rankin scale score ≤ 2 at 6 months (minimum score 0, maximum score 6; lower scores indicate better outcomes)
Measured: 6 months after cardiac arrest
mortality in intensive care
mortality in intensive care
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
mortality at 6 months
mortality at 6 months
Measured: 6 months after cardiac arrest
cumulative probability of resolution of status epilepticus
incidence of the occurrence of resolution of status epilepticus, taking into account death as competing risk (cumulative incidence function)
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with abnormal cholestasis indices
Number of patients with abnormal cholestasis indices (GT-gamma > 3 times the upper limit of normal)
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with third degree atrioventricular block or cardiac arrest recurrence
Number of patients with third degree atrioventricular block or cardiac arrest recurrence
Measured: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Mar 2023
- Study start15 Jan 2022
- Primary completion30 Oct 2025
- Study completion31 Dec 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for Status EpilepticusStudies of the same condition, open and under way.
- 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
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 84 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Milano Bicocca
- Sponsor type
- University, hospital or other
- Collaborators
- Azienda Ospedaliera San Gerardo di Monza, Azienda Ospedaliero-Universitaria di Modena, Azienda Ospedaliera Universitaria Integrata Verona, Ospedale Centrale Bolzano, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Azienda Ospedaliero-Universitaria Careggi, Azienda Ospedaliero-Universitaria di Parma, Santa Chiara Hospital, Ospedale M. Bufalini Cesena, Azienda Ospedaliera Brotzu, Istituto Di Ricerche Farmacologiche Mario Negri
- Responsible party
- Sponsor
- Investigators
- Simone Beretta, MD, PhD, Principal investigator, University of Milano BicoccaMatteo Pozzi, MD, Study chair, Fondazione IRCCS Gerardo dei Tintori Monza
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05756621
- Sponsor's protocol ID
- SUPER-CAT
- Acronym
- SUPER-CAT
- Status last verified
- Jul 2025
- First submitted
- 17 Feb 2023
- Last updated
- 14 Jul 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Mani R, Schmitt SE, Mazer M, Putt ME, Gaieski DF. The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation. 2012 Jul;83(7):840-7. doi: 10.1016/j.resuscitation.2012.02.015. Epub 2012 Feb 23.
PubMed 22366352Lybeck A, Friberg H, Aneman A, Hassager C, Horn J, Kjaergaard J, Kuiper M, Nielsen N, Ullen S, Wise MP, Westhall E, Cronberg T; TTM-trial Investigators. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation. 2017 May;114:146-151. doi: 10.1016/j.resuscitation.2017.01.017. Epub 2017 Feb 3.
PubMed 28163232Cronberg T. Should Postanoxic Status Epilepticus Be Treated Agressively? Yes! J Clin Neurophysiol. 2015 Dec;32(6):449-51. doi: 10.1097/WNP.0000000000000209.
PubMed 26629753Dragancea I, Wise MP, Al-Subaie N, Cranshaw J, Friberg H, Glover G, Pellis T, Rylance R, Walden A, Nielsen N, Cronberg T; TTM trial investigators. Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management. Resuscitation. 2017 Aug;117:50-57. doi: 10.1016/j.resuscitation.2017.05.014. Epub 2017 May 12.
PubMed 28506865Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J; TELSTAR Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Feb 24;386(8):724-734. doi: 10.1056/NEJMoa2115998.
PubMed 35196426Leitinger M, Trinka E, Gardella E, Rohracher A, Kalss G, Qerama E, Hofler J, Hess A, Zimmermann G, Kuchukhidze G, Dobesberger J, Langthaler PB, Beniczky S. Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study. Lancet Neurol. 2016 Sep;15(10):1054-62. doi: 10.1016/S1474-4422(16)30137-5. Epub 2016 Aug 8.
PubMed 27571157Nolan JP, Sandroni C, Bottiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Mariero Olasveengen T, Skrifvars MB, Taccone F, Soar J. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation. 2021 Apr;161:220-269. doi: 10.1016/j.resuscitation.2021.02.012. Epub 2021 Mar 24.
PubMed 33773827Dragancea I, Backman S, Westhall E, Rundgren M, Friberg H, Cronberg T. Outcome following postanoxic status epilepticus in patients with targeted temperature management after cardiac arrest. Epilepsy Behav. 2015 Aug;49:173-7. doi: 10.1016/j.yebeh.2015.04.043. Epub 2015 Jun 24.
PubMed 26117526Beretta S, Coppo A, Bianchi E, Zanchi C, Carone D, Stabile A, Padovano G, Sulmina E, Grassi A, Bogliun G, Foti G, Ferrarese C, Pesenti A, Beghi E, Avalli L. Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Neurology. 2018 Dec 4;91(23):e2153-e2162. doi: 10.1212/WNL.0000000000006615. Epub 2018 Oct 31.
PubMed 30381366Beretta S, Padovano G, Stabile A, Coppo A, Bogliun G, Avalli L, Ferrarese C. Efficacy and safety of perampanel oral loading in postanoxic super-refractory status epilepticus: A pilot study. Epilepsia. 2018 Oct;59 Suppl 2:243-248. doi: 10.1111/epi.14492. Epub 2018 Aug 29.
PubMed 30159874Beretta S, Pozzi M, Tagliabue S, Bianchi E, Rossi E, Pasini F, Giglio A, Cereda GS, Morotti Colleoni C, Pederzoli G, Giovannini G, Orlandi N, Meletti S, Gaiani A, Filipponi S, Cucino A, Normanno M, Mariani I, Scanziani M, Giani M, Diamanti S, Coppo A, DiFrancesco JC, Stabile A, Tinti L, Florio I, Sist C, Corona M, Pinna B, Orlandini F, Cossu G, Ferlisi M, Casartelli-Liviero M, Misirocchi F, Florindo I, Zinno L, Bartolini Y, Longoni M, Russo E, Grippo A, Ferrarese C, Foti G, Avalli L. Dual Antiglutamate Therapy in Super-Refractory Status Epilepticus After Cardiac Arrest (SUPER-CAT Study). Neurology. 2026 Oct 27;107(8):e218565. doi: 10.1212/WNL.0000000000218565. Epub 2026 Oct 5.
PubMed 42837646
Study at a glance
From the registry record, last updated by the sponsor on 14 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- SUPER-refractory Status Epilepticus After Cardiac Arrest: a Multicenter, Retrospective, Cohort Study of Dual Anti-glutamate Therapy With Ketamine and Perampanel
- ClinicalTrials.gov ID
- NCT05756621
- Acronym / sponsor ID
- SUPER-CAT / SUPER-CAT
- Conditions
- Status Epilepticus, Cardiac Arrest
- Keywords
- super-refractory, prognostic indicators, perampanel, ketamine
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 84 participants (actual)
- Lead sponsor
- University of Milano BicoccaUniversity, hospital or other
- Collaborators
- Azienda Ospedaliera San Gerardo di Monza, Azienda Ospedaliero-Universitaria di Modena, Azienda Ospedaliera Universitaria Integrata Verona, Ospedale Centrale Bolzano, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, Azienda Ospedaliero-Universitaria Careggi, Azienda Ospedaliero-Universitaria di Parma, Santa Chiara Hospital, Ospedale M. Bufalini Cesena, Azienda Ospedaliera Brotzu, Istituto Di Ricerche Farmacologiche Mario Negri
- Study start
- 15 Jan 2022 (actual)
- Primary completion
- 30 Oct 2025 (actual)
- Study completion
- 31 Dec 2025 (actual)
- First posted
- 6 Mar 2023 (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.
Status epilepticus (SE) is found in 20-30% of patients in coma after cardiac arrest, is often refractory to medical therapy and is considered a negative prognostic factor. Intensity and duration of treatment of refractory and super-refractory post-anoxic SE pose the ethical dilemma between futility of treatments and, conversely, their premature suspension. A recent study by the Epilepsy Center of the San Gerardo Hospital has shown that patients with super-refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome in more than 40% of cases, if treated with intensive and protracted therapy.
However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A combined anti-glutamatergic therapy with ketamine (anti-NMDA receptor) and perampanel (anti-AMPA receptor), aimed at counteracting the excitotoxicity linked to global cerebral ischemia, could be particularly effective in the treatment of super-refractory SE with post-anoxic etiology. Preliminary results in the first 26 patients treated in the Coordinating Center of the project indicate that this therapy appears safe and highly effective (80% SE resolution, 40% good neurological outcome).
The aim of the SUPER-CAT study is to investigate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with post-anoxic super-refractory status epilepticus, compared to other therapies, using a multi-centre, retrospective, cohort study design.
Detailed description
Status epilepticus (SE) is found in 20-30% of patients in a coma after cardiac arrest, is frequently refractory to medical therapy and is usually considered a poor prognostic factor. The intensity and duration of treatment for post-anoxic refractory and super-refractory SE remains a highly controversial issue, posing the ethical dilemma between futility and premature discontinuation of care.
Although the TELSTAR randomized clinical trial demonstrated the futility of aggressive treatment in post-anoxic patients with generalized periodic pattern, the question remains open about the benefit of aggressive therapy in post-anoxic patients with SE properly defined according to the Salzburg criteria.
The latest guidelines of the European Resuscitation Council recommend the use of electroencephalogram (EEG) both for the neurological prognosis and for the diagnosis of post-cardiac arrest epileptic seizures, define the highly malignant EEG patterns (which do not include status epilepticus; while generalized periodic pattern and suppressed background are included) and recommend treatment of seizures with first-line antiepileptic therapy (levetiracetam or valproate), while there are no recommendations regarding second-line antiepileptic therapy. The same guidelines recommend a multi-modal approach, using different indicators (brainstem reflexes, somatosensory evoked potentials, EEG patterns, neuron-specific enolase [NSE] levels and neuroimaging) to arrive at the formulation of the neurological prognosis. A favorable neurological outcome is present in <15% of post-anoxic SE cases after moderate intensity treatment.
A recent study by the Epilepsy Center of the San Gerardo Hospital ASST Monza on a prospective cohort of 166 consecutive patients with cardiac arrest showed that patients with refractory post-anoxic SE and favorable prognostic indicators can achieve a good functional outcome (CPC 1-2) in > 40% of cases, if treated aggressively and prolonged with second-line anti-epileptic and anesthetic therapy.
However, there is profound uncertainty about the best combination of antiseizure medications and anesthetics to use in this condition. A pilot study of the Epilepsy Center of the San Gerardo ASST Monza hospital has shown an efficacy of 75% of anti-glutamatergic therapy with oral load of perampanel (anti-AMPA receptor), combined with different types of anesthetics (including ketamine, anti -NMDA receptor), in 8 patients with super-refractory post-anoxic SE. All patients included in this series presented the main favorable prognostic indicators (presence of brainstem reflexes, presence of N20 cortical evoked potentials, absence of generalized periodic pattern) and in 60% of cases (5 out of 8 cases) a neuroimaging with mild anoxic damage. The clinical outcome was favorable, with the achievement of functional independence in 50% of cases (4 cases out of 8) after 3 months.
A dual anti-glutamatergic therapy, performed by combining ketamine and perampanel could contrast in a particularly effective way the excitotoxicity linked to the global cerebral ischemia, favoring the resolution of the super-refractory SE and improving the global outcome of the post-cardiac arrest patient. Preliminary results in the first 26 post-anoxic super-refractory SE patients treated in the project Coordinating Center indicate that a dual anti-glutamatergic therapy with ketamine and perampanel appears highly effective (81% SE resolution; 41% good neurological outcome after 6 months) and without significant side effects. The selection of these patients was made on the basis of the multi-modal prognostic indicators described above, in accordance with the current guidelines on neurological prognosis.
The aim of the SUPER-CAT study is to evaluate the efficacy and safety of combined therapy with ketamine and perampanel (dual anti-glutamatergic therapy) in patients with super-refractory SE of post-anoxic aetiology, compared to other therapies, using a multi-centre, retrospective, cohort study design.
The study will be conducted thanks to the collaboration of the Intensive Care and Resuscitation Units and the Epilepsy Centers of 9 Italian hospitals, with the epidemiological-statistical coordination of the Mario Negri Institute for Pharmacological Research in Milan.
Patients with super-refractory status epilepticus after in-hospital or out-of-hospital cardio-circulatory arrest will be enrolled.
The results of the study will allow to compare the feasibility, efficacy and safety of dual anti-glutamate therapy with ketamine and perampanel in super-refractory post-anoxic SE compared to other anti-epileptic and anesthetic therapies used in normal clinical practice. If clinically relevant, these results will lay the foundations for the development of a subsequent randomized clinical trial.
The study has a retrospective observational design, therefore no interventions or modifications in conventional diagnostic and therapeutic procedures will be carried out.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Dual anti-glutamate therapy (DUAL) | – | Drug: KetaminePatients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of "ketamine pattern") + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual dose reduction according to clinical evolution. |
| Control (OTHERS) | – | Drug: Any anti-epileptic and anesthetic therapy, excluding Ketamine and PerampanelPatients who received any antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs ketamine and perampanel. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Patients with super-refractory status epilepticus after cardiac arrest, admitted to the Intensive Care Unit, with continuous EEG monitoring, presence of first-line favorable prognostic indicators (pupillary reflexes and N20 cortical responses bilaterally; absence of periodic EEG pattern). Outcomes will be also analyzed for the following pre-defined population: "Patients with favorable prognostic indicators": patients presenting 5 or more of the following: 1) presence of a pupillary reflex bilaterally; (2) presence of corneal reflex bilaterally; (3) presence of N20 cortical response bilaterally; (4) NSE <68 ng/mL at 24-72 hours from ACC; (5) absence of periodic EEG patterns (GPDs); (6) absence of severe anoxic brain damage on neuroimaging
Key inclusion criteria (6 listed)
- age ≥ 18 years
- patients in coma after cardio-circulatory arrest (CCA) admitted to the Intensive Care Unit and treated with target temperature management (TTM) for the first 24 hours
- initiation of continuous electroencephalographic (cEEG) monitoring within 24-36 hours of CCA
- diagnosis of super-refractory status epilepticus, relapsed after the first cycle of anesthetics (lasting > 24 hours) and antiepileptic therapy, defined according to the international Salzburg criteria9
- presence of pupillary reflex present bilaterally
Key exclusion criteria (3 listed)
- EEG with periodic pattern (generalized periodic discharges; GPDs)
- status epilepticus resolved after the first cycle of anesthetics + antiepileptics
- pregnant women
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 |
|---|---|---|
| KetamineAlso: Perampanel"Dual anti-glutamatergic therapy" (DUAL) intervention group: patients who received ketamine as a continuous i.v. for 3 days (induction dose 1.5-3 mg/kg, followed by maintenance dose 2-10 mg/kg/h; dose adjustment according to EEG target of "ketamine pattern") + oral perampanel via nasogastric tube for 5 days (12 mg if weight > 60 kg; 9 mg if weight 50-60 kg; 6 mg if weight < 50 kg), followed by gradual reduction according to clinical evolution. | Drug | Dual anti-glutamate therapy (DUAL) |
| Any anti-epileptic and anesthetic therapy, excluding Ketamine and PerampanelAlso: Levetiracetam, Valproate, Phenytoin, Lacosamide, Topiramate, Propofol, Midazolam, ThiopentalAny antiseizure and anesthetic therapy according to usual clinical practice, excluding the two anti-glutamate drugs Ketamine and Perampanel | Drug | Control (OTHERS) |
Primary outcome
Number of patients with resolution of status epilepticus
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with resolution of status epilepticus, not followed by relapse and without the use of additional antiepileptic drugs, evaluated over the entire period of stay in the Intensive Care Unit, in the two groups DUAL versus OTHERS
8 secondary outcomes
Number of patients with with time-locked resolution of status epilepticus
Time frame: first 5 days after start of therapy
Number of patients with early favorable neurological outcome
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with favorable long-term neurological outcome
Time frame: 6 months after cardiac arrest
mortality in intensive care
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
mortality at 6 months
Time frame: 6 months after cardiac arrest
cumulative probability of resolution of status epilepticus
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with abnormal cholestasis indices
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Number of patients with third degree atrioventricular block or cardiac arrest recurrence
Time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Jul 2026.
- Background: PubMed 22366352Mani R, Schmitt SE, Mazer M, Putt ME, Gaieski DF. The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia. Resuscitation. 2012 Jul;83(7):840-7. doi: 10.1016/j.resuscitation.2012.02.015. Epub 2012 Feb 23.
- Background: PubMed 28163232Lybeck A, Friberg H, Aneman A, Hassager C, Horn J, Kjaergaard J, Kuiper M, Nielsen N, Ullen S, Wise MP, Westhall E, Cronberg T; TTM-trial Investigators. Prognostic significance of clinical seizures after cardiac arrest and target temperature management. Resuscitation. 2017 May;114:146-151. doi: 10.1016/j.resuscitation.2017.01.017. Epub 2017 Feb 3.
- Background: PubMed 26629753Cronberg T. Should Postanoxic Status Epilepticus Be Treated Agressively? Yes! J Clin Neurophysiol. 2015 Dec;32(6):449-51. doi: 10.1097/WNP.0000000000000209.
- Background: PubMed 28506865Dragancea I, Wise MP, Al-Subaie N, Cranshaw J, Friberg H, Glover G, Pellis T, Rylance R, Walden A, Nielsen N, Cronberg T; TTM trial investigators. Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management. Resuscitation. 2017 Aug;117:50-57. doi: 10.1016/j.resuscitation.2017.05.014. Epub 2017 May 12.
- Background: PubMed 35196426Ruijter BJ, Keijzer HM, Tjepkema-Cloostermans MC, Blans MJ, Beishuizen A, Tromp SC, Scholten E, Horn J, van Rootselaar AF, Admiraal MM, van den Bergh WM, Elting JJ, Foudraine NA, Kornips FHM, van Kranen-Mastenbroek VHJM, Rouhl RPW, Thomeer EC, Moudrous W, Nijhuis FAP, Booij SJ, Hoedemaekers CWE, Doorduin J, Taccone FS, van der Palen J, van Putten MJAM, Hofmeijer J; TELSTAR Investigators. Treating Rhythmic and Periodic EEG Patterns in Comatose Survivors of Cardiac Arrest. N Engl J Med. 2022 Feb 24;386(8):724-734. doi: 10.1056/NEJMoa2115998.
- Background: PubMed 27571157Leitinger M, Trinka E, Gardella E, Rohracher A, Kalss G, Qerama E, Hofler J, Hess A, Zimmermann G, Kuchukhidze G, Dobesberger J, Langthaler PB, Beniczky S. Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study. Lancet Neurol. 2016 Sep;15(10):1054-62. doi: 10.1016/S1474-4422(16)30137-5. Epub 2016 Aug 8.
- Background: PubMed 33773827Nolan JP, Sandroni C, Bottiger BW, Cariou A, Cronberg T, Friberg H, Genbrugge C, Haywood K, Lilja G, Moulaert VRM, Nikolaou N, Mariero Olasveengen T, Skrifvars MB, Taccone F, Soar J. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines 2021: Post-resuscitation care. Resuscitation. 2021 Apr;161:220-269. doi: 10.1016/j.resuscitation.2021.02.012. Epub 2021 Mar 24.
- Background: PubMed 26117526Dragancea I, Backman S, Westhall E, Rundgren M, Friberg H, Cronberg T. Outcome following postanoxic status epilepticus in patients with targeted temperature management after cardiac arrest. Epilepsy Behav. 2015 Aug;49:173-7. doi: 10.1016/j.yebeh.2015.04.043. Epub 2015 Jun 24.
- Background: PubMed 30381366Beretta S, Coppo A, Bianchi E, Zanchi C, Carone D, Stabile A, Padovano G, Sulmina E, Grassi A, Bogliun G, Foti G, Ferrarese C, Pesenti A, Beghi E, Avalli L. Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Neurology. 2018 Dec 4;91(23):e2153-e2162. doi: 10.1212/WNL.0000000000006615. Epub 2018 Oct 31.
- Background: PubMed 30159874Beretta S, Padovano G, Stabile A, Coppo A, Bogliun G, Avalli L, Ferrarese C. Efficacy and safety of perampanel oral loading in postanoxic super-refractory status epilepticus: A pilot study. Epilepsia. 2018 Oct;59 Suppl 2:243-248. doi: 10.1111/epi.14492. Epub 2018 Aug 29.
- Derived from this study: PubMed 42837646Beretta S, Pozzi M, Tagliabue S, Bianchi E, Rossi E, Pasini F, Giglio A, Cereda GS, Morotti Colleoni C, Pederzoli G, Giovannini G, Orlandi N, Meletti S, Gaiani A, Filipponi S, Cucino A, Normanno M, Mariani I, Scanziani M, Giani M, Diamanti S, Coppo A, DiFrancesco JC, Stabile A, Tinti L, Florio I, Sist C, Corona M, Pinna B, Orlandini F, Cossu G, Ferlisi M, Casartelli-Liviero M, Misirocchi F, Florindo I, Zinno L, Bartolini Y, Longoni M, Russo E, Grippo A, Ferrarese C, Foti G, Avalli L. Dual Antiglutamate Therapy in Super-Refractory Status Epilepticus After Cardiac Arrest (SUPER-CAT Study). Neurology. 2026 Oct 27;107(8):e218565. doi: 10.1212/WNL.0000000000218565. Epub 2026 Oct 5.
- Individual participant dataSharing planned: Undecided
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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. This study is not recruiting at the moment.
Simone Beretta, MD, PhD principal investigator
University of Milano Bicocca
Matteo Pozzi, MD study chair
Fondazione IRCCS Gerardo dei Tintori Monza
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Status Epilepticus and Cardiac Arrest, run by University of Milano Bicocca at 10 sites in Italy.
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 6 inclusion and 3 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: finished, as of the sponsor's last update on 14 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in Italy. 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.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of patients with resolution of status epilepticus (time frame: Over the entire period of stay in the Intensive Care Unit (up to 30 days)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05756621, which also lists 11 linked publications.
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 14 Jul 2026.