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Subarachnoid Hemorrhage, AneurysmalPhase 4KETA-BIDNCT05095857

The Anaesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury

A Phase 4 study testing S-ketamine in people with Subarachnoid Hemorrhage, Aneurysmal and Intracerebral Hemorrhage, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial summary

Cortical spreading depolarisations are pathological depolarisation waves that occur frequently after severe acute brain injury and has been associated with poor outcome. S-ketamine has been shown to inhibit cortical spreading depolarisations. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
S-ketamine
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
400 participants
Where
1 siteDenmark
Study dates
15 Sep 2023to 15 Sep 2028
Phase
Phase 4
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 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age ≥ 18 years.
  • Admitted to the NICU with a diagnosis of traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (aSAH) or spontaneous intracerebral haemorrhage (ICH).
  • Planned for surgery with a supratentorial craniotomy or craniectomy.
  • Expected to continue sedation and mechanical ventilation after surgery.

Who cannot join

  • Neither patient or next of kin understand Danish or English.
  • Known allergy to S-ketamine (the active pharmaceutical ingredient or the excipients).
  • Wake-up call to occur immediately after surgery.
  • Pregnancy (all female participants aged ≤ 50 years will have a urine or blood hCG taken to control for pregnancy).
  • Active anti-psychotic treatment before admission.
  • Current abuse of ketamine.
Show all 9Show fewer
  • Decision to withdraw active treatment.
  • ICH secondary to a known brain tumour at the time of inclusion.
  • Since this is an emergency trial informed consent will be obtained from a trial guardian before inclusion of the participant, and informed consent will be sought from next of kin as soon as possible.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Kirsten Møller, Professor contact

Kirsten.Moeller.01@regionh.dk

Denmark1 site, 1 recruiting
  • Rigshospitalet

    Copenhagen

    Trine Hjorslev Andreasen, M.D, trine.hjorslev.andreasen@regionh.dk

    Recruiting

Other trials in Denmark

About this study

Official title: S-ketamine for Cortical Spreading Depolarisation in Patients With Severe Acute Brain Injury

Cortical spreading depolarisations are pathological depolarisation waves that occur frequently after severe acute brain injury and has been associated with poor outcome. S-ketamine has been shown to inhibit cortical spreading depolarisations. The aim of the present study is to examine the efficacy and safety of using S-ketamine for treatment of patients with severe acute brain injury, as well as the feasibility of the trial design.

Read the detailed description

Severe acute brain injury caused by traumatic brain injury (TBI), aneurysmal subarachnoid haemorrhage (aSAH) or intracerebral haemorrhage (ICH) carries a high morbidity and mortality. In all these conditions, clinical neurological deterioration may occur as a consequence of so-called secondary brain injury, which reduces the chance of a good outcome. Thus, neurological deterioration after the initial injury is generally associated with a worse outcome. Cortical spreading depolarisations (SDs) are pathological depolarisation waves that occur frequently after both TBI, SAH, and ICH and have been related to poor outcome. The SDs, which can be detected by electrocorticography (ECoG, using electrodes placed directly on the brain cortex), propagate across the cerebral cortex and are followed by an excessive upregulation of cerebral metabolism and decrease in cerebral blood flow. In vulnerable brain tissue such as in patients after acute primary brain injury, this combination of hypermetabolism and hypoperfusion is thought to increase the risk of ischaemia and infarction. The anaesthetic drug ketamine, which is an NMDA-receptor antagonist, appears to inhibit SDs both in vitro and in patient series.

The present trial is a randomised, blinded, placebo-controlled, parallel-group pilot and feasibility trial, where participants with clustered SD despite physiological optimisation are allocated 1:1 to infusion of S-ketamine versus matching placebo. In the present trial, participants admitted to the neurointensive care unit with TBI, aSAH or ICH and undergoing craniotomy or craniectomy (for clipping of an aneurysm or removal of a space-occupying haematoma). Patients are monitored at the neurointensive care unit, Rigshospitalet and sedated using standard sedatives. Patients will be monitored both with ECoG, intracranial pressure (ICP), brain tissue oxygen tension (PbtO2), and microdialysis. Patients in whom SDs occur will be subjected to a protocol of physiological optimisation targeting ICP, PbtO2, blood glucose and core temperature following clinical guidelines. If clustered SDs occur despite optimisation, patients are randomly allocated to infusion of either S-ketamine or matching placebo (isotonic saline) at a 1:1 allocation ratio with full blinding of the treatment allocation.

The present trial will continue until 160 participants have been randomised. Since only participants with clustered SDs are randomised, the investigators expect to include no more than 400 participants for ECoG monitoring.

The present trial aims to examine the efficacy of S-ketamine on SDs, the safety, and the feasibility of the trial design. Furthermore, surviving patients will be followed up until six months after the injury, and functional outcome will be recorded by the modified Rankin Scale (mRS).

Being tested
S-ketamine, Isotonic saline (placebo)
Keywords
Cortical Spreading Depolarisation, Ketamine
Medical subject headings
Subarachnoid Hemorrhage, Cerebral Hemorrhage, Brain Injuries, Traumatic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • S-ketamineDrug

    Also called Esketamine

    S-ketamines is an NMDA-receptor antagonist with sedative and analgesic properties. It will in the present trial be given in sedative doses (2-3 mg/kg/hour) in case of clustered SDs following a dosing algorithm according to SD occurrence.

  • Isotonic saline (placebo)Other

    Isotonic saline has the same appearance as S-ketamine with both being clear liquids with no bubbles or other distinguishing features.

Study groups in NCT05095857
Study groupRoleWhat they receive
S-ketamineActive comparatorS-ketamine is given as a continuous infusion started at a dose of 2.0 mg/kg/hour. The infusion rate will be re-evaluated after 24 hours, where (1) the infusion will be stopped if 24 hours ensue without SDs, (2) maintained at 2.0 mg/kg/hour if the 24-hour incidence of SDs decreases below the rate of the previous 24 hours but SD is not totally abolished, or (3) increased to 3.0 mg/kg/hour if the incidence of SD is at or above the rate of the previous 24 hours. If the infusion rate has been increased to 3.0 mg/kg/hour, the rate will be returned to 2.0 mg/kg/hour if 24 consecutive hours of ECoG show no SD.
Receives: Drug: S-ketamine
Isotonic salinePlacebo comparatorIsotonic saline is given as placebo. It will be given as a continuous infusion started at a dose corresponding to a dose of S-ketamine of 2.0 mg/kg/hour, and follow the criteria for increasing/decreasing infusion rates as S-ketamine. The infusion rate is read from a table listing different infusion rates (ml/hour) based on participant weight and if the treatment tier corresponds to a S-ketamine dose of 2 or 3 mg/kg/hour.
Receives: Other: Isotonic saline (placebo)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Occurrence of SDs after randomisation

    Efficacy of S-ketamine on the occurrence of cortical spreading depolarisations

    Measured: From randomisation to end of ECoG monitoring, expected to be a maximum of 14 days

Secondary outcomes (2)
  1. Rate of adverse events and adverse reactions

    Measured: During treatment with S-ketamine or placebo, a maximum of 14 days

  2. Functional outcome at 6 months after randomisation

    assessed using modified Rankin Scale

    Measured: 6 months after randomisation

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Oct 2021
  2. Study start15 Sep 2023
  3. Primary completion15 Sep 2028 (estimated)
  4. Study completion15 Sep 2028 (estimated)

Resources

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 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
400 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05095857
Sponsor's protocol ID
H-21056972
Other IDs
2021-003716-12
Acronym
KETA-BID
Status last verified
Jun 2024
First submitted
30 Sep 2021
Last updated
26 Jun 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017 Feb 11;389(10069):655-666. doi: 10.1016/S0140-6736(16)30668-7. Epub 2016 Sep 13.

    PubMed 27637674
  • Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009 Jul;8(7):635-42. doi: 10.1016/S1474-4422(09)70126-7. Epub 2009 Jun 6.

    PubMed 19501022
  • Zhou YT, Tong DM, Wang SD, Ye S, Xu BW, Yang CX. Acute spontaneous intracerebral hemorrhage and traumatic brain injury are the most common causes of critical illness in the ICU and have high early mortality. BMC Neurol. 2018 Aug 27;18(1):127. doi: 10.1186/s12883-018-1127-z.

    PubMed 30149796
  • Gross BA, Jankowitz BT, Friedlander RM. Cerebral Intraparenchymal Hemorrhage: A Review. JAMA. 2019 Apr 2;321(13):1295-1303. doi: 10.1001/jama.2019.2413.

    PubMed 30938800
  • Gruenbaum SE, Zlotnik A, Gruenbaum BF, Hersey D, Bilotta F. Pharmacologic Neuroprotection for Functional Outcomes After Traumatic Brain Injury: A Systematic Review of the Clinical Literature. CNS Drugs. 2016 Sep;30(9):791-806. doi: 10.1007/s40263-016-0355-2.

    PubMed 27339615
  • Gruenbaum SE, Bilotta F. Postoperative ICU management of patients after subarachnoid hemorrhage. Curr Opin Anaesthesiol. 2014 Oct;27(5):489-93. doi: 10.1097/ACO.0000000000000111.

    PubMed 25115766
  • Seder DB, Mayer SA. Critical care management of subarachnoid hemorrhage and ischemic stroke. Clin Chest Med. 2009 Mar;30(1):103-22, viii-ix. doi: 10.1016/j.ccm.2008.11.004.

    PubMed 19186283
  • Sheriff FG, Hinson HE. Pathophysiology and clinical management of moderate and severe traumatic brain injury in the ICU. Semin Neurol. 2015 Feb;35(1):42-9. doi: 10.1055/s-0035-1544238. Epub 2015 Feb 25.

    PubMed 25714866
  • Shah S, Kimberly WT. Today's Approach to Treating Brain Swelling in the Neuro Intensive Care Unit. Semin Neurol. 2016 Dec;36(6):502-507. doi: 10.1055/s-0036-1592109. Epub 2016 Dec 1.

    PubMed 27907954
  • Gradisek P, Osredkar J, Korsic M, Kremzar B. Multiple indicators model of long-term mortality in traumatic brain injury. Brain Inj. 2012;26(12):1472-81. doi: 10.3109/02699052.2012.694567. Epub 2012 Jun 21.

    PubMed 22721420
  • Olsen MH, Orre M, Leisner ACW, Rasmussen R, Bache S, Welling KL, Eskesen V, Moller K. Delayed cerebral ischaemia in patients with aneurysmal subarachnoid haemorrhage: Functional outcome and long-term mortality. Acta Anaesthesiol Scand. 2019 Oct;63(9):1191-1199. doi: 10.1111/aas.13412. Epub 2019 Jun 7.

    PubMed 31173342
  • Cordonnier C, Demchuk A, Ziai W, Anderson CS. Intracerebral haemorrhage: current approaches to acute management. Lancet. 2018 Oct 6;392(10154):1257-1268. doi: 10.1016/S0140-6736(18)31878-6.

    PubMed 30319113
  • Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, Menon DK, Pickard JD, Kirkpatrick PJ. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1343-53. doi: 10.1136/jnnp-2014-307711. Epub 2014 May 20.

    PubMed 24847164
  • Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011 Jan;31(1):17-35. doi: 10.1038/jcbfm.2010.191. Epub 2010 Nov 3.

    PubMed 21045864
  • Hartings JA, Andaluz N, Bullock MR, Hinzman JM, Mathern B, Pahl C, Puccio A, Shutter LA, Strong AJ, Vagal A, Wilson JA, Dreier JP, Ngwenya LB, Foreman B, Pahren L, Lingsma H, Okonkwo DO. Prognostic Value of Spreading Depolarizations in Patients With Severe Traumatic Brain Injury. JAMA Neurol. 2020 Apr 1;77(4):489-499. doi: 10.1001/jamaneurol.2019.4476.

    PubMed 31886870

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing S-ketamine in people with Subarachnoid Hemorrhage, Aneurysmal and Intracerebral Hemorrhage, run by Copenhagen University Hospital, Rigshospitalet at 1 site in Denmark.

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 4 inclusion and 9 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: looking for participants now, as of the sponsor's last update on 26 Jun 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Denmark. 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. Some participants in this study may receive a placebo. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

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 Trine H Andreasen, MD (+4535455982, trine.hjorslev.andreasen@regionh.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Occurrence of SDs after randomisation (time frame: From randomisation to end of ECoG monitoring, expected to be a maximum of 14 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 NCT05095857, which also lists 27 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 26 Jun 2024.

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