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The Anesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury (KETA-BID)

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ClinicalTrials.gov Identifier: NCT05095857
Recruitment Status : Not yet recruiting
First Posted : October 27, 2021
Last Update Posted : January 27, 2022
Sponsor:
Collaborator:
Copenhagen Trial Unit, Center for Clinical Intervention Research
Information provided by (Responsible Party):
Trine Hjorslev Andreasen, Rigshospitalet, Denmark

Brief 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. 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.

Condition or disease Intervention/treatment Phase
Subarachnoid Hemorrhage, Aneurysmal Intracerebral Hemorrhage Traumatic Brain Injury Drug: S-ketamine Other: Isotonic saline (placebo) Phase 4

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).

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: S-ketamine for Cortical Spreading Depolarisation in Patients With Severe Acute Brain Injury
Estimated Study Start Date : March 1, 2022
Estimated Primary Completion Date : December 1, 2026
Estimated Study Completion Date : December 1, 2026

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: S-ketamine
S-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.
Drug: S-ketamine
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.
Other Name: Esketamine

Placebo Comparator: Isotonic saline
Isotonic 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.
Other: Isotonic saline (placebo)
Isotonic saline has the same appearance as S-ketamine with both being clear liquids with no bubbles or other distinguishing features.




Primary Outcome Measures :
  1. Occurrence of SDs after randomisation [ Time Frame: From randomisation to end of ECoG monitoring, expected to be a maximum of 14 days ]
    Efficacy of S-ketamine on the occurrence of cortical spreading depolarisations


Secondary Outcome Measures :
  1. Rate of adverse events and adverse reactions [ Time Frame: During treatment with S-ketamine or placebo, a maximum of 14 days ]
  2. Functional outcome at 6 months after randomisation [ Time Frame: 6 months after randomisation ]
    assessed using modified Rankin Scale


Other Outcome Measures:
  1. All-cause mortality [ Time Frame: assessed at 6 months after randomisation ]
  2. Number of participants with signs of ischaemia or infarction on computed tomography (CT) or magnetic resonance imaging (MRI). [ Time Frame: Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation ]
    Last scan performed on clinical indication before discharge from NICU or semi-intensive care unit

  3. Occurrence of metabolic crisis (defined as microdialysis (MD)-lactate/pyruvate ratio >40, MD-glucose < 0.8 μmol/L) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  4. Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  5. Dosage of standard sedatives and analgesics [ Time Frame: Postrandomisation period, expected up to 21 days ]
  6. Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  7. Number of episodes of neurological worsening [ Time Frame: Postrandomisation period, expected up to 21 days ]
  8. Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH [ Time Frame: Postrandomisation period, expected up to 21 days ]
  9. Fraction of participants included in the trial out of all eligible participants [ Time Frame: Assessed after 2 years or when one-third of the 160 participants have been randomised ]
    Feasibility outcome

  10. Fraction of participants who are randomised of all included [ Time Frame: Assessed after 2 years or when one-third of the 160 participants have been randomised ]
    Feasibility outcome



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age ≥ 18 years.
  • Admitted to the NICU with a diagnosis of TBI, aneurysmal SAH or spontaneous ICH.
  • Planned for surgery with a craniotomy or craniectomy.
  • Expected to continue sedation and mechanical ventilation after surgery.

Exclusion Criteria:

  • Patient and next of kin do not read or understand spoken Danish.
  • 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 blood hCG taken to control for pregnancy).
  • Active anti-psychotic treatment before admission
  • Current abuse of ketamine.

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.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05095857


Contacts
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Contact: Trine H Andreasen, MD +4535455982 trine.hjorslev.andreasen@regionh.dk
Contact: Kirsten Møller, Professor Kirsten.Moeller.01@regionh.dk

Sponsors and Collaborators
Rigshospitalet, Denmark
Copenhagen Trial Unit, Center for Clinical Intervention Research
Investigators
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Principal Investigator: Trine H Andreasen, MD Rigshospitalet, Denmark
Publications:

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Responsible Party: Trine Hjorslev Andreasen, MD, Principal Investigator, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT05095857    
Other Study ID Numbers: H-21056972
First Posted: October 27, 2021    Key Record Dates
Last Update Posted: January 27, 2022
Last Verified: January 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Trine Hjorslev Andreasen, Rigshospitalet, Denmark:
Cortical Spreading Depolarisation
Ketamine
Additional relevant MeSH terms:
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Brain Injuries
Brain Injuries, Traumatic
Subarachnoid Hemorrhage
Cerebral Hemorrhage
Hemorrhage
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Pathologic Processes
Intracranial Hemorrhages
Cerebrovascular Disorders
Vascular Diseases
Cardiovascular Diseases
Ketamine
Esketamine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anesthetics, Dissociative
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
Central Nervous System Depressants
Excitatory Amino Acid Antagonists
Excitatory Amino Acid Agents
Neurotransmitter Agents