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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05095857
Recruitment Status : Not yet recruiting
First Posted : October 27, 2021
Last Update Posted : January 11, 2022
Sponsor:
Collaborator:
Copenhagen Trial Unit, Center for Clinical Intervention Research
Information provided by (Responsible Party):
Trine Hjorslev Andreasen, Rigshospitalet, Denmark

Tracking Information
First Submitted Date  ICMJE September 30, 2021
First Posted Date  ICMJE October 27, 2021
Last Update Posted Date January 11, 2022
Estimated Study Start Date  ICMJE March 1, 2022
Estimated Primary Completion Date December 1, 2026   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 21, 2021)
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
Original Primary Outcome Measures  ICMJE
 (submitted: October 14, 2021)
Occurrence of clustered SDs after randomisation [ Time Frame: During treatment with S-ketamine or placebo, a maximum of 14 days ]
Efficacy of S-ketamine on clustered cortical spreading depolarisations
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 21, 2021)
  • Rate of adverse events and adverse reactions [ Time Frame: During treatment with S-ketamine or placebo, a maximum of 14 days ]
  • Functional outcome at 6 months after randomisation [ Time Frame: 6 months after randomisation ]
    assessed using modified Rankin Scale
Original Secondary Outcome Measures  ICMJE
 (submitted: October 14, 2021)
  • Rate of adverse events and adverse reactions [ Time Frame: During treatment with S-ketamine or placebo, a maximum of 14 days ]
  • Functional outcome at 6 months after ictus of brain injury [ Time Frame: 6 months after ictus of brain injury ]
    assessed using modified Rankin Scale
Current Other Pre-specified Outcome Measures
 (submitted: December 21, 2021)
  • All-cause mortality [ Time Frame: assessed at 6 months after randomisation ]
  • 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
  • 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 ]
  • Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Dosage of standard sedatives and analgesics [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Number of episodes of neurological worsening [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • 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
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: October 14, 2021)
  • All-cause mortality [ Time Frame: assessed at 6 months after ictus of brain injury ]
  • 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
  • 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 ]
  • Occurrence of local cerebral hypoxia (PbtO2 <20 mmHg for more than 20 minutes) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Dosage of standard sedatives and analgesics [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Number of imaging procedures (CT of the brain, CT-angiography, digital subtraction angiography, MRI) [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Number of episodes of neurological worsening [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • Occurrence of delayed cerebral ischemia (DCI) in participants with aSAH [ Time Frame: Postrandomisation period, expected up to 21 days ]
  • 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
  • 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
 
Descriptive Information
Brief Title  ICMJE The Anesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury
Official Title  ICMJE Effect of S-ketamine on Cortical Spreading Depolarisation and Cerebral Metabolic Crisis in Patients With Severe Acute Brain Injury
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.
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).

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Subarachnoid Hemorrhage, Aneurysmal
  • Intracerebral Hemorrhage
  • Traumatic Brain Injury
Intervention  ICMJE
  • 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
  • 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.
Study Arms  ICMJE
  • 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.
    Intervention: Drug: S-ketamine
  • 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.
    Intervention: Other: Isotonic saline (placebo)
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: October 14, 2021)
400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 1, 2026
Estimated Primary Completion Date December 1, 2026   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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).
  • Immediate wake-up call planned after surgery.
  • Pregnancy (all female participants aged ≤ 50 years will have a blood hCG to control for pregnancy).
  • Current abuse of ketamine.
  • Active anti-psychotic treatment.

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Trine H Andreasen, MD +4535455982 trine.hjorslev.andreasen@regionh.dk
Contact: Kirsten Møller, Professor Kirsten.Moeller.01@regionh.dk
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05095857
Other Study ID Numbers  ICMJE H-21056972
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Trine Hjorslev Andreasen, Rigshospitalet, Denmark
Study Sponsor  ICMJE Rigshospitalet, Denmark
Collaborators  ICMJE Copenhagen Trial Unit, Center for Clinical Intervention Research
Investigators  ICMJE
Principal Investigator: Trine H Andreasen, MD Rigshospitalet, Denmark
PRS Account Rigshospitalet, Denmark
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP