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

June 24, 2024 updated by: Trine Hjorslev Andreasen, Rigshospitalet, Denmark

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Estimated)

400

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • 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.

Exclusion Criteria:

  • 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.
  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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 Names:
  • 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
From randomisation to end of ECoG monitoring, expected to be a maximum of 14 days

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of adverse events and adverse reactions
Time Frame: During treatment with S-ketamine or placebo, a maximum of 14 days
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
6 months after randomisation

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
All-cause mortality
Time Frame: assessed at 6 months after randomisation
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
Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation
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
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
Postrandomisation period, expected up to 21 days
Dosage of standard sedatives and analgesics
Time Frame: Postrandomisation period, expected up to 21 days
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
Postrandomisation period, expected up to 21 days
Number of episodes of neurological worsening
Time Frame: Postrandomisation period, expected up to 21 days
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
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
Assessed after 2 years or when one-third of the 160 participants have been randomised
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
Assessed after 2 years or when one-third of the 160 participants have been randomised

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Rigshospitalet, Denmark

Collaborators

Copenhagen Trial Unit, Center for Clinical Intervention Research

Investigators

  • Principal Investigator: Trine H Andreasen, MD, Rigshospitalet, Denmark

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 15, 2023

Primary Completion (Estimated)

September 15, 2028

Study Completion (Estimated)

September 15, 2028

Study Registration Dates

First Submitted

September 30, 2021

First Submitted That Met QC Criteria

October 14, 2021

First Posted (Actual)

October 27, 2021

Study Record Updates

Last Update Posted (Actual)

June 26, 2024

Last Update Submitted That Met QC Criteria

June 24, 2024

Last Verified

June 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H-21056972
  • 2021-003716-12 (EudraCT Number)

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Traumatic Brain Injury

Clinical Trials on S-ketamine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Jordan

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe