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

Primary Purpose

Subarachnoid Hemorrhage, Aneurysmal, Intracerebral Hemorrhage, Traumatic Brain Injury

Status

Recruiting

Phase

Phase 4

Locations

Denmark

Study Type

Interventional

Intervention

S-ketamine

Isotonic saline (placebo)

About this trial

This is an interventional treatment trial for Subarachnoid Hemorrhage, Aneurysmal focused on measuring Cortical Spreading Depolarisation, Ketamine

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

RigshospitaletRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

S-ketamine

Isotonic saline

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Occurrence of SDs after randomisation

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

Secondary Outcome Measures

Rate of adverse events and adverse reactions

Functional outcome at 6 months after randomisation

assessed using modified Rankin Scale

Full Information

NCT ID

NCT05095857

First Posted

September 30, 2021

Last Updated

September 20, 2023

Sponsor

Rigshospitalet, Denmark

Collaborators

Copenhagen Trial Unit, Center for Clinical Intervention Research

1. Study Identification

Unique Protocol Identification Number

NCT05095857

Brief Title

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

Acronym

KETA-BID

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2023

Overall Recruitment Status

Recruiting

Study Start Date

September 15, 2023 (Actual)

Primary Completion Date

December 1, 2026 (Anticipated)

Study Completion Date

December 1, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Rigshospitalet, Denmark

Collaborators

Copenhagen Trial Unit, Center for Clinical Intervention Research

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Subarachnoid Hemorrhage, Aneurysmal, Intracerebral Hemorrhage, Traumatic Brain Injury

Keywords

Cortical Spreading Depolarisation, Ketamine

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

400 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

S-ketamine

Arm Type

Active Comparator

Arm Description

Arm Title

Isotonic saline

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

S-ketamine

Other Intervention Name(s)

Esketamine

Intervention Description

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.

Intervention Type

Other

Intervention Name(s)

Isotonic saline (placebo)

Intervention Description

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

Primary Outcome Measure Information:

Title

Occurrence of SDs after randomisation

Description

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

Time Frame

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

Secondary Outcome Measure Information:

Title

Rate of adverse events and adverse reactions

Time Frame

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

Title

Functional outcome at 6 months after randomisation

Description

assessed using modified Rankin Scale

Time Frame

6 months after randomisation

Other Pre-specified Outcome Measures:

Title

All-cause mortality

Time Frame

assessed at 6 months after randomisation

Title

Number of participants with signs of ischaemia or infarction on computed tomography (CT) or magnetic resonance imaging (MRI).

Description

Last scan performed on clinical indication before discharge from NICU or semi-intensive care unit

Time Frame

Before discharge from NICU or the semi-intentisive care unit, expected up to be no later than day 21 postrandomisation

Title

Occurrence of metabolic crisis (defined as microdialysis (MD)-lactate/pyruvate ratio >40, MD-glucose < 0.8 μmol/L)

Time Frame