The Anesthetic Ketamine as Treatment for Patients With Severe Acute Brain Injury (KETA-BID)
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| ClinicalTrials.gov Identifier: NCT05095857 |
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Recruitment Status :
Not yet recruiting
First Posted : October 27, 2021
Last Update Posted : January 27, 2022
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Subarachnoid Hemorrhage, Aneurysmal Intracerebral Hemorrhage Traumatic Brain Injury | Drug: S-ketamine Other: Isotonic saline (placebo) | Phase 4 |
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 (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 |
| Arm | Intervention/treatment |
|---|---|
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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.
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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 |
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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.
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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. |
- 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
- 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
- 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
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
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
| Contact: Trine H Andreasen, MD | +4535455982 | trine.hjorslev.andreasen@regionh.dk | |
| Contact: Kirsten Møller, Professor | Kirsten.Moeller.01@regionh.dk |
| Principal Investigator: | Trine H Andreasen, MD | Rigshospitalet, Denmark |
| 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 |
| 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 |
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Cortical Spreading Depolarisation Ketamine |
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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 |