Ketamine in Acute Brain Injury Patients. (BIKe)

• ClinicalTrials.gov Identifier: NCT05097261
• Recruitment Status: Recruiting
• First Posted: October 28, 2021
• Last Update Posted: October 28, 2021
• Sponsor: Geert Meyfroidt, MD, PhD
• Collaborators: University of Liege; Centre Hospitalier Régional de la Citadelle; AZ Delta; AZ Sint-Jan AV; AZ Turnhout
• Information provided by (Responsible Party): Geert Meyfroidt, MD, PhD, KU Leuven

Study Description

Brief Summary:

Although, in the past years, an increasing use of ketamine in Traumatic Brain injury (TBI) has been reported as an adjunct to other sedatives, there is no evidence from randomized clinical trial to support this practice.

The BIKe (Brain Injury and Ketamine) study is a double-blind placebo controlled randomized multicenter clinical trial to examine the safety and feasibility of using ketamine as an adjunct to a standard sedative strategy in TBI patients.

Condition or disease	Intervention/treatment	Phase
Brain Injuries, Traumatic	Drug: Ketamine; Drug: Placebo	Phase 4

Detailed Description:

In this study the effects of ketamine as an adjunct to an standard sedation regime in adult TBI patients will be investigated on the therapy intensity level and intracranial pressure. All patients will receive propofol for sedation to control ICP, to a maximum dose of 4 mg/kg/h. If the ICP is not controlled at the maximum dose of propofol, midazolam will be added, to a maximum dose of 0.3 mg/kg/h, as part of the current standard of care in the Participating Sites. All patients will receive remifentanil, fentanyl or sufentanil infusions for pain relief. The study medication (ketamine or placebo) will be started after randomization.

As part of the current standard of care in the Participating Sites, the decision for decompressive craniectomy and/or barbiturate coma will be taken after multidisciplinary consultation between the treating intensivist and neurosurgeon.

The decision to stop or reduce sedation, lies with the treating physician, based on the level of ICP control, the absence of clinical or radiological signs of deterioration of the neurologic state. In the case of barbiturate coma, the study drug will be discontinued. During and following decompressive craniectomy, the sedative regime (propofol/midazolam/study drug/ opioids) will be continued. In case of suspected or threatening Propofol-Related Infusion syndrome, propofol will be stopped and switched to midazolam. In case of hypertriglyceridemia >200 mg/dL, propofol will be reduced and if necessary, midazolam will be associated to allow control of sedation. During surgical procedures related to the traumatic brain injury or not, the study drug will not be discontinued. The use of open label administration of ketamine is not allowed during the course of the trial, i.e until hospital discharge.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Supportive Care
• Official Title: Brain Injury and Ketamine: a Prospective, Randomized Controlled Double Blind Clinical Trial to Study the Effects of Ketamine on Sedative Sparing and Intracranial Pressure in Traumatic Brain Injury Patients.
• Actual Study Start Date: September 6, 2021
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: December 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ketamine; Racemic ketamine® will be administered by continuous infusion in a prefilled 50 ml syringe at a concentration of 50 mg/ml, undiluted. The ketamine dose is 1 mg/kg/h, to a maximum dose of 120 mg/hour, which corresponds to an infusion rate of 0.02 ml/kg/h to a maximum rate of 2.4 ml/h. Study patients weighing over 120 kg will not exceed the maximum dose of 120mg/kg of ketamine. The study medication will be started within 6 hours after randomization. The IMP, ketamine, will be provided directly to each Participating Site by the official supplier of ketamine for Belgium (Pfizer).	Drug: Ketamine; Racemic ketamine® will be administered by continuous infusion in a prefilled 50 ml syringe at a concentration of 50 mg/ml, undiluted. The ketamine dose is 1 mg/kg/h, to a maximum dose of 120 mg/hour, which corresponds to an infusion rate of 0.02 ml/kg/h to a maximum rate of 2.4 ml/h.; Other Name: Ketalar
Active Comparator: Placebo; The placebo (NaCl 0.9%) will be provided in the same type syringes and administered at the same infusion rate as the IMP (0.02 ml/kg/h to a maximum rate of 2.4 ml/h).	Drug: Placebo; Placebo (NaCl 0.9%) will be provided in the same type syringes and administered at the same infusion rate as the IMP (0.02 ml/kg/h to a maximum rate of 2.4 ml/h).; Other Name: Saline

Outcome Measures

Primary Outcome Measures :

1. Change in therapeutic intensity of intracranial pressure (ICP) reducing measures, assessed by the TIL score (Therapy Intensity Level) [ Time Frame: From date of randomization (and start study drug) until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
   The primary efficacy endpoint will be the reduction in daily Therapy Intensity Level (TIL) score, based on the highest score in each item per day until study drug discontinuation (calculated every day on the available data at 7:00 AM). Scales for TIL score range from 0 (minimum) to 38 (maximum). Higher scores are related to worse outcome.

Secondary Outcome Measures :

1. Intracranial pressure (ICP) [ Time Frame: From date of randomization until study drug discontinuation or or date of death from any cause, whichever came first, assessed up to 6 months. ]
   The average of hourly validated intracranial pressure (mmHg) measurements per 24 hours
2. Duration of sedation [ Time Frame: defined as the start of the first infusion of either propofol, midazolam and/or dexmedetomidine to the cessation of the last uninterrupted infusion of either propofol, midazolam, opioids and/or dexmedetomidine, assessed up to 6 months. ]
   Total duration of the first period of sedative treatments (propofol, midazolam and/or dexmedetomidine)
3. Propofol [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed at ICU discharge, assessed up to 6 months. ]
   Total dose of propofol in mg per 24 hours
4. Mechanical ventilation [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
   Total duration of mechanical ventilation, defined as all types of ventilation where positive end expiratory pressure is applied, expressed in cm H2O (5 cm H2O minimum).
5. Midazolam [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
   Total dose of midazolam in mg per 24 hours
6. ICU length of stay [ Time Frame: From ICU admission until ICU discharge (end of stay is defined as application for discharge in the hospital computer system, or death), assessed up to 6 months. ]
   Length of stay (number of days) in ICU
7. Hospital length of stay [ Time Frame: From admission to hospital until end of stay in hospital (dead or alive), assessed up to 6 months. ]
   Length of stay in hospital (days)
8. Richmond Agitation-Sedation scale (RASS) [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
   Average daily RASS. Scale ranges from +4 (combative) until -5 (Unarousable).
9. Delirium [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
   Number of delirium-free days, assessed 3 times per day with the Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method for the ICU (CAM-ICU delirium scale).
10. eGOS [ Time Frame: 6 months after the onset of TBI ]
    extended Glasgow Outcome Scale (eGOS)
11. ICU mortality [ Time Frame: From date of randomization until ICU discharge, assessed up to 6 months. ]
    Mortality during ICU stay
12. In-hospital mortality [ Time Frame: From date of randomization until hospital discharge, assessed up to 6 months. ]
    Mortality during hospital stay
13. Barbiturate coma incidence [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
    The incidence of barbiturate coma
14. Barbiturate coma duration [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]
    The duration of barbiturate coma
15. Decompressive craniectomy [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months, assessed up to 6 months. ]
    The incidence of decompressive craniectomy
16. Propofol Infusion Syndrome (PRIS) [ Time Frame: From date of randomization until study drug discontinuation or date of death from any cause, whichever came first, assessed up to 6 months. ]

    Incidence of PRIS documented and diagnosed by the attending physician and defined as:

    • Cardiac manifestations, not explained by a coronary ischemic event:

      • Acute refractory bradycardia leading to asystole, or
      • ECG: widening of QRS-complex, or Brugada-syndrome-like patterns (particularly Type 1: Coved-type ST-segment elevation >2mm in >1 of V1-V3 followed by a negative T-wave), or ventricular tachy-arrhythmias

    • Combined with one or more of the following:

      • Unexplained metabolic acidosis (base deficit > 10 mmol/L)
      • Rhabdomyolysis (Creatinine kinase at least five times the upper limit of normal)
      • Hyperlipidaemia (triglyceride levels > 150 mg/dl)
      • Enlarged or fatty liver, apparent on CT or echography
    • All occurring in patients receiving propofol for > 24h
    • Diagnosed by the attending physician

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Traumatic brain injury patients
• Age >= 18 years
• Admitted to the ICU

• Within 72 hours after admission to the initial hospital:

  • ICP monitoring in place (parenchymal probe, ventricular catheter, or both)
  • Requiring sedation

Exclusion Criteria:

• Known pregnancy and/or lactation
• Imminent or actual brain death upon inclusion
• Allergy or intolerance to the study medication
• Pre-existing neurocognitive disorders, pre-existing congenital or non-congenital brain dysfunction.
• Inability to obtain informed consent
• Inclusion in an interventional randomised controlled trial of which the PI indicates that co-inclusion specifically in the BIKe study is prohibited.
• Therapy restriction code upon inclusion.
• Porphyria
• Glaucoma

Contacts and Locations

Contacts

Contact: Liese Mebis, PhD; 003216343125; liese.mebis@uzleuven.be

Locations

Belgium

AZ Delta; Not yet recruiting

Brugge, Belgium

Contact: Marc Bourgeois, MD; PhD

UZLeuven; Recruiting

Leuven, Belgium, 3001

Contact: Liese Mebis, PhD, MSc +3216343125 liese.mebis@uzleuven.be

Principal Investigator: Geert JP Meyfroidt, MD, PhD

Sub-Investigator: Veerle De Sloovere, MD

CHR de la Citadelle Liège; Not yet recruiting

Liège, Belgium

Contact: Hugues Maréchal, MD, PhD

CHU de Liège; Not yet recruiting

Liège, Belgium

Contact: Didier Ledoux, MD, PhD

AZ Turnhout; Not yet recruiting

Turnhout, Belgium

Contact: Eva Boonen, MD, PhD

Sponsors and Collaborators

Geert Meyfroidt, MD, PhD

University of Liege

Centre Hospitalier Régional de la Citadelle

AZ Delta

AZ Sint-Jan AV

AZ Turnhout

Investigators

• Principal Investigator: Geert Meyfroidt, MD PhD; Associate Professor of Medicine

More Information

• Responsible Party: Geert Meyfroidt, MD, PhD, Associate Professor of Medicine, KU Leuven
• ClinicalTrials.gov Identifier: NCT05097261
• Other Study ID Numbers: S60859; 2017-004698-15 ( EudraCT Number )
• First Posted: October 28, 2021
• Last Update Posted: October 28, 2021
• Last Verified: October 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Ketamine; 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; Molecular Mechanisms of Pharmacological Action