ELASTIC: External Lumbar Drainage to Reduce ICP in Severe TBI: a Phase 1 Clinical Trial

Sponsor

Brain Trauma Foundation (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05889650

Collaborator

Uniformed Services University of the Health Sciences (U.S. Fed), University of Kansas (Other), The Cleveland Clinic (Other), Weill Medical College of Cornell University (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this phase 1 randomized controlled safety and feasibility clinical trial are to determine the safety of external lumbar drainage (ELD) in select patients with severe Traumatic Brain Injury (TBI). The main questions it aims to answer are (i) if ELD is feasible and (ii) safe to perform in severe TBI patients who have radiological evidence of patent basal cisterns and midline shift <5mm without increasing the risk of neurological worsening or cerebral herniation.

All participants will receive routine usual care. The study group will additionally have ELD for cerebrospinal fluid (CSF) drainage. A comparison will be made between the usual treatment plus ELD (interventional) groups, and the usual treatment (control) groups on incidence rate of neurological worsening or cerebral herniation events, and whether total hours with raised intracranial pressure (ICP) are different.

Condition or Disease	Intervention/Treatment	Phase
Severe Traumatic Brain Injury Intracranial Hypertension	Procedure: External Lumbar drainage	N/A

Detailed Description

This is a randomized controlled trial to determine the safety and feasibility of external lumbar drainage (ELD) of cerebrospinal fluid (CSF) as an adjunct to existing treatments to lower brain pressure, in select patients suffering severe traumatic brain injury (TBI). This trial is funded by the Department of Defense, Uniformed Services University of Health Sciences, Center for Neuroscience and Regenerative Medicine (CNRM).

Following a severe TBI, the brain swells and the pressure in the cranium rises causing further brain injury, The goal of treatment of such patients is to use treatments that lower brain swelling or pressure - directly by removing blood clots or indirectly by trying to lower the volume of contents in the cranium, viz. CSF or blood. Routinely a drain is placed in the skull to drain CSF out to provide space for brain swelling, thus keeping intracranial pressure (ICP) low. In some instances, all treatments available are unable to control swelling and the skull may need to be removed from one side, and in spite of this patients may die or suffer severe neurological injury and remain disabled.

Several non-randomized studies have shown that ELD is very effective in lowering intracranial pressure (ICP) in an immediate and lasting manner. While historical concerns remain that the brain may shift downwards causing herniation, this is not supported by recent studies. However, due to the historic nature of such teachings, some physicians may not use this potentially effective treatment in treating severe TBI patients with high ICP.

Therefore, in this trial we will determine the safety ELD in treating severe TBI patients, in a randomized controlled manner, whereby two-thirds of the patients will be randomized to routine usual treatments and either early or late ELD, and a third to only routine usual treatments. The patient randomized to ELD will receive this in addition to all other usual treatments, and no available treatment will be withheld

The secondary objectives are to determine if routine quantitative pupillometry and brain compliance measured using non-invasive ICP (nICP) can be used for safety determination and monitoring of ELD by evaluating:

Correlation with ELD safety score
Temporally changes prior to occurrence of any 'critical neuro-worsening events

Comparison / Usual treatment All participants will undergo usual treatment as per evidence- and guidelines-based Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC) algorithm (36, 71). Routine non-invasive automated infra-red pupillometry will be performed bilaterally every hour as part of routine neurological checks for neuro-worsening in addition to hourly Glasgow Coma Scale (GCS) score checks and other routine intensive care unit (ICU) protocols. No treatment will be withheld. ICP monitoring will be performed with intra-parenchymal monitor or external ventricular drainage (EVD) as per local protocols.

RISKS TO HUMAN SUBJECTS:

The assessments for this study involve risk and benefits to patients in excess of routine standard of care treatment. The risks related to the intervention i.e. placement of lumbar drain and drainage of CSF, are critical neurological worsening events related to cerebral herniation such as decrease in GCS score, development of new motor deficit, or rarely death. These events will be recorded for all patients and prompt treatment will be instituted accordingly, including an emergent computed tomography (CT) scan (36). Clinical protocols exist at all neurotrauma ICUs for such neuro-worsening events and neurointensivists and neurotrauma surgeons are well placed to manage them medically or surgically in routine care of severe TBI patients.

Background 'Event rate' for critical neuro-worsening events with usual treatment: To estimate background 'event rate' of critical neuro-worsening events, we analyzed the Brain Trauma Foundation (BTF)-New York State TBI-trac® registry from 1997-2004, with 4789 TBI patients, of which 3590 had CT data and 2616 were between the age of 18-65 years. When inclusion / exclusion criteria for age and CT findings were applied, 50.3% of these were eligible for the study. The mean incident risk of having new pupillary asymmetry at any point after admission was 22.0% (95% confidence intervals (CI): 19.9-24.3%), risk of motor worsening was 18.0% (95% CI: 12.6-25.0%) for those with motor score 1-4, and 16.4% (95% CI: 12.1-21.9%) for all motor scores with deterioration. Finally, risk of 2-week mortality was 22.4% (95% CI 20.2-24.8%). This data provides us with an expected event rate, though the comparison will still be made between control and intervention arms of the study, per protocol. Given the high incidence of these events occurring as natural history of the disease, they will be classified as anticipated Serious adverse events (SAEs).

Human Subjects Protections:

Pressure and Volume protected lumbar CSF drainage: In the studies reviewed, ELD was set to drain at 0-20 mmHg or drained at fixed volume. In order to increase safety, we will perform ELD in patients without high ICP at 15 mmHg and those with high ICP at 20 mmHg and additionally volume-limit drainage to 10 ml/hour.

Procedure safety:

Indication:

ELD will be utilized as the first intervention in the 2nd tier of SIBICC protocol, which will invariably be preceded by gradual increase in ICP. As per SIBICC protocol, a CT scan will be obtained prior to advancement to 2nd tier and ELD placement.

Contra-indications:

ELD will NOT be utilized to lower ICP during sudden ICP crises associated with neuro-worsening. Hypertonic saline, mannitol, hyperventilation, and review for surgery will be utilized as per clinical routine.

ELD will NOT be placed in lieu of an EVD. ELD will NOT be performed in patients undergoing hemicraniectomy.

Safety Monitoring: Given the greatest risk of neuro-worsening from herniation is soon after drainage is commenced, all patients will undergo automated pupillometry for pupillary size, symmetry, light reactivity and neurological pupillary index (NPI) every 15 minutes for 1 hour following ELD placement and start of CSF drainage. Following the first hour, pupillometry will be performed hourly. If NPI drops by 1 point within the 1st hour, a head CT may be obtained to review any craniocaudal shift.

SAFETY REPORTING: All unanticipated SAEs will be reported to the steering committee, local site institutional research boards (IRBs) as well as the overall IRB, within 24 hours. Anticipated SAE and adverse events (AEs) will be reported in annual reports.

Data Safety and Monitoring Board (DSMB):

A DSMB of a pool of 7 experienced trauma neurosurgeons and neurointensivists of international standing, will review every neuro-worsening events, as defined above, in each arm of the study. The DSMB will meet every 6 months to review anticipated SAEs. DSMB will review unanticipated SAE including deaths within 48 hours, and will make determinations of association of unanticipated adverse events with interventions.

Potential benefits of the proposed research to participants:

As this is an interventional study, the research participants may gain direct benefit or suffer harm. At conclusion of the study, the overall results will be included in a summary report mailed to all participants. In the field of TBI management, this study has potential benefits in treating post-traumatic intracranial hypertension, which is the main mechanism of neurological deterioration following severe TBI and improving functional outcome for participants.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

2-stage randomization2-stage randomization

Masking:

Single (Outcomes Assessor)

Masking Description:

Unaware of randomisation arm

Primary Purpose:

Treatment

Official Title:

External Lumbar Drainage to Abort Severe Traumatic IntraCranial Hypertension: A Phase 1 Randomized, Allocation-concealed, Open-label, Safety and Feasibility Clinical Trial

Anticipated Study Start Date :

Sep 1, 2023

Anticipated Primary Completion Date :

May 1, 2025

Anticipated Study Completion Date :

Aug 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1st stage - prophylactic External lumbar drainage @15mmHg if intracranial pressure is not raised on admission	Procedure: External Lumbar drainage ELD @ 15 or 20mmHg based on intervention arm with maximum of 10ml/hour drainage
Experimental: 2nd stage - treatment External lumbar drainage @20mmHg if / when intracranial pressure >20mmHg and tier 1 therapies cannot achieve ICP<20mmHg	Procedure: External Lumbar drainage ELD @ 15 or 20mmHg based on intervention arm with maximum of 10ml/hour drainage
No Intervention: Usual treatment Usual treatment as per SIBICC algorithm

Arm

Intervention/Treatment

Experimental: 1st stage - prophylactic

External lumbar drainage @15mmHg if intracranial pressure is not raised on admission

Procedure: External Lumbar drainage

ELD @ 15 or 20mmHg based on intervention arm with maximum of 10ml/hour drainage

Experimental: 2nd stage - treatment

External lumbar drainage @20mmHg if / when intracranial pressure >20mmHg and tier 1 therapies cannot achieve ICP<20mmHg

Procedure: External Lumbar drainage

ELD @ 15 or 20mmHg based on intervention arm with maximum of 10ml/hour drainage

No Intervention: Usual treatment

Usual treatment as per SIBICC algorithm

Outcome Measures

Primary Outcome Measures

Safety of ELD in selected Severe TBI patients [10 days]
Rate of occurrence of herniation events or death in 3 arms
Feasibility of ELD in selected Severe TBI patients [10 days]
Proportion of patients able to undergo treatment as per randomised arm

Secondary Outcome Measures

Reduction in ICP burden using ELD in selected severe TBI patients [10 days]
Total number of hours with ICP>20mmHg
Utility of non-invasive ICP based brain compliance to predict safety of ELD [10 days]
worsening of nICP based compliance in 6 hours preceding herniation events with occurrence of such events
Utility of automated pupillometry to predict safety of ELD [10 days]
worsening of Pupillometry based reactivity index in 6 hours preceding herniation events with occurrence of such events

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

18-65 years age
Glasgow Coma Scale (GCS) 3-8
Pupils symmetric and bilaterally reactive
Midline shift ≤5mm at the level of foramen of Monro on admission or post-operative brain CT
Patent (complete or partial) quadrigeminal cisterns on admission or post-operative brain CT
First randomization and intervention may be commenced within 24 hours of injury
ELD safety score ≥5

Exclusion Criteria:

GCS >8
Cisterns on CT completely effaced
Midline shift on CT >5mm
GCS 3 with dilated and fixed pupils
Uncal or tonsillar herniation on admission or post-operative brain CT
Temporal lobe contusions
Penetrating TBI
Primary hemicraniectomy
Pregnancy
Prisoners
Patients previously lacking capacity to consent or refuse treatment, or with advanced directives to forego aggressive care
Pre-existing conditions affecting functional status or life expectancy to less than 1 year
Contra-indications for ELD placement: coagulopathy, use of anticoagulants or anti-thrombotics, thrombocytopenia <50,000, or severe spinal deformity.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
2	University of Texas	San Antonio	Texas	United States	78249

Sponsors and Collaborators

Brain Trauma Foundation
Uniformed Services University of the Health Sciences
University of Kansas
The Cleveland Clinic
Weill Medical College of Cornell University

Investigators

Principal Investigator: Halinder S Mangat, MD MSc, Brain Trauma Foundation; Kansas University Medical Center Research Institute
Principal Investigator: Jamshid Ghajar, MD PhD, Brain Trauma Foundation
Principal Investigator: Gregory Hawryluk, MD PhD, The Cleveland Clinic