Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT)

Traumatic Brain Injury Clinical Trial

— INDICT  

Official title:

Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT): a Phase 2 Randomized, Feasibility Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05337618
• Other study ID #: Not yet assigned
• Status: Recruiting
• Phase: Phase 2
• Start date: December 16, 2022
• Est. completion date: September 20, 2026

Study information

• Verified date: September 2023
• Source: University of Cincinnati
• Contact: Jed A Hartings, PhD
• Phone: 513-295-2370
• Email: jed.hartings[@]uc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study is a randomized Phase 2 trial to determine the feasibility of real-time electrocorticographic monitoring of spreading depolarizations (SD) to guide implementation of a tier-based protocol of intensive care therapies, aimed at SD suppression, for the management of patients who have undergone acute operative treatment of severe traumatic brain injury.

Description:

The goal of acute TBI treatment is to minimize secondary damage that evolves over hours to days after the primary injury. Until now, however, there have been no methods for monitoring heterogeneous pathologic mechanisms to identify patients for appropriate neuroprotection therapies. Using invasive monitoring, investigators have documented that spreading depolarizations (SD), a cytotoxic dysfunction of cerebral gray matter that has been well-characterized through 60 years of research in animal models, are the dominant pathophysiologic process in peri-lesion cortex of many, but not all, severe TBI patients. Furthermore, it was found that the occurrence of SD as a secondary injury process in patients is an independent predictor of worse neurologic outcomes. Thus, monitoring of SD as a heterogeneous mechanism in TBI may allow selective use of therapy in only those patients who might benefit.

Here the investigators will conduct a randomized Phase 2 feasibility trial that uses real-time SD monitoring to guide implementation of a tier-based protocol of intensive care therapies aimed at SD suppression. The study is based on the hypothesis that outcomes from severe TBI can be improved by targeting intensive care therapies to suppress the pathology of SDs as a brain marker and mechanism of secondary injury. The objective of this study is to test the feasibility of this approach to intensive care management of severe TBI in a Phase 2 trial that uses real-time SD monitoring to guide administration of prescribed therapies to suppress SD. The aims are to (1) determine the feasibility of real-time SD monitoring to guide intensive care management of severe TBI, and (2) determine the effect of SD-guided vs. standard care management to reduce secondary brain insults in severe TBI.

This is a randomized Phase 2 clinical trial enrolling approximately 72 patients at 3 sites. Patients requiring neurological surgery for emergency treatment of TBI will be enrolled. The need for surgery allows for the placement of an electrode strip on the brain during surgery for subsequent electrocorticography (ECoG). ECoG data will be monitored continuously in real-time for the occurrence of SDs during intensive care. When SDs are observed, these patients (~60%, or n=43) will be randomized 1:1 to either standard (control) or SD-guided care. In the standard care arm, treatment will follow local and national guidelines with blinding to further ECoG results. In the SD-guided arm, treatment will follow a tiered-based protocol with escalation and de-escalation based on efficacy to suppress further SD pathology. Treatments will include use of ketamine sedation and adjusted targets for plasma glucose, cerebral perfusion pressure, temperature, and end-tidal CO2.

As outcomes, the accuracy of real-time SD scoring and compliance with protocol tier assignment and therapy implementation will be assessed. The burden of SD pathology, other measures of cerebral physiology (intracranial and cerebral perfusion pressures, and brain oxygenation), and medical complications will also be compared between the two study arms.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 72
• Est. completion date: September 20, 2026
• Est. primary completion date: April 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

(1) clinical indication for emergency craniotomy with dural opening to treat acute TBI within 72 hr post-trauma

Exclusion Criteria:

1. persistent bilateral non-reactive pupils or other evidence of non-survivable injury,

2. decompressive craniectomy to treat refractory ICP subsequent to diffuse injury, (3) co-enrollment in another therapeutic TBI trial, and

(4) pregnancy

Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Traumatic Brain Injury

Intervention

Diagnostic Test:
• Full-band Electrocorticography
Diagnosis of spreading depolarizations in continuous electrocorticography

Combination Product:
• Treatment Algorithm
Protocol for escalation and de-escalation of physiologic-targeted and pharmacologic therapies to treat and prevent spreading depolarizations

Locations

Country	Name	City	State
United States	University of Cincinnati	Cincinnati	Ohio

Sponsors (3)

Lead Sponsor	Collaborator
University of Cincinnati	University of New Mexico, University of Pennsylvania

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Burden of spreading depolarizations	Spreading depolarization events will be scored based on review of electrocorticographic recordings. The number of depolarizations per recording day over the period of monitoring will serve as the measure of total burden. The burdens computed for patients will be compared between the two randomization arms.	During the period of intensive care invasive monitoring, up to two weeks after injury
Secondary	Burden of elevated intracranial pressure	The time integral of the continuously monitored intracranial pressure signal above 22 mmHg will be computed for each patient as the measure of burden. The burdens computed for patients will be compared between the two randomization arms.	During the period of intensive care invasive monitoring, up to two weeks after injury
Secondary	Burden of cerebral hypoxia	The time integral of the continuously monitored cerebral oxygenation below 20 mmHg will be computed for each patient as the measure of burden. The burdens computed for patients will be compared between the two randomization arms.	During the period of intensive care invasive monitoring, up to two weeks after injury
Secondary	Burden of low cerebral perfusion	The time integral of the continuously monitored cerebral perfusions pressure below 60 mmHg will be computed for each patient as the measure of burden. The burdens computed for patients will be compared between the two randomization arms.	During the period of intensive care invasive monitoring, up to two weeks after injury
Secondary	Glasgow Outcome Score-Extended	Scores on the GOS-E will be compared between the two randomization arms	6 months post-injury