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Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT) (INDICT)

Primary Purpose

Traumatic Brain Injury

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Full-band Electrocorticography
Treatment Algorithm
Sponsored by
University of Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of CincinnatiRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

SD-Guided Care

Standard ICU Care

Arm Description

In this arm, ECoG data will be reviewed for SDs in real-time using the bedside clinical CNS monitor. As a secondary measure, recognition of SDs will be facilitated by custom software on a laptop that receives data from the CNS monitor. Data on SD occurrence will be used to guide treatment in a tier-based therapeutic escalation and de-escalation protocol with the goal of SD suppression. Therapies to be used among the tiers include adjusted targets for MAP, CPP, PaCO2, plasma glucose, temperature, as well as ketamine pharmacotherapy. Changes between tiers are determined by the success or failure of SD suppression at the given treatment level.

Management in the Standard ICU Care arm will follow published national guidelines consisting of common ICU-based targets for physiologic intervention that are thought to mitigate the development of secondary brain injuries. Continuous ECoG monitoring will be performed for seizure monitoring, but information on the course of SDs in these patients will not be used to guide care. To enforce blinding to SD-related ECoG data, the ECoG bedside software will be locked with password protection to prevent displays with frequency filtering and time/amplitude scales that are necessary to identify SDs.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
Glasgow Outcome Score-Extended
Scores on the GOS-E will be compared between the two randomization arms

Full Information

First Posted
April 5, 2022
Last Updated
September 11, 2023
Sponsor
University of Cincinnati
Collaborators
University of New Mexico, University of Pennsylvania
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1. Study Identification

Unique Protocol Identification Number
NCT05337618
Brief Title
Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT)
Acronym
INDICT
Official Title
Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT): a Phase 2 Randomized, Feasibility Trial
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Recruiting
Study Start Date
December 16, 2022 (Actual)
Primary Completion Date
April 1, 2026 (Anticipated)
Study Completion Date
September 20, 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cincinnati
Collaborators
University of New Mexico, University of Pennsylvania

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief 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.
Detailed 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.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Participants will be randomized to one of two study groups based on a block design with randomized block sizes of 2, 4 or 6 determined individually for each study site.
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
72 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
SD-Guided Care
Arm Type
Experimental
Arm Description
In this arm, ECoG data will be reviewed for SDs in real-time using the bedside clinical CNS monitor. As a secondary measure, recognition of SDs will be facilitated by custom software on a laptop that receives data from the CNS monitor. Data on SD occurrence will be used to guide treatment in a tier-based therapeutic escalation and de-escalation protocol with the goal of SD suppression. Therapies to be used among the tiers include adjusted targets for MAP, CPP, PaCO2, plasma glucose, temperature, as well as ketamine pharmacotherapy. Changes between tiers are determined by the success or failure of SD suppression at the given treatment level.
Arm Title
Standard ICU Care
Arm Type
No Intervention
Arm Description
Management in the Standard ICU Care arm will follow published national guidelines consisting of common ICU-based targets for physiologic intervention that are thought to mitigate the development of secondary brain injuries. Continuous ECoG monitoring will be performed for seizure monitoring, but information on the course of SDs in these patients will not be used to guide care. To enforce blinding to SD-related ECoG data, the ECoG bedside software will be locked with password protection to prevent displays with frequency filtering and time/amplitude scales that are necessary to identify SDs.
Intervention Type
Diagnostic Test
Intervention Name(s)
Full-band Electrocorticography
Intervention Description
Diagnosis of spreading depolarizations in continuous electrocorticography
Intervention Type
Combination Product
Intervention Name(s)
Treatment Algorithm
Intervention Description
Protocol for escalation and de-escalation of physiologic-targeted and pharmacologic therapies to treat and prevent spreading depolarizations
Primary Outcome Measure Information:
Title
Burden of spreading depolarizations
Description
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.
Time Frame
During the period of intensive care invasive monitoring, up to two weeks after injury
Secondary Outcome Measure Information:
Title
Burden of elevated intracranial pressure
Description
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.
Time Frame
During the period of intensive care invasive monitoring, up to two weeks after injury
Title
Burden of cerebral hypoxia
Description
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.
Time Frame
During the period of intensive care invasive monitoring, up to two weeks after injury
Title
Burden of low cerebral perfusion
Description
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.
Time Frame
During the period of intensive care invasive monitoring, up to two weeks after injury
Title
Glasgow Outcome Score-Extended
Description
Scores on the GOS-E will be compared between the two randomization arms
Time Frame
6 months post-injury

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: (1) clinical indication for emergency craniotomy with dural opening to treat acute TBI within 72 hr post-trauma Exclusion Criteria: persistent bilateral non-reactive pupils or other evidence of non-survivable injury, decompressive craniectomy to treat refractory ICP subsequent to diffuse injury, (3) co-enrollment in another therapeutic TBI trial, and (4) pregnancy
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jed A Hartings, PhD
Phone
513-295-2370
Email
jed.hartings@uc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Karmen Herzig
Phone
513-558-0440
Email
herzigkm@ucmail.uc.edu
Facility Information:
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45267
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jed A Hartings, PhD
Phone
513-295-2370
Email
jed.hartings@uc.edu

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Access to trial IPD can be requested by qualified researchers engaging in independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). Data will also be shared through the Federal Interagency Traumatic Brain Injury Registry (FITBIR).

Learn more about this trial

Improving Neurotrauma by Depolarization Inhibition With Combination Therapy (INDICT)

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