Importance of Substance P in Intracranial Pressure Elevation Following Traumatic Brain Injury (NK1)

Traumatic brain (TBI) injury is the major cause of morbidity and mortality worldwide especially in population under 40 years of age and has a significant socioeconomic impact. TBI results from the head impacting with an object or from acceleration/deceleration forces that produce vigorous movement of the brain within the skull, with the resultant mechanical forces potentially damaging neurones and blood vessels and causing irreversible, primary brain injury. Primary injury leads to activation of cellular and molecular responses which lead to disruption of the blood-brain barrier causing the brain to swell. As the intracranial space is not expandable (i.e. is fixed), this swelling leads to increase in intracranial pressure (ICP) compromising blood supply to the rest of the brain leading to secondary brain injury. As we are unable to reverse the primary injury, current protocols use supportive measures to control the ICP and ensure optimal blood supply to the brain in an attempt to minimize secondary injury. Our understanding of the factors involved in the initiation and propagation of brain swelling in TBI is growing and the role of neuroinflammatory cytokines in this process is increasingly recognized. In preclinical models of TBI, a specific inflammatory cytokine termed substance P (SP) is found to be associated with blood-brain barrier disruption and development of brain oedema in the immediate phase following injury. The aim of this study is to examine the role of SP in the genesis of cerebral oedema and elevation of ICP and thus secondary injury following human TBI. This would be achieved by blocking SP function with a SP receptor antagonist Fosaprepitant (IVEMEND®, Merck) in the first 24 hours following TBI and then continuously measuring ICP and assessing the evolvement of TBI using magnetic resonance imaging.

Study Overview

• Status: Withdrawn
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: Fosaprepitant

Detailed Description

All severe traumatic brain injury patients admitted to the Cambridge University Hospital's Neurosciences Critical Care Unit who require insertion of a triple bolt for multimodal neuromonitoring (intracranial pressure-ICP, microdialysis-MD and brain tissue oxygen partial pressure-PbtO2) will be screened for participation in this study. Eligible patients will have an initial MRI scan in the first 24 hours from injury. Following this, and within 24 hours from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant)will be administered at a dose of 300 mg, intravenously over 1 hour. Patients will then have a follow up MRI scan in the 24 hour following IVAMEND administration. Continuous ICP and PbtO2 monitoring as well as hourly microdialysis sampling will start immediately following insertion of monitors and at least 6 hours before and will continue for at least 12 hours after IVAMEND administration. ICP will continue to be monitored continuously in the 5 days following administration of IVAMEND. Microdialysis samples collected over the period of 6 hours before and 12 hours after the administration of Fosaprepitant will be stored and consequently used to measure the concentration of Substance P, nitric oxide (NO) and inflammatory cytokines.

• Study Type: Interventional
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with traumatic brain injury requiring intracranial pressure monitoring
• Age 18-65 years
• Abnormal CT scan

Exclusion Criteria:

• Bilateral fixed and dilated pupils
• Bleeding diathesis
• Devastating injuries; patient not expected to survive > 24 hours
• Brainstem damage
• Pregnancy
• Sedation with Midazolam
• Patients under 18 years of age

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Treatment; There is only one arm in this study. Intracranial pressure and brain swelling will be monitored before and after administration of fosaprepitant	Drug: Fosaprepitant; Within 24 hours from injury, IVAMEND (the intravenous formulation of the NK-1 antagonist fosaprepitant) will be administered at a dose of 300 mg, intravenously over 1 hour.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction in intracranial pressure	Intracranial pressure will be measured continuously for up to 5 days after intervention	up to 5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in brain tissue oxygen tension	Brain Tissue Oxygen will be measured continuously for up to 5 days after intervention	up to 5 days
Improvement in lactate/pyruvate ratio on microdialysis monitoring	Microdialysis will be measured continuously for up to 5 days after intervention	up to 5 days

Collaborators and Investigators

• Sponsor: Arun Gupta
• Collaborators: Cambridge University Hospitals NHS Foundation Trust
• Investigators: Principal Investigator: Arun Gupta, MD PhD, Cambridge University Hospitals NHS Foundation Trust

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2021
• Primary Completion (Anticipated): December 1, 2022
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: January 21, 2017
• First Submitted That Met QC Criteria: January 26, 2017
• First Posted (Estimate): January 30, 2017

Study Record Updates

• Last Update Posted (Actual): November 3, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Intracranial Hypertension; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Neurokinin-1 Receptor Antagonists; Aprepitant; Fosaprepitant
• Other Study ID Numbers: 212176

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• 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