Traumatic brain injury (TBI) is the leading cause of death and disability in the first four decades of life with a financial burden on the economy greater than stroke. Despite the obvious need, there are no approved drug treatments for TBI. The neuroinflammatory response associated with TBI may further stress cells that survived the primary insult (contusion) causing consequential brain damage. Activation of the excitatory P2X7 receptor in the brain by relatively high levels of ATP – as likely occur in TBI – promotes a pro-inflammatory environment that may add to the volume of brain damage. Supportive literature is available from animal models of neurotrauma, which respond favourably to P2X7 receptor antagonists. Hence, our hypothesis is that the inflammation and secondary brain damage that evolves hours or days after the primary insult is amenable to treatment by blocking the excitatory P2X7 receptor to tip the balance away from the proinflammatory environment to improve clinical outcome. We will test this hypothesis by evaluating the safety of the clinical stage P2X7 receptor antagonist, CE-224,535, in patients with TBI, the ability of the drug to access the injured brain tissue and to potentially favourably modify the neuroinflammatory response in patients with TBI and so lead to improved clinical outcome. The project progression will be milestone driven with minimal outputs from the project including an enhanced understanding of the role of the P2X7 receptor in the inflammation storm associated with TBI. However, positive clinical data will encourage further development of P2X7 receptor antagonists to meet the unmet need for a drug to improve the clinical outcomes following TBI.

Method

We propose to conduct a randomised, dose-finding clinical trial to identify a dose of CE-224,535 that is tolerable and active in TBI patients (see Clinical Trial Schema below). Patients will be randomised to receive standard of care only, or to receive standard of care plus a dose of CE-224,535.

Burn wound infections (BWI) can cause delayed healing, poor scarring and invasive infection leading to sepsis which can result in death of the patient. Burn wound infection and secondary sepsis are considered the most serious complications in thermally injured patients. Invasive BWI undoubtedly requires intravenous or oral antibiotics; however, nosocomial BWI can also be targeted with a wide variety of topical agents such as silver nitrate, povidone-iodine, topical antibiotics or acetic acid. To date, no consensus regarding superiority of a certain topical agent for the prevention or treatment of BWI has been reached.

Acetic acid has been used as an antibacterial agent for thousands of years, recently acetic acid has been a widely used topical antiseptic agent for the treatment of burns wounds. The study is a double-blinded, prospective, controlled, randomised study which will establish an optimal dose of acetic acid in treating bacterial load in colonised burn wounds.

Method

Following consent, patients who have a ≥1% total body surface area BSA burn injury/ies which are colonised with a specifically identifiable bacteria will be randomly allocated to receive 0.5% or 2% acetic acid application for 3 consecutive days (10 evaluable patients will be recruited into each study arm). Efficacy will be assessed by measuring the bacterial load from microbiology burn wound swabs, which will be taken daily from the beginning of treatment for 3 days. Tolerability of acetic acid application will be assessed by measuring a patient’s pain scores with a Visual Analogue Scale (VAS). Furthermore, the antimicrobial activity of acetic acid will be measured by extracting fluid from removed burns dressings and assessing the minimum inhibitory concentrations (MIC) to establish if active acetic acid is still present.

In a previous study of 100 major trauma patients with an Injury Severity Score of 16 or higher, we aimed to understand the immune and endocrine response to injury to identify factors associated with poor outcomes. The outcomes included loss of muscle, sepsis, infections, multi-organ failure and death. We measured a range of biomarkers every day for one month after injury, then monthly to 6 months with a final sampling at 1-year post-injury. Measurements included bicep muscle thickness, serum pro- and anti-inflammatory cytokines, immune cell function (neutrophil bactericidal function) and steroid hormone levels. One of the findings was that patients lost significant amounts of muscle in the first weeks after injury and that this was associated with very low levels of the androgenic steroid hormone DHEA. This hormone is not only important for muscle maintenance, but it also enhances neutrophil function and the low levels may increase susceptibility to infection.

Method

In this study, we are testing the hypothesis that restoring serum levels of DHEA soon after trauma will reduce muscle loss and improve immune function, specifically neutrophil function. The study involved using three doses of DHEA (50, 100 and 200 mg) given orally or sublingual, the latter to see if the first-pass metabolism affects serum levels of DHEA supplements. Patients involved are young victims of major trauma, or older hip fracture patients so that we can also assess the impact of the age of the patient. Patients are given DHEA for 3 days starting before day 7 post-injury and blood samples are taken at regular intervals and levels of DHEA assessed by LC-MS. On day 3 of supplementation and prior to supplementation neutrophil bactericidal function is also assessed.

Traumatic optic neuropathy (TON) causes visual loss in 2% of patients with traumatic brain injury (TBI). TON includes primary disruption of optic nerve axons and secondary degeneration for example due to subsequent compression.  Despite significant research into different treatments including corticosteroids and erythropoietin, no neuroprotective or axonal protective agent has proven benefit.  However, where optic nerve compression exists, surgical decompression is standard.

Whist symptomatic visual loss occurs in 2% of patients after TBI, recent evidence suggests that at least 50% of patients with moderate to severe TBI have TON on clinical testing and we hypothesise that the severity of retinal ganglion cell death relates to the extent of global neuronal loss after TBI.

The optic nerve is an accessible CNS tract, formed entirely by axons of retinal ganglion cells located in the inner retina. Optical coherence tomography (OCT) allows direct, non-invasive, assessment of retinal nerve fibre and retinal ganglion cell structural integrity in patients, whilst visual function testing allows detailed characterisation of the functional consequences of any abnormality.

Method

We plan to retrospectively and prospectively assess the effects of time to decompression on functional outcome after traumatic optic nerve decompression by examining records of past patients who have had optic nerve compression and prospectively following patients with traumatic optic nerve compression to relate retinal ganglion cell loss to rapidity of decompression. We also plan to image retinal ganglion cells using OCT as part of the Red Diamond study to relate retinal findings to TBI severity.

Lastly, we plan to add OCT and visual function assessments to the RECOS study to relate retinal findings to the development of CTE.