Antisecretory Factor In Severe Traumatic Brain Injury (AFISTBI)

Evaluation of Antisecretory Factor in Treatment of Severe Traumatic Brain Injury With Multimodal Monitoring

This study evaluates the addition of Salovum, an egg yolk powder enriched for antisecretory factor, to standard care of participants with severe traumatic brain injury. Half of the participants will be administered Salovum while the other half will be given a placebo egg yolk powder, not enriched for antisecretory factor. Intracranial pressure (ICP), partial brain oxygen pressure (PtbO2), microdialysis of metabolites and inflammatory mediators and trauma intensity level (TIL) will be assessed in all patients.

Cerebral edema accounts for an essential part of the morbidity and mortality in severe traumatic brain injury but can also arise in other cerebral pathologies such as infectious and ischemic conditions such e.g. stroke and meningitis. Cerebral edema can lead to an elevated intracranial pressure (ICP) with impact on both perfusion and diffusion in the brain. AF (antisecretory factor) is a 41 kilodalton endogenous and essential protein with proposed antisecretory and anti-inflammatory effects. AF is homologous to S5A and Rpn10 proteins which are parts of the 26S proteasome subunit. AF also shows close homology to angiocidin a protein with reported anti-proliferative and anti-angiogenic properties. The AF protein is cleaved into several active peptides, one of which has been synthesized within a 16 amino acid peptide (AF-16) that has been used in animal experimental studies. Salovum® is a product based on the egg yolk powder B221®, and contains high levels of AF. Salovum® is classified as a food for special medical purposes (FSMP) by the European Food Safety Agency. AF has shown clinical effects in Mb Ménière, mastitis and meningitis. Experimentally AF-16 and AF have been shown to reduce intracranial pressure and improve outcome in models of traumatic brain injury (TBI) and herpes encephalitis. Preliminary results show reduction of ICP and improved outcome in human traumatic brain injury. A randomized, prospective, double-blinded phase 2-3 in participants with severe traumatic head injury is ongoing at Tygerberg University Hospital, Cape Town, South Africa (ClinicalTrials.gov identification number: NCT03339505). The antisecretory factor is an endogenous protein and no antibody formation has been demonstrated in human administration. Although Salovum® has been given to hundreds of patients, no side effects have been recorded. Egg yolk allergy is a contraindication but no cases of triggered allergy have been reported. The mechanisms underlying the effects of antisecretory factor on cerebral edema are not clarified. Immune modulation through effects on myeloid cells, proteasome modulation and effects on ion pumps have been proposed. The present study intends to clarify mechanisms behind the proposed effect of antisecretory factor in cerebral edema In the present study participants with severe traumatic brain injury as defined in inclusion and exclusion criteria will be randomised to either treatment with Salovum or placebo egg powder during 5 days after enrolment. Randomisation will be performed in blocks and randomisation envelopes will be used with the number inside the envelope. Salovum and normal egg powder will be suspended with tap water and administered through the gastric feeding tube. All participants will receive standard care for severe TBI according to the treatment algorithm at the Neuro Intensive Care Unit (NICU), Department of Neurosurgery, Skåne University Hospital, Lund, Sweden. The algorithm prescribes invasive monitoring of ICP, PtbO2 and metabolites (cerebral microdialysis). As this algorithm includes stepwise co-interventions in order to control ICP and cerebral perfusion pressure (CPP) the TIL score will be used to compensate for the bias of increased co-interventions in either arm. At follow up patients will be assessed for mortality and Glasgow Outcome Scale-Extended (GOSE)

traumatic brain injury, cerebral edema, antisecretory factor, inflammatory cytokines, cerebral oxygen monitoring, intracranial pressure, microdialysis

Participants with severe TBI and scheduled for multimodal monitoring will be randomised to active or placebo treatment.

Egg powder enriched for antisecretory factor and placebo egg powder with the same color, taste and texture,

Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)

Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)

Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis

Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis

Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma

Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma

Inclusion Criteria: Severe traumatic brain injury, Glasgow Outcome Scale (GCS) <9 at admission to NICU. Clinical indication for insertion of intracranial pressure monitor, intracerebral oxygen pressure monitor and microdialysis catheter. Consultation with relatives or consent from guardians. Exclusion Criteria: Known egg yolk allergy. Unilateral or bilateral fixed and dilated pupil after initial operative intervention.

Individual patient data that underlie published results will be made available after publication.after de identification.

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