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.

Study Overview

• Status: Recruiting
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Dietary supplement: Placebo egg yolk powder; Dietary supplement: Salovum

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Peter Siesjö, MD, PhD; Phone Number: +4646171274; Email: peter.siesjo@med.lu.se
• Study Contact Backup: Name: David Cederberg, MD; Phone Number: +4646177655; Email: david.cederberg@med.lu.se

Study Locations

• Sweden
  • Lund, Sweden, 22185
    • Recruiting
    • Skane University Hopsital
    • Contact: David Cederberg, MD; Email: david.cederberg@med.lu.se

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 years to 66 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Egg yolk powder not enriched for antisecretory powder	Dietary supplement: Placebo egg yolk powder; Normal egg yolk powder
Experimental: Salovum; Egg yolk powder enriched for antisecretory powder	Dietary supplement: Salovum; Active egg yolk powder; Other Names: Antisecretory factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICP mean	Measured by an intracranial pressure sensor	During intervention, 5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of inflammatory cytokines	Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis	During intervention, 5 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ICP area under curve	Measured by an intracranial pressure sensor	During intervention, 5 days
Treatment intensity level	Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)	During intervention, 5 days
Rate of cerebral metabolism	Lactate/pyruvate ratio assessed by online microdialysis	During intervention, 5 days
Mortality	Mortality due to traumatic brain injury	At 30 days and 12 months
Concentration of brain damage markers	Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma	During intervention, 5 days
ICP mean	Measured by an intracranial pressure sensor	Change from baseline during intervention, up to 6 days
ICP area under curve	Measured by an intracranial pressure sensor	Change from baseline during intervention, up to 6 days
Concentration of inflammatory cytokines	Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis	Change from baseline during intervention, up to 6 days
Morbidity	Assessed by Glagow Outcome Scale-Extended (GOSE). Minimum 1 (full recovery). MAXIMUM 8 (DEAD)	At 6 and 12 months
Intracerebral oxygen partial pressure	Measured by an intracranial oxygen sensor	During intervention, 5 days
Intracerebral oxygen partial pressure	Lactate/pyruvate ratio assessed by online microdialysis	Change from baseline during intervention, up to 6 days
Treatment intensity level	Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)	Change from baseline during intervention, up to 6 days
Rate of cerebral metabolism	Lactate/pyruvate ratio assessed by online microdialysis	Change from baseline during intervention, up to 6 days
Concentration of brain damage markers	Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma	Change from baseline during intervention, up to 6 days

Collaborators and Investigators

• Sponsor: Peter Siesjö
• Collaborators: Skane University Hospital; Lantmannen Medical AB
• Investigators: Principal Investigator: Peter Siesjö, MD, PhD, Skåne University Hospital

Publications and helpful links

General Publications

• Al-Olama M, Lange S, Lonnroth I, Gatzinsky K, Jennische E. Uptake of the antisecretory factor peptide AF-16 in rat blood and cerebrospinal fluid and effects on elevated intracranial pressure. Acta Neurochir (Wien). 2015 Jan;157(1):129-37. doi: 10.1007/s00701-014-2221-7. Epub 2014 Sep 24.
• Ilkhanizadeh S, Sabelstrom H, Miroshnikova YA, Frantz A, Zhu W, Idilli A, Lakins JN, Schmidt C, Quigley DA, Fenster T, Yuan E, Trzeciak JR, Saxena S, Lindberg OR, Mouw JK, Burdick JA, Magnitsky S, Berger MS, Phillips JJ, Arosio D, Sun D, Weaver VM, Weiss WA, Persson AI. Antisecretory Factor-Mediated Inhibition of Cell Volume Dynamics Produces Antitumor Activity in Glioblastoma. Mol Cancer Res. 2018 May;16(5):777-790. doi: 10.1158/1541-7786.MCR-17-0413. Epub 2018 Feb 5.
• Clausen F, Hansson HA, Raud J, Marklund N. Intranasal Administration of the Antisecretory Peptide AF-16 Reduces Edema and Improves Cognitive Function Following Diffuse Traumatic Brain Injury in the Rat. Front Neurol. 2017 Feb 14;8:39. doi: 10.3389/fneur.2017.00039. eCollection 2017.
• Lonnroth I, Oshalim M, Lange S, Johansson E. Interaction of Proteasomes and Complement C3, Assay of Antisecretory Factor in Blood. J Immunoassay Immunochem. 2016;37(1):43-54. doi: 10.1080/15321819.2015.1042544.
• Johansson E, Al-Olama M, Hansson HA, Lange S, Jennische E. Diet-induced antisecretory factor prevents intracranial hypertension in a dosage-dependent manner. Br J Nutr. 2013 Jun 28;109(12):2247-52. doi: 10.1017/S0007114512004552. Epub 2012 Nov 16.
• Hansson HA, Al-Olama M, Jennische E, Gatzinsky K, Lange S. The peptide AF-16 and the AF protein counteract intracranial hypertension. Acta Neurochir Suppl. 2012;114:377-82. doi: 10.1007/978-3-7091-0956-4_73.
• Jennische E, Bergstrom T, Johansson M, Nystrom K, Tarkowski A, Hansson HA, Lange S. The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increase of intracranial pressure. Brain Res. 2008 Aug 28;1227:189-97. doi: 10.1016/j.brainres.2008.05.083. Epub 2008 Jun 11.
• Lange S, Lonnroth I. The antisecretory factor: synthesis, anatomical and cellular distribution, and biological action in experimental and clinical studies. Int Rev Cytol. 2001;210:39-75. doi: 10.1016/s0074-7696(01)10003-3.
• Johansson E, Lonnroth I, Lange S, Jonson I, Jennische E, Lonnroth C. Molecular cloning and expression of a pituitary gland protein modulating intestinal fluid secretion. J Biol Chem. 1995 Sep 1;270(35):20615-20. doi: 10.1074/jbc.270.35.20615.
• Reen L, Cederberg D, Marklund N, Visse E, Siesjo P. Antisecretory factor in severe traumatic brain injury (AFISTBI): protocol for an exploratory randomized placebo-controlled trial. Trials. 2025 Feb 7;26(1):43. doi: 10.1186/s13063-025-08760-7.

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2020
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: September 23, 2019
• First Submitted That Met QC Criteria: October 3, 2019
• First Posted (Actual): October 7, 2019

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 16, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: intracranial pressure; traumatic brain injury; microdialysis; inflammatory cytokines; cerebral edema; antisecretory factor; cerebral oxygen monitoring
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Brain Injuries; Brain Injuries, Traumatic; Brain Edema; Gastrointestinal Agents; Antidiarrheals; antisecretory factor
• Other Study ID Numbers: 2019-00553

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual patient data that underlie published results will be made available after publication.after de identification.
• IPD Sharing Time Frame: From 3 months after publication to 24 months after publication.
• IPD Sharing Access Criteria: Anyone who wishes to access the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No