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Antisecretory Factor In Severe Traumatic Brain Injury (AFISTBI)

Primary Purpose

Traumatic Brain Injury

Status
Recruiting
Phase
Phase 2
Locations
Sweden
Study Type
Interventional
Intervention
Salovum
Placebo egg yolk powder
Sponsored by
Peter Siesjö
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring traumatic brain injury, cerebral edema, antisecretory factor, inflammatory cytokines, cerebral oxygen monitoring, intracranial pressure, microdialysis

Eligibility Criteria

10 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Skane University HopsitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Salovum

Arm Description

Egg yolk powder not enriched for antisecretory powder

Egg yolk powder enriched for antisecretory powder

Outcomes

Primary Outcome Measures

ICP mean
Measured by an intracranial pressure sensor
ICP area under curve
Measured by an intracranial pressure sensor
ICP mean
Measured by an intracranial pressure sensor
ICP area under curve
Measured by an intracranial pressure sensor
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)
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)

Secondary Outcome Measures

Intracerebral oxygen partial pressure
Measured by an intracranial oxygen sensor
Intracerebral oxygen partial pressure
Lactate/pyruvate ratio assessed by online microdialysis
Rate of cerebral metabolism
Lactate/pyruvate ratio assessed by online microdialysis
Rate of cerebral metabolism
Lactate/pyruvate ratio assessed by online microdialysis

Full Information

First Posted
September 23, 2019
Last Updated
June 20, 2023
Sponsor
Peter Siesjö
Collaborators
Skane University Hospital, Lantmannen Medical AB
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1. Study Identification

Unique Protocol Identification Number
NCT04117672
Brief Title
Antisecretory Factor In Severe Traumatic Brain Injury
Acronym
AFISTBI
Official Title
Evaluation of Antisecretory Factor in Treatment of Severe Traumatic Brain Injury With Multimodal Monitoring
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 10, 2020 (Actual)
Primary Completion Date
March 31, 2024 (Anticipated)
Study Completion Date
September 30, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Peter Siesjö
Collaborators
Skane University Hospital, Lantmannen Medical AB

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 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.
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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury
Keywords
traumatic brain injury, cerebral edema, antisecretory factor, inflammatory cytokines, cerebral oxygen monitoring, intracranial pressure, microdialysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Participants with severe TBI and scheduled for multimodal monitoring will be randomised to active or placebo treatment.
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
Egg powder enriched for antisecretory factor and placebo egg powder with the same color, taste and texture,
Allocation
Randomized
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Egg yolk powder not enriched for antisecretory powder
Arm Title
Salovum
Arm Type
Experimental
Arm Description
Egg yolk powder enriched for antisecretory powder
Intervention Type
Dietary Supplement
Intervention Name(s)
Salovum
Other Intervention Name(s)
Antisecretory factor
Intervention Description
Active egg yolk powder
Intervention Type
Dietary Supplement
Intervention Name(s)
Placebo egg yolk powder
Intervention Description
Normal egg yolk powder
Primary Outcome Measure Information:
Title
ICP mean
Description
Measured by an intracranial pressure sensor
Time Frame
Change from baseline during intervention
Title
ICP area under curve
Description
Measured by an intracranial pressure sensor
Time Frame
Change from baseline during intervention
Title
ICP mean
Description
Measured by an intracranial pressure sensor
Time Frame
During intervention, 5 days
Title
ICP area under curve
Description
Measured by an intracranial pressure sensor
Time Frame
During intervention, 5 days
Title
Treatment intensity level
Description
Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)
Time Frame
Change from baseline during intervention
Title
Treatment intensity level
Description
Treatment intensity level (TIL) scale. Minimum 0 (no intervention to control intracranial pressure (ICP)), maximum 38 points (maximum efforts to control ICP)
Time Frame
During intervention, 5 days
Secondary Outcome Measure Information:
Title
Intracerebral oxygen partial pressure
Description
Measured by an intracranial oxygen sensor
Time Frame
Change from baseline during intervention
Title
Intracerebral oxygen partial pressure
Description
Lactate/pyruvate ratio assessed by online microdialysis
Time Frame
During intervention, 5 days
Title
Rate of cerebral metabolism
Description
Lactate/pyruvate ratio assessed by online microdialysis
Time Frame
Change from baseline during intervention
Title
Rate of cerebral metabolism
Description
Lactate/pyruvate ratio assessed by online microdialysis
Time Frame
During intervention, 5 days
Other Pre-specified Outcome Measures:
Title
Inflammatory cytokine secretion
Description
Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis
Time Frame
Change from baseline during intervention
Title
Concentration of inflammatory cytokines
Description
Interleukin-6 (Il-6), interleukin-8 (IL-8) and monocyte chemotactic protein (MCP-1) assessed from microdialysate and plasma by multiplex analysis
Time Frame
During intervention, 5 days
Title
Mortality
Description
Mortality due to traumatic brain injury
Time Frame
At 30 days and 12 months
Title
Disability
Description
Assessed by Glagow Outcome Scale-Extended (GOSE). Minimum 1 (full recovery). MAXIMUM 8 (DEAD)
Time Frame
At 6 and 12 months
Title
Concentration of brain damage markers
Description
Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma
Time Frame
Change from baseline during intervention
Title
Concentration of brain damage markers
Description
Glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE) assessed from microdialysate and plasma
Time Frame
During intervention, 5 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
10 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Peter Siesjö, MD, PhD
Phone
+4646171274
Email
peter.siesjo@med.lu.se
First Name & Middle Initial & Last Name or Official Title & Degree
David Cederberg, MD
Phone
+4646177655
Email
david.cederberg@med.lu.se
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Siesjö, MD, PhD
Organizational Affiliation
Skane University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Skane University Hopsital
City
Lund
ZIP/Postal Code
22185
Country
Sweden
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David Cederberg, MD
Email
david.cederberg@med.lu.se

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.
Citations:
PubMed Identifier
29431617
Citation
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.
Results Reference
background
PubMed Identifier
28261150
Citation
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.
Results Reference
background
PubMed Identifier
25897558
Citation
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.
Results Reference
background
PubMed Identifier
25248325
Citation
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.
Results Reference
background
PubMed Identifier
23153478
Citation
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.
Results Reference
background
PubMed Identifier
22327727
Citation
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.
Results Reference
background
PubMed Identifier
18586012
Citation
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.
Results Reference
background
PubMed Identifier
11580208
Citation
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.
Results Reference
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PubMed Identifier
7657640
Citation
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.
Results Reference
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Antisecretory Factor In Severe Traumatic Brain Injury

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