Clinical trial NCT03339505: Effect of Antisecretory Factor, Given as a Food Supplement to Adult Patients With Severe Traumatic Brain Injury
Official title: Salovum (Antisecretory Factor) in Patients With Severe Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Brain Trauma
Lead sponsor: Skane University Hospital
Sponsor class: OTHER
Collaborators: name: University of Stellenbosch
First posted: 2017-11-13
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, double blinded and prospective.
Primary purpose: TREATMENT

Brief summary: The present trial intends to assess whether Salovum®, an egg powder enriched for antisecretory factor given to patients with severe traumatic brain injury will improve outcome compared to a control group given placebo egg powder.

100 patients with GCS\<9 will be enrolled and randomised to active or placebo treatment during maximum 5 days. Salovum® or placebo will be administered orally by nasogastric feeding tubes.

Primary endpoint will be overall 30 data mortality. Secondary endpoints will be intracranial pressure and treatment intensity level.

Detailed description: Treatment of increased ICP, using Anti-secretory Factor, in patients with severe head trauma Brain edema, defined as an increased fluid content in either the extracellular or intracellular space, arise in both trauma and in conjunction with other brain pathologies such as infectious diseases, intracranial tumors and ischemic events, i.e. stroke. The mechanisms underlying the formation of edema are not fully understood. In the injured brain, leakage over the blood brain-barrier arise which leads to transport of fluid from the blood to the extracellular space, causing an extracellular or vasogenic edema. Damage to cell membranes and disruption of cell function causes an intracellular or cytotoxic edema. Although one type of edema may predominate initially, one type most likely leads to another. In addition to the physiological, flow-related changes that arise, the edema is also worsened by the inflammatory response to damage. In the injured brain, disease associated molecular patterns (DAMP), and pro-inflammatory cytokines that can give rise to both intracellular and extracellular edema are released.

If the edema becomes expansive enough to give rise to a significant increase in intracranial pressure the circulation of the brain is threatened and surgical intervention inevitable. The most common procedure is hemicraniectomy, a procedure intended to add more space for the edematous brain to expand. The procedure itself is risky, and re-operations due to hematoma, CSF-leakage and more are common. Furthermore, it is not known how the procedure itself affects the brain in terms of increased edema, tearing of the brain etc.

Antisecretory factor, AF is a 41 kDa protein that exists in most mammals. It was first discovered due to its ability to inhibit experimental diarrhea. Endogenous AF secretion increases after exposure to bacterial toxins and an increase in AF secretion in combination with an inflammatory reaction may be a part of normal defense against the secretory and inflammatory component in diarrhea and other pathological processes involving membrane leakage and inflammation. AF has been shown to modulate pro-inflammatory and anti- inflammatory cytokine release. AF has also been shown to be effective against vertigo symptoms in Meniere's disease, which is believed to be caused by an abnormal collection of lymph around the balance nerve. AF and AF16 (the functional terminal 16 amino-acid peptide) have been tested in animal models of cerebral edema such as herpes encephalitis and traumatic brain injury with significant reduction of intracranial pressure, morbidity and mortality AF is commercially available for human use as Salovum®, an egg yolk powder B221® enriched for AF. It is available in pharmacies without prescription, but can also be prescribed as a dietary supplement in Sweden. Salovum® is classified as a "medical food" by the Swedish Pharmaceutical Agency and the European Union. Salovum® is currently registered in the Republic of South Africa.

Hypothesis Cerebral edema in traumatic brain injury is caused by inflammation triggered by tissue damage. The anti-secretory and anti-inflammatory compound Salovum® has the potential to counteract this and thus reduce cerebral edema in traumatic brain injury. Furthermore, the reduction of cerebral edema is hypothesized to decrease intracranial pressure, reduce the development of secondary brain damage and subsequently reduce treatment intensity levels and death.

Aims and Objectives Though, the number of patients with severe traumatic head injury in Sweden is decreasing and the need for a larger, randomized trial in a centre with large volumes of traumatic brain injury is needed The primary focus for scientific investigation is to evaluate if AF given as a dietary supplement (Salovum®) will reduce 30-day mortality in adult patients with severe traumatic brain injury. The secondary aims are to investigate whether AF will reduce intracranial pressure and treatment intensity levels - TIL, during intervention.

Methodology The outlined study is a phase-2, prospective, double-blinded, randomized, placebo-controlled trial. After inclusion patients will be randomized to active Salovum® or placebo egg powder treatment every 4th hour during 5 days. Treatment of patients will be according to current algorithms at the study site.

Study population 100 adult (age 18+) patients with severe traumatic brain injury, where ICP-monitoring is deemed necessary, will be included in the study.

Patient samples A venous whole blood sample will be drawn before and after treatment in all patients. The blood sample will be frozen and stored at the study site for further analysis.

Anticipated benefits In an ongoing Swedish study, preliminary results indicate that AF has a very potent ICP- lowering effect in patients with severe TBI and other pathologies encompassing cerebral edema, which might prove an effect on 30-day mortality in this trial.

Eligibility criteria: Inclusion Criteria:

1. Adult of either gender between 18 and 65 years.
2. Non-penetrating, isolated severe traumatic brain injury
3. GCS \>3 and GCS\<9 on admission or within 48 hours after injury\*
4. Admission to study hospital within 24 hours of injury\*
5. No known history of allergy to egg-protein
6. Planned for intracranial pressure monitoring
7. Absence of bilaterally dilated pupils
8. CT scan with traumatic pathology that is more than an isolated epidural hematoma

   * Within 24 hours of injury (for patients with GCS \< 9 on admission) or Within 24 hours of deterioration (among patients deteriorating to GCS \< 9 within 48 hours of injury)

Exclusion Criteria:

1. No consent 2. Systolic blood pressure below 90 mm Hg post resuscitation 3. Epidural hematoma with no other signs of intra-cranial injury 4. Penetrating injury 5. Non-fulfillment of inclusion criteria after screening and inclusion procedures.

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Primary outcomes:
measure: 30 day mortality
timeFrame: 30 days
Secondary outcomes:
measure: TIL - Treatment Intensity Level
timeFrame: 0-5 days
measure: ICP - Intracranial Pressure
timeFrame: 0-5 days
Other outcomes:
Locations:
city: Cape Town
country: South Africa
facility: Department of Neurosurgery, Tygerberg Hospital, Francie Van Zijl Dr
Study officials:
affiliation: University of Stellenbosch
name: Adriaan J Vlok, Professor
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Zaman S, Mannan J, Lange S, Lonnroth I, Hanson LA. B 221, a medical food containing antisecretory factor reduces child diarrhoea: a placebo controlled trial. Acta Paediatr. 2007 Nov;96(11):1655-9. doi: 10.1111/j.1651-2227.2007.00488.x.
citation: Laurenius A, Wangberg B, Lange S, Jennische E, Lundgren BK, Bosaeus I. Antisecretory factor counteracts secretory diarrhoea of endocrine origin. Clin Nutr. 2003 Dec;22(6):549-52. doi: 10.1016/s0261-5614(03)00057-8.
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.
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citation: Cederberg D, Harrington BM, Vlok AJ, Siesjo P. Effect of antisecretory factor, given as a food supplement to adult patients with severe traumatic brain injury (SASAT): protocol for an exploratory randomized double blind placebo-controlled trial. Trials. 2022 Apr 23;23(1):340. doi: 10.1186/s13063-022-06275-z.