Effect of Antisecretory Factor, Given as a Food Supplement to Adult Patients With Severe Traumatic Brain Injury

Brain Trauma Clinical Trial

— SASAT  

Official title:

Salovum (Antisecretory Factor) in Patients With Severe Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03339505
• Other study ID #: Ethics Reference #: M16/10/040
• Status: Completed
• Phase: Phase 3
• Start date: September 17, 2017
• Est. completion date: October 10, 2022

Study information

• Verified date: October 2022
• Source: Skane University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: October 10, 2022
• Est. primary completion date: October 10, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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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Related Conditions & MeSH terms

• Brain Injuries
• Brain Injuries, Traumatic
• Brain Trauma

Intervention

Dietary Supplement:
• Salovum
Dietary supplement with high concentration of anti-secretory factor
• Placebo
Placebo for Salovum

Locations

Country	Name	City	State
South Africa	Department of Neurosurgery, Tygerberg Hospital, Francie Van Zijl Dr	Cape Town

Sponsors (2)

Lead Sponsor	Collaborator
Peter Siesjö	University of Stellenbosch

Country where clinical trial is conducted

South Africa, 

References & Publications (10)

Al-Olama M, Lange S, Lönnroth 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. — View Citation

Al-Olama M, Wallgren A, Andersson B, Gatzinsky K, Hultborn R, Karlsson-Parra A, Lange S, Hansson HA, Jennische E. The peptide AF-16 decreases high interstitial fluid pressure in solid tumors. Acta Oncol. 2011 Oct;50(7):1098-104. doi: 10.3109/0284186X.2011.562240. Epub 2011 Mar 4. — View Citation

Alam NH, Ashraf H, Olesen M, Salam MA, Gyr N, Meier R. Salovum egg yolk containing antisecretory factor as an adjunct therapy in severe cholera in adult males: a pilot study. J Health Popul Nutr. 2011 Aug;29(4):297-302. — View Citation

Eide PK, Eidsvaag VA, Hansson HA. Antisecretory factor (AF) exerts no effects on intracranial pressure (ICP) waves and ICP in patients with idiopathic normal pressure hydrocephalus and idiopathic intracranial hypertension. J Neurol Sci. 2014 Aug 15;343(1-2):132-7. doi: 10.1016/j.jns.2014.05.054. Epub 2014 Jun 2. — View Citation

Hanner P, Rask-Andersen H, Lange S, Jennische E. Antisecretory factor-inducing therapy improves the clinical outcome in patients with Ménière's disease. Acta Otolaryngol. 2010 Feb;130(2):223-7. doi: 10.3109/00016480903022842. — View Citation

Laurenius A, Wängberg 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. — View Citation

Leong SC, Narayan S, Lesser TH. Antisecretory factor-inducing therapy improves patient-reported functional levels in Meniere's disease. Ann Otol Rhinol Laryngol. 2013 Oct;122(10):619-24. — View Citation

Ulgheri C, Paganini B, Rossi F. Antisecretory factor as a potential health-promoting molecule in man and animals. Nutr Res Rev. 2010 Dec;23(2):300-13. doi: 10.1017/S0954422410000193. Epub 2010 Aug 5. Review. — View Citation

Zaman S, Aamir K, Lange S, Jennische E, Silfverdal SA, Hanson LÅ. Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo-controlled, randomised study. Acta Paediatr. 2014 Jun;103(6):659-64. doi: 10.1111/apa.12581. Epub 2014 Mar 10. — View Citation

Zaman S, Mannan J, Lange S, Lönnroth 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	30 day mortality	Death within 30 days of trauma	30 days
Secondary	TIL - Treatment Intensity Level	TIL is scored at the end of each 24 hour period in the NICU, where 0 is lowest intensity and 38 is maximum intensity	0-5 days
Secondary	ICP - Intracranial Pressure	ICP in mm Hg is recorded every hour during 0-5 days	0-5 days