21 Jul Thymosin alpha 1 in the pRevention of pAncreatic infeCtion following acute nEcrotizing pancreatitis: a double-blinded multi-centered, randomized control trial

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Project abbreviation: TRACE research

Overall trial start date:

Overall trial end date: 10/12/2020

Recruitment start date: 18/03/2017

Background and Objective

Infected pancreatic necrosis (IPN) and its related septic complications are the major causes of death in patients with acute necrotizing pancreatitis(ANP)[1].When compared with patients with sterile necrosis, patients with IPN suffered substantial increase in mortality ranging from 14% to 69% due to sepsis and its related multiple organ failure, despite advances in critical care, surgical interventions and antibiotics[2]. Therefore, prevention of pancreatic infection is of great clinical value in the treatment of ANP. In past years, numerous attempts had been made to prevent or delay the development of IPN including antibiotic prophylaxis, selective gut decontamination and probiotics, but none of them has been clinically proved with high-quality evidence[3-5]. Immunosuppression and disorders characterized by decreased HLA-DR expression and unbalanced CD3/CD4+/CD8+ T cells of peripheral blood mononuclear cell (PBMC) are reported to be associated with the development of IPN[6, 7]. Our previous study also found that early enteral could moderate the excessive immune response during the early stage of severe acute pancreatitis without leading to subsequent immunosuppression, and ultimately improve the outcome of the patients[8].Thus immunomodulatory treatment could potentially intervene in the evolution of secondary infection of pancreatic necrosis, resulting in better outcome. Unfortunately, study regarding the immune status in patients with any type of acute pancreatitis (AP) is rare, let alone appropriate treatment aiming to balance patients’ immune function. Thymosin alpha 1 has been shown to have immunomodulatory properties and is reported to be beneficial in patients with sepsis[9, 10], majorly through the involvement of distinct Toll-like receptors (TLRs) acting on different dendritic cells (DC) subsets and involving the MyD88-dependent signaling pathway. However, the effect of thymosin alpha 1 in patients with AP is rarely reported in the literature. The only randomized clinical study conducted by our group years before proved that the use of Thymosin alpha 1 is associated with improved cellular immunity and reduced infection rate in a group of ANP patients[11]. However, no further study was published yet and the clinical significance of this study is limited due to small sample size and single-center nature. Therefore, a multi-center, randomized study with large sample size and proper design is warranted to evaluate the role of Thymosin Alpha 1 in treating ANP.

 

Hypothesis

The hypothesis is that administration of Thymosin Alpha 1 could prevent IPN and improve immune function and other clinical outcomes in patients with ANP.

 

Primary outcome

The incidence of IPN during the index admission.

 

Population

Inclusion Criteria

  1. Symptoms and signs of AP based on abdominal pain suggestive of AP, serum amylase at least three times the upper limit of normal and/or characteristic findings of AP on CT or less commonly MRI or transabdominal ultrasonography according to the Revised Atlanta Criteria.
  2. Less than 1week from the onset of abdominal pain.
  3. Age between 18 and 70 years.
  4. Acute Physiology and Chronic Health Evaluation (APACHE II) score ≥8 during the last 24hours before enrolment.
  5. Balthazar CT score ≥5 (presence of pancreatic necrosis).
  6. Written informed consent obtained.

Exclusion Criteria

  1. Pregnant pancreatitis.
  2. History of chronic pancreatitis.
  3. Malignancy-related AP.
  4. Receiving early intervention or surgery due to abdominal compartment syndrome or other reasons before admission.
  5. Patients with a known history of severe cardiovascular, respiratory, renal or hepatic diseases defined as (1) greater than New York Heart Association Class II heart

failure (Class II not included), (2) active myocardial ischaemia or (3) cardiovascular intervention within previous 60 days, (4) history of cirrhosis or (5) chronic kidney disease with creatinine clearance <40mL/min or (6) chronic obstructive pulmonary disease with the requirement for home oxygen.

  1. Patients with preexisting immune disorders such as AIDS.A patient will be considered eligible if he/she meets the inclusion criteria and does not meet any of the exclusion criteria. Allocation will be performed after signed consent is obtained.

 

References

1 Dellinger EP, Forsmark CE, Layer P, et al. Determinant-based classification of acute pancreatitis severity: an international multidisciplinary consultation. Ann Surg 2012;256:875–80.

2 Tenner S, Baillie J, DeWitt J, et al. American College of gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013;108:1400–15.

3 Wittau M, Mayer B, Scheele J, et al. Systematic review and meta analysis of antibiotic prophylaxis in severe acute pancreatitis. Scand J Gastroenterol 2011;46:261–70.

4 Luiten EJ, Hop WC, Lange JF, et al. Controlled clinical trial of selective decontamination for the treatment of severe acute pancreatitis. Ann Surg 1995;222:57–65.

5 Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008;371:651–9.

6 Bakker OJ, van Brunschot S, van Santvoort HC, et al. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med 2014;371:1983–93.

7 Uehara S, Gothoh K, Handa H, et al. Immune function in patients with acute pancreatitis. J Gastroenterol Hepatol 2003;18:363–70.

8 Yu W-K, Li W-Q, Li N, et al. Mononuclear histocompatibility leukocyte antigen-DR expression in the early phase of acute pancreatitis. Pancreatology 2004;4:233–43.

9 Minkov GA, Yovtchev YP, Halacheva KS. Increased circulating CD4+CD25+CD127low/neg regulatory T-cells as a prognostic biomarker in acute pancreatitis. Pancreas 2017;46:1003–10.

10 Sun J-K, Mu X-W, Li W-Q, et al. Effects of early enteral nutrition on immune function of severe acute pancreatitis patients. World J Gastroenterol 2013;19:917–22.

11 Yang N, Ke L, Tong Z, et al. The effect of thymosin α1 for prevention of infection in patients with severe acute pancreatitis. Expert Opin Biol Ther 2018;18:53–60