Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT01367821
Other study ID # 10040
Secondary ID 10/H0408/53
Status Recruiting
Phase N/A
First received May 31, 2011
Last updated October 4, 2012
Start date May 2011
Est. completion date December 2012

Study information

Verified date October 2012
Source University of Nottingham
Contact Abeed H Chowdhury, MBChB MRCS
Phone 441158231144
Email abeed.chowdhury@nottingham.ac.uk
Is FDA regulated No
Health authority United Kingdom: Research Ethics Committee
Study type Observational

Clinical Trial Summary

Patients with obstructive jaundice (OJ) often require surgical, endoscopic or radiological interventions to facilitate biliary drainage and relieve jaundice. However it is known that patients with OJ have increased surgical risks than non-jaundiced patients undergoing the same procedures. Surgery for severe OJ is associated with a significant post-operative mortality (10-15%) and morbidity (30-65%). The commonest complications are related to sepsis but the pathophysiological mechanisms behind this susceptibility to bacterial infection are not clear. Recent work has shown a pivotal role of bile in the maintenance of enterocyte tight junctions and the expression of tight junction-associated proteins which could account for the translocation of enteric bacteria and bacterial products to mesenteric lymph node complexes, the portal circulation and subsequently the liver. Some of these bacterial products, such as endotoxin and quorum sensing signalling molecules (QSSMs), have immunomodulatory properties which may dampen normal immune responses to infection resulting in life-threatening organ dysfunction. Bacterial endotoxin and quorum sensing signalling molecules (QSSMs) represent good candidates for the mediators of this immune suppression and although there is a compelling case for their involvement in the pathogenesis of sepsis, evidence to support their involvement in the aetiology of infection in OJ is currently lacking.


Description:

Obstructive jaundice (OJ) is a condition where a blockage of flow of bile from the liver leads to the accumulation of bile products in the blood resulting in yellowing and itching of the skin. Common causes of OJ include gallstones and also tumours of the pancreas or bile duct. Relieving this type of jaundice and treating the underlying cause can include endoscopic or surgical procedures. It is known however, that patients with OJ have increased surgical risks than non-jaundiced patients who undergo the same operations. Studies have shown that surgery for severe OJ is associated with a postoperative mortality in the region of 10-15% and morbidity rates of 30-65%. Complications related to bacterial infection are common and patients developing severe infections may require treatment with broad spectrum antibiotics with care in intensive or high dependency units.

Although antibiotics have proved invaluable in treating postoperative infections they carry the potential for adverse effects. Antibiotics can suppress normal gut bacteria and allow disease causing bacteria to proliferate, such as Clostridium difficile. This usually manifests as mild-to-moderate diarrhoea but can occasionally cause life-threatening bowel inflammation. The widespread use of antibiotics is also central to the development of bacterial strains with antibiotic resistance. This clinical problem also has economic, political and environmental implications for the National Health Service. Adherence to measures of infection control, education and antibiotic policy can minimise antibiotic resistance; however the limits surrounding such approaches have led to a demand for novel or alternative strategies.

It has recently been discovered that bacteria are able to communicate by producing specialised molecules known as quorum sensing signalling molecules (QSSMs). An accumulation of QSSMs in their surrounding environment allow for the bacteria to quantify the size of colonies. At specific colony sizes the concentration of QSSMs reaches a critical threshold leading to the activation of genes that cause an infection. Disruption of quorum sensing has been shown to reduce the severity of infection in animal studies and this has led to the development of inhibitors of quorum sensing as a possible strategy in antibacterial therapy.

Previous work conducted at the University of Nottingham has demonstrated that QSSMs also influence the number and function of a specific type of immune cell known as 'antigen presenting cells'. These cells are pivotal in allowing the immune system to recognise components of bacteria as foreign and thereby mount the appropriate response. It was found that large numbers of these types of cells underwent programmed cell death (cell suicide) in the presence of QSSMs compared to when QSSMs were absent. This mirrors the situation in blood sampled from patients with severe infections where there is a greater proportion of cell deaths among antigen presenting cells than other types of immune cell.

It is likely that the susceptibility to infectious complications in patients with obstructive jaundice is due to the interplay of various factors. The absence of intestinal bile has implications for the integrity of the bowel wall as a barrier, changes in gut microflora flora and translocation of both bacteria and their products. In addition, it is clear that a form of immune dysfunction occurs, which dampens the normal response following exposure to bacterial products. This immune dysfunction may avert powerful inflammatory cascades resulting in life-threatening multi organ dysfunction but at the expense of conditions that favour bacterial survival. QSSMs represent good candidates for the mediators of this immune dysfunction and although there is a compelling case for their involvement in the pathogenesis of sepsis, definitive evidence to support their role in infective processes in OJ is currently lacking.


Recruitment information / eligibility

Status Recruiting
Enrollment 50
Est. completion date December 2012
Est. primary completion date December 2012
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Both
Age group 18 Years to 75 Years
Eligibility Inclusion Criteria:

- Obstructive jaundice

- Willing to participate and able to give informed consent

- Alcohol abstinence during study

Exclusion Criteria:

- Acute Physiology and Chronic Health Evaluation (APACHE) II Score =8

- Severe neutropaenia

- Smokers/substance abuse

- Diabetes Mellitus

- Oral/IV Steroids

- On regular antibiotics

- Patients with active cholangitis

- Patients who have a history liver transplantation or chronic liver disease

Study Design

Observational Model: Cohort, Time Perspective: Prospective


Locations

Country Name City State
United Kingdom Queen's Medical Centre Nottingham Nottinghamshire

Sponsors (1)

Lead Sponsor Collaborator
University of Nottingham

Country where clinical trial is conducted

United Kingdom, 

References & Publications (8)

Blamey SL, Fearon KC, Gilmour WH, Osborne DH, Carter DC. Prediction of risk in biliary surgery. Br J Surg. 1983 Sep;70(9):535-8. — View Citation

Boontham P, Robins A, Chandran P, Pritchard D, Cámara M, Williams P, Chuthapisith S, McKechnie A, Rowlands BJ, Eremin O. Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis. Clin Sci (Lond). 2008 Dec;115(11):343-51. doi: 10.1042/CS20080018. — View Citation

Diggle SP, Crusz SA, Cámara M. Quorum sensing. Curr Biol. 2007 Nov 6;17(21):R907-10. — View Citation

Han XC, Li JL, Han G. Surgical mortality in patients with malignant obstructive jaundice: a multivariate discriminant analysis. Hepatobiliary Pancreat Dis Int. 2003 Aug;2(3):435-40. — View Citation

Martin CA, Hoven AD, Cook AM. Therapeutic frontiers: preventing and treating infectious diseases by inhibiting bacterial quorum sensing. Eur J Clin Microbiol Infect Dis. 2008 Aug;27(8):635-42. doi: 10.1007/s10096-008-0489-3. Epub 2008 Mar 6. — View Citation

Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF. Association of preoperative biliary drainage with postoperative outcome following pancreaticoduodenectomy. Ann Surg. 1999 Aug;230(2):131-42. Review. — View Citation

Wang Q, Gurusamy KS, Lin H, Xie X, Wang C. Preoperative biliary drainage for obstructive jaundice. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005444. doi: 10.1002/14651858.CD005444.pub2. Review. Update in: Cochrane Database Syst Rev. 2012;9:CD005444. — View Citation

Williams P. Bacillus subtilis: a shocking message from a probiotic. Cell Host Microbe. 2007 Jun 14;1(4):248-9. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary Change in monocyte cytokine responses to endotoxin stimulation Evaluation of monocyte cytokine responses to endotoxin stimulation at specified time points Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 No
Secondary Change in concentration of systemic quorum sensing signaling molecules Evaluation of the presence of quorum sensing signalling molecules in the systemic circulation at specified time points Baseline (pre ERCP) and post ERCP days 1, 7, 14 and 30 No
See also
  Status Clinical Trial Phase
Active, not recruiting NCT04621916 - Preventing Inhibitor Recurrence Indefinitely Phase 4
Recruiting NCT06243289 - Improving KIdney Transplantation With Cellular Therapy Study
Recruiting NCT03591302 - Delayed Blood Stem Transplantation in HLA Matched Kidney Transplant Recipients to Eliminate Immunosuppressive Drugs. Phase 1
Completed NCT04525456 - Immune Responses With Reduxium N/A
Recruiting NCT04314518 - The Correlation Between Immunological Reaction of the Seminal Fluid in the Mother's Blood and Pregnancy Complications
Enrolling by invitation NCT04571203 - Kidney and Hematopoietic Cell Transplants Using a Regimen to Promote Hematopoietic Cell Engraftment Phase 1
Enrolling by invitation NCT01117077 - The Immune Tolerance Mechanism Induced by IL-17-producing Regulatory T Cells in the Orthotopic Liver Transplant Recipients With Aspergillosis N/A
Terminated NCT05010174 - Long-term Safety Follow-up in Recipients Who Previously Received Medeor's Cellular Immunotherapy Products
Active, not recruiting NCT03744325 - Immune Responses in Hen's Egg Oral Immunotherapy N/A
Completed NCT03383211 - Immune Response to BCG Vaccination in Neonates Born to HIV and LTBI Infected and Non-infected Mothers
Recruiting NCT02861872 - Intra-peritoneal Chemotherapy in Ovarian Cancer N/A
Active, not recruiting NCT00319657 - Kidney and Blood Stem Cell Transplantation That Eliminates Requirement for Immunosuppressive Drugs Phase 1/Phase 2
Completed NCT01538485 - Vitamin D Supplementation and Regulatory FoxP3+ T Cells in the GUT Phase 4
Completed NCT03393793 - HEart trAnsplantation Registry of piTie-Salpetriere University Hospital
Completed NCT01996774 - Immunologic Profile of Children With Severe Allergies to Peanuts and Nuts After Induction of Tolerance N/A
Recruiting NCT03292445 - Inducing Graft Tolerance in HLA Haplotype Matched Related and 3 Ag Matched Unrelated Living Donor Kidney Transplantation Early Phase 1
Active, not recruiting NCT05745792 - Clinico-immunological Characterization and Immune Tolerance Breakdown in HU-autoimmunity
Completed NCT02642237 - The Effects of Preceding LPS Administration on the Fluenz-induced Immune Response N/A
Completed NCT01414504 - Pneumococcal Conjugate Vaccine Followup Phase 2
Not yet recruiting NCT06147375 - Efficacy and Safety of Immunosuppressive Withdrawal After Pediatric Liver Transplantation N/A