Clinical trial NCT06716541: Biodegradable Stents in Liver Transplant RecipIents for Treatment of Biliary Anastomotic Strictures
Official title: Biodegradable Stents Versus Plastic Stents for Treatment of Biliary Anastomotic Strictures in Liver Transplant RecipIents
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Liver Transplant, Complications
Biliary Anastomotic Stenosis
Endoscopic Retrograde Cholangiopancreatography
Lead sponsor: Institute for Clinical and Experimental Medicine
Sponsor class: OTHER_GOV
First posted: 2024-12-04
Enrollment: 70
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Biliary complications after liver transplantation (LT) remain common and are associated with higher morbidity in liver transplant recipients and liver graft failure. Anastomotic biliary strictures are the most common biliary strictures after LT. Today, the gold standard for treatment remains endoscopic retrograde cholangiopancreatography (ERCP) with either multiple plastic stenting (MPS) or fully covered metal stents. These methods have disadvantages such as the need for repeated ERCP procedures, high costs or the risk of migration.

Biodegradable stents (BDS) are a novel type of stents made from various synthetic polymers or their copolymers, which are now being used in a variety of medical fields, including the pancreatobiliary tract.The use of biodegradable stents has shown good potential in the treatment of benign biliary strictures. However, overall data on their endoscopic use in liver transplant recipients, particularly in the treatment of anastomotic biliary strictures, are scarce. Most studies have either been in animal models, using percutaneously implanted stents, or in non-transplanted patients. There are no randomised controlled trials investigating their use in LT patients. Based on the available evidence, the use of BDS in the treatment of anastomotic biliary strictures in liver transplant recipients appears to be a promising technique that may be as effective as the standard treatment with MPS, but may reduce the number of ERCP procedures and eliminate the risk of migration.

The aim of this randomised prospective study is to compare the difference in rates of anastomotic stricture resolution between the active (BDS) and control (MPS) groups to demonstrate non-inferiority of the biodegradable stents. Outcomes will be classified as complete resolution (no significant stricture at the anastomotic site on imaging and resolution of cholestasis), significant response (relative stricture and resolution of cholestasis) or failure (persistent stricture and/or persistent cholestasis). Secondary outcomes are technical feasibility, immediate and late complications.

Detailed description: Liver transplantation (LT) is nowadays a standard treatment method of end-stage liver disease, primary liver cancer and acute liver failure.

Biliary complications (BCs) following liver transplantation are the leading source of morbidity and liver graft failure and are associated with up to 10% mortality rate. The incidence of BCs remains high, being reported in 10-25% in cadaveric donors (DDLT) and in more than 30% in living donor liver transplantations (LDLT), despite improved both preoperative and postoperative care and enhanced surgical technique. Anastomotic biliary strictures (ABS) are together with bile leaks the most common biliary complication occurring any time after LT, but being primarily found within the first year LT. The incidence ranges between 5-15% in DDLT and 13-36% in LDLT. Anastomotic strictures are typically present at the site of anastomosis, tend to be short, single and constitute up to 86% of all biliary strictures. The clinical presentation can differ from patients being asymptomatic to some presenting with symptoms of biliary obstruction (jaundice, fever, chills, nausea, abdominal pain). The clinical picture can resemble also other conditions and it is important to differentiate biliary complication (BC) from other similarly presenting entities such as acute rejection, hepatic artery thrombosis, recurrence of primary sclerosing cholangitis or acute hepatitis). The gold standard for diagnosis of BCs is MRCP with reported sensitivity and specificity of up to 95%.

The first line therapy of BCs is endoscopic retrograde cholangiopancreatography (ERCP), in case of failure or altered anatomy percutaneous approach may be indicated. If both methods fail surgery is required. ERCP is an invasive endoscopic technique used primarily for therapy of pancreatobiliary tract. It is associated with risk of complications such as acute pancreatitis, bleeding, acute cholangitis or in rare cases perforation.

There are two standard approaches in the treatment of anastomotic biliary strictures, similarly to the treatment of other benign strictures of the bile duct. First, the use of multiple plastic stents (MPS) requiring their repeated endoscopic exchanges may be employed. Alternatively, a single self-expandable metal stent is placed for a longer period of time.

The endoscopic therapy of anastomotic strictures using multiple plastic stents typically requires multiple stent exchanges, starting with placing a single stent and adding multiple stents during further sessions. The sessions are scheduled every 1 to 3 months. The resolution of the anastomotic stricture is usually achieved in 12months, exposing the patient typically to 3-4 ERCP procedures. MPS technique was firstly described and put in practice in a single center study by Costamagna et al. with clinical success rate in 89%. After that many other studies have been published regarding this topic, including a meta-analysis, where the resolution rate of strictures were reported in 94%-100%. Finally in 2017 by Koksa et al. was reported a review demonstrating that in patients with more than 12 months of stenting, with higher total number of stents and number of stents inserted per session, a higher resolution rate and a lower recurrence rate were showed. Alternative option for the endoscopic treatment of ABS is the use of a single fully covered self-expandable metal stent (FC-SEMS), in studies showing similar rates of ABS resolution compared to MPS method with the advantage of not repeating ERCP to place multiple stents, although with higher risk of migration.

The use of endoscopically inserted biodegradable stents is a novel technique with a potential to overcome some downsides of standard treatment with MPS and FC-SEMS. Biodegradable stents are made of different synthetic polymers or their co-polymers. First use of biodegradable stents in the GI tract was described in the setting of an esophageal stricture in 1996 and was later used in small intestine and colon for benign strictures. In the pancreatobiliary tract biodegradable stents have begun to be used in the recent years, mostly for benign biliary strictures such as those caused by chronic pancreatitis and in postoperative cystic duct leaks. Most of the reported experience comes from percutaneously inserted stents. The experience with endoscopic insertion of biodegradable stents is very limited and the data about use of biodegradable stents in liver transplant recipients are extremely scarce.

A systematic review on the use of biodegradable stents in biliary tract by Siiki at al. reviewed studies from 1997 to 2017. This review included 12 animal and 7 human studies. In human studies biodegradable stents were inserted in 4 studies percutaneously and in 3 studies endoscopically. The main indications were benign biliary strictures, postoperative cystic duct leaks, leaks from hepaticojejunal anastomosis, strictures of hepaticojejunal anastomosis, bilioenteric anastomosis strictures or chronic pancreatitis. In all studies stents made out of polydioxanone with time of degradation between 3-6 months were used. The studies proved good feasibility and safety of BDS in both animal and human setting and demonstrated their successful use in the treatment of benign biliary strictures and cystic bile duct leaks. In the first and biggest study with the endoscopic use of biodegradable stents in humans in treatment of cystic duct leaks and benign biliary strictures (BBS), the overall clinical success rate in treatment of BBS was noted in 83% with no secondary hyperplastic strictures. Surprisingly quite high rate of acute cholangitis occurred, in 23% after 90 days, although all cases were mild.

In another recent systematic review and metanalysis by Almeida et al. biodegradable stents were compared to multiples plastic stent implantation in benign biliary strictures. In total 9 studies met the inclusion criteria and were analyzed. Biodegradable stent group (BDBS) consisted of one retrospective and two prospective cohort studies, where stents were deployed both endoscopically and percutaneously with a minimal follow up of 20,8 months. In contrast the MPS group consisted of one randomized control trial comparing the use of multiple plastic stents to FCSEMS for different types of benign biliary strictures, and 5 cohort studies from which were 4 retrospective and one was prospective with a minimal follow up of 78,4 months. The overall success rate to achieve long-term stricture resolution was 83% for the BDBS group and 84% for the MPS group. The average number of interventions in the MPS group was 3 in contrast to 1 in the BDBS group (per case). In a majority of cases the stents were placed percutaneously and only one cohort study included endoscopically released BDBS (13 patients). The treatment-related complication rate was reported for acute cholangitis, acute pancreatitis, stent migration and abdominal pain and was 24,1%, 0,7 %, 1,5 %, 0, 8% for BDBS and 6,1%, 2,7%, 6,8% and 6,8 % for MPS.

An observational single center study by Dopazo et al. reported 20 adult and pediatric patients where BDS were used for benign biliary strictures after liver transplantation using a transhepatic approach. The overall feasibility was 100%, the overall clinical success including both anastomotic and nonastomotic strictures was 75%. The clinical success was higher in anastomotic strictures (81,25%). Only one case of acute pancreatitis was observed.

Based on the available evidence, BDS have shown promising results with good stent patency, feasibility, efficacy and safety profile. Therefore, BDS may represent a novel treatment modality and an alternative to current techniques in the management of biliary anastomotic strictures with a reduced number of ERCPs. However, prospective comparative data are needed.

The investigators aim to compare the use of biodegradable stents with the multiple stenting technique using plastic stents for the treatment of biliary anastomotic strictures and to demonstrate the non-inferiority of biodegradable stents, as well as the safety profile and technical feasibility.

Eligibility criteria: Inclusion Criteria:

* Age ≥18 years
* Liver transplant recipients
* Duct-to-duct biliary anastomosis
* Anastomotic biliary stricture (cholestasis unexplained by other causes and/or liver biopsy showing altered biliary drainage and/or anastomotic stricture on MRCP)
* Signed informed consent

Exclusion Criteria:

* Hepaticojejunoanastomosis
* Physical and/or psychological inability to understand the aims of the research and to adequately cooperate
* Pregnancy

Primary outcomes:
measure: Persisting anastomotic stricture resolution
timeFrame: 12+6 months
measure: Number of ERCPs
timeFrame: 12 months
Secondary outcomes:
measure: Initial anastomotic stricture resolution
timeFrame: 12 months
measure: Technical feasibility
timeFrame: 12 months
measure: Safety
timeFrame: 12 months
measure: Number of stents placed
timeFrame: 12 months
measure: Duration of stenting
timeFrame: 12 months
measure: Degradation of biodegradable stents
timeFrame: 6 months
measure: Quality of life
timeFrame: 12 months
measure: Cost
timeFrame: 12 months
Other outcomes:
Locations:
city: Prague
country: Czech Republic
facility: Institute for Clinical and Experimental Medicine, Department of Gastroenterology and Hepatology
Study officials:
affiliation: Institute for Clinical and Experimental Medicine
name: Tomas Hucl, Prof
role: PRINCIPAL_INVESTIGATOR
References: