Neoplasms

Digestive System Diseases

Gland and Hormone Related Diseases

All Conditions

Symptoms and General Pathology

Rare Diseases

Pancreatic Neoplasms

Neoplasm Metastasis

Hyperbilirubinemia

Cholestasis

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Bile Duct Diseases

Biliary Tract Diseases

Pancreatic Cancer

Antineoplastic Agents

All Drugs and Chemicals

Gemcitabine

Paclitaxel

Albumin-Bound Paclitaxel

Bilirubin

Tubulin Modulators

Antimitotic Agents

Antimetabolites

4 dose levels may be given in this arm as follows: nab-paclitaxel 75 mg/m2; gemcitabine 600 mg/m2 nab-paclitaxel 100 mg/m2; gemcitabine 800 mg/m2 nab-paclitaxel 125 mg/m2; gemcitabine 800 mg/m2 nab-paclitaxel 125 mg/m2; gemcitabine 1000 mg/m2

6 dose levels may be given in this arm as follows: nab-paclitaxel 75 mg/m2 nab-paclitaxel 75 mg/m2; gemcitabine 600 mg/m2 nab-paclitaxel 100 mg/m2; gemcitabine 600 mg/m2 nab-paclitaxel 125 mg/m2; gemcitabine 600 mg/m2 nab-paclitaxel 125 mg/m2; gemcitabine 800 mg/m2 nab-paclitaxel 125 mg/m2; gemcitabine 1000 mg/m2

Subjects will receive nab-paclitaxel as an intravenous infusion over approximately 30 minutes on Days 1, 8 and 15 of a 28-day cycle.

nab-paclitaxel

Gemcitabine will be administered immediately after nab-paclitaxel as an intravenous infusion over approximately 30 minutes on Days 1, 8 and 15 of a 28-day cycle.

Alfredo Romano, MD

The purpose of this study is to determine the safety and pharmacokinetic profile of nab®-paclitaxel (ABI-007) plus gemcitabine in subjects with advanced pancreatic cancer who have cholestatic hyperbilirubinemia secondary to bile duct obstruction.

There are 2 treatment cohorts in this study based on the predose total bilirubin levels on Cycle 1 Day 1 (Cohort 1 \> 1.5 x Upper Limit of Normal \[ULN\] to 3 x ULN bilirubin and Cohort 2 \> 3 x ULN to 5 x ULN). Enrollment of subjects into Cohort 2 will only proceed after a review of the safety and pharmacokinetic (PK) data for all subjects in Cohort 1 has been completed by the Safety Monitoring Committee. The study is following a 3+3 dose escalation scheme within each dose level cohort group. A total of 3 subjects will initially be enrolled to the starting dose level in each cohort. The dose of the study regimen in each cohort will be escalated (or reduced) according to tolerability.

Pharmacokinetic and Safety Study of Nab®-Paclitaxel (ABI-007) Plus Gemcitabine in Subjects With Advanced Pancreatic Cancer Who Have Cholestatic Hyperbilirubinemia

A Phase 1, Multicenter, Open-label, Dose-escalation Study to Investigate the Safety and Pharmacokinetics of Nab®-Paclitaxel (ABI-007) Plus Gemcitabine in Subjects With Advanced Pancreatic Cancer Who Have Cholestatic Hyperbilirubinemia Secondary to Bile Duct Obstruction

Determination of Maximum Tolerated Dose which is defined as the highest dose which induced a dose limiting toxicity in 0 or 1 out of 6 subjects during their first cycle of treatment.

Area under the plasma concentration-time curve

Apparent volume of distribution at the steady state

Objective tumor response based on computed tomography (CT)/ Magnetic Resonance Imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors (RECIST Version) 1.1 guidelines per Investigator assessment

Progression-free survival according to RECIST Version 1.1 guidelines per investigator assessment

Number of participants who are alive or dead

Incidence of treatment-emergent adverse events (TEAE) and serious adverse events. TEAE are defined as any event that begins or worsens in grade after the start of Investigational Product through 28 days after the last does of Investigational Product.

Evaluate the pharmacokinetic profile of gemcitabine

Celgene

Constriction, Pathologic

Calculi

Gallstones

Cholelithiasis

Cholecystolithiasis

Choledocholithiasis

Bile Duct Neoplasms

Common Bile Duct Neoplasms

Pathological Conditions, Anatomical

Common Bile Duct Diseases

Gallbladder Diseases

Biliary Tract Neoplasms

Patients with need for cholangioscopy due to gallstones or histological evaluation of strictures

cholangioscopy with Frimberger duodenoscope system by the company of Karl Storz GmbH

cholangioscopy (Frimberger)

Thomas Rösch, Prof. Dr.

Karl Storz GmbH (Gesellschaft mit beschränkter Haftung) company developed a cholangioscopic device, which is designed to give a better flexibility to the cholangioscopy tip in order to enable optimal diagnostic and therapeutic precondition. Other than the conventional mother-baby technique, the insertion of the cholangioscope (baby part) is done by a port at the side of a specially developed duodenoscope (mother part) which is prepositioned distally to the control unit, near to the patient's mouth. Better manoeuverability of the device tip will lead to both a better accuracy in taking biopsies as well as a better flexibility in lithotripsy manoeuvres. This study is designed to test the efficiency of the device in relation to this assumption.

Cholangioscopy is a subsidiary treatment in endoscopic retrograde cholangiopancreaticography (ERCP), used for special issues. In the context of ERCP, a long,thin shaped device is introduced through the working channel of a duodenoscope and then through the papilla into the biliary duct.

Inspection of the biliary duct can be used for tumor biopsies as well as for gall stone lithotripsy by laser or electrohydraulic technique.

Manoeuverability of cholangioscopes is limited by the length of the scope, even more, since most of the device body is stuck in the working channel.

The newly designed cholangioscope by the company of Karl Storz GmbH is introduced through a shortened working channel. Introduction of the cholangioscope is done by an innovative side port for the cholangioscope at 70 cm from the insertion tube's distal end. This leads to a better flexibility of the device tip. Better manoeuverability of the device tip will lead to both a better accuracy in taking biopsies as well as a better flexibility in lithotripsy manoeuvres.

This study is designed to test the efficiency of the device in relation to this assumption.

Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones

1. complete lithotripsy in a single session
2. rate of right positive malignoma diagnostics (sensitivity)

Number of complications during examination and during monitoring over 24 hours post procedure

Time of procedure and success of stone extraction in %

Number of biopsies taken. Evaluation of quality of biopsies by pathologists (pathological department of University Hospital Hamburg Eppendorf).

Minimum number of bioptic manoeuvres: 3 Comparison with brush cytology (3 brush manoeuvres with 12 smear preparations) by reference cytologist (Dr. Topalidis, Hannover)

KARL STORZ GmbH & Co. KG, Tuttlingen, Germany

Universitätsklinikum Hamburg-Eppendorf

Infections

Carcinoma

Carcinoma, Hepatocellular

Hepatitis A

Hepatitis

Liver Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Liver Neoplasms

Hematinics

Liver Extracts

IDN-6556

Placebo

The purpose of the study is to test the safety and effectiveness of IDN-6556 in preventing liver damage that normally occurs when livers are transported before being transplanted and in the immediate post-transplant period.

The occurrence of apoptosis in liver ischemia/reperfusion injury has been well characterized in animal models. In this context apoptosis has specifically been observed in sinusoidal endothelial cells and hepatocytes, and this has also been associated with an increase in activated caspase-3 in liver tissue extracts. The use of caspase inhibitors to prevent apoptosis during liver storage and transplantation may reduce ischemia/reperfusion injury and hence improve graft function after transplantation. Suppression of apoptosis by caspase inhibitors may also allow for longer ischemic times allowing organs to be transported greater distances. In addition, suppression of apoptosis may lower the risk involved in using suboptimal donor organs.

Safety and Efficacy Study of a Caspase Inhibitor in Patients Undergoing Liver Transplantation

Safety, Tolerability and Efficacy Study of a Caspase Inhibitor, IDN-6556, in Patients Undergoing Orthotopic Liver Transplantation (OLT)

Idun Pharmaceuticals

Conatus Pharmaceuticals Inc.

Cholangiocarcinoma

Jaundice

Bile Duct Cancer

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who do not have cholestasis preoperatively.

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who had cholestasis and underwent ERCP (endoscopic retrograde choledochopancreatography) with stenting to normalize the enterohepatic circulation.

Patients planned for pancreaticoduodenectomy or liver resection (with or without hepaticojejunostomy) who have cholestasis preoperatively and did not undergo drainage.

From the patients participating in the study i) blood, ii) tissue from resected material, iii) bile, iv) stool, v) urine, vi) jejunal content and vii) information on the itch severity will be collected.

Biospecimen sampling

Steven Olde Damink, MD, PhD

Jan Bednarsch, MD, PhD

Rationale: Bile salts are potent signalling molecules influencing various metabolic and functional processes. Bile salts exert these functions by activating nuclear (e.g. FXR ) and plasma cell membrane-bound receptors (e.g. TGR5) which are expressed in several tissues (e.g. liver, small intestine, colon, kidney and gallbladder). Bile salts regulate their own biosynthesis by controlling the transcription of the hepatic bile salt synthetic enzyme CYP7A1. Two pathways are involved in the negative feedback control of bile salt synthesis: i) the hepatic FXR-SHP pathway and ii) the ileal FXR-FGF19 pathway. Studies showed that the latter is more prominent in controlling CYP7A1 transcript levels (viz. bile salt synthesis). Thus, bile salts are synthesized in the liver, excreted in bile and expelled by the gallbladder into the proximal intestine (to aid in lipid absorption and digestion) and reabsorbed in the terminal ileum to recycle back to the liver via portal blood. Bile salts reclaimed from the intestinal lumen by the ileocyte, activate FXR. This induces the expression of an enterokine, FGF19, which signals via portal blood to the liver to activate its receptor which initiates downstream signalling to repress bile salt synthesis. The FXR/FGF19 signalling pathway is the subject of the present study.

Patients with obstructive cholestasis (=accumulation of bile) caused by malignancies (e.g. pancreatic cancer, cholangiocarcinoma) have a perturbed enterohepatic cycle. Obstructive cholestasis is associated with i) gut barrier dysfunction, ii) endotoxemia, iii) bacterial overgrowth and iv) liver injury. Previous study showed that FGF19 is expressed in the liver of patients with obstructive cholestasis. However, knowledge about the contribution of FGF19 protein by the gut in obstructive cholestasis has thus far been unexplored. Preliminary findings revealed that FGF19 is produced by the portal drained viscera (viz. intestine) of non-cholestatic patients undergoing liver surgery. The inter-organ signalling of FGF19 in an obstructed entero-hepatic cycle has not yet been characterized and likewise the metabolic and other functional effects of inflicted FGF19 signalling during cholestasis have not been clarified.

The hypothesis is that the FXR-FGF19 pathway is disturbed in patients with obstructive cholestasis, and this is associated with organ injury and metabolic dysfunction. The investigators postulate that FGF19 is not produced by the terminal ileum under conditions of obstructive cholestatic, but production is shifted to the liver and this affects metabolic processes.

The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients or post-cholestatic patients (drained patients) by calculating fluxes across the portal drained organs. Secondly, the investigators aim to investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function) of a disturbed FXR-FGF19 pathway in humans. This study will provide insights that may lead to potential therapeutic strategies for patients with a disturbed enterohepatic cycle (e.g. cholestatic liver diseases).

Study population: Adult (\>18 years old) cholestatic (cholestasis group), drained (restored enterohepatic cycle) and non-cholestatic patients (controls, normal enterohepatic circulation) undergoing pancreaticoduodenectomy (Whipple procedure) for hepatopancreaticobiliary malignancies (e.g. pancreatic cancer, cholangiocarcinoma) or liver resection for hepatic malignancies (e.g. cholangiocarcinoma, colorectal liver metastases) are eligible for this study.

Study period: inclusion is planned from 1.12.2017 until 1.12.2024

Because bile salts are biological emulsifiers, they play an essential role in digestion and absorption of dietary lipids and fat soluble vitamins. Bile salts also act as potent signaling molecules targeting bile salt sensing nuclear and plasma cell membrane bound receptors. Several metabolic and biological processes are influenced by activation of these receptors, including bile salt and glucose homeostasis, thermogenesis, intestinal barrier function and liver regeneration.

Bile salts are synthesized in the liver, and efficiently returned to the liver via the intestinal lumen and portal blood (enterohepatic circulation = EHC). Hepatic bile salt content is tightly regulated at multiple levels to maintain non-toxic levels. The transcription factor Farnesoid X Receptor (FXR) plays a key role in bile salt homeostasis by regulating synthesis, biliary excretion, intestinal reuptake and metabolism of bile salts. Genetic deficiency of FXR in mice results in impaired gut barrier function, dysregulated hepatic metabolism and impaired recovery from cholestatic liver injury. Bile salts repress their own biosynthesis, and this encompasses activation of FXR by bile salts in the enterohepatic tissue and controlling the transcription of Cyp7a1 in the liver (rate limiting enzyme of bile salt synthesis). Activated hepatic FXR represses the bile salt synthetic enzyme Cyp7a1 by inducing the expression of Shp. On the other hand, activated FXR in the ileum induces the expression of FGF19 which signals to the liver to repress the expression of Cyp7a1. The liver is considered to be the primary target of FGF19 as it expresses both components of the FGF19 -receptor complex (FGFR4-βklotho). Animal experiments demonstrated a crucial role of intestinal FXR in preventing bacterial overgrowth and maintaining intestinal integrity in a mouse model of obstructive cholestasis. Moreover, intestinal FXR activation ameliorated cholestatic liver injury in bile duct-ligated mice. This emphasizes that an intact EHC is crucial to maintain tissue homeostasis in the small intestine and the liver.

Intraluminal bacterial overgrowth, translocation of microbial endotoxins, increased intestinal permeability, activation of intestinal and hepatic inflammatory cascades and endotoxemia occurs frequently in patients with obstructive cholestasis (e.g. pancreatic cancer and cholangiocarcinoma). Absence of bile in the intestinal tract is associated with these anomalies. The investigators postulate that normal bile flow in patients with obstructive cholestasis is impaired and therefore bile salt signaling is impaired leading to dysregulation in enterohepatic tissues. To further improve our understanding of bile salt-FGF19 signaling across different abdominal organs, the investigators will obtain blood samples not only from the radial artery, the portal and the hepatic vein, but also from the superior mesenteric vein, inferior mesenteric vein, the splenic vein and the renal vein. By including these blood vessels, the investigators will be able to obtain information about the contribution of the small intestine, the colon, the spleen and the kidneys, separately in the production or extraction of FGF19 in humans. Namely, arteriovenous differences (ΔAV) and net organ fluxes (flow x ΔAV) serve as a quantitative measure of metabolite exchange across the portal drained viscera (PDV), the splanchnic area and the small intestine, colon, spleen and kidneys.

The hypothesis is that FGF19 inter-organ flux shifts during obstructive cholestasis towards production or release of FGF19 by other abdominal organs rather than the small intestine. Serum FGF19 elevation and FGF19 mRNA expression in the liver of patients with obstructive cholestasis support this concept.

The aim of this study is to investigate FGF19 signalling in patients with cholestasis compared to non-cholestatic patients by calculating fluxes across the portal drained organs. Secondly, the investigators will investigate the metabolic and functional consequences (glucose, lipid homeostasis, cholestatic itch, gut barrier function, bile salt composition) of a disturbed FXR-FGF19 pathway in humans. Findings from this study will provide novel insights into enterohepatic bile salt-FGF19 signaling in humans and may lead to potential therapeutic strategies in cholestatic liver diseases.

Primary objective

• Determine in vivo inter-organ fluxes of FGF19 in patients with obstructive cholestasis compared with non-cholestatic patients and drained patients

Secondary objectives

* Determine organ fluxes of bile salts (species) in patients with obstructive cholestasis compared with non-cholestatic patients (control group) and drained patients (restored EHC group)
* Determine gene expression of genes implicated in bile salt and FGF19 signaling in enterohepatic tissues (liver, jejunum, gallbladder, common bile duct, white adipose tissues), and skeletal muscle tissue of patients with obstructive cholestasis compared with non-cholestatic patients (control group) and drained patients (restored EHC group).
* Determine microbiota of patients with obstructive cholestasis compared with non-cholestatic patients (control group) and drained patients (restored EHC group) in preoperative stool and intraoperative intraluminal fecal content.
* Determine bile salt composition in patients with non-cholestatic patients (control group) and drained patients (restored EHC group) in plasma, urine and bile.
* Determine whether fluxes of metabolites (e.g. bile salts, FGF19) are related to cholestatic itch

From the patients participating in the study i) blood, ii) tissue from resected material, iii) bile, iv) stool, v) urine, vi) jejunal content and vii) information on the itch severity will be collected. Since the blood vessels indicated below are easily accessible in patients undergoing pylorus-preserving pancreaticoduodenectomy (pp Whipple) or liver resection, these patients are eligible for the study and will be included. Prior to blood sampling, the blood flow of the portal vein and hepatic artery will be measured immediately with the Transonic blood flow meter. Blood will be sampled from the following vessels:

portal vein, hepatic vein, superior mesenteric vein, inferior mesenteric vein, splenic vein, renal vein, radial artery

Arteriovenous differences (ΔAV) and net organ fluxes (flow x ΔAV) are a quantitative measure of the role of the liver, PDV, the splanchnic area, small intestine, colon, spleen and the kidneys in producing or extracting FGF19 and bile salts. The fluxes will be calculated by measuring plasma levels of metabolites and determining blood flow in these vessels.

All patients undergoing pp Whipple or liver resection have an arterial catheter during surgery from which the investigators can sample blood. The mentioned veins (6x) will be punctured directly using 25G needles. 10 ml of arterial blood and 10 ml intra-abdominal blood from the different vessels separately will be sampled once during surgery resulting in a total amount of sampled blood of maximally 70 ml. All blood samples will be collected in both pre-chilled EDTA and heparinized vacuum tubes and centrifuged at 3500 rpm at 4°C for 10 minutes. Plasma will be stored in Eppendorf cups at -80°C until further analysis. Blood flow will be measured using intra-operative Duplex ultrasonography.

Tissues will be explored by histology (histochemistry, immunohistochemistry/fluorescent), and for detailed analysis of genes implicated in bile salt-FGF19 signaling and metabolic processes (e.g. glucose homeostasis, lipid homeostasis). The following tissues (from resected material) during surgery will be collected allowing detailed study of genes implicated in bile salt-FGF19 signaling in enterohepatic tissues:

liver specimen (in case of liver resection), gallbladder specimen, common bile duct specimen, proximal jejunal specimen (in case of hepaticojejunostomy during surgical procedure), white adipose tissue (WAT) \[subcutaneous, omental, visceral\], rectus abdominis muscle

Previous study showed that human bile contains high levels of FGF19. However, the exact functional role of FGF19 in bile is not known. Therefore, bile will be collected intra-operatively to investigate the effect of obstructive cholestasis on FGF19 levels in bile. Bile will be collected by puncture of the gallbladder after removal or from the hepatic bile duct in case the gallbladder is not in situ.

The gut microbiota plays a major role in bile salt homeostasis by secondary modification and deconjugation of primary bile salts. The microbial composition (e.g. shift in bile salt hydrolase producing bacteria) of preoperative stool and proximal jejunal content during surgery will be analyzed. Plasma from the three patient groups (control, drained and cholestatic) will be analyzed for markers of enterocyte function (e.g. citrulline) and enterocyte damage (e.g. IFABP), transmural damage (SM22), endotoxins (LBP), pro-inflammatory cytokines (IL-6 and TNF-alpha) and novel markers for hepatic inflammation (Cathepsin).

Cholestatic pruritis (itch) is common in patients with obstructive cholestasis. The source of itch is currently unknown, and bile salts are implicated in the development of cholestatic itch. Therefore the investigators would like to ask the patients to score their itch intensity on the day before surgery by means of a Visual Analogue Scale (VAS, a scale from 0 (no itch) to 10 (worst itch possible)). In addition, the investigators will ask them to fill in a short questionnaire, the 5D itch scale. Metabolites implicated in itch (e.g. bile salts) will be analyzed in the blood samples to calculate fluxes and these will be correlated with the preoperative VAS scores and 5D itch scale.

Urine will also be collected preoperatively of all patients to investigate whether cholestasis influences the route of bile salt excretion (from biliary excretion to renal excretion). Bile salt composition will be analyzed in urine with liquid chromatography mass spectrometry (LC-MS).

Main study parameters/endpoints: The main study parameter is the net organ flux of FGF19 across abdominal organs calculated by measuring FGF19 levels in human plasma using an enzyme-linked immuno-sorbent assay (ELISA) in cholestatic versus non-cholestatic patients and drained patients. Human plasma will be obtained during surgery from 7 vessels i) radial artery, ii) mesenteric superior vein, iii) mesenteric inferior vein, iv) renal vein, v) splenic vein, vi) hepatic vein and vii) portal vein to calculate net organ fluxes. Secondary parameters are expression of genes related to bile salt and FGF19 signaling in enterohepatic tissues (liver, jejunum, gallbladder, common bile duct, white adipose tissue and skeletal muscle tissue), genes implicated in glucose and lipid homeostasis, FGF19 levels in bile, gut microbiota, cholestatic itch and bile salt composition in urine.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients planned for a Whipple procedure or liver resection are included. Informed consent will be obtained either at the outpatient ward or at the day of admission, with one week time to decide. Patients will then also have time to ask questions.

Blood from these patients will be sampled during surgery under general anesthesia from the portal vein, hepatic vein, superior mesenteric vein, inferior mesenteric vein, splenic vein, renal vein and the radial artery. The experimental set-up consists of 1 time arterial blood sampling (10ml) and 1 time intra-abdominal blood sampling (6x10ml) which is maximal 70 ml in total. During surgery blood flow will be measured of the portal vein and hepatic artery to precisely calculate organ fluxes. The portal vein and hepatic artery are easy accessible for flow measurement with the Transonic flow meter. This device is CE-certified and used routinely to measure actual blood flow. No risks are associated with measuring of these blood flows.

Additionally, bile will be sampled during surgery (4 ml) from the gallbladder or hepatic duct during surgery, and biopsies will be taken from the liver (1, in case of liver resection), gallbladder (1), jejunum (1, in case of hepaticojejunostomy), common bile duct (CBD, 1). white adipose tissue (WAT, from three sites; subcutaneous, omental and visceral adipose tissue) and rectus abdominis muscle for gene expression studies of genes. Moreover, perioperative stool and urine, and jejunal content during surgery (in case of hepaticojejunostomy) will be collected for detailed analysis of microbiota/bile salt composition to investigate the effect of obstructive cholestasis on these parameters. Patients will be assessed for severity of itch by a questionnaire (visual analog scale and 5D itch scale) on the day before surgery to correlate fluxes to cholestatic itch.

The methods applied, i.e. arterial and intra-abdominal blood sampling and collecting liver/jejunal biopsies as part of planned resection, have been used previously without any consequences for the surgical procedures or the patients. In comparison to previously ethical approved protocols, bile (4 ml) will be sampled from the gallbladder or hepatic duct during surgery, and biopsies of the gallbladder (1x), CBD (1x) and WAT (3x), as well as stool will be collected one time preoperatively. There are no additional risks related to the collection of bile and tissues since these are part of the resected tissues. The biopsy of the small intestine, white adipose tissue, and rectus abdominis muscle will be taken from parts that will be resected during the surgery or from the surgical incision site, thus preventing the risk for permanent complications. Potential peroperative bleeding of the tissue will be electrocoagulated by the surgeon. Abdominal biopsies will be taken by skilled hepatopancreaticobiliary surgeons. No further risk is associated with the collection of preoperative stool and urine. Although the results of this project have no direct positive effects for the patients involved, they do contribute to the understanding of the role of bile salts and FGF19 signaling under cholestatic conditions. Insights from this study would provide novelty and substantial knowledge in possible effects of FGF19 therapy in cholestatic liver injury.

From the patients participating in the study i) blood, ii) tissue from resected material, iii) bile, iv) stool, v) urine, vi) jejunal content and vii) information on the itch severity will be collected. Since the blood vessels indicated below are easily accessible in patients undergoing pylorus-preserving pancreaticoduodenectomy (pp Whipple) or liver resection, these patients are eligible for the study and will be included.

FGF19 in Obstructive Cholestasis: "Unveil the Signal"

A factor which signals to the liver to repress the expression of Cyp7a1 (rate limiting enzyme of bile salt synthesis)

Bile salts are synthesized in the liver, and efficiently returned to the liver via the intestinal lumen and portal blood

in liver, proximal jejunum, gallbladder, common bile duct, subcutaneous adipose tissue, omental adipose tissue, visceral adipose tissue, and rectus abdominis muscle

by means of a Visual Analogue Scale (VAS, a scale from 0 (no itch) to 10 (worst itch possible))

In stool, jejunal content, plasma, and urine

RWTH Aachen University

Nicole Hildebrand

Coordinating Investigator

Percutaneous transhepatic cholangiography biliary drainage is compared tot endoscopic biliary drainage in the management of malignant biliary obstruction not amenable to ERCP

Percutaneous transhepatic cholangiography vs. endoscopic biliary drainage

Schalk van der Merwe, MD, PhD

Frederik Nevens, MD, PhD

Werner Van Steenbergen, MD, PhD

Chris Verslype, MD, PhD

David Cassiman, MD, PhD

Wim Laleman, MD, PhD

Geert Maleux, MD, PhD

Patients with obstructive jaundice due to locally advanced/metastatic malignancy with dilated intrahepatic bile ducts will be recruited from the department of Gastroenterology and Hepatology at the University Hospital of Leuven.

This population will have failed ERCP or will be considered when ERCP is not possible due to altered surgical anatomy.

Patients will be randomized to either PTC or EUS guided biliary drainage

Background:

Advanced biliary tract malignancy complicated by obstructive jaundice has been traditionally managed by palliative stent placement at ERCP. In 3-12% of patients with advanced disease tumour involvement of the small bowel or peri-ampullary region may preclude the use of ERCP necessitating percutaneous transhepatic biliary drainage (PTBD) or surgery1. However these techniques have been associated with high complication rates and significant morbidity2. PTBD necessitates traversing the parietal and visceral peritoneum causing a potential for a bile leak and bleeding into the peritoneal cavity. This procedure is also associated with significant pain, lengthy hospital stays and an overall reduction in quality of life, and even procedure related mortality. Indeed the Society of Interventional Radiology (SIR) quality improvements guidelines established the procedural risk of severe major complications including sepsis, bleeding and procedural related death at 2.5% and less severe complications including pain and prolonged hospital admissions at 20%.

In recent years various groups have described endoscopic ultrasound guided access of the left system allowing placement of metal or plastic stents either across the distal stricture or deploying the stent in the stomach (hepatico-gastrostomy), with high technical success3. Retrograde cannulation normally performed from the duodenal bulb allows access to the biliary tract above a malignant stricture with the intent to either pass a guide wire through the papilla and then perform a rendezvous procedure, or the placement of a covered metal stent into the stomach (choledochoenterostomy)10. Cannulation of a dilated segment 2 or 3 sectoral duct is also possible from the proximal stomach where the endoscopist performs all procedures in an antegrade fashion5. Currently these procedures are selectively performed in centres by expert endoscopists from mainly tertiary care academic expert centres including in Leuven. Collectively EUS biliary drainage is technically successful in 75-92% of cases, however reports of bile leaking and peritonitis have been described5.

Various obstacles however still exist to extend the general applicability of this technique outside expert centres. Firstly, no randomized control trials exist comparing the safety and efficacy of EUS biliary access to Percutaneous Transhepatic Cholangiography (PTC). Secondly, current endoscopic techniques utilize standard endoscopic accessories not specifically developed to be utilized within the biliary system when advanced through the gastric wall. Thirdly, specific EUS strategies are needed to prevent or reduce complications associated with percutaneous approaches.

Concept and preliminary experimental data

Hypothesis

Based on the literature we hypothesize that:

* Endoscopic ultrasound guided biliary drainage is more effective than percutaneous biliary drainage in the management of obstructive jaundice
* EUS guided biliary drainage is associated with a reduced incidence of major (bile peritonitis, procedure related mortality, hematobilia) and minor (abdominal pain, prolonged hospital stay) complications.
* EUS guided biliary drainage is more cost effective compared to percutaneous biliary drainage

Aims of proposed research

Based on the current literature we propose a randomized pilot study assessing the following specific end points

* EUS biliary drainage is as effective as percutaneous biliary drainage in achieving resolution of cholestasis
* EUS biliary drainage is not associated with an increased risk of complications compared to percutaneous biliary drainage.

Methodology

Study population. Patients with obstructive jaundice due to locally advanced/metastatic malignancy with dilated intrahepatic bile ducts will be recruited from the department of Gastroenterology and Hepatology at the University Hospital of Leuven.

This population will have failed ERCP or will be considered when ERCP is not possible due to altered surgical anatomy.

Patients will be randomized to either PTC or EUS guided biliary drainage

Inclusion criteria:

* Patients older than 18 years presenting with malignant obstructive jaundice
* Locally advanced primary or metastatic malignancy involving the biliary tract
* Patients in whom an ERCP have failed or where an ERCP is not possible due to surgically altered anatomy (eg. Post-Whipple).

Exclusion criteria:

• Resectable biliary tract malignancy with curative intent

Endoscopic method

Linear array endoscopic ultrasound (Pentax, Pentax Hitachi, Montvale, NJ) will be used to identify the dilated left system. The Doppler mode was used to differentiate intrahepatic bile ducts from portal and hepatic vein branches. A 19G needle (Echo-19, Cook, Limerick, Ireland) will be used to puncture a peripherally located dilated segment 2 or 3 duct under EUS guidance. Under fluoroscopic control a cholangiogram will be obtained and a standard 0.035 guide-wire (Hydra Jag wire, Boston Scientific, Natick, MA Boston Scientific) will be advanced into the biliary system. Next a 6Fr cystotome (Endoflex, Voerde, Germany) will be used to create a trans-gastric tract through the liver parenchyma to the dilated biliary system. The guidewire will be manipulated across the stricture into the duodenal lumen. A Hurricane biliary dilation balloon 4cm x4mm (Boston Scientific, Natick, MA Boston Scientific) will be advanced through the tract and used to dilate the common bile duct stricture without balloon dilation at the level of the gastric wall liver interface. A 10mmx 80mm uncovered self expandable metallic stent (SEMS) will be advanced and deployed under fluoroscopy across the papilla and past the duodenal obstruction when present.

In patients were the left ductal system is not dilated, biliary access will be obtained from the duodenal bulb and a covered metal stent will be deployed in the stomach (choledocho-enterostomy).

In patients with duodenal obstruction a Wallstent will be placed at the same session as part of standard of care.

Novel research perspectives and expected outcomes

* Our research will address a very difficult clinical problem in an unique way: comparing the standard of care biliary drainage procedure (PTC) to EUS guided biliary drainage.
* We expect to demonstrate that EUS guided biliary drainage is as effective as PTC
* We also expect to show that EUS guided biliary drainage is associated with a reduced incidence of complications and reduced hospital stay.

Study endpoints

* Primary endpoints

  * Pain: Post-procedural pain as measured by visual analogue score (VAS) at 2, 24, and 72 hours following the procedures
  * Biochemical changes: Bilirubin decrease at 2 and 4 weeks
* Secondary endpoints

  * Major complications including bile leak, bleeding, sepsis or death
  * Duration of procedures in minutes
  * Length of ICU and hospital stay
  * Minor complications

Statistics power calculations It is assumed that 50% of the patients will experience prolonged pain after PTC defined as pain lasting more than 48 hours and requiring analgesics. 48 patients in total (24 per group) are then needed to detect with 80% power a difference with EUS, expecting 10% of the patients having prolonged pain after EUS. The sample size calculation is based on a two-sided Fisher's Exact test (with alpha=5%). To compensate for potential dropout, 7 additional patients in total will be recruited. Therefor the sample size will comprise of 55 patients. Exact 95% confidence intervals will be calculated for the proportion major complications in both groups. Proportions will be compared using a Fisher's Exact test. A Mann-Whitney U test will be used to compare the actual VAS scores and changes in VAS scores between groups. A log-rank test will be used to compare the length of hospital stay (LOS), censoring potential deceased patients at a value exceeding the highest observed LOS.

P-values smaller than 0.05 will be considered significant. Statistical analyses will be performed using SAS software, version 9.2 of the SAS System for Windowsld be given when defining the endpoints.

Investigators:

Department of Internal Medicine, Division of Hepatology: Prof. Frederik Nevens, Prof. Werner van Steenbergen, Prof. Chris Verslype, Prof. Wim Laleman, Prof. David Cassiman, Prof. Schalk van der Merwe

Department of Interventional radiology:

Prof. Geert Maleux, Dr. Sam Heye, Dr. Johan Vaninbroukx

Percutaneous Transhepatic Cholangiography Versus Endoscopic Ultrasound Guided Biliary Drainage

Percutaneous Transhepatic Cholangiography Versus Endoscopic Ultrasound Guided Biliary Drainage in Advanced Biliary Tract Malignancy That Failed ERCP (PETRUS Study): A Randomized Pilot Study

- Primary endpoints

* Pain: Post-procedural pain as measured by visual analogue score (VAS) at 2, 24, and 72 hours following the procedures
* Biochemical changes: Bilirubin decrease at 2 and 4 weeks

- Secondary endpoints

* Major complications including bile leak, bleeding, sepsis or death
* Duration of procedures
* Length of ICU stay
* Minor complications

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Pharmacokinetic and Safety Study of Nab®-Paclitaxel (ABI-007) Plus Gemcitabine in Subjects With Advanced Pancreatic Cancer Who Have Cholestatic Hyperbilirubinemia	NCT02267707	Pancreatic Neop... Cholestasis	nab-paclitaxel Gemcitabine	18 Years -	Celgene
Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones	NCT01683240	Choledocholithi... Common Bile Duc... Cholestasis	cholangioscopy ...	18 Years -	Universitätsklinikum Hamburg-Eppendorf
Safety and Efficacy Study of a Caspase Inhibitor in Patients Undergoing Liver Transplantation	NCT00080236	Liver Transplan... Hepatitis Cholestasis Carcinoma, Hepa...	IDN-6556 Placebo	18 Years -	Conatus Pharmaceuticals Inc.
FGF19 in Obstructive Cholestasis: "Unveil the Signal"	NCT05718349	Cholestasis Icterus Cholangiocarcin... Pancreatic Neop... Liver Metastasi...	Biospecimen sam...	18 Years - 75 Years	Academisch Ziekenhuis Maastricht
Safety and Efficacy Study of a Caspase Inhibitor in Patients Undergoing Liver Transplantation	NCT00080236	Liver Transplan... Hepatitis Cholestasis Carcinoma, Hepa...	IDN-6556 Placebo	18 Years -	Conatus Pharmaceuticals Inc.
Prospective Multicenter Evaluation of a New Short-access-cholangioscope for Biliary Duct Strictures and Gall Stones	NCT01683240	Choledocholithi... Common Bile Duc... Cholestasis	cholangioscopy ...	18 Years -	Universitätsklinikum Hamburg-Eppendorf
FGF19 in Obstructive Cholestasis: "Unveil the Signal"	NCT05718349	Cholestasis Icterus Cholangiocarcin... Pancreatic Neop... Liver Metastasi...	Biospecimen sam...	18 Years - 75 Years	Academisch Ziekenhuis Maastricht
Percutaneous Transhepatic Cholangiography Versus Endoscopic Ultrasound Guided Biliary Drainage	NCT01686425	Malignant Bilia...	Percutaneous tr...	18 Years -	Universitaire Ziekenhuizen KU Leuven

Spots Global Cancer Trial Database for cholestasis

Every month we try and update this database with for cholestasis cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for cholestasis

Every month we try and update this database with for cholestasis cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for cholestasis cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.