|- candidate number||11035|
|- NTR Number||NTR3262|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||27-jan-2012|
|- Secondary IDs||NL34567.018.11 CCMO|
|- Public Title||Effect of bile drainage and rifampicin on recovery of obstructive cholestatic patients.|
|- Scientific Title||Effect of bile drainage and rifampicin, a pregnane X receptor agonist, on clinical and biochemical recovery of patients with obstructive cholestasis .|
|- ACRONYM||BIDRIP trial|
|- hypothesis||We postulate that:|
1. Restoration of bile flow by means of bile drainage during obstructive cholestasis affects the composition of bile and serum including total bilirubin concentrations and thereby improves jaundice and cholestasis;
2. Restoration of bile flow by means of bile drainage during obstructive cholestasis affects the composition of bile and serum including serum LPA and ATX concentrations, and, thereby, relieving pruritus and improving quality of life in the cholestatic patient;
3 The potent PXR agonist and antipruritogen, rifampicin, does not only beneficially affect pruritus in addition to biliary drainage, but also enhances impaired hepatocellular secretory capacity thereby accelerating clinical and biochemical recovery and, thereby, quality of life of the cholestatic patient;
4. Biliary HCO3- secretion as a protective mechanism against bile acid-induced cholangiocyte damage is impaired more severely in preexistent bile duct disease, than under conditions of local bile duct obstruction and recovers more effectively after drainage and rifampicin treatment.
|- Healt Condition(s) or Problem(s) studied||Jaundice, Rifampicine, Bilirubin, Pruritus, Bile flow, Obstructive cholestasis|
|- Inclusion criteria||1. Male or female with severe obstructive cholestasis for whom biliary drainage by PTC or nasobiliary drainage by ERCP is clinically indicated;|
2. An established diagnosis of obstructive cholestasis by ultrasound-scan (US-scan), magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography (ERCP);
3. Age 18-90 years;
4. Able to understand and give fully informed written consent;
5. Hyperbilirubinemia > 170 Ámol/L;
6. Cholestatic serum enzyme pattern.
|- Exclusion criteria||1. Patients with purely hepatocellular, non-obstructive cholestasis in whom biliary drainage by PTC or ERCP is not clinically indicated;|
2. Patients with known allergy to rifampicin;
3. Patients who are pregnant.
|- mec approval received||yes|
|- multicenter trial||no|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-feb-2012|
|- planned closingdate||1-sep-2014|
|- Target number of participants||50|
|- Interventions||Treatment with rifampicin 150 mg bd for seven days and blood sampling and questionairres.|
Controls will not receive additional rifampicin.
|- Primary outcome||Serum total bilirubin reduction in % after one week of biliary drainage with or without short-term rifampicin treatment.|
|- Secondary outcome||1. Intensity of pruritus (VAS);|
2. Quality of life (Short form 36 and Liver Disease Symptom Index 2.0);
3. Serum: Biliary bile salt profiles, gamma-glutamyltransferase, alkaline phosphatase, Asat, Alat, autotaxin, lysofosfatidic acid, fibroblast growth factor 19 and HCO3-;
4. Bile: Lysofosfatidic acid, autotaxin, fibroblast growth factor 19 and bicarbonate.
|- Timepoints||1. At baseline (T=0);|
2. Day 1;
3. One week after baseline;
4. Four weeks after baseline.
|- Trial web site||N/A|
|- CONTACT FOR PUBLIC QUERIES||Drs. R. Dijk, van|
|- CONTACT for SCIENTIFIC QUERIES||Drs. R. Dijk, van|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Amsterdam|
(Source(s) of Monetary or Material Support)
|Deutsche Crohn and Colitis Vereinigung|
|- Brief summary||The antibiotic rifampicin is identified as an activator of the nuclear receptor pregnane X receptor (PXR). In vitro and in vivo studies have shown that rifampicin, by being a PXR-ligand, has several possible pharmacological targets for the treatment of cholestasis and thereby improves liver cell secretion and cholestasis-induced pruritus. In a pilot study eleven patients with progressive hepatocellular secretory failure (serum bilirubin >255Ámol/L) were successfully treated with rifampicin, resulting in amelioration of bilirubin levels, and pruritus also improved rapidly (article under submission). Rifampicin is effective in cholestasis associated pruritus. It is shown that short-term treatment with PXR agonists such as rifampicin is highly effective and safe. Rifampicin for short duration, not longer than two weeks, is associated with a low risk of hepatotoxicity, Rifampicin-induced hepatitis is only seen after 2-3 months of treatment. |
We would like to study the effect of alleviation of obstructive cholestasis by biliary drainage with or without rifampicin on serum bilirubin levels. On the other hand we also study want to study the effect on cholestatis-induced pruritus. Various cholestatic disorders are associated with pruritus. Recent results of our group suggest that lysophosphatidic acid (LPA) and autotaxin (ATX) play a critical role in cholestatic pruritus. However, the source of increased serum ATX levels remains to be elucidated. Certain substances in bile may induce gene expression of autotaxin. It is our aim to reveal the nature of these substances. Without adequate therapy chronic cholestatic diseases can progress through stages of inflammation and fibrosis to cirrhosis. The function of bile salts during cholestasis is ambiguous: they act as pro-inflammatory agents on the one hand and as signaling ligands via membrane bound and nuclear receptors on the other hand. It is not known how hepatocytes and cholangiocytes gain resistance against these noxious compounds in bile. Our group hypothesized an import role for HCO3- secretion in the biliary tract as a defense mechanism against noxious compounds in bile.
|- Main changes (audit trail)|
|- RECORD||27-jan-2012 - 7-feb-2012|