Prospective, Multicenter Cohort Study on Primary Biliary Cholangitis

Study Overview
=================
Brief Summary
-----------------
The German PBC Cohort is a multi-centric, observational (non-interventional) study with three parallel groups. The main objective of this observational study is to describe the course of Primary biliary cholangitis (PBC) in patients in Germany under routine treatment with approved drugs. Therefore, the effectiveness and safety/tolerability of PBC treatment options in a real-life setting will be evaluated.

Detailed Description
-----------------
Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic liver disease. The course of the disease is characterized by a slow destruction of bile ducts, and progressive cholestasis. Prognosis depends on the development of cirrhosis and its complications. Ursodeoxycholic acid (UDCA) has been established as standard therapy for PBC and improves patients' long-term outcome. However, UDCA is not a uniformly effective drug, and the prognosis of PBC patients insufficiently responding to treatment is markedly worse. For patients with suboptimal treatment response to UDCA obeticholic acid (OCA) as newly approved medication (OCALIVA®) is available as second line treatment. Due to the low prevalence and the slowly progressive course of the disease it is very difficult to investigate the prognosis of subgroups of PBC patients or to evaluate the effectivness of therapeutic interventions on clinical outcomes. Therefore, several national or international registries (UK-PBC Consortium or the Global PBC Study Group) were founded to better characterize the clinical course of PBC patients. Since in Germany a registry for PBC does not exist, the German PBC Cohort is being implemented as observational study to collect data on treatment progress and success in clinical routine that reflects real world conditions in Germany as closely as possible. The effectiveness and safety/tolerability of PBC treatment options (UDCA as standard therapy and second-line treatment options like OCALIVA in case of inadequate UDCA treatment response) will be evaluated. In approximatly 40 sites in Germany routine data is collected. There are no specifications for the diagnosis, therapy and monitoring of the PBC patients. The documentation of the routine data is carried out alongside with guideline recommended treatment intervals of the patients. Furthermore, a critical criterion for the German PBC Cohort study is the involvement of a sufficient number of gastroenterology specialized practices and outpatient clinics that have consciously not been selected based on the strict specifications of a clinical trial and which provide routine treatment for PBC patients. In addition, patient access is designed to be open. Data will be collected on patient groups that represent a majority of the PBC patients in Germany, but who are not being investigated in clinical trials.

Official Title
-----------------
Prospective, Multicenter Cohort Study on Primary Biliary Cholangitis

Conditions
-----------------
PBC, Primary Biliary Cholangitis

Intervention / Treatment
-----------------
* Drug: UDCA
* Drug: Ocaliva


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years Diagnosis of PBC PBC diagnosis (consistent with AASLD and EASL practice guidelines), as demonstrated by the presence of at least two of the following three diagnostic factors: History of elevated ALP levels for 6 months. Positive anti-mitochondrial antibody (AMA) titer or if AMA negative or in low titer (<1:80) => PBC-specific antibodies: anti-GP210 and/or anti-SP100 and/or antibodies against the major M2 components [PDC-E2, 2-oxo-glutaric acid dehydrogenase complex (OADC-E2), branched-chain-2-oxo-acid-dehydrogenase complex, (BCOADC-E2)]. Liver biopsy consistent with PBC. Medication-based treatment with at least one drug approved in Germany for the treatment of PBC Availability of all following essential parameters at the initial diagnosis of PBC prior to the initiation of treatment with UDCA, 12 months after initiation of UDCA and if applicable at time point of secondary incomplete response: Platelet count Alkaline Phosphatase (ALP) Total Bilirubin Aspartate aminotransferase (AST/GOT) Age at initial diagnosis of PBC Patients must meet criteria of one of the cohorts (group 1/2/3) within this NIS according to design written statement of informed consent Exclusion Criteria: Current participation in a phase I to IV interventional clinical trial for PBC or participation in another PBC registry.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Group 1 - Incomplete Responder<br>Primary Incomplete Responder: PBC patients demonstrating an insufficient response to the standard therapy with ursodeoxycholic acid (UDCA) after a minimum of 12 months of treatment (Paris II criteria). Secondary Incomplete Responder: PBC patients demonstrating a satisfactory initial response to UDCA after a minimum of 12 months of treatment (Paris II criteria) followed by a re-increase of ALP ≥1.5 ULN, or AST ≥1.5 ULN, or bilirubin >1 mg/dl at any later time point during continuous UDCA-treatment. | Drug: UDCA<br>* Routine data is collected for UDCA therapy.<br>* Other names: ursodeoxycholic acid;Drug: Ocaliva<br>* Routine data is collected for OCA therapy.<br>* Other names: obeticholic acid;|
| Group 2 - Responder<br>PBC patients demonstrating a satisfactory initial and contin-ued response to UDCA after a minimum of 12 months of treatment (Paris II criteria) without a re-increase of ALP ≥1.5 ULN, or AST ≥1.5 ULN, or bilirubin >1 mg/dl at any later time point during continuous UDCA-treatment. | Drug: UDCA<br>* Routine data is collected for UDCA therapy.<br>* Other names: ursodeoxycholic acid;|
| Group 3<br>Patients newly diagnosed for PBC receiving an approved PBC therapy for the first time. Patients are considered to be newly diagnosed if the initial diagnosis took place no later than six months prior to inclusion into the study. | Drug: UDCA<br>* Routine data is collected for UDCA therapy.<br>* Other names: ursodeoxycholic acid;Drug: Ocaliva<br>* Routine data is collected for OCA therapy.<br>* Other names: obeticholic acid;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systematic registry | A primary outcome measure is not applicable as usual, since this data acquisition is performed to built a newly developed systematic registry which serves to describe - for the first time in Germany - the characteristics and the recent state of usual clinical care of the respective population. Within the 18 months of recruitment and 3 years of individual follow-up for every patient regular analyses will be performed and published, based on a statistical analysis plan which may be yearly updated on request to address the main questions of the responsible PBC consortium. After the end of data acquisition hepatologic scientists may apply with detailed proposals to further use available data. A scientific consortium will than decided on further analyses of data. | from baseline to 36 months after baseline (observational period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comprehensive clinical characterization of German PBC patients | i.e. demographics, biochemical markers, ultrasound, transient elastography, stage of the disease | from baseline to 36 months after baseline | 
| Characterization of PBC therapies | Characterization of UDCA as first line therapy and characterization of approved second-line treatment options such as OCALIVA. Furthermore, safety data on the PBC medications used will be systematically gathered and reported on high-level aggregation with regard to any causality with PBC treatment per cohort. The respective results will be reviewed against the known safety profiles. | from baseline to 36 months after baseline | 
| Treatment response to PBC therapies after 12 months and during longer courses of application | To evaluate the natural progression under PBC drug therapy with respect to response to treatment changes in laboratory results (as ratios of the upper/lower limits of normal or differences to BL values) and characteristics of liver function will be described, e.g.: frequency of hepatic decompensation (occurrence of variceal hemorrhage, ascites, encephalopathy, and/or hepatocellular carcinoma), frequency of liver transplants, frequency of deaths in total and from a liver-related cause, and details on further events of special interest, e.g. for the first time serum bilirubin > ULN and/or alkaline phosphatase > 1.5 ULN, or transient elastography > 9.6 kPa. | from baseline to 12 months after baseline and to 36 months after baseline | 
| Application and analyses of existing prognostic PBC scores to provide information on patients' prognosis. | Details on typical therapeutic measures in treating PBC and patient compliance will be presented. This allows making a statement on quality of PBC treatment in Germany. Effectiveness will be assessed per cohort and compared between physicians' practices and hospital outpatient departments, aggregating data over all participating sites of the respective structure of health care. This refers to GLOBE score and/or Paris II criteria, frequency of hepatic decompensation or frequency of abnormal surrogate parameter (i.e. alkaline phosphatase, bilirubin, ALAT, ASAT or transient elastography). The respective results will be discussed against the results provided from clinical trials to verify everyday suitability of the different PBC therapies. | from baseline to 36 months after baseline | 
| Concomitant Medications | Assessment of selected concomitant medications (e.g. symptomatic treatment of pru-ritus) | from baseline to 36 months after baseline | 
| Concomitant Autoimmune Diseases | Assessment of selected concomitant autoimmune diseases (e.g. overlap syndrome with autoimmune hepatitis) | from baseline to 36 months after baseline | 
| Concomitant Non-Autoimmune Diseases | Assessment of selected concomitant non-autoimmune diseases (i.e. cardiovascular disease, non-alcoholic fatty liver disease, metabolic syndrome, chronic kidney diseases) | from baseline to 36 months after baseline | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ursodeoxycholic acid, UDCA, obeticholic acid, OCALIVA, Cohort, observational study, Bezafibrat, Budesonide