Delayed CNI-based Immunosuppression With Advagraf After MELD-based Liver Transplantation (IMUTECT)

Effect of Delayed CNI-based Immunosuppression With Advagraf on Liver Function After MELD-based Liver Transplantation

Prolonged-release low-dose Advagraf should better protect from CNI-side effects compared to standard immunosuppressive regiments while the rate of rejection is not increased and thus graft function is well maintained. We hypothesize that especially in high-MELD (MELD-score >20) recipients who have a decreased immune competence the prolonged-release low-dose Advagraf concept would better protect from side effects of immunosuppression (i.e. infection). Nevertheless, we assume that also patients with a MELD-score ≤20 will benefit from this concept in regard to lower infection rates and less side effects of immunosuppression.

Study Overview

• Status: Unknown
• Conditions: Liver Graft Dysfunction

Detailed Description

The MELD-score (model of end stage liver disease) was designed to estimate the prognosis after TIPS (transjugular intrahepatic porto-systemic shunt). Nowadays it is the key-score for patients awaiting a liver graft and consists of serum-creatinine, serum-bilirubine and the INR-ratio with values between 6-40. The MELD-based liver allocation follows the sickest patient first strategy which significantly decreased outcome after liver transplantation (LTx) in Germany. There is evidence that the immune competence of very sick patients is decreased. Monocytic HLA-DR status is a marker for the function of the immune system. A reduced monocytic HLA-DR expression is indicative for a suppressed immune system.

Blood levels of Advagraf are slowly increased during the first week until the aimed tacrolimus trough levels are reached. Since therapeutic tacrolimus trough levels are reached not before the end of the first week after transplantation this is a concept for prolonged-release immunosuppression.

We assume, that high-MELD patients (MELD >20) undergoing LTx are immunosuppressed per se. Thus prolonged-release low-dose immunosuppression with Advagraf would decrease both- infection rate (CMV-reactivation, wound infection urinary tract infections, pneumonia, etc.) and side effects of immunosuppression. The immune capacity of patients will be determined by the measurement of monocytic HLA-DR status. To ensure that graft function is not impaired due to rejection episodes, liver function will be determined with the LiMAx-test, a routine procedure in our institution. After 13-C-Methacetin is given to the patient, it is metabolized to paracetamol and 13CO2 by the enzyme CYP1A2 which is localized in hepatocytes. The 13CO2/12CO2 ratio in the exhaled air correlates with liver function.

• Study Type: Observational
• Enrollment (Anticipated): 50

Contacts and Locations

• Study Contact: Name: Peter Schemmer, Prof.; Phone Number: +49-6221-566205; Email: peter.schemmer@med.uni-heidelberg.de
• Study Contact Backup: Name: Georgios Polychronidis, MD; Phone Number: +4962215637727; Email: Georg.polychronidis@med.uni-heidelberg.de

Study Locations

• Germany
  • Heidelberg, Germany, 69120
    • Recruiting
    • University Surgical Clinic
    • Contact: Peter Schemmer, Prof.; Phone Number: +4962215636500; Email: Peter.schemmer@med.uni-Heidelberg.de
    • Contact: Daniela Hall; Phone Number: +4962215636805; Email: Daniela.hall@med.uni-Heidelberg.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with different MELD-scores/Na-MELD-scores undergoing liver transplantation

Description

Inclusion Criteria:

• age >18, <65
• first liver transplantation
• Immunosuppression with Advagraf, MMF, corticosteroid
• surgery and postoperative treatment at the department for general-, visceral- and transplantation surgery

Exclusion Criteria:

• missing informed consent
• re-transplantation
• acute infection: CMV (pp65 positive), pneumonia, urinary tract infection, wound infection, reactivation of Hepatitis B/C

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Advagraf-based immunosuppression; 50 patients after liver transplantation (25 with a MELD-score ≤20 and 25 patients with a MELD-score >20) under CNI-based immunosuppression with Advagraf

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
infection rate (CMV reactivation, wound infection, urinary tract infection, pneumonia)	clinical visit: infection rate (CMV reactivation, wound infection, urinary tract infection, pneumonia)	1-year follow-up per patient

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
liver function (LiMAx)	LiMAx test before liver transplantation, and on postoperative days 1, 3, 7	one week
HLA-DR status	HLA-DR status will be measured before liver transplantation and on postoperative days 3, 5, 7.	one week

Collaborators and Investigators

• Sponsor: Heidelberg University
• Collaborators: Astellas Pharma Inc
• Investigators: Principal Investigator: Peter Schemmer, Prof., University Hospital Heidelberg

Publications and helpful links

General Publications

• Richter S, Polychronidis G, Gotthardt DN, Houben P, Giese T, Sander A, Dorr-Harim C, Diener MK, Schemmer P. Effect of delayed CNI-based immunosuppression with Advagraf(R) on liver function after MELD-based liver transplantation [IMUTECT]. BMC Surg. 2014 Sep 1;14:64. doi: 10.1186/1471-2482-14-64.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Anticipated): August 1, 2015
• Study Completion (Anticipated): December 1, 2015

Study Registration Dates

• First Submitted: January 29, 2013
• First Submitted That Met QC Criteria: January 29, 2013
• First Posted (Estimate): January 31, 2013

Study Record Updates

• Last Update Posted (Estimate): May 28, 2015
• Last Update Submitted That Met QC Criteria: May 27, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: liver function; Advagraf; infection rate; MELD-score; Na-MELD-score; LiMAx-test; HLA-DR status; immunostatus
• Other Study ID Numbers: IMUTECT2013-01