CNI-free de Novo Protocol in Patients Undergoing Liver Transplantation With Renal Impairment (PATRON07)

December 15, 2014 updated by: Hans J Schlitt, Prof. MD, University of Regensburg

A Pilot Study to Determine the Safety and Efficacy of Induction-Therapy, De Novo MPA and Delayed mTOR-Inhibition in Liver Transplant Recipients With Impaired Renal Function. (PATRON-Study)

Background:

Patients undergoing liver transplantation with preexisting renal dysfunction are prone to further renal impairment with the early postoperative use of Calcineurin-inhibitors. However, there is only little scientific evidence for the safety and efficacy of de novo CNI free regimens in patients with impaired renal function undergoing liver transplantation. The objective of the study is to evaluate a de novo calcineurin-inhibitor-free immunosuppressive regimen based on induction therapy with anti-CD25 monoclonal anti- body, mycophenolate mofetil (MMF/MPA), and mTOR-inhibition to determine its safety and to investigate the preliminary efficacy in patients with impaired renal function at the time of liver transplantation. Methods/Design: Patients older than 18 years with renal impairment at the time of liver transplantation due to hepatorenal syndrome, eGFR < 50 ml/min and/or serum creatinine levels > 1.5 mg/dL will be included. Patients will receive a combination therapy with antiCD25-monoclonal antibodies, MMF, steroids and delayed sirolimus (day 10) and will be evaluated with regards to the incidence of steroid resistant acute rejection within the first 30 days after liver transplantation as the primary endpoint. The study is designed as prospective two-step trial requiring a maximum of 29 patients. In the first step 9 patients will be included. If 8 or more patients show no signs of biopsy proven steroid resistant rejection, additional 20 patients will be included. If in the second step a total of 27 or more patients reach the primary end-point the regimen is regarded to be safe and efficient. The follow up period will be one year after transplantation. The aim is to obtain safety and efficacy data for this new and innovative therapy regimen that might be the basis for a large prospective randomized multicenter trial in the future.

Study Overview

Detailed Description

Objectives of this study The objective of the study is to evaluate a de novo CNI-free immunosuppressive regimen based on induction therapy with anti-CD25 monoclonal anti- body, mycophenolate mofetil (MMF/MPA), and delayed mTOR-inhibition. The primary endpoint is defined as the incidence of steroid-resistant acute rejection within the first 30 days after liver transplantation.

Secondary objectives include the incidence of acute rejection(s), the number and the timing of acute rejections per patient within the first year after transplantation. A critical secondary endpoint will be the development of renal function at 1 week, 1, 3, 6 and 12 months after liver transplantation. This includes information on the number of patients requiring renal replacement therapy and its duration. During follow-up of 1 year liver allograft function, infectious complications, treatment failures defined as introduction of CNIs as well as side-effects affecting the hematopoetic system, tolerability, impaired wound-healing, the incidence of hepatic artery thrombosis and mortality will be explicitly documented and investigated.

Trial population The collective we are aiming at are patients older than 18 years with a preexisting renal impairment at the time of liver transplantation. Patients will be eligible if the eGFR < 50 ml/min (Cockcroft-Gault) and/or their serum creatinine levels > 1.5 mg/dL.

Follow-Up Every patient will be followed up for 1 year after transplantation. The primary end-point will be at 30 days after transplantation (Steroid resistant acute rejection). During the first 30 days after transplantation there will be 9 visits where laboratory values (liver, renal and metabolic function, sirolimus trough levels), adverse events and rejection episodes will be recorded. Additionally there will be an ultrasound on day 1 after liver transplantation and on day 10 prior to the initiation of sirolimus to exclude hepatic artery thrombosis.

Between day 30 and 1 year after liver transplantation the patient will be followed up to evaluate the long time outcome and secondary objectives of the trial.

Study Type

Interventional

Enrollment (Actual)

27

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Bavaria
      • Regensburg, Bavaria, Germany, 93053
        • Regensburg University Medical Center, Department of Surgery

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients undergoing primary liver transplantation.
  • Patients older than 18 years.
  • Patients with a hepatorenal syndrome type I or II
  • eGFR < 50 ml/min at the time point of transplantation
  • Serum creatinine levels > 1.5 mg/dL at the time-point of transplantation

Exclusion Criteria:

  • Patients with pre-transplant renal replacement therapy > 14 days.
  • Patients with a known hypersensitivity to mTOR-inhibitors.
  • Patients with a known hypersensitivity to mycophenolate acid.
  • Patients with a known hypersensitivity to anti CD 25-monoclonal antibodies.
  • Patients with platelets < 50.000/nl.
  • Patients with triglycerides > 350 mg/dl and cholesterol > 300 mg/dl refractory to optimal medical treatment prior to initiation of therapy with mTOR inhibition.
  • Severe systemic infections and wound-healing disturbances prior to inclusion.
  • Multiple organ graft recipients.
  • Patients with signs of a hepatic artery stenosis directly prior to initiation of therapy with Sirolimus.
  • Patients with a psychological, familial, sociologic or geographic condition potentially hampering compliance with the study protocol and follow-up schedule.
  • Patients under guardianship (e.g. individuals who are not able to freely give their informed consent).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 1
Prior to reperfusion 500 mg Prednisolone will be administered i.v.. After the transplantation, a combination of anti-CD25-mAB (basiliximab 20 mg on day 0 and day 4 after the procedure), and MMF 2 g/d, 2 applications per day i.v., later conversion to oral intake) will be applied. Earliest, on day 10 after LT Sirolimus will be introduced aiming at 24 hours trough-levels for Sirolimus between 4 and 8 ng/mL. Steroids will be started on day 1 after transplantation with 1mg/kg BW and will be tapered every 2 days for 5 mg to a dosage of 20 mg and for 2.5 mg every two days to 7.5 mg. Thereafter the dosage will be reduced to 5 mg and 2.5 mg for 1 week each and eliminated thereafter. Additionally, every patient with risk constellation will receive cytomegalovirus (CMV) prophylaxis and prophylaxis against Pneumocystis carinii infection during the first 3 months after liver transplantation.

Prior to reperfusion: 500 mg Prednisolone After OLT: anti-CD25-mAB (basiliximab 20 mg on day 0 and day 4 after the procedure)

MMF 2 g/d, 2 applications per day i.v., later conversion to oral intake)

Earliest, on day 10 after LT Sirolimus: 5 mg/d, thereafter a dosage of 2 mg/d (4 and 8 ng/mL)

Steroids: 1mg/kg BW (tapered every 2 days for 5 mg to a dosage of 20 mg, 2.5 mg every two days to 7.5 mg, reduced to 5 mg and 2.5 mg for 1 week each and eliminated thereafter).

Other Names:
  • Simulect
  • CellCept
  • Rapamune
  • DecortinH

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
The primary endpoint is defined as the incidence of steroid-resistant acute rejection within the first 30 days after liver transplantation.
Time Frame: 30 days
30 days

Secondary Outcome Measures

Outcome Measure
Time Frame
mortality
Time Frame: 1 year
1 year
incidence of acute rejection(s)
Time Frame: 1 year
1 year
the number and the timing of acute rejections
Time Frame: 1 year
1 year
the development of renal function at 1 week, 1, 3, 6 and 12 months after liver transplantation
Time Frame: 1 year
1 year
liver allograft function
Time Frame: 1 year
1 year
infectious complications
Time Frame: yes
yes
treatment failures defined as introduction of CNIs
Time Frame: 1 year
1 year
side-effects affecting the hematopoetic system
Time Frame: 1 year
1 year
tolerability
Time Frame: 1 year
1 year
impaired wound-healing
Time Frame: 1 year
1 year
incidence of hepatic artery thrombosis
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Study Director: Andreas A Schnitzbauer, MD, Regensburg University Medical Center, Department of Surgery
  • Study Chair: Hans J Schlitt, MD, Regensburg University Medical Center, Department of Surgery
  • Principal Investigator: Marcus N Scherer, MD, Regensburg University Medical Center, Department of Surgery

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2008

Primary Completion (Actual)

July 1, 2011

Study Completion (Actual)

August 1, 2012

Study Registration Dates

First Submitted

January 17, 2008

First Submitted That Met QC Criteria

January 17, 2008

First Posted (Estimate)

January 30, 2008

Study Record Updates

Last Update Posted (Estimate)

December 16, 2014

Last Update Submitted That Met QC Criteria

December 15, 2014

Last Verified

December 1, 2014

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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