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

NCT00604357 | Completed Phase 3

• 1 other identifier: PATRON07
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

End Stage Liver Disease; Impaired Renal Function

Keywords

CNI free; mTOR inhibition; induction; IL2 receptor antibodies; renal function; liver transplantation

Outcome Measures

Primary Outcomes (1)

• The primary endpoint is defined as the incidence of steroid-resistant acute rejection within the first 30 days after liver transplantation.

  30 days

Secondary Outcomes (11)

• incidence of acute rejection(s)

  1 year

• the number and the timing of acute rejections

  1 year

• the development of renal function at 1 week, 1, 3, 6 and 12 months after liver transplantation

  1 year

• liver allograft function

  1 year

• infectious complications

  yes

Study Arms (1)

1

EXPERIMENTAL

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.

Drug: anti-CD 25 mAb, Sirolimus, MMF

Interventions

anti-CD 25 mAb, Sirolimus, MMF DRUG

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).

Also known as: Rapamune, Simulect, CellCept, DecortinH

1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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).

Sponsors & Collaborators

• University of Regensburg: lead

Study Sites (1)

Regensburg University Medical Center, Department of Surgery

Regensburg, Bavaria, 93053, Germany

Location

Related Publications (2)

• Schnitzbauer AA, Sothmann J, Baier L, Bein T, Geissler EK, Scherer MN, Schlitt HJ. Calcineurin Inhibitor Free De Novo Immunosuppression in Liver Transplant Recipients With Pretransplant Renal Impairment: Results of a Pilot Study (PATRON07). Transplantation. 2015 Dec;99(12):2565-75. doi: 10.1097/TP.0000000000000779.

  PMID: 26018348 DERIVED

• Schnitzbauer AA, Scherer MN, Rochon J, Sothmann J, Farkas SA, Loss M, Geissler EK, Obed A, Schlitt HJ. Study protocol: 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. BMC Nephrol. 2010 Sep 14;11:24. doi: 10.1186/1471-2369-11-24.

  PMID: 20840760 DERIVED

MeSH Terms

Conditions

End Stage Liver Disease; Renal Insufficiency

Interventions

Sirolimus; Basiliximab; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Liver Failure; Hepatic Insufficiency; Liver Diseases; Digestive System Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Andreas A Schnitzbauer, MD

  Regensburg University Medical Center, Department of Surgery

  STUDY DIRECTOR

• Hans J Schlitt, MD

  Regensburg University Medical Center, Department of Surgery

  STUDY CHAIR

• Marcus N Scherer, MD

  Regensburg University Medical Center, Department of Surgery

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor Dr. Hans J Schlitt

Study Record Dates

• First Submitted: January 17, 2008
• First Posted: January 30, 2008
• Study Start: December 1, 2008
• Primary Completion: July 1, 2011
• Study Completion: August 1, 2012
• Last Updated: December 16, 2014

Record last verified: 2014-12

Locations

DE (1)