Study Comparing in Livertransplantation Recipients With Tacrolimus Alone Versus Tacrolimus&Sirolimus

A Multicenter Randomized in Primary Livertransplantation Comparing Longterm Renal Function in Recipients Treated With Tacrolimus Alone and Recipients Treated With a Combination Tacrolimus and Sirolimus

In this study we compare long term renal function in liver transplantation recipients treated with standard dose extended-release tacrolimus alone and recipients treated with a combination of low dose extended-release tacrolimus and low dose sirolimus. The hypothesis is that the patients treated with the combination have better long term renal function than the patients treated with standard dose tacrolimus alone.

Study Overview

• Status: Completed
• Conditions: Liver Disease
• Intervention / Treatment: Drug: Tacrolimus; Drug: Tacrolimus and Sirolimus

Detailed Description

To evaluate the effectiveness and safety of concentration controlled combination of once daily dosed low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels:3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels: 5-10 ng/ml) at 12, 24 and 36 months post-transplant. Moreover, to compare the incidence of de novo malignancy, the quality of life, fatigue and side effects between both treatment arms.

2.1 Primary objectives: To evaluate the effectiveness and safety of concentration controlled combination of low-dose sirolimus (trough levels: 3-5 ng/ml) and extended-release tacrolimus (trough levels: 3-5 ng/ml), in order to provide superior renal function while maintaining comparable rates of patient and graft survival, compared to concentration controlled once - daily extended release tacrolimus (trough levels:-10 ng/ml) control at 12, 24 and 36 months post-transplant.

2.2. Secondary objectives:

• To compare the incidence of de novo and recurrence of cancer between study arm and control arm at 36 months.
• To compare the incidence and severity of biopsy proven acute rejection between study arm and control arm at 12, 24 and 36 months.
• To evaluate renal function at 12, 24 and 36 months (calculated GFR).
• To evaluate the development of new onset diabetes mellitus at 12, 24 and 36 months post transplant
• To evaluate the prevalence of CNI side effects at 12, 24 and 36 months
• To evaluate quality of life (Eq5D) and fatigue severity score at 12, 24 and 36 months
• To evaluate the percentage of patients on combination tacrolimus and sirolimus and converted back to tacrolimus mono-therapy.

• Study Type: Interventional
• Enrollment (Actual): 196
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • UMCG
  • Leiden, Netherlands, 2333 ZA
    • LUMC
  • Rotterdam, Netherlands, 3015CE
    • Erasmus Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Primary liver transplantation or retransplantation within 14 days after first transplantation
• Use of Advagraf at least 2 weeks prior to randomization
• Patent hepatic artery
• Closed abdominal wound
• Stable graft function
• Positive informed consent at time of randomization
• Age 18-70 years

Exclusion Criteria:

• Treatment with investigational drugs within 3 months before start of therapy
• Multi organ transplantation
• cGFR < 30 ml/min
• Proteinuria > 800 mg/24 h
• Hyperlipidemia refractory to optimal medical management (Cholesterol > 9 mmol/l and/or triglycerides > 8.5 mmol/l). Patients with controlled hyperlipidemia are acceptable at the time of randomization.
• Known hypersensitivity to sirolimus or its derivatives
• Thrombocytes < 50 x 109 /L
• Leukocytes < 2.5 x 109 /L
• Haemoglobin < 6 mmol/L
• Biopsy proven rejection 2 weeks prior to randomization
• HIV positivity
• Signs of recurrent or de novo cancer
• Patients with non-HCC malignancies within the past 5 years (excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin)
• Evidence of significant local or systemic infection
• Pregnancy or breast feeding
• Women of child-bearing potential not willing to take oral contraception
• Any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Tacrolimus; Patient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician	Drug: Tacrolimus; Patient received standard-dose of Tracrolimus Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician; Other Names: Advagraf
EXPERIMENTAL: combination Tacrolimus and Sirolimus; Patients receive combination of low-dose extended release Tacrolimus and low-dose Sirolimus	Drug: Tacrolimus and Sirolimus; Arm 1 once daily combination therapy of normal dosed extended-release tacrolimus and prednisone for 3 months and monotherapy once daily extended-release tacrolimus thereafter up to 3 years after liver transplantation. Arm 2 once daily combination therapy of low doses sirolimus and extended-release tacrolimus and prednisone for 3 months and combination therapy of low dose sirolimus and extended-release tacrolimus thereafter for up to 3 years after liver transplantation Continue Advagraf (5-10 ng/ml) and 7.5 mg prednison; lower or discontinue steroids after day 180 at the discretion of the treating physician Conversion to sirolimus (3-5 ng/ml) and decrease Advagraf (3-5 ng/ml); 7.5 mg prednisone and lower or discontinue steroids after day 180 at the discretion of the treating physician; Other Names: Rapamune; Advagraf [Astellas Pharma bv)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Renal function	Percentage of patients with cGFR < 60ml/min	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Malignancies	number of de novo malignancies	3 years
Diabetes Mellitus	Incidence of De novo diabetes mellitus	3 years

Collaborators and Investigators

• Sponsor: Foundation for Liver Research
• Investigators: Principal Investigator: Herold J Metselaar, MD PhD, Erasmus Medical Center

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 7, 2011
• Primary Completion (ACTUAL): May 20, 2021
• Study Completion (ACTUAL): May 20, 2021

Study Registration Dates

• First Submitted: August 27, 2013
• First Submitted That Met QC Criteria: October 8, 2013
• First Posted (ESTIMATE): October 9, 2013

Study Record Updates

• Last Update Posted (ACTUAL): March 18, 2022
• Last Update Submitted That Met QC Criteria: March 17, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Liver transplantation long term renal function; tacrolimus sirolimus
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Calcineurin Inhibitors; Tacrolimus; Sirolimus
• Other Study ID Numbers: LOL-III-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED