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

NCT ID: NCT01958190

Last Updated: 2022-03-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 196 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-02-07
• Study Completion Date: 2021-05-20

Brief Summary

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.

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.

Conditions

Liver Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

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

combination Tacrolimus and Sirolimus

Patients receive combination of low-dose extended release Tacrolimus and low-dose Sirolimus

Group Type: EXPERIMENTAL

Tacrolimus and Sirolimus

Intervention Type: DRUG

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

Interventions

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

Intervention Type: 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

Intervention Type: DRUG

Other Intervention Names

Advagraf [Astellas Pharma bv); Rapamune; Advagraf

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Foundation for Liver Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Herold J Metselaar, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Locations

UMCG

Groningen, , Netherlands

LUMC

Leiden, , Netherlands

Erasmus Medical Center

Rotterdam, , Netherlands

Countries

Netherlands

Other Identifiers

LOL-III-1

Identifier Type: -

Identifier Source: org_study_id