Study Comparing in Livertransplantation Recipients With Tacrolimus Alone Versus Tacrolimus&Sirolimus
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 4 |
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:
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To compare the incidence of de novo and recurrence of cancer between study arm and control arm at 36 months.
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To compare the incidence and severity of biopsy proven acute rejection between study arm and control arm at 12, 24 and 36 months.
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To evaluate renal function at 12, 24 and 36 months (calculated GFR).
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To evaluate the development of new onset diabetes mellitus at 12, 24 and 36 months post transplant
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To evaluate the prevalence of CNI side effects at 12, 24 and 36 months
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To evaluate quality of life (Eq5D) and fatigue severity score at 12, 24 and 36 months
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To evaluate the percentage of patients on combination tacrolimus and sirolimus and converted back to tacrolimus mono-therapy.
Study Design
Arms and Interventions
| 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:
|
| 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:
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Outcome Measures
Primary Outcome Measures
- Renal function [3 years]
Percentage of patients with cGFR < 60ml/min
Secondary Outcome Measures
- Malignancies [3 years]
number of de novo malignancies
- Diabetes Mellitus [3 years]
Incidence of De novo diabetes mellitus
Eligibility Criteria
Criteria
Inclusion Criteria:
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Primary liver transplantation or retransplantation within 14 days after first transplantation
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Use of Advagraf at least 2 weeks prior to randomization
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Patent hepatic artery
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Closed abdominal wound
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Stable graft function
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Positive informed consent at time of randomization
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Age 18-70 years
Exclusion Criteria:
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Treatment with investigational drugs within 3 months before start of therapy
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Multi organ transplantation
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cGFR < 30 ml/min
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Proteinuria > 800 mg/24 h
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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.
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Known hypersensitivity to sirolimus or its derivatives
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Thrombocytes < 50 x 109 /L
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Leukocytes < 2.5 x 109 /L
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Haemoglobin < 6 mmol/L
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Biopsy proven rejection 2 weeks prior to randomization
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HIV positivity
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Signs of recurrent or de novo cancer
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Patients with non-HCC malignancies within the past 5 years (excluding successfully treated squamous cell carcinoma and basal cell carcinoma of the skin)
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Evidence of significant local or systemic infection
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Pregnancy or breast feeding
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Women of child-bearing potential not willing to take oral contraception
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UMCG | Groningen | Netherlands | 9713 GZ | |
| 2 | LUMC | Leiden | Netherlands | 2333 ZA | |
| 3 | Erasmus Medical Center | Rotterdam | Netherlands | 3015CE |
Sponsors and Collaborators
- Foundation for Liver Research
Investigators
- Principal Investigator: Herold J Metselaar, MD PhD, Erasmus Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- LOL-III-1