Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate non-inferiority of an advagraf based immunosuppressive regimen with slower dose tapering and lower starting dose of Advagraf compared with a standard Advagraf-based immunosuppressive regimen in de novo renal transplantation. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.

Detailed Description
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The most widely used immunosuppressive regimen, in adult kidney transplant recipients, consists of an induction therapy accompanied by maintenance with tacrolimus, mycophenolate and steroids. In the long term, tacrolimus is the single most effective immunosuppressive agent. For adult kidney transplant recipients maintenance of therapeutic levels remains crucial regarding the prevention of allograft rejections. Greater blood levels variability is associated with inferior graft survival as well as non-adherence. Lower variability of tacrolimus blood levels after conversion to extended release tacrolimus formulations has been shown. In addition, once-daily administration promotes patient adherence. The latter is one of the major causes for allograft loss. In the first week after kidney transplantation stable tacrolimus blood levels are hardly achievable. Especially extended release tacrolimus formulations often yield high tacrolimus blood levels. High blood levels are a known risk factor for delayed graft function, which leads to a prolonged hospitalization and a reduced graft survival. Additionally high blood levels are associated with polyomavirus infections and may increase the incidence of new-onset diabetes after renal transplantation. Taking this into consideration, authors demand for calcineurin inhibitor (CNI)-free immunosuppression or the delayed onset of CNI therapy after a stable graft function is reached. This would inevitably lead to a higher rate of acute allograft rejections in the early phase after kidney transplantation. Avoiding high tacrolimus levels, especially early after transplantation, to minimize delayed graft function as well as long term undesirable side effects, seems particularly necessary. For early dose adjustments of extended release tacrolimus formulations, more medical experience is needed compared to immediate release formulations. More stable tacrolimus blood levels can be seen after the first week of administration. To avoid high blood levels of tacrolimus, especially early after transplantation, the investigators aim to demonstrate in this study a non-inferiority of a low dose extended release tacrolimus regimen compared to a standard extended release tacrolimus-based immunosuppressive regimen in de novo renal transplantation. Given inclusion criteria and excluding the exclusion criteria, participants will be randomized into two groups, a standard tacrolimus administration group with daily dose adjustments within the first week after transplantation and a fixed dose tacrolimus administration group, without dose adjustments within the first week after transplantation. In the first 6 months after renal transplantation different blood levels of tacrolimus shall be reached. In the case of the standard tacrolimus administration group the investigators aim at tacrolimus blood levels of 7-9 ng/ml in the first 2 months after transplantation and 6-8 ng/ml for days 61 to 180. In the fixed dose tacrolimus administration group, the low extended release tacrolimus dose of 5mg per day well no be changed in the first week after transplantation. For safety reasons blinded measurements will take place in the first week and study officials will be alerted in case of repeated tacrolimus levels > 20 ng/ml. On days 7 to 60 the investigators aim at tacrolimus blood levels of 5-7 ng/ml and from days 61 to 180 4-6 ng/ml. Non inferiority will be assessed by a combined study endpoint consisting of the development of biopsy-proven rejection of BANFF class Ia or higher and/or graft loss and/or patient death within the first six months after renal transplantation.

Official Title
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Slow and Low Start of a Tacrolimus Once Daily Immunosuppressive Regimen: A Multicentre Prospective Randomized Controlled Study

Conditions
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Renal Failure, Renal Insufficiency, Renal Disease, Renal Insufficiency, Chronic

Intervention / Treatment
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* Drug: Advagraf


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: male or female allograft recipients at least 18 years old primary or secondary kidney transplantation deceased or living donor normal immunological risk profile (PRA level > 20%, AB0-compatible donation, negative crossmatch) informed consent of the patient Exclusion Criteria: graft loss due to severe rejection within the first year after transplantation (in case of secondary transplantation) multi-organ recipient patients receiving a kidney from a non-beating donor complete human leukocyte antigen (HLA)-identical living donor (twins) patients with a history of malignancy during the last five years (except squamous or basal cell carcinoma of the skin after successful treatment) patients with uncontrolled infectious disease, particularly patients who are HIV-positive or suffer from chronic hepatitis B or C or tuberculosis patients with severe gastroenteric disorder, particularly severe diarrhea and symptoms of enteric malabsorption patients suffering from liver cirrhosis CHILD B or C or other severe liver disease (aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT), GammaGT ≥ 3-fold increased) thrombopenia < 70,000/mm3 leukopenia < 2,500/mm3 participation in another clinical trial within the last 4 weeks prior to inclusion estimated addiction or other disorders that do not allow the person concerned, the nature and scope and possible consequences of the clinical trial pregnant or breast-feeding women women of childbearing age, except women who meet any of the following criteria: post-menopausal (12 months natural amenorrhea or 6 months amenorrhea with serum > 40 U/ml, postoperatively (6 weeks after bilateral oophorectomy with or without hysterectomy), regular and correct use of a contraceptive method with error rate < 1 % per year (e. g. implants, depot injections, oral contraceptives, intrauterine device IUD), sexual abstinence, vasectomy of the partner evidence that the patient is likely to fail to comply with the protocol (e. g. lack of cooperation) hypersensitivity to Advagraf or a product listed in the prescribing information other component as well as to other macrolides

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard tacrolimus group<br>Control group: Advagraf will be administered as usual (0.2mg/kg bodyweight), trough levels will be measured every day in the first week after kidney transplantation (TX) and Advagraf dose will be adjusted accordingly. | Drug: Advagraf<br>* intervention: different advagraf dosing in the study compared to the control arm, see above<br>* Other names: no other intervention name;|
| Experimental: Fixed dose tacrolimus group<br>Study group: Advagraf will be administered per fix dose 5mg/day, trough levels will be blinded during the first week, there will be no adjustments in the first week after TX. | Drug: Advagraf<br>* intervention: different advagraf dosing in the study compared to the control arm, see above<br>* Other names: no other intervention name;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation) | combined endpoint: defined as biopsy-proven acute rejection, graft loss or death between the groups at month 6 post-transplantation in renal transplantation | 6 months after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of necessary dose modifications to achieve Advagraf target levels in early post-op period | rate of necessary dose modifications in order to achieve Advagraf target levels in the early postoperative period | 6 months after transplantation | 
| Improved renal transplant function in the early postoperative period and 6 months post-op | renal function defined by need for renal replacement therapy as well as by means of glomerular filtration rate | 6 months after transplantation | 
| Lower incidence of delayed graft function (DGF) | rate of DGF defined as need for at least one postoperative hemodialysis | 6 months after transplantation | 
| Reduced incidence of new onset diabetes after renal Transplantation (NODAT) | incidence of NODAT. Diabetes mellitus defined by American Diabetes Association - Guidelines 2016 | 6 months after transplantation | 
| Reduced rates of infection | incidence of viral or other infections | 6 months after transplantation | 
| Incidence of malignancies | incidence rate of biopsy proven malignancies | 6 months after transplantation | 
| Incidence of fractures | incidence rate of radiography or clinically proven fractures | 6 months after transplantation | 
| Incidence of heart failure | incidence rate of heart failure | 6 months after transplantation | 
| Incidence of myocardial infarction | incidence rate of myocardial infarction | 6 months after transplantation | 
| Incidence of venous thrombosis | incidence rate of venous thrombosis proven by color-coded duplex sonography or radiography | 6 months after transplantation | 
| Incidence of peripheral vascular disease | incidence rate of peripheral vascular disease, sonography or radiography proven | 6 months after transplantation | 
| Incidence of cerebrovascular disease | incidence rate of cerebrovascular disease, sonography or radiography proven | 6 months after transplantation | 
| Incidence of hypercholesterolemia | hypercholesterolemia is defined as > upper limit of normal and measured in mmol/L | 6 months after transplantation | 
| Incidence of hypertriglyceridemia | hypertriglyceridemia is defined as > upper limit of normal and measured in mmol/L | 6 months after transplantation | 
| Incidence of hyperlipoproteinemia | hyperlipoproteinemia is defined as low density lipoproteins cholesterol > upper limit of normal and measured in mmol/L | 6 months after transplantation | 
| Incidence of hypolipoproteinemia | hypolipoproteinemia is defined as high density lipoproteins cholesterol < lower limit of normal and measured in mmol/L | 6 months after transplantation | 
| Incidence of dyslipidemia | dyslipidemia is defined as low density lipoproteins cholesterol > upper limit of normal and high density lipoproteins cholesterol < lower limit of normal and each measured in mmol/L | 6 months after transplantation | 
| Incidence of arterial hypertension | blood pressure is measured in mm of mercury (mmHg) and arterial hypertension is defined according to the American College of Cardiology 2017 Guideline for High Blood Pressure in Adults | 6 months after transplantation | 
| Incidence of anemia | anemia is defined as hemoglobin level or erythrocyte count < lower limit of normal and measured in mmol/L or Tpt/L respective | 6 months after transplantation | 
| Incidence of cardiovascular mortality | cardiovascular mortality is defined as death attributable to myocardial ischemia and infarction, heart failure, cardiac arrest because of other or unknown cause, or cerebrovascular accident | 6 months after transplantation | 
| Chronic humoral rejection | Rate of biopsy proven chronic humoral rejections | 6 months after transplantation | 
| Interstitial fibrosis and tubular atrophy as histological changes in renal transplant biopsies | interstitial fibrosis and tubular atrophy are expressed as percentage in biopsy reports | 6 months after transplantation | 
| Incidence of polyomavirus nephropathy | polyomavirus nephropathy is defined by simian virus 40 (SV40) positive histological staining in renal transplant biopsies | 6 months after transplantation | 
| Recurrence rate of the underlying kidney disease requiring renal transplantation | Biopsy proven recurrence of the underlying disease | 6 months after transplantation | 
| Rate of donor-specific antibodies | rate of donor-specific antibodies | 6 months after transplantation |