Tacrolimus Formulation and Glucose Metabolism After Kidney Transplantation (TAGLUMET Trial)

Study Overview
=================
Brief Summary
-----------------
Posttransplantation diabetes mellitus after kidney transplantation mediated by tacrolimus is mainly dependent on dose and peak plasma concentration. To substantiate the potential benefits on glucose metabolism and lipid profile of LCP-tacrolimus compared to standard twice-daily tacrolimus after kidney transplantation, a prospective randomized intraindividual cross-over conversion trial with a comprehensive assessment of glucose metabolism and lipid profile is performed. Primary endpoint is the difference in insulin secretion between treatments, as the principal parameter affected by tacrolimus peak concentrations. Aim of the study is, to assess glucose metabolism under different tacrolimus formulations (LCP-tacrolimus and twice-daily tacrolimus).

Detailed Description
-----------------
Posttransplantation diabetes mellitus (PTDM) is an increasing problem in solid organ transplantation with profound impact on patient and allograft survival. One major contributing factor for the development of PTDM is choice of immunosuppression. Calcineurin inhibitors (CNIs), especially tacrolimus display a substantial diabetogenic potential but remain a cornerstone in maintenance immunosuppression for prevention of rejection and allograft loss. The diabetogenic effect of tacrolimus is mediated predominantly via disturbance of beta-cell function and impaired insulin secretion. There is growing evidence that this effect is dependent on dose and peak plasma concentrations. Once-dailyLCP-tacrolimus has been shown to have lower peak concentrations than twicedaily tacrolimus with comparable efficacy and safety. LCP-tacrolimus has been shown to improve triglyceride levels, compared to twicedaily tacrolimus. In this study, no effect on the incidence of PTDM was observed, however assessed only by fasting plasma glucose, HbA1c and antidiabetic treatment. As 1/3 of patients with diabetes are solely diagnosed via oral glucose tolerance test, this approach is insufficient for proper evaluation of glucose metabolism, including prediabetes as the principal risk factor. From pathophysiologic understanding blood lipids and glucose metabolism are strongly associated, as hypertriglyceridemia correlates with insulin resistance. In combination with the lower peak concentrations, it can be hypothesized that LCP-tacrolimus results in better glucose metabolism after kidney transplantation, compared to twicedaily tacrolimus Better understanding of glucose metabolism under different tacrolimus formulations would address a key component of long-term cardiovascular risk and patient outcome after kidney transplantation.

Official Title
-----------------
Conversion to Extended-release MeltDose® Tacrolimus After Kidney Transplantation - Impact on Glucose Metabolism and Lipid Profile

Conditions
-----------------
Posttransplant Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: LCP-tacrolimus
* Drug: twice-daily tacrolimus


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Stable adult kidney transplant recipients on maintenance immunosuppression, >=12 months after kidney transplantation; stable is defined as no need for diagnostic and therapeutic interventions (e.g. kidney biopsy) Tacrolimus-based immunosuppression in combination with mycophenolic acid or azathioprine and maintenance prednisolone (<= 5 mg/q.d.) for at least 3 months Must be >= 18 years at the time of signing the informed consent Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures. Able to adhere to the study visit schedule and other protocol requirements. Subject (male or female) is willing to use highly effective methods during the study treatment (adequate: combined hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner, sexual abstinence). Females of childbearing potential (FCBP) must agree to pregnancy testing within 7 days from 1st dosing of IMP To abstain from breastfeeding during study participation and 28 days after study drug discontinuation. All subjects must agree not to share medication Exclusion Criteria: patients with known diabetes mellitus or PTDM, or HbA1c>=6.5% fasting plasma glucose on examination day (visit 1) of >= 126 mg/dl (7,0 mmol/l) patients with combined transplantation (e.g. liver-kidney, pancreas-kidney, etc.) patients with acute infection at time of baseline visit patients with known non-adherence patients with rejection therapy or increased dosis of corticosteroids for other reasons within 3 months prior to inclusion. Women during pregnancy and lactation. History of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form of the investigational medicinal product. Participation in other interventional clinical trials (inclusive of the Follow-up period)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCP-tacrolimus (Envarsus®)<br>Patients in this arm start (after randomization) on LCP-tacrolimus therapy. At midterm of study participation (16 weeks), a switch is made to twice-daily tacrolimus (Prograf® ) therapy. The duration of the trial for each subject is expected to be 32 weeks. | Drug: LCP-tacrolimus<br>* Prophylaxis of transplant rejection in liver and kidney allograft recipients<br>* Other names: Envarsus®;|
| Active Comparator: twice-daily tacrolimus (Prograf®)<br>Patients in this arm start (after randomization) on twice daily tacrolimus (Prograf®) therapy. At midterm of study participation (16 weeks), a switch is made to LCP-tacrolimus (Envarsus®) therapy. The duration of the trial for each subject is expected to be 32 weeks. | Drug: twice-daily tacrolimus<br>* Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients<br>* Other names: Prograf®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in insulin secretion | The Difference in insulin secretion is determined by ratio AUC insulin / AUC glucose during OGTT at timepoints 16 and 32 weeks after randomization in intraindividual treatment crossover. | 16 and 32 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differences in parameters of glucose metabolism: fasting plasma glucose | Assessment of fasting plasma glucose determined in [mg/dl]. | 16 and 32 weeks | 
| Differences in parameters of glucose metabolism: OGTT | Assessment of 2h glucose in an extended oral glucose tolerance test (OGTT) determined in [mg/dl]. | 16 and 32 weeks | 
| Differences in parameters of glucose metabolism: insulin sensitivity | Assessment of insulin sensitivity determined in [µmol/l]. | 16 and 32 weeks | 
| Differences in blood lipid levels | Assessment of blood lipid levels determined in [mg/dl]. | 16 and 32 weeks | 
| Allograft function: eGFR | Assessment of eGFR (estimated glomerular filtration rate) determined in [ml/min]. | 16 and 32 weeks | 
| Allograft function: urinary albumin excretion | Assessment of urinary albumin excretion determined in [g/dl]. | 16 and 32 weeks | 
| Drug concentration/dose ratio | Assessment of Drug concentration/dose ratio (C/D Ratio) is determined by Tacrolimus level [ng/ml] related to the dose of tacrolimus taken orally the previous day [mg]: C/D Ratio [ng/ml x 1/mg]. | 16 and 32 weeks |