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

Primary Purpose

Posttransplant Diabetes Mellitus

Status
Active
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
LCP-tacrolimus
twice-daily tacrolimus
Sponsored by
University Hospital Tuebingen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Posttransplant Diabetes Mellitus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University Hospital Tuebingen

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

LCP-tacrolimus (Envarsus®)

twice-daily tacrolimus (Prograf®)

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Differences in parameters of glucose metabolism: fasting plasma glucose
Assessment of fasting plasma glucose determined in [mg/dl].
Differences in parameters of glucose metabolism: OGTT
Assessment of 2h glucose in an extended oral glucose tolerance test (OGTT) determined in [mg/dl].
Differences in parameters of glucose metabolism: insulin sensitivity
Assessment of insulin sensitivity determined in [µmol/l].
Differences in blood lipid levels
Assessment of blood lipid levels determined in [mg/dl].
Allograft function: eGFR
Assessment of eGFR (estimated glomerular filtration rate) determined in [ml/min].
Allograft function: urinary albumin excretion
Assessment of urinary albumin excretion determined in [g/dl].
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].

Full Information

First Posted
May 17, 2022
Last Updated
July 4, 2023
Sponsor
University Hospital Tuebingen
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1. Study Identification

Unique Protocol Identification Number
NCT05396898
Brief Title
Tacrolimus Formulation and Glucose Metabolism After Kidney Transplantation (TAGLUMET Trial)
Acronym
TAGLUMET
Official Title
Conversion to Extended-release MeltDose® Tacrolimus After Kidney Transplantation - Impact on Glucose Metabolism and Lipid Profile
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 16, 2020 (Actual)
Primary Completion Date
August 30, 2023 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital Tuebingen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Posttransplant Diabetes Mellitus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
44 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
LCP-tacrolimus (Envarsus®)
Arm Type
Experimental
Arm Description
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.
Arm Title
twice-daily tacrolimus (Prograf®)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
LCP-tacrolimus
Other Intervention Name(s)
Envarsus®
Intervention Description
Prophylaxis of transplant rejection in liver and kidney allograft recipients
Intervention Type
Drug
Intervention Name(s)
twice-daily tacrolimus
Other Intervention Name(s)
Prograf®
Intervention Description
Prophylaxis of transplant rejection in liver, kidney or heart allograft recipients
Primary Outcome Measure Information:
Title
Difference in insulin secretion
Description
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.
Time Frame
16 and 32 weeks
Secondary Outcome Measure Information:
Title
Differences in parameters of glucose metabolism: fasting plasma glucose
Description
Assessment of fasting plasma glucose determined in [mg/dl].
Time Frame
16 and 32 weeks
Title
Differences in parameters of glucose metabolism: OGTT
Description
Assessment of 2h glucose in an extended oral glucose tolerance test (OGTT) determined in [mg/dl].
Time Frame
16 and 32 weeks
Title
Differences in parameters of glucose metabolism: insulin sensitivity
Description
Assessment of insulin sensitivity determined in [µmol/l].
Time Frame
16 and 32 weeks
Title
Differences in blood lipid levels
Description
Assessment of blood lipid levels determined in [mg/dl].
Time Frame
16 and 32 weeks
Title
Allograft function: eGFR
Description
Assessment of eGFR (estimated glomerular filtration rate) determined in [ml/min].
Time Frame
16 and 32 weeks
Title
Allograft function: urinary albumin excretion
Description
Assessment of urinary albumin excretion determined in [g/dl].
Time Frame
16 and 32 weeks
Title
Drug concentration/dose ratio
Description
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].
Time Frame
16 and 32 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martina Guthoff, PD Dr.
Organizational Affiliation
University Hospital Tuebingen
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Tuebingen
City
Tuebingen
ZIP/Postal Code
72076
Country
Germany

12. IPD Sharing Statement

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

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