PK Study in Diabetic Transplant récipients : From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus

Study Overview
=================
Brief Summary
-----------------
The investigators believe that the pharmacological properties of Envarsus®, well studied in kidney transplantation, may be also suitable after simultaneous kidney and pancreas transplantation than Prograf. Indeed, Envarsus® has demonstrated a clinical efficacy and safety in a complete clinical development plan. This study is to establish the pharmacokinetic profile of tacrolimus prolonged-release (hereafter referred to as 'ENVARSUS®') in diabetics who have undergone kidney and pancreas transplantation, and compare it to the pharmacokinetic profile of standard twice-daily tacrolimus. The study will be conducted in 25 patients hospitalized at Nantes University Hospital.

Detailed Description
-----------------
The study will be conducted in 25 patients hospitalized at Nantes University Hospital. Tacrolimus will be started on the day of surgery (or on the day after) according to Nantes local standard doses and practices. After a stable trough level is achieved (on postoperative day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will be performed (initial dose of 0.17 mg/kg/day) on a single morning oral dosage regimen. A second PK profile will be measured, between 7 to 14 days after initiation of ENVARSUS®. All these PK measurements will take place during the post-operative recovery in the hospital (typically 2-3 weeks). All patients will receive Thymoglobulin or Alemtuzumab induction, Myfortic or Cellcept (or generics), with or without prednisone according to local practices. Anti-infectious prophylaxis will be given according to Nantes local practices.

Official Title
-----------------
Comparison of Pharmacokinetic (PK) Levels Before and After Conversion From Twice-daily Tacrolimus to Once-daily Extended-release Tacrolimus (LCPT) in Diabetic Transplant récipients

Conditions
-----------------
Kidney Transplantation, Pancreas Transplantation, Diabetes

Intervention / Treatment
-----------------
* Drug: Tacrolimus and Tacrolimus Extended Release Oral Tablet [Envarsus]


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patient is willing and able to give informed consent for participation in the trial. Male or Female, aged 18 years or above. Type I Diabetics patients with end stage chronic renal failure Recipient of kidney and pancreas-transplant At least one of the two transplants are functioning at time of PK profile measurements : a patient with early pancreatic graft failure due to thrombosis may be included if the kidney is well functioning Standard immunosuppressive therapy has been started post-operatively, in accordance with local policy, including tacrolimus. In the Investigator's opinion, is able and willing to comply with all trial requirements. Patients with social security. Exclusion Criteria: The participant may not enter the trial if ANY of the following apply: Patient is inappropriate for standard immunosuppressive therapy. Any other significant disease or disorder which, in the opinion of the Investigator, may either put the patients at risk because of participation in the trial, or may influence the result of the trial, or the patient's ability to participate in the trial. Concomitant therapy with drugs potentially interfering with tacrolimus pharmacokinetics, especially those interfering with CYP3A4 (see 4.4 section in tacrolimus / ENVARSUS® summary of product characteristics). Loss of the pancreatic graft due to immunological causes Pregnant or breast-feeding women and female patient with potential childbearing refusing contraception. Vulnerable people: persons deprived of liberty; under trusteeship or under curatorship.

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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus then Envarsus<br>Tacrolimus will be started on the day of surgery. After a stable trough level is achieved (on postoperative day 7-17) the first PK profile will be measured. Subsequently, the switch to ENVARSUS® will be performed | Drug: Tacrolimus and Tacrolimus Extended Release Oral Tablet [Envarsus]<br>* Phase 1: standard dose and frequency tacrolimus, used in accordance with licensing and local protocols. Suitable target trough level should be between 7-14 ng/ml. Phase 2: ENVARSUS® (LCP Tacro - extended release tacrolimus), used once-daily at an initial dose of 0.17mg/kg, dose adjusted to maintain an appropriate therapeutic blood concentration (measured by trough level). Suitable target trough level should be between 7-14 ng/ml.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To characterise the bioavailability of Envarsus® and compare it to the bioavailability of tacrolimus | To characterise the PK profile of extended release tacrolimus (Envarsus®) in diabetic transplant recipients, and compare it to the PK profile of tacrolimus : bioavailability AUC0-24 | Initial tacrolimus PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® PK profile measurement: day 15-32 post SPK transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cmin | Cmin | Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmin | Cmin | Initial tacrolimus and myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Cmax | Cmax | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Cmax | Cmax | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Cavg | Cavg | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myforticin patients only with a functional kidney graft in case of early pancreas thrombosis.: Cavg | Cavg | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: Tmax | Tmax | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis..: Tmax | Tmax | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : Ke | Ke | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: Ke | Ke | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts : t1/2 | t1/2 | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis.: t1/2 | t1/2 | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients with both functional grafts: % fluctuation | % fluctuation | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Further quantification of the PK profile of extended release tacrolimus and Myfortic in patients only with a functional kidney graft in case of early pancreas thrombosis: % fluctuation | % fluctuation | Initial tacrolimus and Myfortic PK profile measurement: day 7-17 post SPK transplantation. Second ENVARSUS® and Myfortic PK profile measurement: day 15-32 post SPK transplantation | 
| Assessment of biological and clinical tolerance/ safety: Incidence of serious adverse events | Incidence of serious adverse events | Months 6, or on leaving hospital if after 6 months (maximum one year after the inclusion) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Tacrolimus, kidney transplant, pancreas transplant