Post Transplant Diabetes Mellitus Clinical Trial
Official title:
Effects on Insulin Secretion and Sensitivity of Two Different Formulations Tacrolimus - Prograf® and Advagraf®
One of the main side-effects of tacrolimus in solid organ transplanted patients is post
transplant diabetes mellitus (PTDM). It is not known if different pharmacokinetic properties
influence the risk of developing PTDM. It is possible that it either is high peak
concentrations of high overall systemic exponation that is responsible for the effect on
insulin secretion. With the new slow-release formulation of tacrolimus (Advagraf) a
different pharmacokinetic profile is introduced to patients and it is of interest to
investigate if this affects insulin secretion and insulin sensitivity of patients.
Hypothesis: The pharmacokinetic profile of tacrolimus affects the insulin secretion in renal
transplant recipients.
Study objectives
The primary objective is to compare insulin secretion (Secr2.phase) between the two
different formulations of Tac.
Secondary objectives are to compare the effect of the two formulations on Secr1.phase,
insulin sensitivity and to investigate possible associations with individual systemic
tacrolimus exposures.
Study design
Twenty adult kidney transplanted patients treated with Prograf® twice daily or Advagraf®
once daily will be included in the study. Eligible patients may be included in a stable
posttransplant phase (no Tac dose adjustments or acute rejection episodes the preceding 2
weeks). A 3-hour hyperglycaemic clamp will be performed while patients are treated with
their standard Tac formulation and repeated 4-6 weeks after switching to the alternative Tac
formulation. The clamp investigation will be done after administration of the morning dose
of Tac. Samples for measurement of Tac whole blood concentrations will be drawn for all
patients up to 24 hours after morning Tac dosing. It is not mandatory for all patients to
perform full 24 hour pharmacokinetic investigations.
Switching to the alternative Tac formulation will be performed in a 1:1 daily dose ratio and
subsequently adjusted according to centre protocol for trough concentrations (5-10 ng/mL).
Patients will meet for trough concentration measurements at Rikshospitalet for appropriate
dose adjustment in the period between the two investigations days.
Patients
The patients will primarily be recruited from the great-Oslo area and all study visits will
be performed at Rikshospitalet. Patients will otherwise follow standard post transplant
procedures at their local hospital during the study period. Patients included in other
clinical trials are also eligible for inclusion in the present study as long as they are not
treated with investigational drugs.
Informed consent will be obtained according to the Declaration of Helsinki and ICH-GCP
guidelines. Patients and investigator will sign the patient information which will be kept
on file. The patient will receive a copy of the patient information. Patient data will be
recorded in Case Report Forms (CRF) and all information will be handled confidentially. Any
complications will be recorded.
Glucose clamp calculations
Lean body mass (lbm) is estimated using Hume's formula [12] which correlates well with
tritiated water or electrical bioimpedance measures [13]. Secr1.phase is calculated as the
area under serum insulin vs. time curve (AUC, trapezoidal rule) during the first 10 min of
the clamp procedure, and Secr2.phase is calculated as the insulin AUC during the last hour
(120-180 min) of the clamp procedure. The same calculations were also performed for
C-peptide concentrations. Glucose disposal rate (GDR) is calculated from the amount of
glucose infused during the last hour of the clamp. The IS index (ISI) is calculated as GDR
[mmol/kg (lbm)*min] divided by mean serum insulin (pmol/l) in the same period. Glucose
clearance is calculated as ISI divided by mean serum glucose during the last 60 min of the
clamp [14].
Pharmacokinetic calculations
Nonlinear mixed effects modeling (NONMEM software version VI and Intel Fortran (version 8)
compilation tool) will be used to analyze the dose-concentration-time data for Tac using a
population approach. The pharmacokinetic profile data will be used to develop a
pharmacokinetics model including the effect of major covariates (e.g. age, gender, body
size, renal function, hematocrit, acute rejection status etc.) on CL/F and V/F from the
24-hour pharmacokinetics investigations. If applicable additional trough concentration data
from the routine follow-up of the patients in the study will be used to develop the model.
Exclusion of patient data will only be allowed if Tac concentrations have not been able to
be measured accurately or in case of unavailable information that may interfere with
pharmacokinetic evaluation, e.g. exact blood sampling time or dose given.
The POSTHOC, MAXEVAL=0 option in NONMEM will be used to estimate individual AUC0-24 and
half-lives for each individual. Actually measured Ctrough, Cmax and Tmax values will also be
used to describe the pharmacokinetic properties of the patients.
Statistical considerations
Sample size:
Based on the assumption that a 15% relative change in insulin secretion between the two
formulations are clinically relevant and a relative standard deviation of 25% 20 patients
are needed to assure a power of 80% at a 5% significance level. Patients that drop-out
during the study will be substituted.
Analysis plan:
The primary end-point will be analyzed per-protocol by comparing the ratio of insulin
sensitivity (Secr2.phase) for the two formulations. Data will be transformed to obtain
normal distribution if appropriate.
Secondary endpoints will be analyzed as follows:
- Insulin Secr1.phase
- Insulin sensitivity index (ISI)
- Association between insulin Secr2.phase, Secr1.phase and ISI and systemic exposure of
Tac (derived from individual NONMEM estimations)
- All analysis above also performed for C-peptide
;
Allocation: Non-Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Prevention
Status | Clinical Trial | Phase | |
---|---|---|---|
Not yet recruiting |
NCT02558452 -
European Transplant Registry of Senior Renal Transplant Recipients on Advagraf
|
N/A |