The aDOPT Trial (Dose Optimisation Prior to Transplant): In kidney transplantation, can pre-transplant blood levels of mycophenolic acid (MPA) help to optimise individual patient's post-transplant mycophenolate mofetil (MMF) dose to improve outcomes?

• Register: ANZCTR
• Last refreshed on: 18 October 2021
• Main ID: ACTRN12615000273583
• Date of registration: 23/03/2015
• Prospective Registration: Yes
• Primary sponsor: Murdoch Children's Research Institute
• Public title: The aDOPT Trial (Dose Optimisation Prior to Transplant): In kidney transplantation, can pre-transplant blood levels of mycophenolic acid (MPA) help to optimise individual patient's post-transplant mycophenolate mofetil (MMF) dose to improve outcomes?
• Scientific title: In adults and children undergoing renal transplantation, does dose individualisation of Mycophenolate Mofetil based on a pre-transplant free MPA pharmacokinetic assessment improve post-transplant drug exposure, compared to post transplant exposure on standard fixed doses - as assessed by an increased proportion of patients within therapeutic range from early (day 3-5) post transplant in the dose individualised group, and again at 2 weeks and 3 months post transplant.
• Date of first enrolment: 01/07/2015
• Target sample size: 60
• Recruitment status: Completed
• URL: https://anzctr.org.au/ACTRN12615000273583.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Pharmacokinetics;
• Phase: Phase 4

Countries of recruitment

Australia

Contacts

• Name: Dr David Metz

• Name: Dr David Metz

Key inclusion & exclusion criteria

Inclusion criteria: Child and adult participants at or near end-stage kidney disease (ESKD), working up to renal transplantation.
Exclusion criteria: -Renal transplant protocols not including mycophenolate mofetil
-Adult ESKD patients on the cadaveric waiting list deemed unlikely to receive a transplant offer within a 2 year window.

Age minimum: 1 Years
Age maximum: No limit
Gender: Both males and females

Health Condition(s) or Problem(s) studied

End-stage kidney disease;Kidney transplantation;Acute transplant rejection;Drug toxicity;
End-stage kidney disease
Kidney transplantation
Acute transplant rejection
Drug toxicity

Inflammatory and Immune System - Other inflammatory or immune system disorders

Renal and Urogenital - Kidney disease

Intervention(s)

This trial involves administering a drug (MMF) at an unapproved time, for the purposes of pharmacokinetic analysis. We plan to compare pre-renal transplant total and free MPA pharmacokinetics with post-renal transplant pharmacokinetics, on the same dose.
This drug is standard care post-renal transplant. Post-transplant intervention is purely the pharmacokinetic assessment.
We aim to test proof-of-concept that a pre-transplant free MPA concentration assessment (TDM) improves early post-transplant MPA exposure, in a prospective pharmacokinetic trial. All patients will have standard dose MMF pre- and post-renal transplant. We will model a virtual data set of the exposure to MPA which would have occurred if we had adjusted the dose based on the pre-transplant PK assessment.

We will additionally model peri-transplant change in total and free MPA pharmacokinetics, and over the first 3 months post transplant. This will include assessment of the between-occasion variability of free MPA pharmacokinetics, to assess the degree to which time-dependant clearance in total MPA relates to plasma protein binding changes in a tacrolimus co-treatment population.

Oral mycophenolate mofetil will be administered for 4 days, at a within 1 month prior to planned living donor renal transplant, with pharmacokinetic assessment on day 4. For planned cadaveric donor renal transplant, there is no restriction on dosing and PK assessment timing (and transplant date is unknown).

Following renal transplantation, mycophenolate mofetil will be administered as part of standard care, and we will perform repeat pharmacokinetic assessment on around day 4, week 1-2, and week 6-12.

The pre-transplant dose will be whatever the treating clinician plans to administer post-transpl

Primary Outcome(s)

Proportion of patients in the TDM-controlled dose arm within therapeutic range in the early post-transplant period.
This will be based on the MPA exposure - the MPA AUC over 12 hours (MPA AUC12). Serum assays of MPA concentration from a dosing interval will be used to estimate the MPA AUC over 12 hours, using the log-linear trapezoidal rule.

A two-group chi-square test with a 0.050 two-sided significance level will have 80% power to detect the difference between a (standard dose) group proportion, p1, of 0.54 and a (individualized dose) group proportion, p2, of 0.790 when the sample size in each group is 55.[At day 3-5, and day 7-14, following renal transplant.]

Secondary Outcome(s)

Population analysis of free MPA pharmacokinetics peri-transplant and in the initial months post transplant, including within-subject variability. Population analysis will be performed based on all MPA concentration assays collected throughout the trial. The analysis will be performed using NONMEM.[The MPA concentration-time profiles will be collected prior to renal transplantation, and at 3 post-transplant dosing intervals. The first will be between day 3-5 post-transplant, the second between days 10-14 post transplant, and third at weeks 6-12 post transplant. The population pharmacokinetic analysis will be performed once all data is collected (at end of 2 year trial period).]

Variance in interpatient total and free MPA AUC12 at early (day 3-5), mid (day 10-14) and late (6-12 weeks) post-transplant. Serum assays of MPA concentration from a dosing interval will be used to estimate the MPA AUC over 12 hours, using the log-linear trapezoidal rule.[At day 3-5, and at day 10-14, and week 6-12, following renal transplant.]

Secondary ID(s)

Nil

Source(s) of Monetary Support

Sandoz PTY LTD

Royal Children's Hospital Foundation Grant

The Magdalene Foundation

Royal Australasian College of Physicians Jacquot Research Entry Scholarship

Ethics review

Status: Approved
Approval date: 08/04/2015
Contact:

Southern Health Human Research Ethics Committee

Results

• Results available: Yes
• Date Posted: 14/10/2021
• Date Completed: 26/10/2017