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Trial registered on ANZCTR


Registration number
ACTRN12615000273583
Ethics application status
Approved
Date submitted
2/03/2015
Date registered
23/03/2015
Date last updated
26/03/2019
Date data sharing statement initially provided
22/03/2019
Type of registration
Prospectively registered

Titles & IDs
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.
Secondary ID [1] 286233 0
Nil
Universal Trial Number (UTN)
U1111-1167-4510
Trial acronym
The aDOPT Trial: Dose Optimisation Prior to Transplant
Linked study record

Health condition
Health condition(s) or problem(s) studied:
End-stage kidney disease 294281 0
Kidney transplantation 294282 0
Acute transplant rejection 294284 0
Drug toxicity 294508 0
Condition category
Condition code
Renal and Urogenital 294607 294607 0 0
Kidney disease
Inflammatory and Immune System 294749 294749 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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-transplant (there is some practice variation between centres and depending on individual patient risk).
For adults this will be either MMF 1g oral twice daily or 1.5g oral twice daily.
For children this will be between 300mg/m2/dose oral twice daily to 600mg/m2/dose oral twice daily.

Adherence will be monitored by medication return, and patients will fill out a dosing sheet to document time of each administration. The day 4 MMF dose will be observed.
Intervention code [1] 291250 0
Treatment: Drugs
Comparator / control treatment
MMF is already standard care post-transplant.
All patients will have standard dose MMF pre- and post-renal transplant.
For adults this will be either MMF 1g oral twice daily or 1.5g oral twice daily. For children this will be between 300mg/m2/dose oral twice daily to 600mg/m2/dose oral twice daily.

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 (a virtual intervention group).

The outcomes are post-transplant exposure to MPA.
The control arm will be the measured MPA exposure on standard dosing.
The intervention arm will be a virtual pharmacokinetically modelled arm of MPA exposure from individualised doses.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 294373 0
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.
Timepoint [1] 294373 0
At day 3-5, and day 7-14, following renal transplant.
Secondary outcome [1] 313128 0
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.
Timepoint [1] 313128 0
At day 3-5, and at day 10-14, and week 6-12, following renal transplant.
Secondary outcome [2] 313129 0
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.
Timepoint [2] 313129 0
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).

Eligibility
Key inclusion criteria
Child and adult participants at or near end-stage kidney disease (ESKD), working up to renal transplantation.
Minimum age
1 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
All patients will receive the treatment - a pre-transplant MMF PK assessment.
The outcomes analysis will be modelled (modelling of exposure on individual dose, and PK modelling of peri-transplant PK changes).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not relevant
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 4
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
The largest analysis of effective TDM-controlled dosing of MMF in the early post transplant period showed 54% of patients within therapeutic range versus 79%, in fixed versus TDM-controlled dosing respectively.

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. Because each patient provides the data for their (measured) standard dose exposure and (modelled) individualised dose exposure, a total of 55 patients are required.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 3530 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 3531 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [3] 3532 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 3534 0
Lady Cilento Children's Hospital - South Brisbane
Recruitment hospital [5] 13471 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [6] 13472 0
Box Hill Hospital - Box Hill
Recruitment postcode(s) [1] 26084 0
3065 - Fitzroy
Recruitment postcode(s) [2] 26085 0
3128 - Box Hill

Funding & Sponsors
Funding source category [1] 290855 0
Charities/Societies/Foundations
Name [1] 290855 0
The Magdalene Foundation
Address [1] 290855 0
PO Box 96
Wandin North Victoria 3139
Australia
Country [1] 290855 0
Australia
Funding source category [2] 302312 0
Hospital
Name [2] 302312 0
Royal Children's Hospital Foundation Grant
Address [2] 302312 0
50 Flemington Road Parkville VIC 3052
Country [2] 302312 0
Australia
Funding source category [3] 302313 0
Charities/Societies/Foundations
Name [3] 302313 0
Royal Australasian College of Physicians Jacquot Research Entry Scholarship
Address [3] 302313 0
145 Macquarie Street
Sydney NSW 2000
Country [3] 302313 0
Australia
Funding source category [4] 302333 0
Commercial sector/Industry
Name [4] 302333 0
Sandoz PTY LTD
Address [4] 302333 0
Level 2, 19 Harris Street, Pyrmont NSW 2009
Country [4] 302333 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
50 Flemington Road
Parkville VIC
3052
Country
Australia
Secondary sponsor category [1] 289545 0
None
Name [1] 289545 0
Address [1] 289545 0
Country [1] 289545 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292471 0
Southern Health Human Research Ethics Committee
Ethics committee address [1] 292471 0
Research Directorate
Monash Health
Monash Medical Centre
246 Clayton Road
Clayton Victoria 3168
Australia
Ethics committee country [1] 292471 0
Australia
Date submitted for ethics approval [1] 292471 0
11/03/2015
Approval date [1] 292471 0
08/04/2015
Ethics approval number [1] 292471 0
14428B

Summary
Brief summary
Each individual differs in how his/her body handles a medication, meaning that even when every patient is given the exact same dose, each person can end up with a very different concentration of the drug in the blood. It is the drug concentration in the body, not the dose given, which determines a drug’s effects – both its benefits and unwanted side effects. This drug concentration is critical for many anti-rejection drugs used in kidney transplantation, because of the delicate balance between giving enough to prevent rejection and loss of the transplant kidney, whilst minimising adverse effects of the medication.

Mycophenolate mofetil (MMF) is one of the most important ‘anti-rejection’ drugs that have improved kidney transplant outcomes. We are testing whether giving patients MMF before their kidney transplant, and testing the concentrations in their blood, allow us to optimally dose each individual's MMF dose from the time of transplant. This potentially means that a patient can be on the best, personalised dose from the start.
This has the potential to reduce transplant rejection rates and improve outcomes, whilst also reducing harmful effects of MMF, with an overall improvement in quality of life.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 55202 0
Dr David Metz
Address 55202 0
Department of Nephrology
Royal Children's Hospital Melbourne
50 Flemington Road
Parkville VIC 3052
Country 55202 0
Australia
Phone 55202 0
+61 3 93455054
Fax 55202 0
Email 55202 0
david.metz@rch.org.au
Contact person for public queries
Name 55203 0
Dr David Metz
Address 55203 0
Department of Nephrology
Royal Children's Hospital Melbourne
50 Flemington Road
Parkville VIC 3052
Country 55203 0
Australia
Phone 55203 0
+61 3 93455054
Fax 55203 0
Email 55203 0
david.metz@rch.org.au
Contact person for scientific queries
Name 55204 0
Dr David Metz
Address 55204 0
Department of Nephrology
Royal Children's Hospital Melbourne
50 Flemington Road
Parkville VIC 3052
Country 55204 0
Australia
Phone 55204 0
+61 3 93455054
Fax 55204 0
Email 55204 0
david.metz@rch.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not part of current HREC approval.
What supporting documents are/will be available?
No other documents available
Summary results
No Results