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Trial registered on ANZCTR


Registration number
ACTRN12617000358347
Ethics application status
Approved
Date submitted
28/02/2017
Date registered
8/03/2017
Date last updated
20/05/2020
Date data sharing statement initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Better Evidence for Selecting Transplant Fluids (BEST-Fluids)
Scientific title
An investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial evaluating the effect of Plasmalyte versus 0.9% saline on early kidney transplant function in deceased donor kidney transplantation.
Secondary ID [1] 291301 0
NCT03829488
Universal Trial Number (UTN)
U1111-1193-5857
Trial acronym
BEST-Fluids
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Delayed graft function in deceased donor kidney recipients. 302270 0
Condition category
Condition code
Renal and Urogenital 301863 301863 0 0
Kidney disease
Surgery 301906 301906 0 0
Other surgery

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Plasma-Lyte Registered Trademark 148 (Plasmalyte)

Dose administered - to be determined by the treating physician as a routine intravenous fluid therapy for all maintenance, replacement and resuscitation purposes.

Duration of administration - administered pre-, intra, and post-operatively until fluid is no longer required or 48 hours post-transplant

Mode of administration - intravenous

Intervention code [1] 297331 0
Treatment: Other
Comparator / control treatment
Isotonic sodium chloride (0.9% saline)

Dose administered - to be determined by the treating physician as a routine intravenous fluid therapy for all maintenance, replacement and resuscitation purposes.

Duration of administration - administered pre-, intra, and post-operatively until fluid is no longer required or 48 hours post-transplant

Mode of administration - intravenous
Control group
Active

Outcomes
Primary outcome [1] 301292 0
The proportion of participants with Delayed Graft Function. Measured as receiving treatment with any form of dialysis in the first seven days after transplant collected from ANZDATA
Timepoint [1] 301292 0
7 days post-transplant
Secondary outcome [1] 332244 0
Early Kidney Transplant Function, a ranked composite of
a. Duration of Delayed Graft Function
Description: Participants who require dialysis within seven days post-transplant, the time from transplant to the final dialysis treatment in days (up to 84 days/12 weeks) will be ranked from best to worst (longer times are worse).
b. Rate of recovery of kidney transplant graft function
Description: for participants who do not require dialysis, graft function assessed using the creatinine reduction ratio on post-transplant day two (CRR2) will be ranked from best to worst (smaller reductions are worse).
Timepoint [1] 332244 0
a. Duration of Delayed Graft Function - 12 Weeks
b. Rate of recovery of kidney transplant graft function - 2 Days
Secondary outcome [2] 332245 0
Creatinine reduction ratio measured using serum assay.
Timepoint [2] 332245 0
Day one and two post-transplant (creatinine reduction ratio).

Secondary outcome [3] 332246 0
Serum creatinine trends over 52 weeks.
Timepoint [3] 332246 0
Trends over 52 weeks. Taken post-op (at arrival at recovery room), Day 1 (6-9am after post-op), Day 2 (24 hours after day 1), Day 7 (7 days after post-op), Day 28 (28 days after post-op), week 12 (84 days after post-op), week 26 (182 days after post-op) and week 52 (364 days after post-op).
Secondary outcome [4] 332247 0
Incidence of serum potassium greater than or equal to 5.5 mmol/L.measured by serum assay.
Timepoint [4] 332247 0
First 48 hours post-transplant.
Secondary outcome [5] 332248 0
Treatment for hyperkalaemia with dialysis, Ca2+-gluconate, insulin, beta-agonists, sodium bicarbonate or ion exchange resins in the first 48 hours post-transplant.
Timepoint [5] 332248 0
First 48 hours post-transplant.
Secondary outcome [6] 332249 0
Incidence of significant fluid overload defined as >5% weight gain (baseline to day 2).
Timepoint [6] 332249 0
Baseline to day 2.
Secondary outcome [7] 332250 0
Aggregate urine output until day 2 post-transplant.
Timepoint [7] 332250 0
Until day 2 post-transplant.
Secondary outcome [8] 332251 0
Requirement for inotropic support both intra- and post-operatively to Day 2.
Timepoint [8] 332251 0
Intra- and post-operatively to Day 2.
Secondary outcome [9] 332252 0
Number of acute rejection episodes in the first 52 weeks as reported by ANZDATA routine data capture and as assessed by treating physicians.
Timepoint [9] 332252 0
52 weeks
Secondary outcome [10] 332253 0
Number of renal transplant biopsies performed in the first 28 days post-transplant.
Timepoint [10] 332253 0
First 28 days post-transplant.
Secondary outcome [11] 332254 0
Mortality up to 52 weeks.
Timepoint [11] 332254 0
52 weeks
Secondary outcome [12] 332255 0
Graft survival as reported by ANZDATA and assessed by treating physician.
Timepoint [12] 332255 0
52 weeks
Secondary outcome [13] 332256 0
Graft function (estimated glomerular filtration rate; eGFR) at 4, 12, 26 and 52 weeks.
Timepoint [13] 332256 0
4, 12, 26 and 52 weeks.
Secondary outcome [14] 332257 0
Health-related quality of life measured using EQ-5D-5L for adults, and EQ-5D-Y in children under 18 years.
Timepoint [14] 332257 0
Baseline, day 7, day 28, week 12, week 26, and week 52.
Secondary outcome [15] 332258 0
Length of hospital stay over 12 months using linked data state and country based health data
Timepoint [15] 332258 0
12 months
Secondary outcome [16] 332327 0
The number of dialysis sessions,
Timepoint [16] 332327 0
The number of dialysis sessions (in the first 28 days).
Secondary outcome [17] 332328 0
The total duration of dialysis in days.

Timepoint [17] 332328 0
Total duration of dialysis in days (from transplant to the final dialysis treatment).
Secondary outcome [18] 332423 0
The proportion of subjects with a decrease in serum creatinine of greater than or equal to 10% on three consecutive days in the first 7 days post-transplant;
Timepoint [18] 332423 0
Decrease in serum creatinine of greater than or equal to 10% on three consecutive days in the first 7 days post-transplant.
Secondary outcome [19] 332430 0
Peak potassium level. measured by serum assay.
Timepoint [19] 332430 0
In the first 48 hours post-transplant.
Secondary outcome [20] 332435 0
Death-censored graft survival at 52 weeks as reported by ANZDATA and assessed by treating physician.
Timepoint [20] 332435 0
52 weeks
Secondary outcome [21] 332436 0
Healthcare resource use over 12 months using linked data state and country based health data.
Timepoint [21] 332436 0
12 months
Secondary outcome [22] 332437 0
Cost-effectiveness over 12 months using linked data state and country based health data
Timepoint [22] 332437 0
12 months

Eligibility
Key inclusion criteria
1. Adult or child with ESKD, of any cause, on maintenance dialysis, or who has chronic kidney disease with an estimated glomerular filtration rate of <15 mL/min/1.73m2 (as determined by the CKD-EPI equation for adults or the bedside Schwartz equation for children)

2. Planned deceased donor kidney transplant from a brain-death (DBD) or circulatory-death (DCD) organ donor expected to occur within the next 24 hours

3. Written informed consent, or consent given by their parent or guardian (if age <18), or other authorised person.
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Planned live donor kidney transplant (except where this is cancelled in favour of transplantation from a deceased donor)

2. Planned multi-organ transplant (dual or en-bloc kidney transplants are not excluded)

3. Be a child with a weight <20 kg, or a child that the treating physician believes should not be included in a study of blinded fluids due to their small body size

4. Known hypersensitivity to the trial fluid preparations or packaging.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Screening will occur when subjects come for their usual visit to their treating physician. The patient will have an initial consultation with a study renal physician to discuss study participation. This will include a preliminary eligibility check. Randomisation will occur on the day that trial consent is obtained or within 1 month of consent being obtained.

Fluid kits will be numbered and allocated on randomsiation. The fluid treatment allocation lists will be prepared by the unblinded trial statistician, and will be programmed into the central web-based randomisation system. This will maintain the allocation concealment for all users of the randomisation system and those handling the medication, including participant, phyisican, study other healthcare providers, outcome assessors and the central clinical research associate.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed using an external web-based system, accessed via the ANZDATA registry real time entry system. Participants will be randomised 1:1 to either Plasmalyte or 0.9% saline using an adaptive minimisation method. Minimisation will be based on factors associated with DGF and graft outcomes, including: a) Transplant centre, b) Deceased donor status (DBD, DCD), c) Machine perfusion (No, Yes), and d) Australian Kidney Donor Risk Index (KDRI) tertile. The KDRI is a composite measure of donor quality based on eight donor characteristics known at the time of transplantation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
An investigator-initiated, pragmatic, registry-based, multi-centre, double-blind, randomised controlled trial evaluating the effect of Plasmalyte versus 0.9% saline on early kidney transplant function in deceased donor kidney transplantation.
Phase
Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The effect of treatment, Plasmalyte versus saline, on the primary outcome will be analysed using a log-binomial regression model, with treatment group, three minimisation variables (donor status [DBD, DCD], machine perfusion [No, Yes], KDRI tertile), and ischaemic time as predictor variables (fixed effects) in the model and study centre as a random effect. Sensitivity analyses will adjust for potential confounding due to any baseline characteristics that are substantially unbalanced between the treatment groups Pre-specified subgroup effects, including variables in the dynamic allocation algorithm, will be assessed by adding tests of interaction (treatment by subgroup variable) to the treatment group effect in log-binomial regression models.
The effect of treatment on secondary outcomes will be analysed using statistical methods appropriate for the type of outcome. Secondary outcomes are variously ordinal, binary, count, and time-to-event. Treatment groups will be compared on binary secondary outcomes using log-binomial regression. Ordinal outcomes will be analysed with a Wilcoxon rank-sum test and ordinal logistic regression. Count outcomes will be analysed with Poisson regression models. If there is under- or over-dispersion, residuals will be examined to determine the most suitable model (e.g., quasi-Poisson regression, negative binomial regression). Continuous outcomes will be compared using linear regression or an appropriate non-parametric test if assumptions are not met. Mortality and graft survival will be analysed using Kaplan-Meier curves and the log rank test.
Analyses will be by intention to treat; participants will be included in the intention to treat analysis if they are randomised and receive a deceased donor kidney transplant within 48 hours of randomisation. Participants whose transplant does not proceed will be excluded from analysis of the primary and secondary outcomes, although those who receive study fluids will be included in analysis of safety outcomes.
Adverse events will be tabulated by treatment group. Depending on the amount and type of data, differences between treatment groups on adverse events may be tested by binary logistic or Poisson regression.
All analyses will be described in a detailed statistical analysis plan made publicly available before data analysis commences and treatment allocations are unblinded.

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)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 7581 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 7582 0
Princess Alexandra Hospital - Woolloongabba
Recruitment hospital [3] 7583 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [4] 7585 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [5] 12997 0
Westmead Hospital - Westmead
Recruitment hospital [6] 12998 0
Prince of Wales Hospital - Randwick
Recruitment hospital [7] 12999 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [8] 13416 0
St Vincent's Hospital (Melbourne) Ltd - Fitzroy
Recruitment hospital [9] 13417 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [10] 15664 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [11] 15665 0
Sydney Children's Hospital - Randwick
Recruitment hospital [12] 16725 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 15475 0
2050 - Camperdown
Recruitment postcode(s) [2] 15476 0
4102 - Woolloongabba
Recruitment postcode(s) [3] 15477 0
5000 - Adelaide
Recruitment postcode(s) [4] 15479 0
3084 - Heidelberg
Recruitment postcode(s) [5] 25482 0
2145 - Westmead
Recruitment postcode(s) [6] 25483 0
2031 - Randwick
Recruitment postcode(s) [7] 25484 0
6150 - Murdoch
Recruitment postcode(s) [8] 26018 0
3065 - Fitzroy
Recruitment postcode(s) [9] 26019 0
3168 - Clayton
Recruitment postcode(s) [10] 29073 0
4101 - South Brisbane
Recruitment postcode(s) [11] 30327 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 8697 0
New Zealand
State/province [1] 8697 0
Auckland, Christchurch, Wellington

Funding & Sponsors
Funding source category [1] 295772 0
Government body
Name [1] 295772 0
Medical Research Future Fund -Lifting Clinical Trials and Registries Capacity (MRFF-LCTRC), Department of Health
Address [1] 295772 0
Research Committee Secretariat NHMRC, GPO Box 1421, Canberra ACT 2601
Country [1] 295772 0
Australia
Funding source category [2] 295773 0
Other
Name [2] 295773 0
The Royal Australasian College of Physicians (RACP)
Address [2] 295773 0
PO Box 10601
Wellington 6143
Country [2] 295773 0
New Zealand
Funding source category [3] 296865 0
Government body
Name [3] 296865 0
Health Research Council (HRC)
Address [3] 296865 0
Level 3, 110 Stanley Street, Auckland, 1010
Country [3] 296865 0
New Zealand
Funding source category [4] 301777 0
Commercial sector/Industry
Name [4] 301777 0
Baxter Healthcare Corporation
Address [4] 301777 0
One Baxter Parkway, Deerfield. Illinois 60015 USA
Country [4] 301777 0
United States of America
Primary sponsor type
Other
Name
Australasian Kidney Trials Network (University of Qld)
Address
Translational Research Institute
Level 5 East
37 Kent Street
WOOLLOONGABBA QLD 4102
Country
Australia
Secondary sponsor category [1] 294620 0
None
Name [1] 294620 0
Address [1] 294620 0
Country [1] 294620 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297065 0
Nothern A
Ethics committee address [1] 297065 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 297065 0
New Zealand
Date submitted for ethics approval [1] 297065 0
06/04/2017
Approval date [1] 297065 0
22/06/2017
Ethics approval number [1] 297065 0
17/NTA/62
Ethics committee name [2] 297070 0
SLD Royal Prince Alfred Ethics Committee
Ethics committee address [2] 297070 0
c/- Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [2] 297070 0
Australia
Date submitted for ethics approval [2] 297070 0
10/04/2017
Approval date [2] 297070 0
21/11/2017
Ethics approval number [2] 297070 0
X17-0201 & HREC/17/RPAH/308

Summary
Brief summary
Delayed or slow graft function (DGF), i.e. the requirement for dialysis, or poor kidney transplant graft function early after transplantation, affects 20-50% of deceased donor kidney transplants, and increases the risk of graft failure and mortality. DGF reflects acute kidney injury caused by ischaemia-reperfusion injury during transplantation, and is driven by donor, recipient and transplant factors.

Intravenous fluids are a critical, albeit inexpensive, aspect of care that impacts early transplant function. Currently, isotonic sodium chloride (‘normal’ or 0.9% saline) is standard of care at the majority of transplant centres. However, 0.9% saline may be harmful due to its high chloride content relative to plasma, which causes metabolic acidosis and may promote acute kidney injury, and thus DGF. Studies of low-chloride balanced solutions versus normal saline in transplantation have shown reduced acidosis, but have been too small to show differences in transplant outcomes.

The BEST-Fluids study (Better Evidence for Selecting Transplant Fluids) is a clinical trial investigating the difference between two standard practice fluids (Plasmalyte and normal saline) used before, during and after surgery in improving the lives of people who have a kidney transplant.

The primary outcome investigates the requirement of dialysis in participants with delayed graft function (proportion of participants who require dialysis within first seven days) . Secondary outcomes include graft function, survival, and cost-effectiveness. This trial will show if Plasmalyte is better to normal saline in kidney transplantation, may result in cost savings and will rapidly translate into clinical practice.
Trial website
https://aktn.org.au/best-fluids/
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 72858 0
Prof Steven Chadban
Address 72858 0
Medicine, Central Clinical School, Royal Prince Alfred Hospital & University of Sydney, Missenden Street, Camperdown, NSW, 2050
Country 72858 0
Australia
Phone 72858 0
+61 2 9515 6600
Fax 72858 0
Email 72858 0
Steve.Chadban@health.nsw.gov.au
Contact person for public queries
Name 72859 0
Ms Julie Varghese
Address 72859 0
Australasian Kidney Trials Network, Faculty of Medicine (CHSR), The University of Queensland, Translational Research Institute, Level 5, 37 Kent Street, Woolloongabba, QLD, 4102
Country 72859 0
Australia
Phone 72859 0
+61 7 3443 7346
Fax 72859 0
Email 72859 0
best.fluids@uq.edu.au
Contact person for scientific queries
Name 72860 0
Dr Michael Collins
Address 72860 0
Department of Renal Medicine
Auckland City Hospital
Park Road
Auckland 1023
Country 72860 0
New Zealand
Phone 72860 0
+64 9 367 0000
Fax 72860 0
Email 72860 0
michael.collins@adhb.govt.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Yes Individual participant data that underlie the results reported in the primary publication, after de-identification (text, tables, figures and appendices) will be available for individual participant data meta-analysis.
When will data be available (start and end dates)?
Beginning 2 years and ending 5 years following main publication. Proposals may be
submitted up to 5 years following article publication. After 5 years, the data will be
available in our University's data warehouse but without investigator support other than
deposited metadata.
Available to whom?
Investigators whose proposed use of the data has been approved by an independent review committee, identified for this purpose.
Available for what types of analyses?
For individual participant meta-analysis.
How or where can data be obtained?
An independent review board will assess proposals based on the following criteria: sound
science, benefit-risk balancing and research team expertise.
What supporting documents are/will be available?
No other documents available
Summary results
No Results