Trial registered on ANZCTR


Trial ID
ACTRN12613001370796
Ethics application status
Approved
Date submitted
10/12/2013
Date registered
13/12/2013
Date last updated
6/09/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
0.9% saline vs. Plasma-Lyte 148 for Intensive Care Fluid Therapy. (the SPLIT study)
Scientific title
A multi-centre, cluster randomised, double cross over, feasibility trial investigating the effect of using 0.9% saline or Plasma-lyte 148 as fluid therapy on the risk of developing acute kidney injury in intensive care patients
Secondary ID [1] 283744 0
None
Universal Trial Number (UTN)
U1111-1136-3741
Trial acronym
The SPLIT study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Intravenous Fluid Management in Critical Illness 290712 0
Condition category
Condition code
Cardiovascular 291080 291080 0 0
Other cardiovascular diseases
Anaesthesiology 291081 291081 0 0
Other anaesthesiology
Infection 291082 291082 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
0.9% saline for intravenous fluid therapy in intensive care. The rate, duration, and frequency of fluid administration will determined by the treated clinician. All fluid used for either fluid resuscitation or crystalloid rehydration will be 0.9% saline unless a specific indication exists for another fluid. Each of the four study ICUs will be randomly assigned, in alternating seven week blocks, to use blinded 0.9% saline or Plasma-Lyte 148 as the default resuscitation fluid. There will be no wash-out period between treatments. Each patient will receive the treatment they were assigned at the time of their ICU admission for the entire duration of their ICU admision irrespective of whether a cross-over occurs while they are admitted.
Intervention code [1] 288431 0
Treatment: Other
Comparator / control treatment
Plasma-lyte 148 for intravenous fluid therapy in intensive care. The rate, duration, and frequency of fluid administration will determined by the treated clinician. All fluid used for either fluid resuscitation or crystalloid rehydration will be Plasma-Lyte 148 unless a specific indication exists for another fluid. Each of the four study ICUs will be randomly assigned, in alternating seven week blocks, to use blinded 0.9% saline or Plasma-Lyte 148 as the default resuscitation fluid. There will be no wash-out period between treatments. Each patient will receive the treatment they were assigned at the time of their ICU admission for the entire duration of their ICU admision irrespective of whether a cross-over occurs while they are admitted.
Control group
Active

Outcomes
Primary outcome [1] 291067 0
The proportion of patients with either acute kidney injury or failure based on on creatinine levels in accordance with RIFLE criteria
Timepoint [1] 291067 0
Highest value measured during the patient's stay in the Intensive Care Unit (censored at day 90)
Secondary outcome [1] 305947 0
Delta creatinine (the difference between the pre-randomisation creatinine and the peak creatinine). The creatinine values used will be serum creatinine measures taken for clinical purposes.
Timepoint [1] 305947 0
The baseline creatinine will be the creatinine measured at study enrolment. The peak creatinine will be the highest creatinine measured in the Intensive Care Unit (censored at day 90). The creatinine values used will be serum creatinine measures taken for clinical purposes.
Secondary outcome [2] 305948 0
the cumulative incidence of acute kidney injury by category based on creatinine levels and classified into the following groups: Risk, Injury, Failure, Loss, and End stage renal failure. The creatinine values used will be serum creatinine measures taken for clinical purposes.
Timepoint [2] 305948 0
based on the highest value measured during the patient's stay in the Intensive Care Unit (censored at day 90)
Secondary outcome [3] 305949 0
proportion of patients requiring renal replacement therapy
Timepoint [3] 305949 0
during the course of their ICU admission
Secondary outcome [4] 305950 0
proportion of patients requiring renal replacement therapy (among those patients who require renal replacement therapy in the Intensive Care Unit)
Timepoint [4] 305950 0
after hospital discharge
Secondary outcome [5] 305951 0
proportion of patients requiring mechanical ventilation
Timepoint [5] 305951 0
during the course of their ICU admission
Secondary outcome [6] 305952 0
duration of mechanical ventilation (among patients who require mechanical ventilation)
Timepoint [6] 305952 0
during the course of their ICU admission
Secondary outcome [7] 305953 0
Length of ICU admission (days)
Timepoint [7] 305953 0
Time from enrolment until ICU discharge
Secondary outcome [8] 305956 0
Length of hospital admission (days)
Timepoint [8] 305956 0
time from enrolment until hospital discharge
Secondary outcome [9] 305957 0
proportion of patients who require readmission to ICU
Timepoint [9] 305957 0
within their index hospital admission
Secondary outcome [10] 308113 0
the cumulative incidence of acute kidney injury by KDIGO stage category based on creatinine levels and classified into the following groups: KDIGO stage 1, KDIGO stage 2, and KDIGO stage 3. The creatinine values used will be serum creatinine measures taken for clinical purposes.
Timepoint [10] 308113 0
based on the highest serum creatinine value measured during the patient's stay in the Intensive Care Unit (censored at day 90)

Eligibility
Key inclusion criteria
Patients admitted to the study ICU who require crystalloid fluid therapy
Minimum age
No limit
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. patients currently receiving or expected to require renal replacement therapy within six hours of ICU admission 2. patients who are usually on dialysis for end stage renal failure 3. patients who are admitted to the ICU solely for consideration of organ donation or for palliative care 4. patients previously enrolled in the SPLIT study

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)
The study is a cluster cross over trial in which the entire ICU will be randomly assigned to using either 0.9% saline or plasma-lyte 148 for routine fluid therapy. Each of four study ICUs will use each treatment strategy twice over the 28 weeks of the study. The allocation of study treatments in each cluster will be determined ahead of time by the study statistician. Masked study fluid appropriate for each study block which is labelled either 'fluid A' or 'fluid B' will be delivered to each study unit by Baxter Pty Ltd (who will prepare blinded study fluids for this study). Allocation concealment will be maintained until all analyses (including post hoc analyses) are complete.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The order of study treatments will be determined at random by the study statistician using a computer algorithm.
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
Crossover
Other design features
Multicentre, cluster, double cross over.
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Analyses will be conducted on an intention-to-treat basis. Primary and secondary outcomes will be analysed using longitudinal analysis techniques accounting for attending hospital and drug sequence. Binomial outcomes will be assessed using generalized estimating equations (GEE) with results reported as Odds Ratios (95%CI) while continuous outcomes will be analysed using generalised linear modelling (GLM) and reported as either differences (95%CI) or ratios (95%CI) as appropriate. Sensitivity analysis will be performed adjusting for an a-priori defined list of covariates (presence or absence of trauma, APACHE-III admission diagnosis, age, ICU admission source, APACHE-II score, and baseline serum creatinine level) with results reported both overall and at an individual hospital level. All analysis will be performed using SAS version 9.3 (SAS Institute Inc., Cary, USA) and a two-sided p-value of 0.05 will be considered to be statistically significant.

Due to the current lack of established statistical methodologies for calculating sample size for cluster cross over trials with binary outcome variables, we have not performed any sample size calculations for this study. However, the data obtained in this study will be used to facilitate modelling of sample size requirements for a larger scale study. This study will enrol between 2,000 and 3,000 patients over a 28-week period and will be the largest prospective clinical trial comparing 0.9% saline to plasma-lyte 148 ever conducted.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Anticipated
Actual
Recruitment outside Australia
Country [1] 5672 0
New Zealand
State/province [1] 5672 0
Auckland, Wellington, and Christchurch

Funding & Sponsors
Funding source category [1] 288414 0
Government body
Name [1] 288414 0
Health Research Council of New Zealand
Address [1] 288414 0
PO Box 5541, Wellesley Street, Auckland 1141
Country [1] 288414 0
New Zealand
Funding source category [2] 288415 0
Commercial sector/Industry
Name [2] 288415 0
Baxter Pty Ltd
Address [2] 288415 0
Baxter Dr, Old Toongabbie NSW 2146, Australia
Country [2] 288415 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Medical Research Institute of New Zealand
Address
Private Bag 7902
Wellington 6242
Country
New Zealand
Secondary sponsor category [1] 287122 0
None
Name [1] 287122 0
Address [1] 287122 0
Country [1] 287122 0
Other collaborator category [1] 277723 0
Hospital
Name [1] 277723 0
Capital Coast District Health Board
Address [1] 277723 0
Private Bag 7902
Wellington South 6242
Country [1] 277723 0
New Zealand
Other collaborator category [2] 277724 0
Hospital
Name [2] 277724 0
Canterbury District Health Board
Address [2] 277724 0
Private Bag 4710
Christchurch 8104
Country [2] 277724 0
New Zealand
Other collaborator category [3] 277725 0
Hospital
Name [3] 277725 0
Auckland District Health Board
Address [3] 277725 0
Private Bag 92024
Auckland Mail Centre
Auckland 1142
Country [3] 277725 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290294 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 290294 0
Ministry of Health
No 1 The Terrace
PO Box 5013
Wellington 6011

Ethics committee country [1] 290294 0
New Zealand
Date submitted for ethics approval [1] 290294 0
Approval date [1] 290294 0
10/12/2013
Ethics approval number [1] 290294 0
12NTB57

Summary
Brief summary
The administration of intravenous fluid is a common therapy in acutely unwell patients. The study will provide preliminary data from a large interventional trial to inform clinicians looking after acutely unwell patients as to whether 0.9% saline or Plasma-Lyte 148 'Registered Trademark' is the preferred fluid for routine use in the ICU.
Trial website
Trial related presentations / publications
Manuscript published. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, McGuinness S,
Mehrtens J, Myburgh J, Psirides A, Reddy S, Bellomo R; SPLIT Investigators;
ANZICS CTG. Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney
Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical
Trial. JAMA. 2015 Oct 27;314(16):1701-10. doi: 10.1001/jama.2015.12334. Erratum
in: JAMA. 2015 Dec 15;314(23):2570.
Public notes

Contacts
Principal investigator
Name 44898 0
Dr Paul Young
Address 44898 0
c/o Intensive Care Unit
Wellington Hospital
Private Bag 7902
Newtown
Wellington 6242
Country 44898 0
New Zealand
Phone 44898 0
+6448060441
Fax 44898 0
Email 44898 0
paul.young@ccdhb.org.nz
Contact person for public queries
Name 44899 0
Ms Diane Mackle
Address 44899 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242

Country 44899 0
New Zealand
Phone 44899 0
+64 4 805 0147
Fax 44899 0
Email 44899 0
diane.mackle@ccdhb.org.nz
Contact person for scientific queries
Name 44900 0
Ms Diane Mackle
Address 44900 0
Medical Research Institute of New Zealand
Private Bag 7902
Wellington 6242
Country 44900 0
New Zealand
Phone 44900 0
+64 4 805 0147
Fax 44900 0
Email 44900 0
diane.mackle@ccdhb.org.nz