Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615001261505p
Ethics application status
Submitted, not yet approved
Date submitted
2/11/2015
Date registered
19/11/2015
Date last updated
19/11/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
Starship Hospital wide feasibility Study comparing Plasma-Lyte 148 (Registered Trademark) with 0.9% Saline with for all crystalloid fluid therapy in inpatients requiring IV fluids.
Scientific title
A single-centre, feasibility trial comparing Plasma-Lyte 148 (Registered Trademark) with 0.9% saline for all crystalloid fluid therapy in inpatients of a children's hospital requiring IV fluids.
Secondary ID [1] 287761 0
nil known
Universal Trial Number (UTN)
U1111-1175-6359
Trial acronym
SHIPS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
paediatric illness 296645 0
hyperchloraemia 296646 0
Condition category
Condition code
Other 296874 296874 0 0
Research that is not of generic health relevance and not applicable to specific health categories listed above

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is designed to provide high quality feasibility data for a future multi-centre cluster randomized cross-over study. Children attending Starship Children’s Hospital, who require IV fluids will be assigned to use either 0.9% saline or Plasma-Lyte 148 (Registered Trademark) as the primary crystalloid fluid therapy in a blinded fashion, in alternating four week blocks. Blinded study fluid will be used for fluid therapy in situations where the two study fluids are regarded as equivalent by the treating clinician, and will be administered for all resuscitation and maintenance fluid for up to 28 days after enrollment. Both 0.9% saline and Plasma-Lyte 148 (Registered Trademark) will be available for open-label administration in the rare situations, where, in the opinion of the treating specialist, there is a clinical indication for one fluid or the other.

As per standard practice in children, the blinded study fluids will be available with and without added glucose, and the glucose will be clearly labelled on the bags as per current labeling guidelines. The amount and rate of fluid administration, along with the concentration of glucose will be determined by the clinicians managing the patient according to clinical need and in line with Starship Hospital's recommended best practice guidelines.

The daily amount of all intravenous fluids administered (both blinded study fluid, open label crystaloids and other fluids such as blood products), will be recorded in the case report form for all participants.
Intervention code [1] 293158 0
Treatment: Other
Intervention code [2] 293272 0
Treatment: Drugs
Comparator / control treatment
This feasibility study will compare 2 standard therapies, so the use of the term 'control' may be slightly misleading. In Starship hospital, 0.9% Saline is more frequently administered than Plasmalyte (although for many children's hospitals the contrary is true). Therefore 0.9% saline will be denoted control.
Control group
Active

Outcomes
Primary outcome [1] 296476 0
As a feasibility trial, primary and secondary outcomes are of similar importance. length of hospital stay has been chosen as the primary outcome, but the main trial to follow may use a different primary outcome based on the data and outcomes obtained from analysis of this trial. Data to calculate length of hospital stay (date and time of admission and discharge) will be collected by the research nurses and entered into the case report form. The hospital clinical information system data will be used to examine for large discrepancies in the 'data validation' phase, prior to analysis.
Timepoint [1] 296476 0
data collection will be censored at 28 days after the last enrollment, which is 84 days after the trial commences enrolling
Secondary outcome [1] 318527 0
difference between baseline (pre-fluid administration) and peak creatinine, with levels measured by the biochemistry laboratories as per usual clinical care (no blood tests performed specifically for this trial)
Timepoint [1] 318527 0
peak level between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days)
Secondary outcome [2] 318528 0
The cumulative incidence of acute kidney injury based on creatinine and urine output, according to the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Acute Kidney Injury3 will be calculated.
Timepoint [2] 318528 0
worst KDIGO score between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days)
Secondary outcome [3] 318529 0
Differences in fluid volumes received, urine output or fluid balance will be analysed where available. Data will be analysed as both differences in daily fluids and differences over the data collection period (discharge from hospital or 28 days after enrollment).
Timepoint [3] 318529 0
This data will be collected retrospectively after the patient has received study fluid for 2 or more days, and will continue to be collected until 24 hours after IV fluid is no longer received or censoring of data collection (discharge from hospital or 28 days post enrollment).
Secondary outcome [4] 318530 0
As safety measures, the proportion of each group requiring unplanned readmission to ICU, renal replacement therapy and in-hospital mortality will be analysed. Each of these fields will have an associated tick box on the patient's case report form, with an associated field to enter the date(s) the event(s) occurred.
Timepoint [4] 318530 0
any occurence of the event between enrllment in the trial (when IV fluids commence) and censoring of data collection (discharge from hospital or 28 days or 28 days post enrollment)
Secondary outcome [5] 318946 0
differences between groups in serum sodium , with levels measured by the biochemistry laboratories or gas anaysers as per usual clinical care (no blood tests performed specifically for this trial)
Timepoint [5] 318946 0
peak and trough levels between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days post enrollment).
Secondary outcome [6] 318947 0
differences between groups in serum chloride, with levels measured by the biochemistry laboratories and gas analysers as per usual clinical care (no blood tests performed specifically for this trial)
Timepoint [6] 318947 0
peak and trough levels between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days or 28 days post enrollment)
Secondary outcome [7] 318948 0
differences between groups in bicarbonate levels, with levels measured by the biochemistry laboratories as per usual clinical care (no blood tests performed specifically for this trial)
Timepoint [7] 318948 0
peak and trough level between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days post enrollment)
Secondary outcome [8] 318949 0
differences between groups in arterial and/or venous/capillary pH, , with levels measured by the biochemistry laboratories or gas analysers as per usual clinical care (no blood tests performed specifically for this trial)
Timepoint [8] 318949 0
peak and trough pH between fluid administration commencing and censoring of data collection (discharge from hospital or 28 days post enrollment)

Eligibility
Key inclusion criteria
Patients admitted to Starship Children’s Hospital who require isotonic crystalloid fluid therapy. This includes patients presenting via the emergency department, operating theatres, ICU or directly to any inpatient ward (including interhospital transfers). Due to admission criteria of Starship, this will predominantly be children less than 15 years of age, but will include some older children and adults with specific conditions such as congenital heart disease and inborn errors of metabolism.
Minimum age
No limit
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-The clinician managing the patient has a need to administer a particular isotonic crystalloid solution.
-The child is under 44 weeks corrected gestational age.

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)
there is masking/blinding, but no allocation concealment. Everyone presenting to hospital for 28 days will be allocated to the same arm of the trial.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Time course - those presenting to Starship Hospital (who require intravenous fluids) in the first 28 days of the trial will be assigned to receive fluid A, and those presenting in the subsequent 28 days will receive fluid B
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
Other
Other design features
fluids will be blinded as to whether they contain 0.9% Saline or Plasma-Lyte 148 (Registered Trademark), and denoted fluid A or fluid B (manufactured by Baxter Pty Ltd as blinded study fluids). All investigators, and clinical staff will be informed of the trial fluid in use for each 28 day block (that is fluid A or fluid B), but not whether fluid A or fluid B represents Saline or Plasma-Lyte 148. The fluids will clearly have marked whether they contain glucose or not. Participants and their families will be similarly blinded.
Phase
Not Applicable
Type of endpoint/s
Safety
Statistical methods / analysis
Analyses of clinical outcome will be conducted on an intention-to-treat basis. As a feasibility study we will investigate various methodologies for analysis of the data. The distribution of the primary outcome of length of stay is expected to be highly skewed, which may be best suited to transformation into a more normal distribution suitable for more standard parametric analysis, or may be better suited to methods that “allow’ for the skew such as generalised linear modelling. Multivariable modelling to adjust for Primary outcome will undergo log transformation and confirmation of normality prior to parametric analysis.

Binomial outcomes will be assessed using generalized estimating equations (GEE) with as associations described using Odds Ratios and 95%confidence intervals (CI) while continuous outcomes will be analysed using generalised linear modelling (GLM) and reported as either mean differences (with 95%CI) or ratios (with 95%CI) as appropriate. Sensitivity analysis will be performed adjusting for an a-priori defined list of covariates (baseline serum creatinine level, medical or surgical, ICU, elective admission, diagnostic criteria) will be undertaken. Other continuous and binomial outcomes will be investigated similarly, and odds ratios and 95% confidence intervals calculated. All analyseis will be performed using SAS version 9.3 (SAS Institute Inc., Cary, USA) or JMP version 11 and a two-sided p-value of 0.05 will be considered to be statistically significant.

This study will provide data to better allow statistical modelling of the number of clusters required, and the overall sample size for a future large scale multi-centre cluster randomised cross-over study. From the study groups we will ascertain estimates of the distribution/variation of the outcome measures, across various hospital environments, under the specific conditions of this study protocol. The degree of variation between hospital environments may provide a useful insight into how much level of variation can exist between different centres. Power and sample size calculations for a future cluster randomized crossover study, based upon the data of this study, will be undertaken using published methods such as that of Reich et al.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2016
Actual
Date of last participant enrolment
Anticipated
26/04/2016
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
840
Accrual to date
Final
Recruitment outside Australia
Country [1] 7284 0
New Zealand
State/province [1] 7284 0
Auckland

Funding & Sponsors
Funding source category [1] 292301 0
Government body
Name [1] 292301 0
New Zealand Health Research Council
Country [1] 292301 0
New Zealand
Primary sponsor type
Hospital
Name
Starship Hospital Paediatric Intensive Care Research Department
Address
Starship Children's Hospital
Private Bag 92024
Auckland 1142
New Zealand
Country
New Zealand
Secondary sponsor category [1] 290984 0
None
Name [1] 290984 0
N/A
Address [1] 290984 0
N/A
Country [1] 290984 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 293777 0
Health and DIsability Ethics Committees
Ethics committee address [1] 293777 0
Ministry of Health
Ethics Department
Freyberg Building
Reception – Ground Floor
20 Aitken Street
Wellington 6011
Ethics committee country [1] 293777 0
New Zealand
Date submitted for ethics approval [1] 293777 0
18/11/2015
Approval date [1] 293777 0
Ethics approval number [1] 293777 0

Summary
Brief summary
The administration of intravenous (IV) fluid is an extremely common therapy in children requiring hospital care. Recent research strongly suggests we must increase the concentration of sodium in intravenous fluid routinely given to hospitalised children, in order to minimise the potentially dangerous complication of low serum sodium concentration. Hence, fluids currently considered appropriate to administer for ongoing IV fluid maintenance include 0.9% saline or Plasma-Lyte (Registered Trademark) 148.

0.9% saline and Plasma-Lyte 148 have both been routinely administered to children as IV ‘bolus’ resuscitation (10-20 mls/kg given over 5-30 minutes) fluid for decades. The choice of which fluid is administered is largely dependent on the institution and the prescribing habits of individual clinicians. For example, children in Victoria commonly receive Plasma-Lyte 148, while those in New South Wales commonly receive 0.9% Saline. Theoretical benefits have been attributed to Plasma-Lyte 148 over 0.9% saline, but current clinical data is insufficient to recommend one of these fluids over the other. Recent research has also supported that fluids containing 0.9% saline or Plasma-Lyte 148 should be routinely given for ongoing IV fluid maintenance in children, in addition to their current use for IV ‘bolus’ fluids. Once again there is insufficient clinical data to recommend one fluid over the other, despite IV fluid prescription being the second most common prescription to occur in children admitted to hospital (second to analgesia/anti-pyretics). Plasma-Lyte 148 is considerably more expensive than 0.9% saline. Thus there is an urgent need for an interventional trial comparing 0.9% saline to Plasma-Lyte 148 for both IV fluid bolus and maintenance therapy in children admitted to hospital. The results of such a study will widely inform national and international fluid prescribing guidelines for children.

This study will assign two clusters of participants by alternating treatments over consecutive time periods. It is designed to provide high quality feasibility data for a future multi-centre cluster randomized cross-over study of the same design. Children attending Starship Children’s Hospital, who require IV fluids will be assigned to use either 0.9% saline or Plasma-Lyte 148 as the primary crystalloid fluid therapy in a blinded fashion, in alternating four week blocks. Blinded study fluid will be used for fluid therapy in situations where the two study fluids are regarded as equivalent by the treating clinician. Children require varying amounts of glucose within the fluid administered, thus both glucose and non-glucose containing versions of the study fluids will be available and clearly labelled. As per current practice, clinicians will be able to add extra glucose and/or potassium to intravenous fluid bags.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61254 0
Dr Brent McSharry
Address 61254 0
Paediatric Intensive Care Unit
Starship Children's Hospital
Private Bag 92024
Auckland 1142
New Zealand
Country 61254 0
New Zealand
Phone 61254 0
+64 21 245 9769
Fax 61254 0
Email 61254 0
brentm@adhb.govt.nz
Contact person for public queries
Name 61255 0
Dr Brent McSharry
Address 61255 0
Paediatric Intensive Care Unit
Starship Children's Hospital
Private Bag 92024
Auckland 1142
New Zealand
Country 61255 0
New Zealand
Phone 61255 0
+64 21 245 9769
Fax 61255 0
Email 61255 0
brentm@adhb.govt.nz
Contact person for scientific queries
Name 61256 0
Dr Brent McSharry
Address 61256 0
Paediatric Intensive Care Unit
Starship Children's Hospital
Private Bag 92024
Auckland 1142
New Zealand
Country 61256 0
New Zealand
Phone 61256 0
+64 21 245 9769
Fax 61256 0
Email 61256 0
brentm@adhb.govt.nz

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