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Trial registered on ANZCTR


Registration number
ACTRN12622000533796
Ethics application status
Approved
Date submitted
21/03/2022
Date registered
5/04/2022
Date last updated
23/03/2023
Date data sharing statement initially provided
5/04/2022
Date results information initially provided
23/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Route of administration of phosphate replacement in the ICU
Scientific title
Prospective, randomized, parallel group, electronic medical record (EMR)-embedded, clinical trial to determine whether enteral phosphate replacement is non-inferior to intravenous phosphate replacement in critically ill patients with hypophosphatemia
Secondary ID [1] 306729 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
hypophosphatemia 325715 0
critical illness 325716 0
Condition category
Condition code
Metabolic and Endocrine 323058 323058 0 0
Other metabolic disorders
Diet and Nutrition 323059 323059 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study will compare two routes of phosphate replacement in critically ill patients with hypophosphatemia; enteral or paraenteral (intravenous). Both routes are current standard care.

Participants assigned to the 'enteral route' will receive phosphate tablets (500mg per tablet). The decision regarding single dose or regular (once, twice or three times per day) will be that of the treating physician and will be based on a variety of factors, including the severity of hypophosphatemia. The equivalent of 500mg of oral phosphate is 16.1mmol of phosphate. Additionally, there are 20.4mmol of sodium bicarbonate (350 mg) and 3.1mmol of potassium bicarbonate (315mg).

Participants assigned 'parenteral route' will receive either sodium dihydrogen phosphate or potassium dihydrogen phosphate, or both, depending on the treating physician discretion. Similarly, this is guided by factors including serum sodium and potassium concentrations. The dose of phosphate will vary from 10 to 45mmol with maximal rate of administration of 20mmol per hour and decided by the intensive care (ICU) team.

Medical records will be monitored frequently to ensure adherence to intervention arm.
Intervention code [1] 323173 0
Treatment: Drugs
Comparator / control treatment
This study will compare two routes of phosphate replacement in critically ill patients with hypophosphatemia; enteral or paraenteral (intravenous). Both routes are current standard care.
Control group
Active

Outcomes
Primary outcome [1] 330825 0
The primary outcome measure is serum phosphate level measured before phosphate replacement and 24 hours after replacement.
Timepoint [1] 330825 0
Prior to phosphate replacement and 24 hours after replacement.
Secondary outcome [1] 407734 0
Serum phosphate level daily for seven days
Timepoint [1] 407734 0
Daily for seven days
Secondary outcome [2] 407735 0
Healthcare cost for enteral phosphate and intravenous phosphate use per patient.

In this analysis, the endpoints that represent treatment effectiveness will be cases with severe hypophosphatemia, blood stream infections, number of days in ICU, and deaths. The type of health economic analysis will be decided based on the difference in the effectiveness between the two treatment arms. If there is robust evidence showing that an endpoint is identical between enteral and parenteral phosphate replacement, a cost-minimisation analysis will be conducted; otherwise, a cost-effectiveness analysis will be performed.

Total cost associated with each intervention will be calculated based on cost of the medication, cost of delivery of the treatment, cost of adverse events associated with the intervention, and hospital costs. In the cost-minimisation analysis, the total costs, adjusted for the difference in the patient baseline characteristics, will be compared between the two interventions. In the cost-effectiveness analysis, incremental cost per case of severe hypophosphatemia, per blood stream infection prevented, per day in ICU reduced, and per death prevented in patients receiving enteral phosphate replacement compared to parenteral phosphate replacement will be calculated.

The cost will be calculated based on the sum of all the cost from medications, delivery of the treatment, cost of adverse event associated with the treatment including but not limited to blood stream infection, fluid overload, hospital stay. All of above detail will be sourced from data-linkage to the electronic medical record (EPIC) and financial records, collected manually.
Timepoint [2] 407735 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [3] 407736 0
Amount of waste used in delivery enteral phosphate and intravenous phosphate for 50 patients in each group.

A pragmatic methodology to provide novel information about healthcare waste will be utilised. To quantify waste, landfill, and environmental impact of phosphate replacement a nested cohort study of 100 administrations for hypophosphatemia (50 enteral and 50 intravenous) will be conducted.

The pharmaceutical waste amassed for one patient from each study arm (enteral and intravenous), including glass vials of sodium and potassium dihydrogen phosphate, syringes used to aspirate phosphate solution from vials, blunt aspiration needle and fluid bags used to dilute phosphate for infusion, and plastic box and carton packaging of enteral phosphate tablets will be weighed then multiply to the number of phosphate replacements for 50 patients in each arm and presented with weight (g, kg). The different groups of waste with weight will illustrate the environmental impact of each route of administration.
Timepoint [3] 407736 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [4] 407737 0
Doses of phosphate replaced.

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.

Timepoint [4] 407737 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [5] 407738 0
Volume of IV fluid administered with phosphate.

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [5] 407738 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [6] 407739 0
Volume of IV fluid administered per day.

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [6] 407739 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [7] 407740 0
Fluid balance.

This information will be collected from the fluid balance chart of each participant's electronic medical record, where it is collected as standard care.
Timepoint [7] 407740 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [8] 407741 0
Blood sodium concentration

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [8] 407741 0
Measured daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [9] 407742 0
Blood pressure

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [9] 407742 0
pre-, during, and one-hour post phosphate replacement
Secondary outcome [10] 407743 0
Number of patients who develop severe hypophosphatemia (phosphate < 0.3mmol/L)

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [10] 407743 0
Monitored daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [11] 407744 0
Blood stream infections

This information will be collected from the participant's electronic medical record.
Timepoint [11] 407744 0
Monitored daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [12] 407745 0
Duration of admission to ICU

This information will be collected from the participant's electronic medical record where it is collected as standard practice.
Timepoint [12] 407745 0
Participant's discharge from ICU
Secondary outcome [13] 407746 0
Duration of admission to hospital

This information will be collected from the participant's electronic medical record where it is collected as standard practice.
Timepoint [13] 407746 0
Participant's discharge from hospital
Secondary outcome [14] 407747 0
Mortality

This information will be collected from the participant's electronic medical record where it is collected as standard practice.
Timepoint [14] 407747 0
Censored to participant's discharge from hospital
Secondary outcome [15] 408012 0
Blood pH

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [15] 408012 0
Measured daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [16] 408013 0
Blood potassium concentration

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [16] 408013 0
Measured daily throughout the entire duration of the participant's stay in ICU.

Eligibility
Key inclusion criteria
All adult patients admitted to RMH ICU who require phosphate replacement with serum phosphate level <0.75mmol/l.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Serum phosphate concentration <0.3mmol/L, i.e., severe hypophosphatemia
- Either enteral or parenteral replacement is not possible (i.e., no enteric feeding tube, intolerance of enteral feeding with gastric aspiration >300ml or no intravenous line)
- Treating clinician believes that either enteral or parenteral phosphate replacement is indicated for this patient

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a computerised sequence generator
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
electronic medical record (EMR) embedded, non-inferiority clinical trial
Phase
Phase 4
Type of endpoint/s
Statistical methods / analysis
Characteristics of the participants in each treatment group will be summarized using the appropriate summary statistics. For the continuous outcomes, an analysis of covariance model will be fit for each of the time points. For binary outcomes, a logistic regression model with the treatment group included as an indicator variable will be used. The analysis will be intention to treat. There should be minimal missing data, however the extent and pattern of missing data will be exaluated.

Statistical methods will be led by Dr Emily Karahalios (Biostatistician with Methods and Implementation Support for Clinical and Health Research Hub, MISCH) with analyses conducted using Stata (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC).

In the health economic analysis, the endpoints that represent treatment effectiveness will be: cases with severe hypophosphatemia, blood stream infections, number of days in ICU, and deaths. The type of health economic analysis will be decided based on the difference in the effectiveness between the two treatment arms. If there is robust evidence showing that an endpoint is identical between enteral route and parenteral phosphate replacement, a cost-minimization analysis will be conducted, otherwise a cost-effectiveness analysis will be performed.

Total cost associated with each intervention will be calculated based on cost of the medication, cost of delivery of the treatment, cost of adverse events associated with the intervention, and hospital costs. In the cost-minimization analysis the total costs, adjusted for the difference in the patient baseline characteristics will be compared between the two interventions. In the cost-effectiveness analysis, incremental cost per case of severe hypophosphatemia, per blood stream infection prevented, per day in ICU reduced, and per death prevented in patients receiving enteral phosphate replacement compared to parenteral phosphate replacement will be calculated.

Probabilistic sensitivity analysis will be conducted using the bootstrap method. The health economic analysis will be overseen by Dr An Duy Tran (Health Economist at Methods and Implementation Support for Clinical and Health Research Hub, MISCH).

A pragmatic methodology to provide novel information about healthcare waste will be utilised. To quantify waste, landfill, and environmental impact of phosphate replacement a nested cohort study of 100 administrations for hypophosphatemia (50 enteral and 50 intravenous) will be conducted.

The pharmaceutical waste amassed for one patient from each study arm (enteral and intravenous), including glass vials of sodium and potassium dihydrogen phosphate, syringes used to aspirate phosphate solution from vials, blunt aspiration needle and fluid bags used to dilute phosphate for infusion, and plastic box and carton packaging of enteral phosphate tablets will be weighed then multiply to the number of phosphate replacements for 50 patients in each arm and presented with weight (g, kg). The different groups of waste with weight will illustrate the environmental impact of each route of administration.

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
20/04/2022
Actual
20/04/2022
Date of last participant enrolment
Anticipated
20/04/2023
Actual
30/06/2022
Date of last data collection
Anticipated
20/10/2023
Actual
Sample size
Target
120
Accrual to date
Final
145
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 21997 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 37099 0
3050 - Parkville

Funding & Sponsors
Funding source category [1] 311060 0
Hospital
Name [1] 311060 0
Royal Melbourne Hospital
Country [1] 311060 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
Royal Melbourne Hospital
300 Grattan Street Parkville, Victoria 3050
Country
Australia
Secondary sponsor category [1] 312391 0
None
Name [1] 312391 0
N/A
Address [1] 312391 0
N/A
Country [1] 312391 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310605 0
Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 310605 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 310605 0
Australia
Date submitted for ethics approval [1] 310605 0
Approval date [1] 310605 0
15/12/2021
Ethics approval number [1] 310605 0
HREC/81779/MH-2021

Summary
Brief summary
Phosphate is a very important electrolyte and, as such, low phosphate serum levels must be treated promptly. In the Intensive Care Unit (ICU) critically ill patients are at risk of low phosphate levels and phosphate ions are frequently administered via the enteral or parenteral (intravenous) route. There is little data on which route is best but there is a tenfold cost differential between the enteral and parental preparations. In addition, there may be more healthcare waste associated with the parenteral route. Given the potential but unproven advantages of the enteral route, this study aims compare the safety and effectiveness of phosphate replacement via the enteral and paraenteral routes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 118238 0
A/Prof Adam Deane
Address 118238 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 118238 0
Australia
Phone 118238 0
+61 3 9342 9254
Fax 118238 0
Email 118238 0
adam.deane@mh.org.au
Contact person for public queries
Name 118239 0
Ms Brianna Tascone
Address 118239 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 118239 0
Australia
Phone 118239 0
+61 3 9342 9252
Fax 118239 0
Email 118239 0
brianna.tascone@mh.org.au
Contact person for scientific queries
Name 118240 0
A/Prof Adam Deane
Address 118240 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 118240 0
Australia
Phone 118240 0
+61 3 9342 9254
Fax 118240 0
Email 118240 0
adam.deane@mh.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
At this stage no IPD will be available.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
15470Study protocol  adam.deane@mh.org.au
15471Statistical analysis plan  adam.deane@mh.org.au



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.