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Trial registered on ANZCTR


Registration number
ACTRN12623000248662
Ethics application status
Approved
Date submitted
23/02/2023
Date registered
8/03/2023
Date last updated
4/10/2023
Date data sharing statement initially provided
8/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Route of administration of magnesium replacement in the ICU
Scientific title
Prospective, randomized, parallel group, electronic medical record (EMR)-embedded, clinical trial to determine whether the enteral route is non-inferior to parenteral magnesium replacement in critically ill patients with mild to moderate hypomagnesemia.
Secondary ID [1] 309052 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypomagnesemia 329105 0
Critical Illness 329106 0
Condition category
Condition code
Metabolic and Endocrine 326079 326079 0 0
Other metabolic disorders
Diet and Nutrition 326080 326080 0 0
Other diet and nutrition disorders

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

Those assigned enteral route will receive either Mag-sup (magnesium aspartate dihydrate tablets) 500mg per tablet, which is equivalent to 37.4 mg or 1.55 mmol of elemental magnesium, or Blackmores BIO MAGNESIUM (magnesium-calcium-vit B6-vit D3) tablets (300mg of elemental magnesium or 12.5 mmol per tablet). The decision regarding single dose or regular (once, twice or three times per day) will be decided by the treating physician who will make their decision considering several factors including the severity of hypomagnesemia.

Those assigned the parenteral route will receive magnesium sulfate, where the dose of magnesium will vary from 10 to 20 mmol and depend on decision by the ICU clinician. The magnesium sulfate is diluted in 100 ml of 0.9% saline and administered over a minimum of one hour.

Medical records will be monitored frequently to ensure adherence to intervention arm.
Intervention code [1] 325491 0
Treatment: Drugs
Comparator / control treatment
This study will compare two routes of magnesium replacement in critically ill patients with hypomagnesemia; enteral or parenteral (intravenous). Both routes are current standard care.
Control group
Active

Outcomes
Primary outcome [1] 333945 0
The primary outcome measure is serum magnesium level measured before magnesium replacement and 24 hours after replacement.
Timepoint [1] 333945 0
Prior to magnesium replacement and 24 hours after replacement.
Secondary outcome [1] 418840 0
Healthcare cost for enteral magnesium and parenteral magnesium use per patient.

In the health economic analysis, the endpoints that represent treatment effectiveness will be cases with severe hypomagnesemia, 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 our study shows that our primary outcome is non-inferior between enteral route and parenteral magnesium 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 cost. 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 hypomagnesemia, per blood stream infection prevented, per day in ICU reduced and per death prevented in patients receiving enteral magnesium replacement compared to parenteral magnesium replacement will be calculated.
Timepoint [1] 418840 0
Measured throughout the entire duration of the participants stay in ICU
Secondary outcome [2] 418909 0
Environmental impact and the amount of waste used in delivery of enteral magnesium and parenteral magnesium for 50 patients in each group.

A pragmatic methodology to provide novel information about healthcare waste will be utilised. To quantify the carbon impacts of magnesium replacement, we will conduct a nested cohort study of 100 administrations for hypomagnesemia (50 enteral and 50 intravenous) using consequential life cycle assessment (LCA).

We will collect all the consumables associated with providing intravenous magnesium and enteral magnesium replacement. This will include glass vials of magnesium sulfate, all packaging, syringes used to aspirate magnesium solution from vials, blunt aspiration needles, and fluid bags used to dilute magnesium for infusion. This data, along with end-of-life impacts (medical waste and landfill), will be modelled in SimaPro LCA software, using international and Australian background databases (ecoinvent and AusLCI). Reporting will be provided in kg CO2 equivalents (kg CO2e), showing the consequential carbon impacts of each route of administration.
Timepoint [2] 418909 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [3] 418910 0
Daily serum magnesium levels
Timepoint [3] 418910 0
Daily for seven days post randomisation
Secondary outcome [4] 418911 0
Urinary magnesium excretion

Urine samples will be analysed to measure magnesium concentration at different time points. Excreted magnesium will be assessed by comparing baseline urine magnesium concentration and concentration after replacement with both intravenous and enteral magnesium.
Timepoint [4] 418911 0
The first sample will be at baseline and taken right after enrolment. The second urine sample will be taken between 4 and 6 hours after replacement and the third will be between 24 and 48 hours after replacement.
Secondary outcome [5] 418912 0
Number of patients who develop severe hypomagnesemia (magnesium < 0.35 mmol/L)

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [5] 418912 0
Monitored daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [6] 418913 0
Blood albumin concentration

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [6] 418913 0
Measured daily throughout the entire duration of the participant's stay in ICU
Secondary outcome [7] 418914 0
Doses of magnesium replaced

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [7] 418914 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [8] 418915 0
Volume of IV fluid administered with magnesium

This information will be collected from the participant's electronic medical record where it is recorded as part of standard care.
Timepoint [8] 418915 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [9] 418916 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 [9] 418916 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [10] 418917 0
Fluid balance.

This information will be collected from the fluid balance chart of each participant's electronic medical record, where it is recorded as standard care.
Timepoint [10] 418917 0
Measured throughout the entire duration of the participant's stay in ICU.
Secondary outcome [11] 418918 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 [11] 418918 0
Pre, during, and one-hour post magnesium replacement
Secondary outcome [12] 418919 0
Atrial Fibrillation

This information will be collected from the participant’s electronic medical record.
Timepoint [12] 418919 0
Monitored daily throughout the entire duration of the participants stay in the ICU.
Secondary outcome [13] 418920 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 [13] 418920 0
Participant's discharge from ICU
Secondary outcome [14] 418921 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 [14] 418921 0
Participant's discharge from hospital
Secondary outcome [15] 418922 0
Blood stream infections

This information will be collected from the participant's electronic medical record.
Timepoint [15] 418922 0
Monitored daily throughout the entire duration of the participant's stay in ICU.
Secondary outcome [16] 418923 0
Mortality

This information will be collected from the participant's electronic medical record where it is collected as standard practice.
Timepoint [16] 418923 0
Censored to participant's discharge from hospital

Eligibility
Key inclusion criteria
All adult patients admitted to the RMH ICU who require magnesium replacement with serum magnesium level of <0.7 mmol/L
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Serum magnesium concentration <0.7 mmol/l and new cardiac arrhythmia; or serum magnesium concentration less than or equal to 0.35 mmol/l (ie., severe hypomagnesemia)
- Either enteral or parenteral replacement is not possible (ie., no enteric feeding tube, intolerance of enteral feeding with gastric aspiration >300ml or no intravenous line)
- Treating clinician believes that either enteral or parenteral magnesium is indicated for this patient
-Patient's currently having enteral magnesium replacement order

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, we will fit an analysis of covariance model for each of the time points. In other words, we will fit a linear regression model with the measurement as the outcome variable, treatment group included as an indicator variable, and adjusted for baseline value of the outcome measurement. For binary outcomes, we will fit a logistic regression model with the treatment group included as an indicator variable. The analysis will be intention to treat. There should be minimal missing data. However, we will investigate the extent and pattern of missing data.

All statistical analysis will be overseen and verified by Dr Emily Karaharios. Dr Karahalios is an Associate Professor in Biostatistics with the Methods and Implementation Support for Clinical and Health (MISCH) Research Hub at the University of Melbourne. Analyses will be conducted using Stata (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC).

The health economic analysis will be overseen by Dr An Tran-Duy (Health Economist at Methods and Implementation Support for Clinical and Health Research Hub, MISCH).

In the health economic analysis, the endpoints that represent treatment effectiveness will be cases with severe hypomagnesemia, 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 our study shows that our primary outcome is non-inferior between enteral route and parenteral magnesium 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 cost. 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 hypomagnesemia, per blood stream infection prevented, per day in ICU reduced and per death prevented in patients receiving enteral magnesium replacement compared to parenteral magnesium replacement will be calculated.

Probabilistic sensitivity analysis will be conducted using the bootstrap method.

Dr Scott McAlister, Research Fellow in the Centre for Health Policy at the Melbourne School of Population and Global Health, University of Melbourne, will advise and oversee our measurement of the environmental impacts of magnesium replacement.

We propose a pragmatic methodology to provide novel information about this secondary outcome. To quantify the carbon impacts of magnesium replacement, we will conduct a nested cohort study of 100 administrations for hypomagnesemia (50 enteral and 50 intravenous) using consequential life cycle assessment (LCA).

We will collect all the consumables associated with providing intravenous magnesium and enteral magnesium replacement. This will include glass vials of magnesium sulfate, all packaging, syringes used to aspirate magnesium solution from vials, blunt aspiration needles, and fluid bags used to dilute magnesium for infusion. This data, along with end-of-life impacts (medical waste and landfill), will be modelled in SimaPro? LCA software, using international and Australian background databases (ecoinvent and AusLCI). Reporting will be provided in kg CO2 equivalents (kg CO2e), showing the consequential carbon impacts of each route of administration.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/04/2023
Actual
7/06/2023
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
330
Accrual to date
126
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24127 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment postcode(s) [1] 39636 0
3050 - Parkville
Recruitment postcode(s) [2] 39635 0
3050 - Royal Melbourne Hospital

Funding & Sponsors
Funding source category [1] 313255 0
Hospital
Name [1] 313255 0
Royal Melbourne Hospital
Country [1] 313255 0
Australia
Primary sponsor type
Hospital
Name
Royal Melbourne Hospital
Address
300 Grattan Street Parkville, Victoria 3050
Country
Australia
Secondary sponsor category [1] 314987 0
None
Name [1] 314987 0
n/a
Address [1] 314987 0
n/a
Country [1] 314987 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312487 0
Royal Melbourne Hospital Human Research Ethics Committee
Ethics committee address [1] 312487 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street
Parkville VIC 3050
Australia
Ethics committee country [1] 312487 0
Australia
Date submitted for ethics approval [1] 312487 0
Approval date [1] 312487 0
11/01/2023
Ethics approval number [1] 312487 0
HREC/91010/MH-2022

Summary
Brief summary
Magnesium is a crucial electrolyte and low serum magnesium concentrations must be treated promptly to avoid adverse effects. In the intensive care unit, critically ill patients are at risk of low magnesium concentrations magnesium ions are frequently administered via the enteral or parenteral (intravenous) route. There is sparse data as to which route to use but there is likely to be at least a tenfold cost differential between the enteral and parental preparations. In addition, there may be more waste and subsequent environmental impact associated with parenteral route. Given the potential but unproven advantages of the enteral route we wish to compare the safety and effectiveness of magnesium replacement via the enteral route and parenteral routes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124834 0
A/Prof Adam Deane
Address 124834 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 124834 0
Australia
Phone 124834 0
+61 3 9342 9254
Fax 124834 0
Email 124834 0
adam.deane@mh.org.au
Contact person for public queries
Name 124835 0
Miss Olivia Gigli
Address 124835 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 124835 0
Australia
Phone 124835 0
+61 3 9342 9255
Fax 124835 0
Email 124835 0
olivia.gigli@mh.org.au
Contact person for scientific queries
Name 124836 0
A/Prof Adam Deane
Address 124836 0
Level 5, Building B The Royal Melbourne Hospital 300 Grattan Street, Parkville Victoria 3050
Country 124836 0
Australia
Phone 124836 0
+61 3 9342 9254
Fax 124836 0
Email 124836 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
18432Study protocol  adam.deane@mh.org.au
18433Statistical 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.