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Trial registered on ANZCTR


Registration number
ACTRN12619000121167
Ethics application status
Approved
Date submitted
9/01/2019
Date registered
25/01/2019
Date last updated
5/04/2019
Date data sharing statement initially provided
25/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Vitamin B1 (thiamine) administration in enterally-fed critically ill patients with hypophosphatemia: A prospective, randomised clinical trial
Scientific title
Effect of exogenous vitamin B1 (thiamine) administration on blood lactate concentrations in enterally-fed, critically ill patients with hypophosphatemia
Secondary ID [1] 296981 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 310945 0
Hypophosphatemia 310946 0
Thiamine deficiency 310989 0
enteral nutrition 310990 0
Condition category
Condition code
Metabolic and Endocrine 309611 309611 0 0
Other metabolic disorders
Diet and Nutrition 309612 309612 0 0
Other diet and nutrition disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: Thiamine (200mg every 12 hours)

Thiamine (100mg/mL) will be administered intravenously as 200mg in 100mL sodium chloride 0.9% over 30 minutes. Infusions will occur twice daily while participants remain in the ICU, for a maximum of seven days, and only in participants randomised to receive the intervention. Fidelity to the intervention will be monitored regularly by research staff through review of nurses notes and medication charts.

Alternative name: Vitamin B1
Intervention code [1] 313253 0
Treatment: Drugs
Comparator / control treatment
Control: Standard care

Participants randomised to the control arm will have plasma phosphate concentrations measured twice daily, and continue to receive the standard care provided to all patients admitted to the ICU. This includes daily (or more frequently as required) arterial blood gas analysis. All other co-interventions, such as phosphate replacement and nutrition will occur as per standard care which is at the discretion of the treating clinician.
Control group
Active

Outcomes
Primary outcome [1] 318572 0
Delta of arterial blood lactate concentration at completion of trial


Timepoint [1] 318572 0
Arterial blood lactate will be recorded four times daily (at approximately 6 hour intervals) while the patient is in the ICU and participating in the trial (up to seven days). A sophisticated statistical approach that leverages multiple time points will then be utilised to calculate the change in arterial blood lactate concentrations during trial participation.
Secondary outcome [1] 365402 0
Thiamine concentration
Thiamine concentrations will be measured using high performance liquid chromatography at selected sites, using blood and urine samples.
Timepoint [1] 365402 0
Blood for thiamine concentration analysis will be obtained at baseline, at completion of the first thiamine infusion and at four and six hours post infusion (for those randomised to the receive the intervention). If the participant remains in ICU, this blood panel will be repeated following three full days of treatment.

In patients randomised to the control arm, only two blood samples will be collected: at baseline and at 1000h on study day three (if the participant remains in ICU).

Urine for thiamine concentration analysis will be obtained at baseline, and six hours post first thiamine infusion. If the participant remains in ICU, urine will be collected at the same timepoints following three full days of treatment.
Secondary outcome [2] 365417 0
Blood glucose concentration
Timepoint [2] 365417 0
Blood glucose will be recorded four times daily (at approximately 6 hour intervals) while the patient is in the ICU and participating in the trial (up to seven days).
Secondary outcome [3] 365418 0
Phosphate concentration
Serum phosphate assays will be carried out on blood samples to determine phosphate concentrations.
Timepoint [3] 365418 0
Twice daily during ICU admission until study drug is ceased.
Secondary outcome [4] 365419 0
Serum creatinine
Timepoint [4] 365419 0
Daily during ICU admission until study drug is ceased.
Secondary outcome [5] 365421 0
Arterial blood pH
Timepoint [5] 365421 0
Arterial pH will be recorded four times daily (at approximately 6 hour intervals) while the patient is in the ICU and participating in the trial (up to seven days).
Secondary outcome [6] 365422 0
Thiamine administration
The amount of thiamine administered via the oral route will be calculated using data collected from the ICU Fluid Balance Chart concerning the type and volume of enteral nutrition administered to trial participants whilst enrolled in the study. This chart is completed daily by all nursing staff as part of standard care offered to all patients admitted to the ICU.
Timepoint [6] 365422 0
The type and volume of enteral nutrition administered will be recorded daily during ICU admission until study drug is ceased.
Secondary outcome [7] 365423 0
ICU mortality, censored at 90 days
Timepoint [7] 365423 0
At day 90.
Secondary outcome [8] 365424 0
Hospital mortality, censored at 90 days
Timepoint [8] 365424 0
At day 90.
Secondary outcome [9] 365425 0
Number of alive and ICU free days, censored at 90 days.
This is a composite secondary outcome calculated as the number of days alive and out of the ICU. We will rely on data from medical records, patient databases, and patient-reports to assess this outcome.
Timepoint [9] 365425 0
At day 90.
Secondary outcome [10] 365426 0
Duration of vasopressor therapy, censored at seven days.
We will collect data from nurses notes, ICU observation charts and/or ICU fluid balance charts to assess this outcome.
Timepoint [10] 365426 0
At day seven.

Eligibility
Key inclusion criteria
• Critically ill patient admitted to the ICU
• Receiving enteral nutrition (EN) for <= 72 hours in this ICU admission
• A serum phosphate <= 0.65mmol./L in the last 24 hours while receiving EN
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients who have received >= 100mg of intravenous (IV) thiamine in the previous 48 hours
• Patient is anticipated to be discharged from the ICU today or tomorrow
• Treating clinician believes that either treatment (to receive or not to receive IV thiamine) is in the best interest of the patient
• Aged < 18 years
• Patients with a known or suspected hypersensitivity to thiamine
• Patients receiving palliative care
• Pregnancy
• Patients admitted for consideration of organ donation
• Patients previously enrolled in this trial
• Patients with a known latex allergy
• Patients with documented or suspected acute beri-beri disease
• Patients with documented or suspected acute Wernicke's encephalopathy

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)
Subjects will be allocated a Patient Study Number upon enrollment, and randomised through the online study database. Study researchers will be blinded to the allocation until after each patient has been randomised.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed through the online study database, in accordance with a randomisation table generated from a software program.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The findings of this study will be analysed by a biostatistician using parametric and/or non-parametric statistical approaches as appropriate (based on the distribution of data).
For the primary outcome, plasma lactate, analysis will be undertaken modelling the mean concentration over time by assignment group. These profiles are likely to be non-linear, and this will be explored during analysis. The interaction effects between plasma lactate, glucose, phosphate, and pH will also be explored by assignment group.

ICU and hospital mortality will be analysed by Kaplan-Meier curves between group differences assessed by a log-rank test. Multi-variate factor effects will be assessed by Cox proportional hazards regression.

ICU free days, and the duration of vasopressor therapy will be assessed by non-parametric regression.

Sample size estimation and justification
We have based our sample size on published data from other investigators. Donnino and colleagues (Donnino MW, et al. Crit Care Med 2016;44(2):360-367.) reported a significant reduction in blood lactate in patients with sepsis who received thiamine administration when analysing using repeated measures modelling (P=0.006). Based on visual inspection of the published profiles of concentration over time and assuming baseline equality in our trial we have estimated the sample size to detect a change in lactate at T=24. Donnino and colleagues reported the median (IQR) of the change in lactate (Thiamine: 44% (29%, 49%) vs. placebo: 20% (-20%, 47%); P=0.18). Using these point estimates we have assumed that mean is equal to median and standard deviation is equal to the interquartile range divided by 1.35. With these assumptions the mean (Standard Deviation) change in lactate is 45(15)% for participants assigned thiamine and 20(50)% assigned placebo. Using Satterthwaite's t test for unequal variances, 72 participants would be required for a two-sided a error of 0.05 and ß error of 0.2 to detect a difference between groups of 25% or more. To allow for dropouts and missing data we have inflated the number of participants by ˜20% and so require 90 participants (45 in each group).

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)
SA,VIC
Recruitment hospital [1] 12822 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [2] 12823 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [3] 12824 0
The Alfred - Prahran
Recruitment hospital [4] 12825 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [5] 12826 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 25292 0
3050 - Parkville
Recruitment postcode(s) [2] 25293 0
3084 - Heidelberg
Recruitment postcode(s) [3] 25294 0
3004 - Prahran
Recruitment postcode(s) [4] 25295 0
3220 - Geelong
Recruitment postcode(s) [5] 25296 0
5000 - Adelaide
Recruitment outside Australia
Country [1] 21166 0
New Zealand
State/province [1] 21166 0
Wellington

Funding & Sponsors
Funding source category [1] 301553 0
Hospital
Name [1] 301553 0
Royal Melbourne Hospital
Address [1] 301553 0
Royal Melbourne Hospital
300 Grattan Street, Parkville, Victoria 3050
Country [1] 301553 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] 301250 0
None
Name [1] 301250 0
Address [1] 301250 0
Country [1] 301250 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302286 0
Melbourne Health Human Research Ethics Committee
Ethics committee address [1] 302286 0
Office for Research
The Royal Melbourne Hospital
Level 2 South West
300 Grattan Street, Parkville, Victoria, 3050
Ethics committee country [1] 302286 0
Australia
Date submitted for ethics approval [1] 302286 0
Approval date [1] 302286 0
22/11/2018
Ethics approval number [1] 302286 0
HREC/45186/MH-2018

Summary
Brief summary
Adequate thiamine is an essential co-factor to utilise glucose. There is biological plausibility that phosphate deficiency may identify a cohort at greater risk of thiamine deficiency, and that these deficiencies are synergistic. However, currently, critically ill enterally-fed patients with hypophosphatemia do not receive pharmacological administration of thiamine. Data from the use of thiamine in a wide range of settings suggest that the dose regimen to be evaluated in this trial is tolerable and safe, and this is consistent with the Australian Register of Therapeutic Goods listing of thiamine. However, to the best of our knowledge, there are no studies in the ICU population to evaluate whether pharmacological administration of thiamine to this cohort of patients provides biological, physiological, or even clinical advantages. This multi-site randomised, controlled trial will test whether the intervention (thiamine) administered to patients with hypophosphatemia significantly reduces the primary outcome, blood lactate, which is a robust marker of clinical outcome.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 89698 0
A/Prof Adam Deane
Address 89698 0
Level 5, Building B
The Royal Melbourne Hospital
300 Grattan Street, Parkville
Victoria 3050
Country 89698 0
Australia
Phone 89698 0
+61 3 9342 9254
Fax 89698 0
Email 89698 0
adam.deane@mh.org.au
Contact person for public queries
Name 89699 0
Ms Deborah Barge
Address 89699 0
Level 5, Building B
The Royal Melbourne Hospital
300 Grattan Street, Parkville
Victoria 3050
Country 89699 0
Australia
Phone 89699 0
+61 3 9342 9235
Fax 89699 0
Email 89699 0
deborah.barge@mh.org.au
Contact person for scientific queries
Name 89700 0
A/Prof Adam Deane
Address 89700 0
Level 5, Building B
The Royal Melbourne Hospital
300 Grattan Street, Parkville
Victoria 3050
Country 89700 0
Australia
Phone 89700 0
+61 3 9342 9254
Fax 89700 0
Email 89700 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?
Study protocol
Statistical analysis plan
Summary results
No Results