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Trial registered on ANZCTR


Registration number
ACTRN12622001409763
Ethics application status
Approved
Date submitted
13/10/2022
Date registered
4/11/2022
Date last updated
14/07/2024
Date data sharing statement initially provided
4/11/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The effects of glucagon-like peptide-1 on glycaemia in the critically ill.
Scientific title
A randomised, double-blind, double dummy placebo controlled study of the effects of insulin and glucagon-like peptide-1 on glycaemic CONTROL in the critically ill.
Secondary ID [1] 306494 0
Nil
Universal Trial Number (UTN)
Trial acronym
CONTROL
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Critical illness 325358 0
Stress-induced hyperglycaemia 325359 0
Condition category
Condition code
Metabolic and Endocrine 322742 322742 0 0
Other endocrine disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The CONTROL study aims to compare glycaemic control between exogenous intravenous glucagon-like peptide-1 (GLP-1) and insulin infusions for the management of stress-induced hyperglycaemia in critically ill patients.

A total of 40 sedated and mechanically ventilated critically ill patients with stress hyperglycaemia will be recruited from the Intensive Care Unit at the Royal Adelaide Hospital (RAH). Participants will be randomised and blinded to the intervention or control arm and commenced on either therapy over a 48-hour period.

GLP-1 and Placebo:
- Synthetic GLP-1 will be reconstituted by the Royal Adelaide Hospital Department of Pharmacy as a solution in 4% albumin and presented in an opaque syringe for intravenous infusion.
- The placebo will be 4% albumin presented in an opaque syringe and indistinguishable from the active drug (GLP-1).

Insulin and Placebo:
- Insulin will be diluted by pharmacy with 0.9% saline to 1 Unit per mL and presented in an opaque syringe for intravenous infusion. This is the standard of care insulin brand and concentration used in the RAH ICU.
- Placebo will be 0.9% saline presented in an opaque syringe and indistinguishable from the active drug (insulin).

Intervention arm:
Intravenous GLP-1 at an initial dose of 1.2 pmol/kg/min (10 mL/hr).
‘Placebo insulin’ (0.9% saline) titrated accordingly.

Following consent, a subcutaneous continuous glucose monitor (CGM) will be placed on the abdomen of the patient. Glucose concentrations will be recorded at 5 minute intervals with results blinded to the bedside clinical staff and study investigators. Blood glucose concentrations will also be measured hourly using a portable glucose meter and eight hourly using arterial blood gas measurements (as per standard care).

4 hours before study commencement, nasogastric feeds will be held. Prior to the study commencing, the nasogastric tube will be aspirated and the volume recorded and discarded. Glucose absorption will be assessed using 3-O-methyl-D-gluco-pyranose (3-OMG). Nasogastric feeds will be recommenced at T = 0 with a bolus of 3 g of 3-OMG dissolved in 50 mL of enteral formula and then a continuous rate determined by the treating physician. Blood samples of 5 mL will be collected every 30 minutes until T = 360 min (total of 13 samples = 65 mL of blood) and gastric residual volume will be measured 6-hourly by nasogastric aspirates throughout the study period. Blood samples will be analysed for plasma 3-OMG concentration using High Performance Liquid Chromatography (HPLC). The rate of glucose absorption is indicated by the area under the 3-OMG concentration curve, peak 3-OMG concentration and the time to peak concentration.

Blood samples will be taken to quantify plasma concentrations of C-peptide, glucagon, GLP-1 and GIP. 3mL blood samples will be taken at study commencement and subsequently at T = 30, 60, 90, 120, 150, 180,210, 240, 270, 300, 330, 360 minutes and at study completion (T = 48 hours). The study will be censored at T = 48 hours and patients returned to usual care.
Intervention code [1] 322922 0
Treatment: Drugs
Comparator / control treatment
The group receiving current standard of care (intravenous insulin infusion) for treating hyperglycaemia in critically ill patients.

Control arm:
Intravenous ‘placebo GLP-1’ (4% albumin) at an initial rate equivalent to 1.2 pmol/kg/min (10 mL/hr).
Insulin (1 Unit per mL) titrated as per the Insulin infusion protocol (adapted from the Royal Adelaide Hospital Unit Medical Manual).
Control group
Active

Outcomes
Primary outcome [1] 332647 0
The total time outside target glucose range (4 - 9.9 mmol/L) represented as the percentage of time for all patients in each study arm (intravenous GLP-1 and insulin infusions) recorded using continuous subcutaneous glucose monitoring data.
Timepoint [1] 332647 0
During study infusion (0-48 hours)
Secondary outcome [1] 414220 0
The combined absolute area under curve (AUC) outside target glucose range will be calculated based upon the continuous subcutaneous glucose monitoring data.
Timepoint [1] 414220 0
During study infusion (0-48 hours)
Secondary outcome [2] 414222 0
The percentage of time above the target range, defined as hyperglycaemia (greater than 10 mmol/L) as per the continuous glucose monitoring data.
Timepoint [2] 414222 0
During study infusion (0-48 hours)
Secondary outcome [3] 414223 0
The percentage of time below the target range, defined as hypoglycaemia (less than 4.0 mmol/L) as per the continuous glucose monitoring data.
Timepoint [3] 414223 0
During study infusion (0-48 hours)
Secondary outcome [4] 414224 0
Glycaemic variability: The mean (GluAve) and standard deviation (GluSD) calculated from the entire set of blood glucose concentrations from continuous subcutaneous glucose monitoring data. Relative variability will be calculated as the coefficient of variability (GluCV = GluSD * 100/GluAve).
Timepoint [4] 414224 0
During study infusion (0-48 hours)
Secondary outcome [5] 414250 0
Plasma concentrations of glucose-dependent insulinotropic polypeptide (GIP).
Timepoint [5] 414250 0
0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360 mins after the infusion has commenced and at study completion T = 48 hours
Secondary outcome [6] 414411 0
Plasma concentrations of glucagon-like peptide-1 (GLP-1).
Timepoint [6] 414411 0
0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360 mins after the infusion has commenced and at study completion T = 48 hours
Secondary outcome [7] 414412 0
Plasma concentrations of C-peptide.
Timepoint [7] 414412 0
0, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360 mins after the infusion has commenced and at study completion T = 48 hours
Secondary outcome [8] 415549 0
The number of patients meeting withdrawal criteria as per the study screening and enrolment logs.
Timepoint [8] 415549 0
At completion of study
Secondary outcome [9] 415550 0
Total enteral nutrition delivered per day (kcal and mL), collected via electronic patient medical records.
Timepoint [9] 415550 0
During study infusion (0-48 hours)

Eligibility
Key inclusion criteria
All mechanically ventilated critically ill patients admitted to the Royal Adelaide Hospital Intensive Care Unit are eligible if:
• Aged equal to or between 18 and 80 years old
• Stress hyperglycaemia with a blood glucose of greater than or equal to 11.1 mmol/L
• About to commence or commenced intravenous insulin
• Expected to be in ICU until the end of the next calendar day
Minimum age
18 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• History of type 1 or type 2 diabetes mellitus
• Glycated haemoglobin (HbA1c) is greater than or equal to 6.5%
• Contraindication to enteral nutrition
• Expected to be eating orally before the end of the next calendar day
• Pregnancy (a ßHCG will be performed on all women of child-bearing age)
• Haemoglobin is less than 80 g/L
• Patients with traumatic brain injury (albumin contraindicated)
• Previous surgery on the oesophagus, stomach or small intestine
• History of pancreatitis
• Death during ICU is deemed inevitable

Withdrawal criteria is classified as:
• BGL is greater than 12 mmol/L for more than 10 hours despite maximal insulin or GLP-1 therapy.
• BGL is greater than 16 mmol/L after 6 hours of study commencement (i.e. T is greater than 6 hours)
• BGL is greater than 20 mmol/L at any time point
• BGL is less than 2.2 mmol/L at any point.
• Two or more episodes of vomiting or overt regurgitation within a 12-hour period.
• Next of kin may withdraw consent at any time.

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 participant allocation will be concealed during screening to all investigators. The randomisation schedule will be known only to the trial statistician and uploaded to a secure web-based platform (REDCap) from where study participants will be allocated.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be restricted via computer generated, variable size blocks in a 1:1 ratio, targeting 20 participants per group.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Anonymised data will be analysed by a biostatistician. The main analyses will be conducted on an intention to treat basis using standard statistical methods for categorical and continuous data. Demographic and glucose data will be analysed using independent samples t-tests, Chi-square, Fisher’s exact and Mann-Whitney tests as appropriate.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/12/2022
Actual
14/02/2023
Date of last participant enrolment
Anticipated
31/01/2025
Actual
Date of last data collection
Anticipated
28/02/2025
Actual
Sample size
Target
40
Accrual to date
23
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 23241 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 38611 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 310839 0
Charities/Societies/Foundations
Name [1] 310839 0
Diabetes Australia
Country [1] 310839 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
Royal Adelaide Hospital
Port Road, Adelaide 5000 South Australia
Country
Australia
Secondary sponsor category [1] 312094 0
Charities/Societies/Foundations
Name [1] 312094 0
Diabetes Australia
Address [1] 312094 0
Diabetes Australia National Corporate Office

Postal Address: GPO Box 3156 Canberra 2600
Office Location: Tenant B, 19-23 Moore Street, Turner ACT, Australia, 2612
Country [1] 312094 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 310404 0
Central Adelaide Local Health Network Human Research Ethics Committee (CALHN HREC)
Ethics committee address [1] 310404 0
Ethics committee country [1] 310404 0
Australia
Date submitted for ethics approval [1] 310404 0
25/08/2022
Approval date [1] 310404 0
30/08/2022
Ethics approval number [1] 310404 0
2022/HRE00174

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 117542 0
Dr Mark Plummer
Address 117542 0
Intensive Care Unit,
Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 117542 0
Australia
Phone 117542 0
+61 402669167
Fax 117542 0
Email 117542 0
mark.plummer@sa.gov.au
Contact person for public queries
Name 117543 0
Mark Plummer
Address 117543 0
Intensive Care Unit,
Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 117543 0
Australia
Phone 117543 0
+61 402669167
Fax 117543 0
Email 117543 0
mark.plummer@sa.gov.au
Contact person for scientific queries
Name 117544 0
Mark Plummer
Address 117544 0
Intensive Care Unit,
Royal Adelaide Hospital,
Port Road, Adelaide, SA 5000
Country 117544 0
Australia
Phone 117544 0
+61 402669167
Fax 117544 0
Email 117544 0
mark.plummer@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
No individual participant data will be available due to patient confidentiality.


What supporting documents are/will be available?

No Supporting Document Provided



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.