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Trial registered on ANZCTR


Registration number
ACTRN12614001189617
Ethics application status
Approved
Date submitted
3/11/2014
Date registered
12/11/2014
Date last updated
2/08/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Short-Term Exenatide Therapy in Acute Ischaemic Stroke - A Randomised, Open-Label, Parallel-Group Study
Scientific title
Short-Term Exenatide Therapy in Hyperglycaemia and Acute Ischaemic Stroke - A Randomised, Open-Label, Parallel-Group Study to Determine the Effect of Exenatide on Blood Glucose Levels
Secondary ID [1] 285586 0
Nil
Universal Trial Number (UTN)
Trial acronym
GLP-1 and Acute Stroke
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Ischaemic Stroke 293421 0
Hyperglycaemia 293422 0
Diabetes 293452 0
Condition category
Condition code
Stroke 293697 293697 0 0
Ischaemic
Metabolic and Endocrine 293698 293698 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Continuous intravenous administration of 20ug exenatide per 24 hours for up to 72 hours.
Intervention code [1] 290536 0
Treatment: Drugs
Comparator / control treatment
Continuous intravenous administarion of insulin for up to 72 hours. The dose of insulin will be titration to maintain blood glucose level within the target range of 5 - 10mmol/L.
Control group
Active

Outcomes
Primary outcome [1] 293506 0
Blood glucose levels within target range within the first 24 hours after commencing exenatide treatment. The target range of blood glucose levels is 5 - 10mmol/L.
Timepoint [1] 293506 0
24 hours
Primary outcome [2] 293507 0
Determining the frequency and duration of hypoglycaemia in participants receiving exenatide versus insulin therapy. Hypoglycaemia is defined as a blood glucose level < 4mmol/L.
Timepoint [2] 293507 0
72 hours.
Primary outcome [3] 293508 0
Feasability of exenatide administration in the setting of acute ischaemic stroke. This will be assessed through the use of a clinical staff survey that will compare the difficulty of use of IV exenatide vs. insulin, as well as assessing the time and resources required for both therapies.
Timepoint [3] 293508 0
72 hours.
Secondary outcome [1] 311197 0
Change in National Institutes of Health Stroke Scale (NIHSS) from baseline, 24 hours, 3 days and 3 months.
Timepoint [1] 311197 0
24 hours, 72 hours, 3 months.
Secondary outcome [2] 311200 0
Modified Rankin Scale rating at 3 months.
Timepoint [2] 311200 0
3 months.
Secondary outcome [3] 311201 0
Safety and tolerability of exenatide therapy in patients with acute ischaemic stroke. Safety will be assessed by determining the number of episode of hypoglycaemia in the exenatide arm. Furthermore, the incidence of adverse events, specifically gastrointestinal side effects in the exenatide arm, will be evaluated.
Timepoint [3] 311201 0
72 hours.

Eligibility
Key inclusion criteria
- Patient presenting with acute ischaemic stroke, as confirmed by routine neurological assessment
- Blood glucose level > 10mmol/L on blood glucose testing during the first 72 hours after admission to the Acute Stroke Ward
- Age > 18 years
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Type 1 diabetes mellitus
- Initial NIHSS > 20
- Life expectancy below 12 months
- Pre morbid modified Rankin Score above 3
- Impaired liver function, defined as alanine aminotransferase (ALT) > 3 times the upper limit of normal
- Impaired renal function, defined as eGFR < 30 ml/min/1.73m2
- History of pancreatitis
- History of pancreatic cancer
- History of medullary thyroid cancer or multiple endocrine neoplasia II
- Known allergy to exenatide
- Suspected or known abuse of alcohol or narcotics
- Pregnancy or lactation

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)
Recruitment and Consent: Patients who are admitted to the Acute Stroke Ward will be screened for eligibility to participate in the study. Laboratory results will be accessed, to obtain the initial blood glucose level reading determined by standard blood glucose testing. In addition, the blood glucose level will be determined by finger-prick testing, and the use of a blood glucose monitor. Furthermore, a neurological clinician will be consulted, to determine the diagnosis of the patient, in terms of stroke type. Potential participant medical records will also be accessed, to confirm that the patient satisfies the study inclusion and exclusion criteria.

Patients will be approached by a member of the study research team, and the study aims and procedures will be explained to them in detail. The patient will also be given a copy of the Participant Information Sheet and Consent Form. Written informed consent will be obtained from all participants, prior to study procedures taking place.

In the instance that a potential study participant is unable to give written informed consent, written informed assent from the next-of-kin will be obtained.

Randomisation: Block randomisation will be used, such that balance across the two treatment groups is achieved. On site randomisation will be carried out by a clinical study nurse, through the use of light-impermeable envelopes containing study arm allocation. The study nurse will ensure allocation of patients to the correct treatment group. In addition, participants will be stratified, based on their current use of insulin, such that there is equal distribution of patients that take insulin (prior to study entry) across the treatment arms. Study researchers and clinicians will be un-blinded to the treatment arm allocation, due to the differences in the treatment protocol for GLP-1 versus insulin.

Study Population: Male and female patients, aged greater than 18 years, admitted to the Acute Stroke Ward with ischaemic stroke, as confirmed by routine clinical assessment and radiological investigation including CT brain, presenting with a blood glucose level of great than 10mmol/L, who are willing to be randomised to continuous IV infusion of insulin/glucose or exenatide for up to 72 hours or until discharge from hospital.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Sample Size Estimation: The total number of enrolled patients will be 30, with 15 in each arm. As this is a pilot study looking at feasibility, as well preliminary safety and efficacy of exenatide treatment in this population, the results will inform further clinical investigations and larger trial designs.

Through biostatistical consultation, it has been determined that the above sample size will also allow for testing the feasibility of implementing GLP-1 therapy in this setting, and further allow monitoring of adverse events. With n = 15 in the GLP-1 therapy arm, there is over 80% power to detect a drop in blood glucose level from 10mMol/L to 8mMol/L (assuming a standard deviation of 2).

In addition, a comparison of insulin versus GLP-1 therapy is possible with the above sample size, as assuming the two treatments will give rise to the same reduction in blood glucose levels, there will be 80% power to conclude that they were within 2mMol/L, with alpha = 0.1. (As this is a pilot study, alpha = 0.1 has been used.).

Interim Analyses: After 16 patients have been recruited to the study (approximately 50% of the total number of participants to be recruited) an interim analysis of the efficacy of GLP-1 at lowering blood glucose levels, as well as the safety of GLP-1 therapy in the study population will be carried out. The frequency of requirement of insulin rescue therapy in the GLP-1 treatment arm will also be determined.

Recruitment
Recruitment status
Completed
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)
NSW
Recruitment hospital [1] 3113 0
Royal North Shore Hospital - St Leonards
Recruitment postcode(s) [1] 8860 0
2065 - Royal North Shore Hospital

Funding & Sponsors
Funding source category [1] 290180 0
Hospital
Name [1] 290180 0
Department of Endocrinology, RNSH - Clinical Trials Research Fund.
Address [1] 290180 0
Department of Diabetes, Endocrinology & Metabolism,
Level 3, Acute Services Building,
Royal North Shore Hospital,
Reserve Road,
St Leonards,
NSW 2065
Country [1] 290180 0
Australia
Primary sponsor type
Government body
Name
Northern Sydney Local Health District
Address
Northern Sydney Local Health District,
Building 51, Royal North Shore Hospital Campus,
Reserve Road,
St Leonards, NSW 2065

Country
Australia
Secondary sponsor category [1] 288891 0
None
Name [1] 288891 0
Address [1] 288891 0
Country [1] 288891 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291889 0
Northern Sydney Local Health District Human Research Ethics Committee
Ethics committee address [1] 291889 0
Research Office
Kolling Building, Level 13,
Royal North Shore Hospital,
Reserve Road,
St Leonards, NSW 2065
Ethics committee country [1] 291889 0
Australia
Date submitted for ethics approval [1] 291889 0
Approval date [1] 291889 0
07/08/2014
Ethics approval number [1] 291889 0
HREC/14/HAWKE/131

Summary
Brief summary
As hyperglycaemia in acute ischaemic stroke is associated with increased infarct size and worse functional outcomes, therapies that can maintain normoglycaemia during stroke are of significant clinical importance. GLP-1 analogues, including exenatide, are a potential therapeutic option for the effective regulation of blood glucose levels in acute stroke, without the risk of inducing hypoglycaemia, which can be associated with intensive insulin therapy. GLP-1 therapy is more straightforward to implement and does not require dose adjustment over time, as is necessary for intensive insulin therapy. This may result in less of a burden on treating clinical staff. Furthermore, administration of GLP-1 may have direct beneficial effects on neuronal cell survival and result in neuroprotection, as suggested by animal studies and preliminary clinical data. Thus, the use of a GLP-1 receptor agonist in the management of hyperglycaemia in acute ischaemic stroke (AIS) may confer a benefit in morbidity and mortality for patients long-term.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52454 0
Prof Greg Fulcher
Address 52454 0
Department of Diabetes, Endocrinology & Metabolism,
Level 3, Acute Services Building,
Royal North Shore Hospital,
Reserve Road,
St Leonards, NSW 2065
Country 52454 0
Australia
Phone 52454 0
+ 61 2 9463 1680
Fax 52454 0
Email 52454 0
greg.fulcher@sydney.edu.au
Contact person for public queries
Name 52455 0
Dr Rachel McGrath
Address 52455 0
Department of Diabetes, Endocrinology & Metabolism,
Level 3, Acute Services Building,
Royal North Shore Hospital,
Reserve Road,
St Leonards, NSW 2065
Country 52455 0
Australia
Phone 52455 0
+61 2 9463 1470
Fax 52455 0
Email 52455 0
Rachel.McGrath@health.nsw.gov.au
Contact person for scientific queries
Name 52456 0
Dr Rachel McGrath
Address 52456 0
Department of Diabetes, Endocrinology & Metabolism,
Level 3, Acute Services Building,
Royal North Shore Hospital,
Reserve Road,
St Leonards, NSW 2065
Country 52456 0
Australia
Phone 52456 0
+61 2 9463 1470
Fax 52456 0
Email 52456 0
Rachel.McGrath@health.nsw.gov.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary