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Trial registered on ANZCTR


Registration number
ACTRN12619000497101
Ethics application status
Approved
Date submitted
21/03/2019
Date registered
27/03/2019
Date last updated
27/03/2019
Date data sharing statement initially provided
27/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of exenatide once weekly on gastric emptying in type 2 diabetes
Scientific title
Effect of exenatide once weekly on gastric emptying of, and the postprandial glycaemic and cardiovascular responses to, a carbohydrate meal in type 2 diabetes.
Secondary ID [1] 297722 0
Nil known
Universal Trial Number (UTN)
Not applicable
Trial acronym
EXQWT2DM
Linked study record
Not applicable

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 312050 0
Condition category
Condition code
Metabolic and Endocrine 310611 310611 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
1. Exenatide QW 2mg or Exenatide Placebo to be injected, subcutaneously, once a week for 8 weeks. The injection is administered by one of the investigators to remove any issues relating to compliance.

2. A gastric emptying study using the gold standard technique (scintigraphy) will be performed at baseline and at 8 weeks. The carbohydrate meal used to measure gastric emptying rate is a standardised mashed potato meal (369 kcal) comprising 65g powdered potato and 20g glucose reconstituted with 250ml boiling water and labelled with 20 MBq 99mTc-sulphur colloid and will include 5g 3-O-methylglucose (3-O-MG, Sigma Aldrich, USA). This equates to an effective radiation dose of 0.5mSv per study. On one occasion, at t=240 minutes, the volunteer will drink 100 ml of water labelled with 4MBq of 99mTc-sulphur colloid and a lateral image of the stomach will be acquired to derive correction factors for gamma ray attenuation. This equates to a total dose of 1.1mSv (including the lateral dose), which is within The RAH Radiation Safety Guidelines (upper limit 5mSv) and has been approved previously by the Research Ethics Committee of the Royal Adelaide Hospital.
Intervention code [1] 313964 0
Treatment: Drugs
Comparator / control treatment
Placebo will be identical to exenatide QW in appearance (without the active ingredient). Placebo will be supplied as a single dose kit containing a vial of powder, a pre-filled syringe of diluent, a vial connector and two needles (one spare). The powder is suspended using the diluent supplied. The diluent is a clear, colourless to pale yellow to pale brown solution. Placebo consists of sucrose encapsulated within biodegradable polyglactin microspheres. During dose preparation, a custom diluent is added to these microspheres, which are dispersed into the diluent to create a suspension. Following administration of the suspension, the polymer biodegrades over time. The diluent contains carmellose sodium, sodium chloride, polysorbate 20, monobasic sodium phosphate monohydrate, dibasic sodium phosphate (as heptahydrate), sodium hydroxide (pre-filled pen only), and water for injections.
Control group
Placebo

Outcomes
Primary outcome [1] 319464 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on gastric emptying, measured by scintigraphy, in type 2 diabetes.
Timepoint [1] 319464 0
8 weeks
Secondary outcome [1] 368273 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on postprandial glycaemia in response to a standardised meal. Blood glucose concentrations will be measured immediately using a glucose oxidase analyser (Yellow Springs Institute, USA). Plasma and serum will be separated from the remainder of each sample and stored at – 80 degree Celsius for subsequent measurements of plasma insulin, C-peptide, and glucagon concentrations by assay.
Timepoint [1] 368273 0
Blood samples are taken on each of the gastric emptying study days (i.e. on Day 1 and at 8 weeks). Blood samples are drawn immediately before ingesting the test meal and at t = 15, 30, 45, 60, 75, 90, 120, 150, 180 and 240 min, where t=0 represents the time of meal completion.
Secondary outcome [2] 368274 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on the rate of absorption of the glucose analogue, 3-O-methylglucose (3-OMG). Plasma will be separated from the blood sample and stored at – 80 degree Celsius for subsequent measurements 3-OMG concentrations by assay.
Timepoint [2] 368274 0
Blood samples are taken on each of the gastric emptying study days (i.e. on Day 1 and at 8 weeks). Blood samples are drawn immediately before ingesting the test meal and at t = 15, 30, 45, 60, 75, 90, 120, 150, 180 and 240 min, where t=0 represents the time of meal completion.
Secondary outcome [3] 368275 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on gastrointestinal symptoms. A total of 9 gastrointestinal symptoms will be assessed using a validated questionnaire with a score of 0=symptom not present, 1=mild symptom, 2=moderate symptom, 3=severe symptom with a total maximum score of 27 (Horowitz M et al, Eur J Nucl Med 1991;18(4):229-34).
Timepoint [3] 368275 0
8 weeks
Secondary outcome [4] 368562 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on blood pressure. An automated blood pressure cuff will be used.
Timepoint [4] 368562 0
Blood pressure is measured on each of the gastric emptying study days (i.e. on Day 1 and at 8 weeks). Blood pressure is assessed immediately prior to meal ingestion (3 3-min measurements will be taken and the average used as the baseline value) and following the meal at 5-min intervals until 120 min and at 15 min intervals until 240 min.

Eligibility
Key inclusion criteria
1. Male or female participants aged 40 – 80 years
2. Female subjects who are post-menopausal; or pre-menopausal with surgical contraception (such as tubal ligation) or an intrauterine device. Pre-menopausal women will require a confirmed negative urine ß-hCG pregnancy test at screening visit.
3. T2DM (World Health Organisation (WHO) criteria) managed by diet alone or on metformin
4. Glycated haemoglobin (HbA1c) greater than or equal to 6.0% and less than 8.5%, in the last 4 months prior to enrolment in the study
5. Body mass index (BMI) 25 – 35 kg/m2
6. Haemoglobin and ferritin in the normal range for gender and age.
7. Participant has provided written informed consent.
Minimum age
40 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Evidence of renal disease (i.e. a creatinine clearance cut-off of less than 50 ml/min. Calculated creatinine clearance will be determined as follows using the Cockcroft-Gault equation: Cr clearance = [140 - age (years) x weight (kg)] / [0.814 x serum creatinine (µmol/L)] (For female subjects, multiply Cr clearance x 0.85)13)
2. Iron stores, or liver function tests outside the following ranges:
Alanine aminotransferase (ALT) less than 55 U/L
Alkaline phosphatase (ALP) 30 - 110 U/L
Aspartate transaminase (AST) less than 45 U/L
Total bilirubin 6 - 24 µmol/L
Haemoglobin 115 – 155 g/L (Females); 135 – 172 g/L (Males)
Ferritin 15 – 200 µg/L (Females); 30 – 300 µg/L (Males)
3. Hepatic or cardiovascular disease, pancreatitis (subjects with past history of acute or chronic pancreatitis, gastric surgery, or known gastroparesis on history or screening biochemistry tests.
4. Participants with any history of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy at least 12 months prior to screening or other malignancies treated with apparent success with curative therapy at least 5 years prior to screening will be excluded.
5. History of any clinically significant disease or disorder which may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer’s ability to participate in the study.
6. Personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
7. History of hyperthyroidism or uncontrolled hypothyroidism.
8. Chronic gastrointestinal symptoms as assessed by questionnaire.
9. Use of drugs potentially affecting gastrointestinal motility (nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids; histamine-2 receptor antagonists, anti-emetics (dopamine antagonists, 5HT-3 receptor antagonists), laxatives, prokinetic agents, anticholinergic agents, cholinergic agents, opioid medications, erythromycin).
10.Current use of anticoagulants.
11. Inability to abstain from smoking for 12 hours prior to the gastric emptying tests.
12. Consumption of more than 2 units alcohol daily on a regular basis.
13. Known or suspected history of alcohol or drug abuse, as judged by the Investigator.
14. History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, or history of hypersensitivity to exenatide or drugs with a similar chemical structure or its components.
15. Known hypersensitivity to IV infusion equipment, plastics, adhesive or silicone, or know history of hypotension or infusion site reactions with IV administration of other medicines
16. Participation in any research studies involving exposure to ionising radiation within the previous 12 months
17. Donated blood in the past 3 months

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)
Randomisation will be carried out by the Pharmacy at the Royal Adelaide Hospital. Allocation will involve contacting the holder of the allocation schedule (RAH Pharmacy) who is at a separate site to provide the medication (so that this is blinded to both the participant and study investigator).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be carried out by the Pharmacy at the Royal Adelaide Hospital using simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
The study will follow a randomised double-blind placebo-controlled parallel design
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis
The two analysis sets include the ‘intervention’ group and the ‘control/placebo’ group. Analysis will be undertaken on a per-protocol basis. Analysis of covariance will be used to compare changes in gastric emptying in each group at 8 weeks, adjusting for baseline values. Secondary endpoints will be analysed in similar fashion. Relationships between the reduction in postprandial glycaemia and change in gastric emptying and between the reduction in postprandial glycaemia and baseline rate of gastric emptying, and the mean values will be compared using Student’s t tests. We will collaborate with our biostatistician prior to reporting the results. The data will be prepared for publication in a peer-reviewed journal. All records will be kept a minimum of 15 years in the Discipline of Medicine and the study will maintain the anonymity of the participants. No medical records will be required for this project. Only the investigators will have access to the research data and results. The Discipline of Medicine, University of Adelaide, will own all data from this study.
Determination of sample size was calculated in consultation with a professional biostatistician. Sample size requirements have been based on power calculations alpha a= 0.05 ß = 0.8, performed with gastric emptying as the outcome variable based on our previous data. Thirty two patients with T2DM (16 in each group) are required to detect a difference of 15% intragastric retention at 120 min after administration of exenatide compared to placebo, allowing for all possible post hoc tests between the study days. Based on our experience, we have estimated an overall ‘dropout rate’ of ~10%.

Recruitment
Recruitment status
Not yet 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
Recruitment hospital [1] 13462 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 26071 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 302251 0
Charities/Societies/Foundations
Name [1] 302251 0
Diabetes Australia Research Trust
Address [1] 302251 0
Level 1, 101 Northbourne Ave, Turner
ACT 2612
Country [1] 302251 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Adelaide Health and Medical Sciences Building
Cnr George St and North Terrace, Adelaide, SA, 5000
South Australia
Country
Australia
Secondary sponsor category [1] 302109 0
None
Name [1] 302109 0
Address [1] 302109 0
Country [1] 302109 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302927 0
Central Adelaide Local Health Network (CALHN) HREC
Ethics committee address [1] 302927 0
Level 3, Roma Mitchell House
136 North Terrace, ADELAIDE SA 5000
Ethics committee country [1] 302927 0
Australia
Date submitted for ethics approval [1] 302927 0
12/11/2018
Approval date [1] 302927 0
12/02/2019
Ethics approval number [1] 302927 0
HREC/18/CALHN/741 R20181106

Summary
Brief summary
This study is designed to evaluate the effects of 8 weeks treatment with the glucagon-like peptide-1 agonist, exenatide (once weekly (QW)), on the rate of stomach emptying, glucose absorption and blood glucose and plasma insulin concentrations in type 2 diabetes. This is a randomised parallel designed study. Subjects recruited into the study who pass screening criteria will be randomised to receive exenatide QW or matching placebo. They will have a gastric emptying study performed using the gold standard technique (scintigraphy) at baseline and at 8 weeks. Immediately following the first gastric emptying study they will commence treatment with exenatide QW or Placebo, administered subcutaneously at weekly intervals. Glucose absorption, blood pressure, blood glucose and plasma insulin will be assessed during each of the gastric emptying measurements.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 91874 0
Prof Karen Jones
Address 91874 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 91874 0
Australia
Phone 91874 0
+61 8 8313 7821
Fax 91874 0
Email 91874 0
karen.jones@adelaide.edu.au
Contact person for public queries
Name 91875 0
Ms Seva Hatzinikolas
Address 91875 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 91875 0
Australia
Phone 91875 0
+61 8 8313 7804
Fax 91875 0
Email 91875 0
seva.hatzinikolas@adelaide.edu.au
Contact person for scientific queries
Name 91876 0
Prof Karen Jones
Address 91876 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 91876 0
Australia
Phone 91876 0
+61 8 8313 7821
Fax 91876 0
Email 91876 0
karen.jones@adelaide.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Data are to remain confidential to maintain participant anonymity
What supporting documents are/will be available?
No other documents available
Summary results
No Results