Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000955415
Ethics application status
Approved
Date submitted
15/07/2016
Date registered
20/07/2016
Date last updated
15/03/2019
Date data sharing statement initially provided
15/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of exenatide once weekly on gastric emptying in healthy subjects..
Scientific title
Effect of exenatide once weekly on gastric emptying in healthy subjects under steady-state concentrations: a randomised controlled trial.
Secondary ID [1] 289702 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 298705 0
Condition category
Condition code
Metabolic and Endocrine 298758 298758 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. 20MBq of 99mTc-sulphur colloid and 7 MBq 67Ga-EDTA are used to perform this study. This equates to an effective radiation dose of 2.25mSv per study, and a total dose of 4.5mSv, 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] 294693 0
Treatment: Drugs
Comparator / control treatment
A total of 40 healthy subjects that have passed the screening test will be randomised to receive either exenatide QW or placebo, to allow for a 25% drop out rate resulting in a total of 30 completed subjects i.e. 15 in each group. 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] 298342 0
To compare the effect of 8 weeks treatment with exenatide QW (once weekly) versus placebo on gastric emptying, measured by scintigraphy.
Timepoint [1] 298342 0
8 weeks
Secondary outcome [1] 323897 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] 323897 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 at t = –5, 15, 30, 45, 60, 75, 90, 105, 120, 180 and 240 min, where t=0 represents the time of meal completion.
Secondary outcome [2] 323899 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] 323899 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 at t = –5, 15, 30, 45, 60, 75, 90, 105, 120, 180 and 240 min, where t=0 represents the time of meal completion.
Secondary outcome [3] 323900 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.
Timepoint [3] 323900 0
8 weeks

Eligibility
Key inclusion criteria
1. Healthy male subjects aged 55 – 70 years
2. Healthy post-menopausal female subjects between 55 – 70 years (“Postmenopausal” will be defined as greater than or equal to 55 y of age or at least 12 months since last menses). Post-menopausal will be defined as amenorrhoea for at least 12 months or more, following cessation of all exogenous hormonal treatments and FSH levels in the post-menopausal range.
3. Body mass index (BMI) 25 – 35 kg/m2
4. Haemoglobin and ferritin in the normal range for gender and age.
5. Subject has provided written informed consent.
Minimum age
55 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
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 (micromol/L)] (For female subjects, multiply Cr clearance x 0.85)).
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: 2 - 24 micromol/L
- Haemoglobin: 115 – 165 g/L (Females); 130 – 180 g/L (Males)
- Ferritin: 15 – 200 micrograms/L (Females); 30 – 300 micrograms/L (Males)
3. Hepatic or cardiovascular disease, pancreatitis (subjects with past history of acute or chronic pancreatitis, or amylase or lipase levels greater than 2 fold upper limit of normal at screening, gastric surgery, or known gastroparesis on history or screening biochemistry tests.
4. Subjects with any history of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy equal to 12 months prior to screening or other malignancies treated with apparent success with curative therapy equal to 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. Serum calcitonin level at screening suggestive of thyroid c-cell hyperplasia (greater than 50 nanogram/l). 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. Evidence of diabetes based on history or HbA1c equal to 6.5% at screening.
9. Use of drugs potentially affecting gastrointestinal motility (these include but are not limited to the following medications: opiates, anticholinergics, levodopa, beta blockers, clonidine, nitrates, tricyclic antidepressants, selective serotonin re-uptake inhibitors, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, or erythromycin)
10. Current history of smoking or consumption of greater than 2 units alcohol daily on a regular basis
11. Known or suspected history of alcohol or drug abuse, as judged by the Investigator.
12. 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.
13. Known hypersensitivity to heparin or IV infusion equipment, plastics, adhesive or silicone, or know history of hypotension or infusion site reactions with IV administration of other medicines
14. Systolic BP less than 90mmHg or greater than 140mmHg; Diastolic BP less than 50mmHg or greater than 90mmHg; Heart rate less than 45 or greater 85 beats per minute at the screening test.
15. Plasma donation within 1 month of screening or blood donation / loss greater than 500ml during the 3 months prior to screening.
16. Participation in any research studies involving exposure to ionising radiation within the previous 12 months
17. Vegetarian diet

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 (RAH). 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. Based on a previous study evaluating gastric emptying and postprandial glycaemia using a similar mixed meal, we would assume an intragastric retention of ~52% at 100 min with SD of 29%. We, therefore, estimate that recruiting 40 participants in total (20 in each group) would detect a 50% increase in retention with alpha 0.05 and power 80%, while allowing for a dropout rate of 25% i.e. 30 patients (15 in each group) will complete the study.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
1/09/2016
Actual
26/10/2016
Date of last participant enrolment
Anticipated
1/01/2018
Actual
4/02/2018
Date of last data collection
Anticipated
Actual
18/05/2018
Sample size
Target
30
Accrual to date
Final
32
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 5808 0
The Royal Adelaide Hospital - Adelaide

Funding & Sponsors
Funding source category [1] 293621 0
Commercial sector/Industry
Name [1] 293621 0
AstraZeneca Pty Ltd
Country [1] 293621 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
North Terrace, Adelaide, SA, 5000
Australia
Country
Australia
Secondary sponsor category [1] 292451 0
University
Name [1] 292451 0
The University of Adelaide
Address [1] 292451 0
North Terrace, Adelaide, SA, 5005
Australia
Country [1] 292451 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295059 0
Human Research Ethics Committee of the Royal Adelaide Hospital
Ethics committee address [1] 295059 0
Ethics committee country [1] 295059 0
Australia
Date submitted for ethics approval [1] 295059 0
05/05/2016
Approval date [1] 295059 0
15/07/2016
Ethics approval number [1] 295059 0
HREC/16/RAH/183 R20160508

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

Contacts
Principal investigator
Name 65722 0
Prof Karen Jones
Address 65722 0
University of Adelaide
Discipline of Medicine
Level 6, Eleanor Harrald Building,
Royal Adelaide Hospital
Frome Rd
ADELAIDE SA 5005
Country 65722 0
Australia
Phone 65722 0
+61 8 8222 5394
Fax 65722 0
+61 8 8223 3870
Email 65722 0
[email protected]
Contact person for public queries
Name 65723 0
Seva Hatzinikolas
Address 65723 0
University of Adelaide
Discipline of Medicine
Level 6, Eleanor Harrald Building,
Royal Adelaide Hospital
Frome Rd
ADELAIDE SA 5005
Country 65723 0
Australia
Phone 65723 0
+61 8 8222 2915
Fax 65723 0
+61 8 8223 3870
Email 65723 0
[email protected]
Contact person for scientific queries
Name 65724 0
Karen Jones
Address 65724 0
University of Adelaide
Discipline of Medicine
Level 6, Eleanor Harrald Building,
Royal Adelaide Hospital
Frome Rd
ADELAIDE SA 5005
Country 65724 0
Australia
Phone 65724 0
+61 8 8222 5394
Fax 65724 0
+61 8 8223 3870
Email 65724 0
[email protected]

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 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.