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Trial registered on ANZCTR


Registration number
ACTRN12616001059459
Ethics application status
Approved
Date submitted
1/08/2016
Date registered
9/08/2016
Date last updated
27/02/2019
Date data sharing statement initially provided
27/02/2019
Date results information initially provided
27/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of extended exposure to lixisenatide on gastric emptying and postprandial glycaemia in patients with type 2 diabetes treated with metformin
Scientific title
Effects of extended exposure to lixisenatide on gastric emptying and postprandial glycaemia in patients with type 2 diabetes treated with metformin
Secondary ID [1] 289813 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes 299738 0
Condition category
Condition code
Metabolic and Endocrine 299674 299674 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention will consist of 56 days treatment with either lixisenatide or placebo (saline). Dosing of lixisenatide will be “stepped up” according to the following schedule:
- 5 mcg subcut, once daily on days 1-7, 10 mcg subcut, once daily on days 8-14, and 20 mcg subcut, once daily on days 15-56
- Patients will have a diary and will need to sign each time an injection was given.
- Patients self administer their injections
Intervention code [1] 295490 0
Treatment: Drugs
Comparator / control treatment
Placebo = normal saline
Control group
Placebo

Outcomes
Primary outcome [1] 299135 0
Change in gastric half-emptying time as assessed by scintigraphy ( a meal will be given while the subject sits against a gamma camera, consisting of 300ml 25% dextrose labelled with 20MBq 99mTc-calcium phytate, and also containing 1.5g [U-13C] glucose, and 1000mg paracetamol to measure gastric emptying simultaneously by the paracetamol absorption test) from baseline to day 56, for lixisenatide versus placebo
Timepoint [1] 299135 0
Gastric emptying will be assessed from the time of ingestion of the meal and for 240 min afterwards. We will then review any change in gastric emptying at day 56 at the final gastric emptying study.
Secondary outcome [1] 326292 0
Postprandial glycaemia (incremental area under the curve) for blood glucose concentration between t = 0 and 240 min, Change from baseline to Day 56. .
Timepoint [1] 326292 0
Venous blood (~3 mL) will be sampled at t= -210, -20, -10, 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 min for subsequent analysis of blood glucose and plasma glucose tracer concentrations. Change from baseline to Day 56.
Secondary outcome [2] 326293 0
HbA1c by serum assay
Timepoint [2] 326293 0
A further sample (5 mL) will be collected at t = -210 min to measure HbA1C. Change from baseline to Day 56. .
Secondary outcome [3] 326294 0
Rate of exogenous glucose appearance
Timepoint [3] 326294 0
Venous blood (~3 mL) will be sampled at t= -210, -20, -10, 0 (meal given), 15, 30, 45, 60, 90, 120, 150, 180 and 240 min for subsequent analysis of d plasma glucose tracer concentrations. Change from baseline to Day 56. .
Secondary outcome [4] 326295 0
Plasma Insulin
Timepoint [4] 326295 0
Blood samples at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma insulin, Change from baseline to Day 56.
Secondary outcome [5] 326350 0
Fructosamine - serum assay
Timepoint [5] 326350 0
A further sample (5 mL) will be collected at t = -210 min to measure Fructosamine. Change from baseline to Day 56. .
Secondary outcome [6] 326351 0
Rate of endogenous glucose production
Timepoint [6] 326351 0
Venous blood (~3 mL) will be sampled at t= -210, -20, -10, 0 (meal given), 15, 30, 45, 60, 90, 120, 150, 180 and 240 min for subsequent analysis of d plasma glucose tracer concentrations
Secondary outcome [7] 326352 0
Plasma C-Peptide
Timepoint [7] 326352 0
Blood samples at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma C-Peptide, Change from baseline to Day 56.
Secondary outcome [8] 326353 0
Plasma Glucagon.
Timepoint [8] 326353 0
Blood samples at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma glucagon, Change from baseline to Day 56.
Secondary outcome [9] 326488 0
Beta cell function (evaluated from insulin secretion rates as determined by deconvolution analysis of postprandial C-peptide concentrations)
Timepoint [9] 326488 0
Blood samples at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma C-Peptide and insulin as above, Change from baseline to Day 56.
Secondary outcome [10] 329202 0
Plasma Paracetamol
Timepoint [10] 329202 0
Blood samples at at t (min)= -20, -10, 0, 15, 30, 45, 60, 75, 90, 120, 150, 180, 210, 240

Eligibility
Key inclusion criteria
Males or females aged greater than 40 years
If females are premenopausal they must have had either a tubal ligation or hysterectomy i.e. are not fertile.
Type 2 diabetes treated with metformin for greater than or equal to 3 months
HbA1c between 6.5 and 9%
Duration of known diabetes greater than or equal to 2 years
Haemoglobin above the lower limit of the normal range (i.e. greater than 135 g/L for men and 115 g/L for women), and ferritin above the lower limit of normal (i.e. greater than 10 mcg/L)
Minimum age
40 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Evidence of renal, hepatic or cardiovascular disease, pancreatitis, gastric surgery, or known gastroparesis. Renal disease: creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation. Subjects will be excluded if creatinine clearance is estimated at less than 30 mL/min. Hepatic disease: subjects will be excluded if there is documented cirrhosis or transaminases or alkaline phosphatase elevated more than 2 times the upper limit of normal. Cardiovascular disease: admission to hospital with heart failure, myocardial infarction or stroke within previous 6 months.
Previous exposure to GLP-1 receptor agonists
Use of drugs potentially affecting gastrointestinal motility (opiates, anticholinergics, levodopa, clonidine, nitrates, , phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, or erythromycin)
Use of any agent other than metformin for control of glycaemia
Premenopausal females, unless they have had a tubal ligation or hysterectomy
Presence of definite autonomic nerve damage (as assessed by standardised cardiovascular reflex tests)
Participation in any research studies involving exposure to ionising radiation within the previous 12 months
Vegetarian diet
Intake of greater than 20 g alcohol on a daily basis, or cigarette smoking
Volunteers who have donated blood in the preceding 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)
Yes allocation concealment. Blinding and randomization by central randomization by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (Research Randomizer - https://www.randomizer.org/)
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
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We have previously established a mean half-emptying time for 150 mL 10% dextrose when consumed with 100g minced beef, as measured by scintigraphy, of 34 min with a standard deviation of 19 min in a group of patients with longstanding diabetes. Therefore, 20 subjects in each group will provide 80% power to detect a 50% increase in the gastric half-emptying time by lixisenatide compared to placebo at 8 weeks (Day 56).
Analysis will be undertaken on a per-protocol basis. Analysis of covariance (ANCOVA) 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 reduction in postprandial glycaemia and change in gastric emptying, between reduction in postprandial glycaemia and baseline rate of gastric emptying, and between reduction in postprandial glycaemia and beta cell function will be examined

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)
SA
Recruitment hospital [1] 6349 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 13892 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 294201 0
Commercial sector/Industry
Name [1] 294201 0
Sanofi
Address [1] 294201 0
Talavera Corporate Centre, Building D,
12-24 Talavera Rd, Macquarie Park NSW 2113
Country [1] 294201 0
Australia
Primary sponsor type
Government body
Name
Central Adelaide Local Health Network
Address
Level 4, Women's Health Centre
Royal Adelaide Hospital
North Terrace,
Adelaide 5000
South Australia
Country
Australia
Secondary sponsor category [1] 293031 0
None
Name [1] 293031 0
Address [1] 293031 0
Country [1] 293031 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295609 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 295609 0
Level 4, Women’s Health Centre
Royal Adelaide Hospital
North Terrace
Adelaide, South Australia, 5000
Ethics committee country [1] 295609 0
Australia
Date submitted for ethics approval [1] 295609 0
30/11/2015
Approval date [1] 295609 0
21/01/2016
Ethics approval number [1] 295609 0
HREC Reference No: HREC/15/RAH/520

Summary
Brief summary
The trial will follow a randomised, double-blind, placebo-controlled parallel group design.

After providing written, informed consent, each subject will attend the Nuclear Medicine Department in the morning (0800) after an overnight fast under “baseline” conditions (day 0). If the subject is normally prescribed metformin, this will be held while fasting and will be taken with the first meal following gastric emptying study. The investigators will confirm the prescribed metformin dose and check that this remains stable at each visit. A standardised meal will be provided the evening before the study. An intravenous cannula will be inserted in each forearm, one for blood sampling and the other for IV infusion of glucose tracer (initial bolus of 28 micromol.kg-1 6,6-2H2 glucose, followed by continuous infusion at a rate of 0.28 micromol.min-1.kg-1 from t = -210 until t = 240 min). At t = -5min, a meal will be given while the subject sits against a gamma camera, consisting of 300ml 25% dextrose labelled with 20MBq 99mTc-calcium phytate, and also containing 1.5g [U-13C] glucose, and 1000mg paracetamol to measure gastric emptying simultaneously by the paracetamol absorption test. The meal will be consumed within 5 minutes. Gastric emptying will be assessed from the time of ingestion of the meal and for 240 min afterwards. Venous blood (~3 mL) will be sampled at t= -210, -20, -10, 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 min for subsequent analysis of blood glucose and plasma glucose tracer concentrations, and additional samples (~10 ml volume) at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma insulin, C-peptide, and glucagon. A further sample (5 mL) will be collected at t = -210 min to measure HbA1C and fructosamine. Heart rate and blood pressure will be monitored every 3 minutes between t = -60 min and t =240 min using an automated recording device ((DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA). At the conclusion of the study, subjects will be offered a light meal before they leave the laboratory.

On the following day (day 1), each subject will then commence a 56 day (8 week) intervention consisting of lixisenatide or matching placebo (saline) administered subcutaneously once daily, 30 min before breakfast, as detailed below. On the final day (day 56), he or she will return to the department for a second gastric emptying study that will be identical to the study protocol for day 0, other than for administration of the final dose of lixisenatide or placebo 30 min before meal ingestion.

Intervention
The intervention will consist of 56 days treatment with either lixisenatide or placebo (saline). Dosing of lixisenatide will be “stepped up” according to the following schedule:
- 5 mcg days 1-7, 10 mcg days 8-14, 20 mcg days 15-56
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67906 0
Prof Chris Rayner
Address 67906 0
University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005
Country 67906 0
Australia
Phone 67906 0
+61 8 82222916
Fax 67906 0
Email 67906 0
chris.rayner@adelaide.edu.au
Contact person for public queries
Name 67907 0
Prof Chris Rayner
Address 67907 0
University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005
Country 67907 0
Australia
Phone 67907 0
+61 8 82222916
Fax 67907 0
Email 67907 0
chris.rayner@adelaide.edu.au
Contact person for scientific queries
Name 67908 0
Prof Chris Rayner
Address 67908 0
University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005
Country 67908 0
Australia
Phone 67908 0
+61 8 82222916
Fax 67908 0
Email 67908 0
chris.rayner@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
What supporting documents are/will be available?
Study protocol
Summary results
Have study results been published in a peer-reviewed journal?
No
Other publications
Have study results been made publicly available in another format?
No
Results – basic reporting
Results – plain English summary