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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

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]

Nil Known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Type 2 Diabetes

Condition category

Condition code

Metabolic and Endocrine

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]

Treatment: Drugs

Comparator / control treatment

Placebo = normal saline

Control group

Placebo

Outcomes

Primary outcome [1]

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]

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]

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]

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]

HbA1c by serum assay

Timepoint [2]

A further sample (5 mL) will be collected at t = -210 min to measure HbA1C. Change from baseline to Day 56. .

Secondary outcome [3]

Rate of exogenous glucose appearance

Timepoint [3]

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]

Plasma Insulin

Timepoint [4]

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]

Fructosamine - serum assay

Timepoint [5]

A further sample (5 mL) will be collected at t = -210 min to measure Fructosamine. Change from baseline to Day 56. .

Secondary outcome [6]

Rate of endogenous glucose production

Timepoint [6]

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]

Plasma C-Peptide

Timepoint [7]

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]

Plasma Glucagon.

Timepoint [8]

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]

Beta cell function (evaluated from insulin secretion rates as determined by deconvolution analysis of postprandial C-peptide concentrations)

Timepoint [9]

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]

Plasma Paracetamol

Timepoint [10]

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

Sex

Both males and females

Can healthy volunteers participate?

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

12/08/2016

Actual

12/08/2016

Date of last participant enrolment

Anticipated

31/05/2017

Actual

10/07/2018

Date of last data collection

Anticipated

Actual

18/09/2018

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

Recruitment hospital [1]

The Royal Adelaide Hospital - Adelaide

Recruitment postcode(s) [1]

5000 - Adelaide

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Sanofi

Address [1]

Talavera Corporate Centre, Building D,
12-24 Talavera Rd, Macquarie Park NSW 2113

Country [1]

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]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Adelaide Hospital Human Research Ethics Committee

Ethics committee address [1]

Level 4, Women’s Health Centre
Royal Adelaide Hospital
North Terrace
Adelaide, South Australia, 5000

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

30/11/2015

Approval date [1]

21/01/2016

Ethics approval number [1]

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

Prof Chris Rayner

Address

University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005

Country

Australia

Phone

+61 8 82222916

Fax

chris.rayner@adelaide.edu.au

Contact person for public queries

Name

Chris Rayner

Address

University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005

Country

Australia

Phone

+61 8 82222916

Fax

chris.rayner@adelaide.edu.au

Contact person for scientific queries

Name

Chris Rayner

Address

University of Adelaide
Discipline of Medicine,
Royal Adelaide Hospital
Level 6, Eleanor Harrald Building
Frome Rd, Adelaide, South Australia 5005

Country

Australia

Phone

+61 8 82222916

Fax

chris.rayner@adelaide.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

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

Source	Title	Year of Publication	DOI
Embase	Effects of sustained treatment with lixisenatide on gastric emptying and postprandial glucose metabolism in type 2 diabetes: A randomized controlled trial.	2020	https://dx.doi.org/10.2337/dc20-0279
Embase	Effects of Sustained Treatment with Lixisenatide on Gastric Emptying and Postprandial Glucose Metabolism in Type 2 Diabetes: A Randomized Controlled Trial.	2020	https://dx.doi.org/10.2337/dc20-0190
Dimensions AI	Serum alanine transaminase is predictive of fasting and postprandial insulin and glucagon concentrations in type 2 diabetes	2023	https://doi.org/10.1016/j.peptides.2023.171092

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added automatically