Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000382178
Ethics application status
Approved
Date submitted
6/03/2019
Date registered
11/03/2019
Date last updated
17/06/2022
Date data sharing statement initially provided
11/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Do glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) account for the entire incretin effect?
Scientific title
Do glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) account for the entire incretin effect in healthy humans?
Secondary ID [1] 297641 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 311911 0
Obesity 311912 0
Condition category
Condition code
Metabolic and Endocrine 310493 310493 0 0
Diabetes
Metabolic and Endocrine 310494 310494 0 0
Normal metabolism and endocrine development and function
Diet and Nutrition 310495 310495 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following a screening visit, each subject will be studied on 4 occasions, separated at least 7 days, in a double-blind randomised crossover design.
On each study day, a silicone rubber catheter will be inserted through an anaesthetised nostril into the stomach, and be positioned with the infusion port located 12 cm below to the pylorus (in the duodenum). The correct positioning of the catheter will be monitored continuously by measurement of the transmucosal potential difference in the stomach (~ -40 mV) and the duodenum (~ 0 mV). For this purpose, an intravenous cannula will be placed subcutaneously in the left forearm and filled with sterile saline as a reference electrode. An intravenous cannula will be placed into a vein of each forearm for hyperglycaemic clamping and infusion of the GIP and/or GLP- antagonist, and blood sampling, respectively.
After that, a hyperglycaemic clamp will be maintained at 5 mmol/L above fasting blood glucose from t = 0 to 270 min. This is achieved by intravenous administration of an initial bolus of 25% dextrose, followed by a 25% dextrose infusion at a rate adjusted according to blood glucose concentrations measured every 5 min. Concurrently, a solution of 100 units of insulin, made up to 500 ml with Gelofusine to yield a final concentration of 0.2 IU/ml, will also be infused intravenously at rates according to a sliding scale used in previous similar studies. An IV infusion of the GIP antagonist GIP(3-30)NH2 at the rate of 800 pmol/kg/min and/or the GLP-1 antagonist exendin9-39 at the rate of 600 pmol/kg/min, or saline control, will run from t = 30 to 270 min. Intraduodenal glucose will be infused at 3 kcal/min from t = 90 to 190 min.
Intervention code [1] 313875 0
Treatment: Drugs
Comparator / control treatment
IV infusion of 0.9% saline;
Control group
Placebo

Outcomes
Primary outcome [1] 319358 0
difference in the increment in area under the curve (AUC) for insulin to intraduodenal glucose between 4 treatments, above that predicted from the slope of the curve prior to intraduodenal glucose.
Timepoint [1] 319358 0
t = 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270 min. t = 0 is when intraluminal catheter is correctly positioned and the hyperglycaemic clamp starts and t = 90 min is when intraduodenal glucose starts.
Secondary outcome [1] 367881 0
differences in plasma C-peptide between 4 treatments.
Timepoint [1] 367881 0
at t = 0, 30, 60, 90, 120, 150, 180, 210, 240 and 270min. t = 0 is when intraluminal catheter is correctly positioned and the hyperglycaemic clamp starts and t = 90 min is when intraduodenal glucose starts.
Secondary outcome [2] 367882 0
differences in plasma glucagon between 4 treatments.
Timepoint [2] 367882 0
at t = 0, 30, 60, 90, 120, 150, 180, 210, 240 and 270min. t = 0 is when intraluminal catheter is correctly positioned and the hyperglycaemic clamp starts and t = 90 min is when intraduodenal glucose starts.
Secondary outcome [3] 367883 0
differences in plasma total GIP between 4 treatments.
Timepoint [3] 367883 0
at t = 0, 30, 60, 90, 120, 150, 180, 210, 240 and 270min. t = 0 is when intraluminal catheter is correctly positioned and the hyperglycaemic clamp starts and t = 90 min is when intraduodenal glucose starts.
Secondary outcome [4] 367884 0
differences in plasma total GLP-1 between 4 treatments.
Timepoint [4] 367884 0
at t = 0, 30, 60, 90, 120, 150, 180, 210, 240 and 270min. t = 0 is when intraluminal catheter is correctly positioned and the hyperglycaemic clamp starts and t = 90 min is when intraduodenal glucose starts.
Secondary outcome [5] 367885 0
differences in the quantity of IV glucose infused (assessed by an experienced research officer and recorded in the study notes) between 4 treatments.
Timepoint [5] 367885 0
Visit 1, 2, 3 and 4.

Eligibility
Key inclusion criteria
• Healthy male and females aged from 18 to 40 years, without a family history of T2DM in any 1st degree relative
• Body mass index (BMI) from 19 to 28 kg/m2
• Haemoglobin above the lower limit of the normal range (ie. greater than 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. greater than 30ng/mL for men and greater than 20mg/mL for women).
Minimum age
18 Years
Maximum age
40 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, tricyclic antidepressants, selective serotonin re-uptake inhibitors, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, prucalopride, or erythromycin)
• Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes on a daily basis
• History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms, pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)
• Other significant illness, including epilepsy, cardiovascular or respiratory disease
• Impaired renal or liver function (as assessed by calculated creatinine clearance less than 90 mL/min or abnormal liver function tests (greater than 2 times upper limit of normal range))
• Donation of blood within the previous 3 months
• Participation in any other research studies within the previous 3 months
• Inability to give informed consent
• Female participants who are pregnant or planning for pregnancy, or are lactating
• Vegetarians

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)
allocation involved contacting the holder of the allocation schedule who was "off-site" or at central administration site (Royal Adelaide Hospital Pharmacy)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
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
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Efficacy
Statistical methods / analysis
A sample size of 14 healthy volunteers is calculated to give 90% power to detect 15% differences in the incretin effect with each antagonist, based on variability in published studies. We will recruit 16 subjects to allow for a modest dropout rate.
Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. repeated measures ANOVA).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
6/05/2019
Actual
4/02/2020
Date of last participant enrolment
Anticipated
1/03/2023
Actual
Date of last data collection
Anticipated
1/05/2023
Actual
Sample size
Target
16
Accrual to date
9
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 13319 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 25919 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 302172 0
Government body
Name [1] 302172 0
NHMRC
Country [1] 302172 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Adelaide Medical School, Level 5 Adelaide Health and Medical Sciences (AHMS) Building,
North Terrace, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 302012 0
None
Name [1] 302012 0
Address [1] 302012 0
Country [1] 302012 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302854 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 302854 0
Ethics committee country [1] 302854 0
Australia
Date submitted for ethics approval [1] 302854 0
02/11/2018
Approval date [1] 302854 0
27/02/2019
Ethics approval number [1] 302854 0
HREC/18/CALHN/736

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

Contacts
Principal investigator
Name 91614 0
Prof Chris Rayner
Address 91614 0
Adelaide Medical School, the University of Adelaide, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91614 0
Australia
Phone 91614 0
+61 8 8313 6693
Fax 91614 0
Email 91614 0
[email protected]
Contact person for public queries
Name 91615 0
Tongzhi Wu
Address 91615 0
Adelaide Medical School, the University of Adelaide, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91615 0
Australia
Phone 91615 0
+61 8 8313 6535
Fax 91615 0
Email 91615 0
[email protected]
Contact person for scientific queries
Name 91616 0
Tongzhi Wu
Address 91616 0
Adelaide Medical School, the University of Adelaide, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91616 0
Australia
Phone 91616 0
+61 8 8313 6535
Fax 91616 0
Email 91616 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
The ethical statement and informed consent do not allow for free data availability.


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.