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Trial registered on ANZCTR


Registration number
ACTRN12621000878875
Ethics application status
Approved
Date submitted
2/06/2021
Date registered
7/07/2021
Date last updated
7/07/2021
Date data sharing statement initially provided
7/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Is metformin better taken before or with meals? An acute evaluation of the impact of timing of metformin administration on intestinal glucose absorption, gut hormone secretion and the blood glucose response to an intraduodenal glucose infusion in type 2 diabetes
Scientific title
Is metformin better taken before or with meals? An acute evaluation of the impact of timing of metformin administration on intestinal glucose absorption, gut hormone secretion and the blood glucose response to an intraduodenal glucose infusion in type 2 diabetes
Secondary ID [1] 304382 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 322175 0
Condition category
Condition code
Metabolic and Endocrine 319861 319861 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following enrolment, each subject will be studied on 4 occasions, separated by at least 7 days, in a double-blind, randomized, crossover design with treatment allocation assigned by the Royal Adelaide Hospital Pharmacy. During the study period, patients will only need to cease their morning dose of metformin on the respective study days to allow for evaluation of the impact of timing of metformin administration on the study outcomes. On the evening preceding the study day (~1900h), participants will be given a standardised evening meal (McCain’s frozen beef lasagne (McCain Foods Proprietary Ltd, Victoria, Australia); 2472kJ) to consume with water. Following this meal, participants will be asked to fast from solids and liquids (water will be allowed until 10 pm) until the following morning, when they will attend the CRF of the AHMS building at 0800h.

On each study day, a silicone rubber catheter (Dentsleeve International Ltd., Mui Scientific, Ontario, Canada) will be inserted through an anaesthetised nostril into the stomach, and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the intraduodenal infusion port located 12 cm distal to the pylorus. 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 on the dorsum of the hand, which will be kept warm with a heat pad to allow sampling of “arterialised” blood.

After correct positioning of the catheter, 1000 mg metformin dissolved in 30 mL water, or 0.9% saline as a control, will be administered intraduodenally over 2 min at t = -60, -30 or 0 min, in a double-blind, randomised fashion, i.e. one of the following 4 treatments:
(i) 1000 mg metformin at t = -60 min + 0.9% saline at t = -30 and 0 min,
(ii) 1000 mg metformin at t = -30 min + 0.9% saline at t = -60 and 0 min,
(iii) 1000 mg metformin at t = 0 min + 0.9% saline at t = -60 and -30 min, or
(iv) 0.9% saline at t = -60, -30 and 0 min.
Commencing at t = 0 min, a solution containing 45 g glucose and 5g 3-OMG (as a marker of intestinal glucose absorption) dissolved in water to a total volume of 180 mL, will be infused into the duodenum over 60 minutes (i.e. 3 kcal/min). At t = 60 min, the catheter will be removed. The participant will be monitored for another 60 min (t = 60 - 120 min) before a light meal is served.

“Arterialised” venous blood (~10 mL) will be sampled at t= -60, -30, 0, 30, 60, 90, 120 min. Blood glucose levels will be measured immediately at the bedside with a glucometer (Medisense Precision QID, Abbott Laboratories, Bedford, MA, USA). Plasma and serum samples will be separated from the remainder of each sample and stored at -80 degree Celsius for subsequent measurements. At the same intervals used for blood sampling, appetite and gastrointestinal sensations (including hunger, desire to eat, fullness, nausea, bloating, headache and abdominal pain) will be assessed using 100 mm visual analogue scales. After a final blood sample is collected, subjects will be served with a light lunch, and once the blood concentrations of subjects have stabilised above 5 mmol/L, subjects will be free to leave the laboratory. The total amount of blood drawn during the screening and 4 study visits will be ~300 mL.
Intervention code [1] 320746 0
Treatment: Drugs
Comparator / control treatment
Placebo controlled - participants will act as their own control in this cross-over study. Placebo will be 0.9% saline
Control group
Placebo

Outcomes
Primary outcome [1] 327734 0
The differences in the iAUC0-120min for serum 3-OMG concentrations between treatments.
Timepoint [1] 327734 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Primary outcome [2] 327737 0
The differences in the iAUC0-120min for plasma glucose concentrations between treatments.
Timepoint [2] 327737 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Primary outcome [3] 328038 0
The differences in the iAUC0-120min for plasma GLP-1 concentrations between treatments.
Timepoint [3] 328038 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Secondary outcome [1] 396382 0
Secondary endpoints will be the iAUC0-120min plasma insulin concentrations between the treatments.
Timepoint [1] 396382 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Secondary outcome [2] 396383 0
The iAUC0-120min plasma glucagon concentrations between the treatments.
Timepoint [2] 396383 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Secondary outcome [3] 397308 0
The iAUC0-120min plasma C-peptide concentrations between the treatments.
Timepoint [3] 397308 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given
Secondary outcome [4] 397941 0
The differences in gastrointestinal symptom assessed by visual analogue scales between the treatments.
Timepoint [4] 397941 0
t= -60, -30, 0, 30, 60, 90, 120 min where t = -60 is when the first dose of metformin/placebo is given

Eligibility
Key inclusion criteria
• Type 2 diabetes (World Health Organisation (WHO) criteria) treated by metformin only (on a stable dose over the last 3 months)
• Body mass index (BMI) from 25 to 35 kg/m2
• Males and females, aged from 40 to 79 years
• Glycated haemoglobin (HbA1c) less than 7.9%
• Haemoglobin above the lower limit of the normal range (ie. above 135g/L for men and 115g/L for women), and ferritin above the lower limit of normal (ie. above 30ng/mL for men and above 20mg/mL for women)
Minimum age
40 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Use of any medication that may influence gastrointestinal motor function, body weight or appetite (e.g. domperidone and cisapride, anticholinergic drugs (e.g. atropine), metoclopramide, erythromycin, hyoscine, orlistat, green tea extracts, Astragalus, St. John's Wort etc.)
• 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 < 90 mL/min or abnormal liver function tests (> 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)
Ssealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Based on data derived from a previous study, 16 subjects will provide at least 90% power (a = 0.01) to detect a ~15% difference in the incremental area under the curve (iAUC) over 120 min for glucose absorption (serum 3-OMG levels) between metformin and placebo, in response to a standardized intraduodenal glucose infusion (3 kcal/min over 60 min). 20 subjects will be recruited to allow for drop-outs.

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

Funding & Sponsors
Funding source category [1] 308752 0
Charities/Societies/Foundations
Name [1] 308752 0
The Hospital Research Foundation
Address [1] 308752 0
Level 1, 62 Woodville Road, Woodville, SA 5011
Country [1] 308752 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Clinical Research Facility, Level 4 Adelaide Health and Medical Sciences (AHMS) Building,
North Terrace, Adelaide, SA 5000
Country
Australia
Secondary sponsor category [1] 309650 0
None
Name [1] 309650 0
N/A
Address [1] 309650 0
N/A
Country [1] 309650 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308670 0
Central Adelaide Local Health Network HREC Human Research Ethics Committee
Ethics committee address [1] 308670 0
Level 3, Roma Mitchell Building | 136 North Terrace, Adelaide, SA 5000
Ethics committee country [1] 308670 0
Australia
Date submitted for ethics approval [1] 308670 0
28/03/2021
Approval date [1] 308670 0
27/05/2021
Ethics approval number [1] 308670 0

Summary
Brief summary
Metformin is the first-line oral glucose-lowering medicine in almost all clinical guidelines on the management of type 2 diabetes (T2D). Standard advice has been to ingest metformin with meals to minimise any gastrointestinal adverse effects. It was long thought that metformin’s main action relates to suppression of glucose output from the liver. However, newer evidence suggests that the gastrointestinal tract is a key site of metformin action, and that administration of metformin at an interval before the meal may be more effective than ingestion with the meal, for lowering postprandial blood glucose levels. We have recently shown that the lowering of postprandial glucose by metformin in patients with T2D is associated with stimulation of the incretin hormone, glucagon-like peptide-1 (GLP-1), and inhibition of intestinal glucose absorption. We now propose to evaluate whether the timing of metformin administration affects glucose absorption, GLP-1 secretion, and the glycaemic response to intraduodenal glucose infusion in metformin-treated patients with T2D.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 111498 0
A/Prof Tongzhi Wu
Address 111498 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111498 0
Australia
Phone 111498 0
+61 8 8313 6535
Fax 111498 0
Email 111498 0
tongzhi.wu@adelaide.edu.au
Contact person for public queries
Name 111499 0
A/Prof Tongzhi Wu
Address 111499 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111499 0
Australia
Phone 111499 0
+61 8 8313 6535
Fax 111499 0
Email 111499 0
tongzhi.wu@adelaide.edu.au
Contact person for scientific queries
Name 111500 0
A/Prof Tongzhi Wu
Address 111500 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111500 0
Australia
Phone 111500 0
+61 8 8313 6535
Fax 111500 0
Email 111500 0
tongzhi.wu@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
The ethical statement and informed consent do not allow for free data availability.
What supporting documents are/will be available?
No other documents available
Summary results
No Results