Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12619000299101
Ethics application status
Approved
Date submitted
22/02/2019
Date registered
27/02/2019
Date last updated
6/07/2021
Date data sharing statement initially provided
27/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Role of bile acids in glucose lowering by metformin
Scientific title
Role of bile acids in glucose lowering by metformin in patients with type 2 diabetes.
Secondary ID [1] 297483 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes mellitus 311675 0
Condition category
Condition code
Metabolic and Endocrine 310299 310299 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following an overnight fast, each subject will be studied on four occasions, separated by at least 7 days, in a double-blind, randomised fashion.

On each study day, a customised multi-lumen silicone catheter will be inserted through an anaesthetised nostril and allowed to pass into the small intestine by peristalsis. The catheter will be positioned with the small intestinal infusion port located 50 cm below to the pylorus (in the jejunum), with an inflatable self-contained balloon (5 cm in length, with a maximum volume of 100 mL) situated 30 cm below the pylorus, that can be inflated as a barrier between the duodenum and the jejunum, and an aspiration channel 25 cm distal to the pylorus (to be used to collect endogenous bile and other proximal gut secretions during the study period). 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).
Once the intraluminal catheter is correctly positioned, one of the following 4 treatments will be administered by a medically qualified investigator:
(i) exclusion of endogenous bile + jejunal 0.9% saline and placebo,
(ii) exclusion of endogenous bile + jejunal 0.9% saline and metformin (1 g)
(iii) inclusion of endogenous bile + jejunal 0.9% saline and metformin (1 g)
(iv) inclusion of endogenous bile + jejunal taurocholic acid (TCA, 4g) and metformin (1 g).
At t=-6 min, metformin (1 g) dissolved in water to a volume of 50 mL or placebo (sodium chloride) will be given via intrajejunal infusion over 5 min. Intrajejunal infusion of either TCA (4 g TCA dissolved in 240 mL 0.9% saline), or 0.9% saline, will be commenced at the rate of 240 mL/hour for 30min (t=-30-0min), and reduced to the rate of 60 mL/hour for 120min (t=0-120min). At t=0min, subjects will also receive a small intestinal glucose infusion (60 g glucose dissolved in water to a total volume of 240 mL, infused over 120 minutes; i.e. 2 mL/min, and 2 kcal/min). At the end of the intrajejunal infusion (ie. at t = 120 min), the catheter will be removed.
Intervention code [1] 313731 0
Treatment: Drugs
Comparator / control treatment
Intrajejunal infusion of 0.9% saline (vs. TCA);
1g Placebo (vs. 1g metformin).
Control group
Placebo

Outcomes
Primary outcome [1] 319188 0
the difference in the iAUC for plasma glucose
Timepoint [1] 319188 0
t= -60, -30, 0, 30, 60, 90, 120, 150, 180 and 240 min, where t = -60 min, metformin or placebo is given; t = -30 min is when intrajejunal TCA or 0.9% saline infusion starts; t = 0 min is when small intestinal glucose infusion starts.
Secondary outcome [1] 367235 0
The Difference in iAUC for plasma GLP-1
Timepoint [1] 367235 0
t= -60, -30, 0, 30, 60, 90, 120, 150, 180 and 240 min, where t = -60 min, metformin or placebo is given; t = -30 min is when intrajejunal TCA or 0.9% saline infusion starts; t = 0 min is when small intestinal glucose infusion starts.
Secondary outcome [2] 367236 0
The differences in iAUC for plasma insulin
Timepoint [2] 367236 0
t= -60, -30, 0, 30, 60, 90, 120, 150, 180 and 240 min, where t = -60 min, metformin or placebo is given; t = -30 min is when intrajejunal TCA or 0.9% saline infusion starts; t = 0 min is when small intestinal glucose infusion starts.
Secondary outcome [3] 367238 0
The differences in iAUC for plasma glucagon
Timepoint [3] 367238 0
t= -60, -30, 0, 30, 60, 90, 120, 150, 180 and 240 min, where t = -60 min, metformin or placebo is given; t = -30 min is when intrajejunal TCA or 0.9% saline infusion starts; t = 0 min is when small intestinal glucose infusion starts.
Secondary outcome [4] 367239 0
The difference in iAUC for plasma total bile acids
Timepoint [4] 367239 0
t= -60, -30, 0, 30, 60, 90, 120, 150, 180 and 240 min, where t = -60 min, metformin or placebo is given; t = -30 min is when intrajejunal TCA or 0.9% saline infusion starts; t = 0 min is when small intestinal glucose infusion starts.

Eligibility
Key inclusion criteria
*Type 2 diabetes (World Health Organisation (WHO) criteria), managed by diet only
*Body mass index (BMI) from 25 to 35 kg/m2
*Males and females, aged from 18 to 75 years
*Glycated haemoglobin (HbA1c) equal to 8.5%
*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
75 Years
Sex
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 (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 < 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)
Sealed Opaque envelops
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 our previous study 16 participants will provide at least 80% power to detect a difference of 180 mmol/L*min in the incremental area under the curve (iAUC 0-240min) for plasma glucose with metformin between exclusion and inclusion of endogenous bile acids, and between supplementation and “no supplementation” of exogenous bile acids. Significance is set at a = 0.016 to allow for corrections of post hoc comparisons between the aforementioned 3 comparative conditions on glucose lowering by metformin. 20 participants will be recruited to allow for dropouts.
Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. repeated measures ANOVA).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/03/2019
Actual
3/04/2019
Date of last participant enrolment
Anticipated
Actual
4/02/2020
Date of last data collection
Anticipated
Actual
11/03/2020
Sample size
Target
16
Accrual to date
Final
19
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 302050 0
Charities/Societies/Foundations
Name [1] 302050 0
Diabetes Australia
Country [1] 302050 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Level 5 Adelaide Health and Medical Sciences (AHMS) Building,
North Terrace
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 301861 0
None
Name [1] 301861 0
Address [1] 301861 0
Country [1] 301861 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302732 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 302732 0
Ethics committee country [1] 302732 0
Australia
Date submitted for ethics approval [1] 302732 0
05/11/2018
Approval date [1] 302732 0
13/02/2019
Ethics approval number [1] 302732 0
R20181104

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

Contacts
Principal investigator
Name 91198 0
Dr Tongzhi Wu
Address 91198 0
Adelaide Medical School, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91198 0
Australia
Phone 91198 0
+61 8 8313 6535
Fax 91198 0
Email 91198 0
[email protected]
Contact person for public queries
Name 91199 0
Tongzhi Wu
Address 91199 0
Adelaide Medical School, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91199 0
Australia
Phone 91199 0
+61 8 8313 6535
Fax 91199 0
Email 91199 0
[email protected]
Contact person for scientific queries
Name 91200 0
Tongzhi Wu
Address 91200 0
Adelaide Medical School, Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace, Adelaide, SA 5000
Country 91200 0
Australia
Phone 91200 0
+61 8 8313 6535
Fax 91200 0
Email 91200 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.