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Trial registered on ANZCTR


Registration number
ACTRN12621000877886
Ethics application status
Approved
Date submitted
2/06/2021
Date registered
7/07/2021
Date last updated
10/05/2023
Date data sharing statement initially provided
7/07/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
More or less? Bile acids and glycaemic control in type 2 diabetes
Scientific title
More or less? The impact of colesevelam on bile acids and glycaemic control in type 2 diabetes
Secondary ID [1] 304384 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 322178 0
Condition category
Condition code
Metabolic and Endocrine 319872 319872 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Following enrolment (within 1-2 weeks), each subject will be randomised to 2 weeks treatment with sachets containing colesevelam (1.875 g twice daily, ie. a total of 3.75 g per day) or placebo (cellulose), in a double-blind, randomised, crossover design facilitated by the Royal Adelaide Hospital Pharmacy. Patients who are on metformin will be asked to withhold this drug from 2 weeks before, until study end (allowing 7 half-lives for tissue ‘wash- out’) to avoid confounding effects on gut hormone secretion. On day 0 and day 15 of each treatment period, subject will attend the laboratory for intrajejunal infusion studies, with at least 2 weeks ‘washout’ period between the two treatment periods. Participants will be contacted by phone at least once a week during the study period to reinforce compliance and check for adverse effects. A faecal sample will be collected before and after each treatment period. Microbiome testing will be conducted using 16S rRNA sequencing to establish which bacteria are present.

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 (other than water) until the following morning, when they will attend the CRF of the AHMS building at 0800h. This will be reinforced by a telephone call from one of the investigators, when any potential adverse events between the study visits will also be sought and documented.

On each study day, 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, and ~10 mL blood will be taken for the measurement of serum 1,5-Anhydroglucitol (1,5-AG) (an established marker of glycaemic control over 2 weeks), triglyceride, cholesterol and lipoprotein levels. Subsequently, 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 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). Inflation of the balloon and aspiration of duodenal content will exclude any potential influence of endogenous bile secretion on the study outcomes, since the presence of TCA in the small intestine may reduce endogenous bile release. 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, a cannula will be placed subcutaneously in the left forearm and filled with sterile saline as a reference electrode. After correct positioning of the catheter, the balloon will be slowly inflated with water (~15 mL) until the subject reports a sensation of pressure without discomfort. An intra-balloon pressure of at least 20 mmHg (a pressure known to be sufficient to achieve full occlusion) will be maintained by continuous monitoring with a pressure gauge throughout the study. The aspiration channel will be connected to negative pressure drainage to allow constant aspiration of secretions from the duodenum, which will be stored for the assessment of overall bile output.

Once the intraluminal catheter is correctly positioned, intrajejunal TCA infusion (2 g dissolved in 100 mL 0.9% saline; pH adjusted to 7) will be administrated over 30 min (t = 0 – 30 min) and then followed by another intrajejunal TCA (2 g dissolved in 100 mL 0.9% saline; pH adjusted to 7) + glucose infusion (60 g glucose dissolved in water to a total volume of 240 mL, infused over 90 minutes; i.e. 2 mL/min, and 2 kcal/min) for 90 min (t = 30 – 120 min). After the intrajejunal infusion (t = 120 min), participants will be monitored for 60 min before the catheter is removed (t = 180 min). “Arterialised” venous blood (~10 mL) will be sampled at t= 0, 30, 60, 90, 120, 150 and 180 min for the subsequent measurement. Gastrointestinal symptoms will be monitored using VAS at the same intervals. After a final blood sample is collected (t = 180 min), participant will be offered a light lunch, and once their blood glucose concentration is stabilised above 5 mmol/L, they will be free to leave the laboratory.
Intervention code [1] 320748 0
Treatment: Drugs
Comparator / control treatment
placebo (cellulose)
Control group
Placebo

Outcomes
Primary outcome [1] 327739 0
The difference in the iAUC0-180min for plasma total GLP-1 between colesevelam and placebo treatments.
Timepoint [1] 327739 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period.
Secondary outcome [1] 396385 0
The differences in iAUC0-180min for plasma glucose between colesevelam and placebo treatments.
Timepoint [1] 396385 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period
Secondary outcome [2] 396386 0
The differences in iAUC0-180min for plasma insulin between colesevelam and placebo treatments.
Timepoint [2] 396386 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period
Secondary outcome [3] 396387 0
The differences in iAUC0-180min for plasma C-peptide between colesevelam and placebo treatments.
Timepoint [3] 396387 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period
Secondary outcome [4] 396388 0
The differences in iAUC0-180min for plasma glucagon between colesevelam and placebo treatments.
Timepoint [4] 396388 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period
Secondary outcome [5] 396389 0
The differences in iAUC0-180min for plasma FGF19 between colesevelam and placebo treatments.
Timepoint [5] 396389 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period
Secondary outcome [6] 396390 0
The changes in serum 1,5-AG between colesevelam and placebo treatments.
Timepoint [6] 396390 0
Visit 1 (baseline 1), visit 2 (treatment 1), visit 3 (baseline 2) and visit 4 (treatment 2)
Secondary outcome [7] 396391 0
The changes in serum cholesterol between colesevelam and placebo treatments
Timepoint [7] 396391 0
Visit 1 (baseline 1), visit 2 (treatment 1), visit 3 (baseline 2) and visit 4 (treatment 2)
Secondary outcome [8] 396392 0
The changes in lipoprotein levels between colesevelam and placebo treatments
Timepoint [8] 396392 0
Visit 1 (baseline 1), visit 2 (treatment 1), visit 3 (baseline 2) and visit 4 (treatment 2)
Secondary outcome [9] 396393 0
The changes in gut microbiome composition between colesevelam and placebo treatments.
Timepoint [9] 396393 0
Visit 1 (baseline 1), visit 2 (treatment 1), visit 3 (baseline 2) and visit 4 (treatment 2)
Secondary outcome [10] 397310 0
The changes in serum triglyceride between colesevelam and placebo treatments.
Timepoint [10] 397310 0
Visit 1 (baseline 1), visit 2 (treatment 1), visit 3 (baseline 2) and visit 4 (treatment 2)
Secondary outcome [11] 397311 0
The differences in iAUC0-180min for plasma PYY between colesevelam and placebo treatments.
Timepoint [11] 397311 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period.
Secondary outcome [12] 397794 0
The differences in gastrointestinal symptom assessed by visual analogue scales between colesevelam and placebo treatments.
Timepoint [12] 397794 0
t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period.

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
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 less than 90 mL/min or abnormal liver function tests (more 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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation 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
Based on data derived from previous studies, 20 T2D subjects will provide > 80% power (a = 0.05) to detect a ~25% difference in change in the incremental area under the curve between t=0-180min (iAUC0-180min) for plasma total GLP-1 between colesevelam and placebo in a crossover design. 25 T2D subjects will be recruited to allow for drop-outs.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
2/08/2021
Actual
6/12/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
25
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 308754 0
Government body
Name [1] 308754 0
Diabetes Australia
Country [1] 308754 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] 309656 0
None
Name [1] 309656 0
Nil
Address [1] 309656 0
Nil
Country [1] 309656 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 308672 0
Central Adelaide Local Health Network HREC Human Research Ethics Committee
Ethics committee address [1] 308672 0
Ethics committee country [1] 308672 0
Australia
Date submitted for ethics approval [1] 308672 0
28/03/2021
Approval date [1] 308672 0
27/05/2021
Ethics approval number [1] 308672 0
2021/HRE00125

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

Contacts
Principal investigator
Name 111506 0
A/Prof Tongzhi Wu
Address 111506 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111506 0
Australia
Phone 111506 0
+61 8 8313 6535
Fax 111506 0
Email 111506 0
tongzhi.wu@adelaide.edu.au
Contact person for public queries
Name 111507 0
Tongzhi Wu
Address 111507 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111507 0
Australia
Phone 111507 0
+61 8 8313 6535
Fax 111507 0
Email 111507 0
tongzhi.wu@adelaide.edu.au
Contact person for scientific queries
Name 111508 0
Tongzhi Wu
Address 111508 0
Adelaide Medical School, the University of Adelaide
Level 6 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 111508 0
Australia
Phone 111508 0
+61 8 8313 6535
Fax 111508 0
Email 111508 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 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.