ANZCTR - Registration

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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]

Nil

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

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]

Treatment: Drugs

Comparator / control treatment

placebo (cellulose)

Control group

Placebo

Outcomes

Primary outcome [1]

The difference in the iAUC0-180min for plasma total GLP-1 between colesevelam and placebo treatments.

Timepoint [1]

t = 0, 30, 60, 90, 120, 150 and 180 min on day 0 and 15 of each treatment period.

Secondary outcome [1]

The differences in iAUC0-180min for plasma glucose between colesevelam and placebo treatments.

Timepoint [1]