Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12615000948594
Ethics application status
Approved
Date submitted
23/07/2015
Date registered
10/09/2015
Date last updated
28/06/2022
Date data sharing statement initially provided
21/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Does blocking intestinal sweet taste sensing decrease glucose absorption in patients with type 2 diabetes?
Scientific title
A blinded placebo-controlled trial to determine whether inhibiting intestinal detection of sweet taste reduces intestinal glucose uptake in healthy subjects and patients with type 2 diabetes
Secondary ID [1] 287139 0
Royal Adelaide Hospital Protocol Number: 150606
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 Diabetes Mellitus 295687 0
Condition category
Condition code
Metabolic and Endocrine 295964 295964 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Healthy subjects and patients with type 2 diabetes will be screened for eligibility then undergo 2 study day visits, separated by at least 2 weeks, in a randomised, double-blinded manner.

All subjects will receive a standardised evening meal prior to the study day, then fast until the following morning, with water allowed after the meal until 10 pm. Patients treated by oral metformin will be instructed to withhold any dose due the evening for 2 days (48 hours) prior to the study visit, and to defer their morning dose until the meal at the end of the study.

On each study day, fasted unsedated subjects will have an intravenous cannula inserted into forearm veins for blood sampling and for infusion of glucose or insulin. Insulin (0.2 IU/mL) or 25% glucose will be infused intravenously at a rate adjusted to achieve hyperglycaemia (12 mmol/L) throughout the study period. Once stably clamped, a small diameter (5.3 mm) video endoscope will be placed in position in the second part of the duodenum via an anaesthetised nostril. Five mucosal biopsies will be collected via endoscope forceps, then the endoscope will be withdrawn. A thin intraduodenal catheter (3.5 mm) will be inserted via an anaesthetised nostril into the second part of the duodenum; positioning will be maintained by continuous measurement of the transmucosal potential difference between antrum and duodenum. An automated blood pressure cuff will be placed around the arm for measurement of blood pressure and heart rate throughout the study period.

Subjects will be randomised to the order of infusions containing the sweetness inhibitor lactisole, or control (no lactisole), on alternative study days.

On a control study day subjects will receive a preload infusion of 0.9% saline (2 mL/min) via the intraduodenal catheter over 30 min. At 30 min (T = 0) a glucose solution will be infused for 120 min (90 g glucose dissolved in water to a volume of 240 mL, 2 mL/min; 3 kcal/min). At T = 120 min a glucose solution containing the non-metabolisable glucose analogue 3-O-methyl glucose (3-OMG, to assess glucose absorption) will be infused via the intraduodenal catheter for 60 min (45 g glucose and 2.4 g of 3-OMG dissolved in water to a volume of 120 mL, 2 mL/min; 3 kcal/min).

On a lactisole study day subjects will receive a preload infusion of 450 ppm lactisole in 0.9% saline (27 mg dissolved in 60 mL; 2 mL/min) via the intraduodenal catheter over 30 min. At 30 min (T = 0) a glucose solution containing 450 ppm lactisole will be infused for 120 min (90 g glucose and 108 mg lactisole dissolved in water to a volume of 240 mL, 2 mL/min; 3 kcal/min). At T = 120 min a glucose solution containing 450 ppm lactisole and the non-metabolisable glucose analogue 3-O-methyl glucose (3-OMG, to assess glucose absorption) will be infused via the intraduodenal catheter for 60 min (45 g glucose, 54 mg lactisole and 2.4 g of 3-OMG dissolved in water to a volume of 120 mL, 2 mL/min; 3 kcal/min).

At the end of glucose infusions (T = 180 min), the intraduodenal catheter will be removed and the endoscope inserted again to collect 5 more duodenal biopsies; bloods will be collected regularly over the 5 hour study. A log of infusion administration will be kept to monitor protocol adherence.
Intervention code [1] 292401 0
Treatment: Other
Comparator / control treatment
On a control study day subjects will receive a preload infusion of 0.9% saline (2 mL/min) via the intraduodenal catheter over 30 min. At 30 min (T = 0) a glucose solution will be infused for 120 min (90 g glucose dissolved in water to a volume of 240 mL, 2 mL/min; 3 kcal/min). At T = 120 min a glucose solution containing the non-metabolisable glucose analogue 3-O-methyl glucose (3-OMG, to assess glucose absorption) will be infused via the intraduodenal catheter for 60 min (45 g glucose and 2.4 g of 3-OMG dissolved in water to a volume of 120 mL, 2 mL/min; 3 kcal/min).
Control group
Placebo

Outcomes
Primary outcome [1] 295647 0
Proportional differences in the incremental area under the curve, peak and/or time-to-peak for serum 3-OMG levels (absorption) for lactisole vs. placebo during intraduodenal glucose infusion; comparison between healthy subjects vs. type 2 patients (composite outcome)
Timepoint [1] 295647 0
T = -10, 0 (commencement of intraduodenal glucose infusion), 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270 and 300 min
Secondary outcome [1] 316087 0
Proportional differences in the incremental area under the curve, peak and/or time-to-peak for plasma incretin hormones for lactisole vs. placebo during intraduodenal glucose infusion; comparison between healthy subjects vs. type 2 patients (composite outcome)
Timepoint [1] 316087 0
T = -10, 0 (commencement of intraduodenal glucose infusion), 10, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270 and 300 min
Secondary outcome [2] 316088 0
Changes in baseline or post-infusion expression of transcript (RNA) and/or protein for glucose sensing and transport/uptake pathway molecules in mucosal biopsies (composite outcome).

Targets assessed include sweet taste receptors (T1R2, T1R3), G-protein (alpha-gustducin), ion channels (Kir6.2, TRPM5) and glucose transporters (SGLT-1, GLUT2).
Timepoint [2] 316088 0
T = -2 (immediately prior to commencement of intraduodenal glucose infusion at T = 0) and 180 min
Secondary outcome [3] 316089 0
Identification of glucose sensing, signalling and transport/uptake pathway molecules in functionally activated (glucose-responsive) cells within mucosal biopsies (composite outcome).

Targets assessed include sweet taste receptors (T1R2, T1R3), G-protein (alpha-gustducin), ion channels (Kir6.2, TRPM5), glucose transporters (SGLT-1, GLUT2) and cell markers (5-HT, GLP-1, GIP).
Timepoint [3] 316089 0
T = 180 min, where T=0 is the start of glucose infusion

Eligibility
Key inclusion criteria
(Healthy) Nondiabetic, healthy volunteers matched as closely as possible for sex and body mass index; body mass index 20-30 kg/m2; HbA1c less than or equal to 7.0%

(Type 2 Diabetic) Volunteers with type 2 diabetes (World Health Organisation criteria) managed by diet alone or metformin; body mass index >20 kg/m2; HbA1c >7.0%
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusion
(Healthy) Significant illness including impairment to cardiovascular or respiratory function that limits a subject’s activity and therefore would represent a risk to undertaking endoscopy safely (American Society of Anaesthesiologists Grade 3 or more); History of gastrointestinal disease, including significant upper gastrointestinal symptoms (assessed by a validated gastrointestinal symptom questionnaire), pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendectomy or cholecystectomy); Diffuse mucosal disease involving the upper gastrointestinal tract, including Crohn’s disease, coeliac disease, or ischaemic changes, evident either macroscopically or on histopathological examination of mucosal biopsies; Haemoglobin below the lower limit of the normal range (ie. <135g/L for men and 115g/L for women), and ferritin below the lower limit of normal (below 20ng/mL for women and 30ng/mL for men); Significant history of migraine; 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); Body mass index greater than 30 kg/m2 or less than 20 kg/m2; Donation of blood within the previous 3 months; Participation in any other research studies within the previous 3 months; Subjects requiring the use of anticoagulant drugs, antiplatelet agents or NSAIDS; Subjects with known coagulopathy; Presence of mucosal abnormalities at endoscopy; Subjects requiring medication that may influence gastrointestinal function; Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day; Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, DepoProvera hormonal contraceptive injection, intrauterine device (IUD), Norplant method); Vegetarian, lactation or pregnancy (verified by urine testing in women of reproductive age; in these subjects, study will be completed during the follicular phase of the menstrual cycle)

(Type 2 Diabetics) Significant illness, other than type 2 diabetes, including impairment to cardiovascular or respiratory function that limits a subject’s activity and therefore would represent a risk to undertaking endoscopy safely (American Society of Anesthesiologists Grade 3 or more); History of gastrointestinal disease, including significant upper gastrointestinal symptoms (assessed by a validated gastrointestinal symptom questionnaire), pancreatitis, or previous gastrointestinal surgery (other than uncomplicated appendectomy or cholecystectomy); Diffuse mucosal disease involving the upper gastrointestinal tract, including Crohn’s disease, coeliac disease, or ischaemic changes, evident either macroscopically or on histopathological examination of mucosal biopsies; Haemoglobin below the lower limit of the normal range (ie. <135g/L for men and 115g/L for women), and ferritin below the lower limit of normal (below 20ng/mL for women and 30ng/mL for men); Significant history of migraine; 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)); Subjects medicated with anti-diabetics other than metformin; Subjects unable to self-monitor blood glucose levels; Volunteers with body mass index less than 20 kg/m2; Donation of blood within the previous 3 months; Participation in any other research studies within the previous 3 months; Subjects requiring the use of anticoagulant drugs, anti-platelet agents or NSAIDS; Subjects with known coagulopathy; Presence of mucosal abnormalities at endoscopy; Subjects requiring medication that may influence gastrointestinal function; Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day; Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, DepoProvera hormonal contraceptive injection, intrauterine device (IUD), Norplant method); Vegetarian, lactation, or pregnancy (verified by urine testing in women of reproductive age; in these subjects, the study will be completed during the follicular phase of the menstrual cycle)

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)
Potential participants will be screened for medical and diet history, medications and lifestyle eligibility and assessed for blood haemoglobin, ferritin, HbA1c, renal and liver function. Study participants will provide written, informed consent and will be randomised and blinded to allocation of lactisole in the preload and main infusion on both study days.

Allocation to the order of infusion protocol will be concealed by schedule, which will be undertaken and held by pharmacy staff of the Royal Adelaide Hospital; allocation will be blind to staff and subjects involved in this project.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
computer-generated random number table
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample sizes are calculated for alpha=0.05 and beta=0.2 from a priori data on the primary outcome measures. The effect size for glucose absorption, the most variable outcome, is 1.052; subject dropouts are incorporated at 15%. All variables will be assessed using ANOVA, with treatment and time factors. Post hoc tests, adjusted for multiple comparisons, will be performed for significant effects. Relationships between transcript expression and other factors will be compared using Pearson correlation coefficient; area-under-the-curve data will be compared using 2-tailed paired Student’s t-tests.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
14/09/2015
Actual
22/03/2016
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
48
Accrual to date
24
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 291701 0
Government body
Name [1] 291701 0
National Health & Medical Research Council
Country [1] 291701 0
Australia
Primary sponsor type
Hospital
Name
Royal Adelaide Hospital
Address
North Terrace
Adelaide SA 5000
Country
Australia
Secondary sponsor category [1] 290376 0
None
Name [1] 290376 0
Address [1] 290376 0
Country [1] 290376 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293224 0
Royal Adelaide Hospital Human Research Ethics Committee
Ethics committee address [1] 293224 0
Ethics committee country [1] 293224 0
Australia
Date submitted for ethics approval [1] 293224 0
Approval date [1] 293224 0
03/07/2015
Ethics approval number [1] 293224 0
HREC/15/RAH/224, RAH Protocol 150606

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

Contacts
Principal investigator
Name 58974 0
A/Prof Richard L Young
Address 58974 0
Discipline of Medicine, University of Adelaide
Level 3, Eleanor Harrald Building
Royal Adelaide Hospital North Terrace, Adelaide SA 5000
Country 58974 0
Australia
Phone 58974 0
+61 8 82222082
Fax 58974 0
+61 8 82223870
Email 58974 0
[email protected]
Contact person for public queries
Name 58975 0
Richard L Young
Address 58975 0
Discipline of Medicine, University of Adelaide
Level 3, Eleanor Harrald Building
Royal Adelaide Hospital North Terrace, Adelaide SA 5000
Country 58975 0
Australia
Phone 58975 0
+61 8 82222082
Fax 58975 0
+61 8 82223870
Email 58975 0
[email protected]
Contact person for scientific queries
Name 58976 0
Richard L Young
Address 58976 0
Discipline of Medicine, University of Adelaide
Level 3, Eleanor Harrald Building
Royal Adelaide Hospital North Terrace, Adelaide SA 5000
Country 58976 0
Australia
Phone 58976 0
+61 8 82222082
Fax 58976 0
+61 8 82223870
Email 58976 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.