The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12618000862246
Ethics application status
Approved
Date submitted
18/05/2018
Date registered
22/05/2018
Date last updated
22/05/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Do low-calorie sweeteners influence intestinal glucose absorption in patients with type 2 diabetes?
Scientific title
A randomised, double-blind, placebo-controlled trial to determine whether diet supplementation with low-calorie sweeteners alters the rate of intestinal glucose absorption in patients with type 2 diabetes
Secondary ID [1] 294913 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 307873 0
Condition category
Condition code
Metabolic and Endocrine 306922 306922 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients with Type 2 Diabetes Mellitus will be screened then undergo 2 study day visits in a randomised, double-blinded manner. Study day 1 will occur prior to diet supplementation, with study day 2 immediately following 2 weeks of diet supplementation with placebo capsules or capsules containing a combination of low-calorie sweeteners (sucralose, 92 mg, acesulfame K, 52 mg). Single capsules will be consumed immediately prior to meals, three times daily. Adherence to intervention will be monitored by capsule return and patient diary.

On each study day, fasted unsedated subjects will have an intravenous cannula inserted into a forearm vein in one arm for blood sampling and a small diameter (5.3 mm) video endoscope placed in position in the second part of the duodenum via an anaesthetised nostril. Five mucosal biopsies will be collected via endoscope forceps, then an intraduodenal glucose infusion commenced for 30 min via the endoscope channel (30 g glucose, together with 3 g of the non-metabolisable glucose analogue 3-O-methy-glucose (3-OMG) dissolved in water to a total volume of 150 mL, infused at 5 mL/min; 4 kcal/min). An additional 5 biopsies will be collected post-infusion; bloods will be collected regularly over 2 hours.
Intervention code [1] 301226 0
Treatment: Other
Comparator / control treatment
Adherence to placebo will be monitored by capsule return and patient diary.
Control group
Placebo

Outcomes
Primary outcome [1] 305907 0
Proportional increase in the incremental area under the curve (iAUC), peak and/or time-to-peak for serum 3-OMG levels (absorption) for sweetener vs. placebo supplementation during intraduodenal glucose infusion
Timepoint [1] 305907 0
T = -10, 0, 10, 20, 30, 40, 50, 60, 90 and 120 min (primary endpoint).
Primary outcome [2] 305952 0
Proportional increase in the incremental area under the curve (iAUC) peak and/or time-to-peak for blood glucose for sweetener vs. placebo supplementation during intraduodenal glucose infusion.
Timepoint [2] 305952 0
T = -10, 0, 10, 20, 30, 40, 50, 60, 90 and 120 min (primary endpoint).
Secondary outcome [1] 347000 0
Composite outcome of proportional increase in the iAUC, peak and/or time-to-peak for plasma gut hormone levels for sweetener vs. placebo supplementation during intraduodenal glucose infusion
Timepoint [1] 347000 0
T = -10, 0, 10, 20, 30, 40, 50, 60, 90 and 120 min (primary endpoint).
Secondary outcome [2] 347001 0
Composite outcome of changes in baseline or post-infusion expression of transcript (RNA) and/or protein for glucose sensing and transport/uptake pathway molecules in mucosal biopsies
Timepoint [2] 347001 0
T = 0 and 30 min (primary endpoint).
Secondary outcome [3] 347002 0
Composite identification of glucose sensing, signalling and transport/uptake pathway molecules in functionally activated (glucose-responsive) cells within mucosal biopsies
Timepoint [3] 347002 0
T = 30 min
Secondary outcome [4] 347003 0
Exploratory changes in microbiome assessed by shotgun sequencing. Taxonomic and functional microbiome characteristics determined using MetaPhlAn2 and HUMAnN2 abundance.
Timepoint [4] 347003 0
Stool samples will be collected from study participant at 0800 on each study day morning, prior to commencement of endoscopic studies.

Eligibility
Key inclusion criteria
Volunteers with Type 2 Diabetes Mellitus (American Diabetes Association criteria) managed by diet alone or metformin. In patients treated with metformin, this drug will be withheld for 48 h prior to each study visit, since it has the capacity to stimulate GLP-1 secretion
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) Significant illness, other than type 2 diabetes, including impairment to cardiovascular or respiratory function that limits a participant’s activity and represents a risk to undertaking endoscopy safely.
ii) 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)
iii) 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.
iv) 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)
v) Significant history of migraine
vi) 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))
vii) Participants medicated with anti-diabetics other than metformin
viii) Participants unable to self-monitor blood glucose levels
ix) Volunteers with body mass index less than 20 kg/m2
x) Donation of blood within the previous 3 months
xi) Participation in any other research studies within the previous 3 months
xii) Participants medicated with opiates, anticholinergics, levodopa, clonidine, nitrates, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, or erythromycin
xiii) Participants with known coagulopathy, or treated with any antiplatelet or anticoagulant medication
xiv) Presence of mucosal abnormalities at endoscopy
xv) Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes per day
xvi) Female patients not using appropriate contraceptive method (ie oral contraceptive pill, diaphragm, DepoProvera hormonal contraceptive injection, intrauterine device (IUD), Norplant method)
xvii) Vegetarian, lactation, or pregnancy (verified by urine testing in women of reproductive age; in these participants, 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)
Allocation will involve contacting the holder of the allocation schedule who was off-site at a central administration site.
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 size is based on variance in the primary endpoint of glucose absorption (plasma 3-OMG) in healthy subjects in ACTRN12615000866505 . This design will provide 80% power (at a=0.05) to detect a 30% change in plasma 3-OMG between placebo and AS groups, based on a priori effect size (1.06) and standard deviation (placebo ±118 µmol/L, AS ±94 µmol/L) and includes an anticipated drop out of 15%.

Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. repeated measures ANOVA), with appropriate post-hoc analyses. Relationships between variables will be assessed by linear regression analysis by Pearson correlation coefficient (r). Blood glucose, gut hormone, and serum 3-OMG incremental area-under-the-curve will be compared using the trapezoidal rule and one-factor ANOVA; the null hypothesis will be rejected at the 0.05 significance. Data will be recorded for expression/transcript levels (relative, absolute) and compared between placebo and AS supplemented participants, and between baseline and post-infusion/30 min. Taxonomic and functional microbiome characteristics will be determined using MetaPhlAn2 and HUMAnN2 abundance.

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
Recruitment hospital [1] 10919 0
The Royal Adelaide Hospital - Adelaide
Recruitment postcode(s) [1] 22681 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 299495 0
Charities/Societies/Foundations
Name [1] 299495 0
Diabetes Australia
Address [1] 299495 0
Level 1, 101 Northbourne Ave
Turner ACT 2612
Country [1] 299495 0
Australia
Funding source category [2] 299507 0
Charities/Societies/Foundations
Name [2] 299507 0
The Hospital Research Foundation
Address [2] 299507 0
60 Woodville Road
Woodville, SA 5011
Country [2] 299507 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Diabetes Australia
Address
Level 1, 101 Northbourne Ave
Turner ACT 2612
Country
Australia
Secondary sponsor category [1] 298798 0
Charities/Societies/Foundations
Name [1] 298798 0
The Hospital Research Foundation
Address [1] 298798 0
60 Woodville Road
Woodville, SA 5011
Country [1] 298798 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300399 0
Central Adelaide Local Health Network Human Research Ethics Committee
Ethics committee address [1] 300399 0
Level 3, Royal Adelaide Hospital
Port Road
ADELAIDE SA 5000
Ethics committee country [1] 300399 0
Australia
Date submitted for ethics approval [1] 300399 0
23/02/2018
Approval date [1] 300399 0
08/05/2018
Ethics approval number [1] 300399 0
HREC/18/CALHN/165 (Reference R20180316)

Summary
Brief summary
Despite increasing use of low calorie sweeteners (LCS) in western diets, and an association between regular, heavy consumption of LCS containing beverages and an increased risk of developing Type 2 Diabetes Mellitus (T2DM), it has only been recently established by our group that LCS supplementation impairs glycaemic control in healthy subjects ACTRN12615000866505. This occurs via augmented intestinal glucose uptake and is likely to involve negative changes in gut microbiota that impair host control of glycaemia.

Patients with T2DM are intuitively likely to be at higher risk of these changes due to higher consumption of LCS, defective control of intestinal sweet taste sensors, and augmented glucose uptake, but whether this is the case, and the degree of increased risk, is yet to be determined.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83534 0
A/Prof Richard L Young
Address 83534 0
Adelaide Medical School, The University of Adelaide
South Australian Health & Medical Research Institute
Nutrition & Metabolism
North Terrace, Adelaide SA 5000
Country 83534 0
Australia
Phone 83534 0
+61 8 8128 4845
Fax 83534 0
Email 83534 0
richard.young@adelaide.edu.au
Contact person for public queries
Name 83535 0
A/Prof Richard L Young
Address 83535 0
Adelaide Medical School, The University of Adelaide
South Australian Health & Medical Research Institute
Nutrition & Metabolism
North Terrace, Adelaide SA 5000
Country 83535 0
Australia
Phone 83535 0
+61 8 8128 4845
Fax 83535 0
Email 83535 0
richard.young@adelaide.edu.au
Contact person for scientific queries
Name 83536 0
A/Prof Richard L Young
Address 83536 0
Adelaide Medical School, The University of Adelaide
South Australian Health & Medical Research Institute
Nutrition & Metabolism
North Terrace, Adelaide SA 5000
Country 83536 0
Australia
Phone 83536 0
+61 8 8128 4845
Fax 83536 0
Email 83536 0
richard.young@adelaide.edu.au

No information has been provided regarding IPD availability
Summary results
No Results