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Trial registered on ANZCTR


Registration number
ACTRN12623000099628
Ethics application status
Approved
Date submitted
19/01/2023
Date registered
27/01/2023
Date last updated
27/01/2023
Date data sharing statement initially provided
27/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Stratifying low-calorie sweeteners for type 2 diabetes risk (“SWEET n SOUR”).
Scientific title
Stratifying low-calorie sweeteners for type 2 diabetes risk in healthy humans.
Secondary ID [1] 308796 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Obesity 328746 0
Type 2 diabetes 328747 0
Condition category
Condition code
Metabolic and Endocrine 325749 325749 0 0
Diabetes
Diet and Nutrition 325750 325750 0 0
Obesity

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
At the screen visit, investigators will explain the study protocol and answer any questions the volunteers may have about what is involved, before the volunteers provide written, informed consent. An intravenous cannula will be inserted and 10 mL fasting venous blood will be collected for blood picture, iron studies, HbA1c, glucose, and liver and kidney function. An oral glucose tolerance test will be performed (75g glucose in 300 mL with addition of 150mg 13C-acetate) with 5mL blood collection at 30, 60, 120, and 180 min for measurement of plasma glucose concentrations. Breath samples will also be collected every 15 min to measure baseline gastric emptying. A urine pregnancy test will be performed in female participants during the screening and prior to each study visit.

Volunteers who pass the screening visit will be randomised in a schedule determined by the Investigational Drugs Pharmacy, RAH, in a double-blind, parallel design, to one of 6 intervention groups (35 participants per group), which will receive the following supplements (each of equivalent sweetness other than placebo) in 3 divided doses to be taken orally in gelatin capsules with each meal for 4 weeks:
(i) acesulfame potassium (Ace-K) (total dose 420mg daily or 140mg three times per day),
(ii) aspartame (420mg daily or 140mg three times per day),
(iii) saccharin (168mg daily or 56mg three times per day),
(iv) stevia (rebaudioside A) (279mg daily or 93mg three times per day)
(v) sucralose (141mg daily or 47mg three times per day), or
(vi) placebo (cellulose only)

The contents of each capsule will be made up to 140mg by the addition of cellulose to the specified dose of each LCS. Compliance with taking capsules will be reinforced by daily mobile phone messages, weekly telephone calls and emails, and evaluated by counting the numbers of capsules remaining on the final study visit.

Each participant will attend for two tube studies, immediately before and at the end of the 4-week intervention. Participants will complete a 3-day diet diary prior to each study day to document their energy, macronutrient and LCS intake. Late on the day preceding each study visit, or on the morning of the visit, subjects will be asked to collect two stool samples, one in a low head-space tube for future microbial transplant, stored at 4 degrees, and one in a custom tube designed for collection point homogenisation and stabilisation at ambient temperature (Norgen tube, for metagenomic assessment). We will provide non-allergenic gloves, a cooler box and ice pack for transport of the former, and will provide non-allergenic gloves and written instructions on proper collection technique for the latter.

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 (or vegetarian lasagne for participants who are vegetarians)) to consume with water. Following this meal, participants will be asked to fast from solids and liquids (water may be consumed until 10 pm) 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.

On each tube study day, the participant’s body weight will be recorded, and 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 duodenum by peristalsis. The catheter will be positioned with the infusion port located 12 cm below to the pylorus (in the duodenum). 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, an intravenous cannula will be placed subcutaneously in the left forearm and filled with sterile saline as a reference electrode. An intravenous cannula will be placed into a forearm vein for blood sampling.

After the correct positioning of the intraduodenal catheter, the participant will be asked to empty his or her bladder. A 150 mL solution containing 30g glucose together with 3g of the glucose absorption marker 3-O-methyl glucose, 3-OMG) will then be infused intraduodenally at 5 mL/min (4 kcal/min) from t = 0 to 30 min, after which the intraduodenal catheter will be removed. Blood will be sampled from the IV cannula, with the arm kept warm with a heat pad, at t = -5, 10, 20, 30, 40, 50, 60, 90, and 120 min (25 mL per time point, total 225 mL per study day). Gastrointestinal symptoms will be monitored using 100mm visual analog scales (VAS) at the same intervals. Plasma will be separated and stored for subsequent measurement of glucose, 3-OMG, insulin, GLP-1, and GIP concentrations. Urine will also be collected at t = 60 and 120 min for measurement of glucose and 3-OMG concentrations. At t = 120 min, a meal will be provided and the participant will be allowed to leave the facility once blood glucose concentrations are stable.

Subjects will also attend the facility 3 weeks into the intervention after an overnight fast, for a follow-up oral glucose tolerance test (75g glucose in 300 mL plus 150mg 13C-acetate), with breath testing for measurement of gastric emptying as at the screening visit, to ascertain whether LCS exposure can modify intestinal feedback so as to accelerate gastric emptying of glucose.
Intervention code [1] 325246 0
Treatment: Other
Comparator / control treatment
Placebo capsule (cellulose)
Control group
Placebo

Outcomes
Primary outcome [1] 333598 0
Differences in blood glucose (iAUC0-120min) between each treatment and placebo.
Timepoint [1] 333598 0
t = -5, 10, 20, 40, 50, 60, 90 and 120 min, where t = 0 is when intraduodenal glucose infusion starts on visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [1] 417691 0
Differences in glucose absorption (iAUC0-120min for serum 3-O-methyl glucose) between each treatment and placebo.
Timepoint [1] 417691 0
t = -5, 10, 20, 40, 50, 60, 90 and 120 min, where t = 0 is when intraduodenal glucose infusion starts on visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [2] 417692 0
Differences in plasma insulin (iAUC0-120min) between each treatment and placebo.
Timepoint [2] 417692 0
t = -5, 10, 20, 40, 50, 60, 90 and 120 min, where t = 0 is when intraduodenal glucose infusion starts on visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [3] 417693 0
Differences in plasma GLP-1 (iAUC0-120min) between each treatment and placebo.
Timepoint [3] 417693 0
t = -5, 10, 20, 40, 50, 60, 90 and 120 min, where t = 0 is when intraduodenal glucose infusion starts on visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [4] 417694 0
Differences in plasma GIP (iAUC0-120min) between each treatment and placebo.
Timepoint [4] 417694 0
t = -5, 10, 20, 40, 50, 60, 90 and 120 min, where t = 0 is when intraduodenal glucose infusion starts on visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [5] 417695 0
Differences in urinary glucose excretion (urine glucose level * urine volume) between each treatment and placebo.
Timepoint [5] 417695 0
Visit 1 (baseline) and visit 3 (week 4) study days.
Secondary outcome [6] 417699 0
Differences in blood glucose levels between each treatment and placebo.
Timepoint [6] 417699 0
t = 0, 30, 60, 90, 120 and 180 where t = 0 is when 75g oral glucose drink is given, on screen visit and visit 2 (week 3) study days.
Secondary outcome [7] 417701 0
Differences in the rate of gastric emptying (measured by breath test) of glucose between each treatment and placebo.
Timepoint [7] 417701 0
Screen visit and visit 2 (week 3) study days.
Secondary outcome [8] 417703 0
Differences in gut microbial taxonomy and function in the stool samples (using MetaPhlAn3 and HUMAnN3 annotations based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database) between each treatment and placebo.
Timepoint [8] 417703 0
Screen visit and visit 3 (week 4) study days.
Secondary outcome [9] 417704 0
Differences in plasma metabolome between each treatment and placebo.
Timepoint [9] 417704 0
Screen visit and visit 3 (week 4) study days.

Eligibility
Key inclusion criteria
- Healthy males and females aged from 18 to 70 years
- Body mass index (BMI) from 18 to 30 kg/m2
- 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
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Habitual use of more than one serve per day of any food or beverage containing a LCS during the past 3 months, ascertained using a LCS frequency questionnaire.
- Use of antibiotics or antifungals within the past 3 months
- Diagnosis of type 1 or 2 diabetes, pre-diabetes (HbA1c above 5.7%, fasting blood glucose above 5.6 mmol/L, or 2h glucose above 7.8 mmol/L on oral glucose tolerance test), or use of any anti-diabetes medication, including metformin
- Phenylketonuria
- Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, prucalopride, or erythromycin)
- Evidence of drug abuse, or consumption of more than 20 g alcohol or 10 cigarettes daily
- History of gastrointestinal disease, including significant upper or lower gastrointestinal symptoms or previous gastrointestinal surgery (other than uncomplicated appendicectomy or cholecystectomy)
- History of any form of heart disease or symptoms of syncope or pre-syncope (including feeling lightheaded or dizzy, feeling unsteady when standing, unexplained falls, fainting, unexplained changes in vision, such as blurring or tunnel vision)
- Other significant illness, including epilepsy or respiratory disease
- Impaired renal or liver function (as assessed by calculated estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73m2 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

Study design
Purpose of the study
Prevention
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
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/03/2023
Actual
Date of last participant enrolment
Anticipated
1/03/2025
Actual
Date of last data collection
Anticipated
1/05/2025
Actual
Sample size
Target
210
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 313012 0
Government body
Name [1] 313012 0
NHMRC
Country [1] 313012 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] 314699 0
None
Name [1] 314699 0
None
Address [1] 314699 0
None
Country [1] 314699 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312275 0
Central Adelaide Local Health Network HREC Human Research Ethics Committee
Ethics committee address [1] 312275 0
Ethics committee country [1] 312275 0
Australia
Date submitted for ethics approval [1] 312275 0
20/11/2022
Approval date [1] 312275 0
19/12/2022
Ethics approval number [1] 312275 0
2022/HRE00302

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

Contacts
Principal investigator
Name 124074 0
Prof Chris Ryaner
Address 124074 0
Adelaide Medical School, the University of Adelaide
Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 124074 0
Australia
Phone 124074 0
+61 8 8313 6693
Fax 124074 0
Email 124074 0
[email protected]
Contact person for public queries
Name 124075 0
Chris Ryaner
Address 124075 0
Adelaide Medical School, the University of Adelaide
Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 124075 0
Australia
Phone 124075 0
+61 8 8313 6693
Fax 124075 0
Email 124075 0
[email protected]
Contact person for scientific queries
Name 124076 0
Chris Ryaner
Address 124076 0
Adelaide Medical School, the University of Adelaide
Level 5 Adelaide Health and Medical Sciences (AHMS) Building, North Terrace,
Adelaide, SA 5000
Country 124076 0
Australia
Phone 124076 0
+61 8 8313 6693
Fax 124076 0
Email 124076 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.