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Trial registered on ANZCTR


Registration number
ACTRN12625000012471p
Ethics application status
Submitted, not yet approved
Date submitted
12/12/2024
Date registered
9/01/2025
Date last updated
9/01/2025
Date data sharing statement initially provided
9/01/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Effects of Renally Excreted low-calorie Sweeteners On URinary gluCose Excretion and whole-body glucose homeostasis: A double-blind, randomised, placebo-controlled Trial in healthy and type 2 diabetes participants (RESOURCE-Trial).
Scientific title
Effects of renally excreted low-calorie sweeteners on urinary glucose excretion and whole-body glucose homeostasis: A double-blind, randomised, placebo-controlled trial in healthy and type 2 diabetes participants
Secondary ID [1] 313550 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 336037 0
Condition category
Condition code
Metabolic and Endocrine 332605 332605 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants who pass the screening will be randomised according to a schedule determined by the Royal Adelaide Hospital Investigational Drugs Pharmacy to one of 3 intervention groups in a double-blind, parallel design. Each group will receive one of the following supplements (doses calculated based on acceptable daily intake (ADI) at 60 kg of body weight) in 3 divided doses to be taken in gelatin capsules with each meal for 2 weeks:

(i) Ace-K (total dose 900 mg daily or 300 mg three times daily),
(ii) sucralose (total dose 300 mg daily or 100 mg three times daily), or
(iii) placebo (cellulose only)

Only the designated pharmacists at the Royal Adelaide Hospital Investigational Drugs Pharmacy will dispense the study compounds. Each capsule will be packaged at the same weight by the addition of cellulose. Compliance with taking capsules will be reinforced by daily mobile phone messages and weekly telephone calls and emails, and will be evaluated by counting the numbers of capsules remaining on the final study visit.

Each participant will attend the Adelaide Health and Medical Science Building Clinical Research Facility] for two hyperglycaemic clamp study visits, immediately before and at the end of the 2-week intervention (Days 0 and 14). Participants will commence their first dose of capsules with the lunch on Day 0 after baseline evaluation, and ingest the last dose of capsules on the morning of Day 14 for post-interventional evaluation. A faecal sample will be collected before the two study days, with subsequent microbiome testing using 16S rRNA sequencing. Participants will also complete a 3-day food diary before commencing the study and each week during the study period, using Research Food Diary (Xyris Software Pty Ltd, Brisbane, QLD, Australia). On the evening preceding each study day (~1900h), participants will consume a standardised evening meal (frozen beef lasagne, McCain Foods Proprietary Ltd, VIC, Australia; 2472kJ) with water. Following this meal, participants will be asked to fast from solids and liquids (water may be consumed until midnight) until the following morning, when they will attend the AHMS CRF at 0800h. This will be reinforced by a telephone call from one of the investigators.

For participants with type 2 diabetes who are taking oral anti-diabetic medication(s), they will be instructed to withhold the doses for ~48h until the end of each study visit. The participant’s body weight will be recorded, and an intravenous cannula will be placed into a vein of each forearm for intravenous dextrose infusion and blood sampling, respectively. Then, a hyperglycaemic clamp will be performed from t = -30 to 120 min (to maintain blood glucose at 10 mmol/L in healthy participants, and 15 mmol/L in participants with type 2 diabetes; these levels of hyperglycaemia have been shown to induce profound urinary glucose excretion in our pilot studies [Protocol No: 2022/HRE00300]). This will be achieved by intravenous administration of an initial bolus of 25% dextrose (volume calculated to elevate blood glucose to the target level from baseline), followed by a 25% dextrose infusion at a rate adjusted according to blood glucose concentrations measured every 5 min using a Yellow Springs Instrument (YSI) analyser. Following an initial 30 min of stabilisation of the hyperglycaemic clamp, participants will be asked to empty their bladder at t = 0 min. Participants will consume 400 mL water every 30 min from t = -30 to 60 min (1600 mL water in total). At the post-intervention visit (Day 14), participants will ingest the final morning dose of the assigned treatment at t = -30 min.

Urine samples will be collected at t = 60 and 120 min. The glucose concentration in the urine will be measured immediately using a YSI analyser. “Arterialised” venous blood will be sampled every 30 min, kept warm with a heat pad, between t = -30 and 120 min for measurement of plasma insulin. Fasting serum creatinine, transaminases and lipids levels will be measured. After the final blood sample is collected, participants will be served a light lunch.

Once the blood concentration has stabilised >4 mmol/L for healthy participants and >5 mmol/L for participants with type 2 diabetes, they will be free to leave the laboratory. The total amount of blood drawn during the study visits will be ~200 mL.
Intervention code [1] 330139 0
Lifestyle
Intervention code [2] 330141 0
Treatment: Other
Intervention code [3] 330140 0
Prevention
Comparator / control treatment
Cellulose capsules
Control group
Placebo

Outcomes
Primary outcome [1] 340121 0
The changes in whole-body glucose homeostasis (reflected by the amount of glucose required to be infused intravenously to maintain the hyperglycaemic clamp) during the treatment period between groups.
Timepoint [1] 340121 0
Day 0 and day 14 post-commencement of supplementation of each treatment group.
Primary outcome [2] 340119 0
The changes in urinary glucose excretion (urine glucose concentration * urine volume) during the treatment period between groups.
Timepoint [2] 340119 0
t = 30 and 120 min, where t = -30 is when glucose clamping starts on day 0 and day 14 post-commencement of supplementation of each group.
Primary outcome [3] 340120 0
The changes in insulin sensitivity during the treatment period between groups.
Timepoint [3] 340120 0
t =0, 30, 60, 90 and 120 min, where t = -30 is when glucose clamping starts on day 0 and day 14 post-commencement of supplementation of each group.
Secondary outcome [1] 442847 0
The changes in gut microbiome before and at the end of each treatment period.
Timepoint [1] 442847 0
On day 0 and day 14 post-commencement of supplementation.
Secondary outcome [2] 442844 0
The changes in plasma insulin levels during the treatment period between groups.
Timepoint [2] 442844 0
t =0, 30, 60, 90 and 120 min, where t = -30 is when glucose clamping starts on day 0 and day 14 post-commencement of supplementation of each group.
Secondary outcome [3] 442846 0
The changes in body weight before and at the end of each treatment period.
Timepoint [3] 442846 0
On day 0 and day 14 post-commencement of supplementation.
Secondary outcome [4] 442845 0
The changes in food intake before and at the end of each treatment period.
Timepoint [4] 442845 0
On day 0 and day 14 post-commencement of supplementation.
Secondary outcome [5] 442843 0
The changes in estimated renal glucose reabsorption during the treatment period between groups.
Timepoint [5] 442843 0
t =0, 30, 60, 90 and 120 min, where t = -30 is when glucose clamping starts on day 0 and day 14 post-commencement of supplementation of each group.

Eligibility
Key inclusion criteria
Participants with type 2 diabetes:
• Type 2 diabetes (American Diabetes Association criteria) managed by diet and/or one or two oral glucose-lowering agents (on stable doses over the last 3 months) except for SGLT2 inhibitors
• Body mass index (BMI) from 20 to 40 kg/m2
• Males and females, aged from 18 to 79 years
• Glycated haemoglobin (HbA1c) from 6.0% to 7.9%
• Body mass index (BMI) from 20 to 40 kg/m2

Healthy participants:
• Healthy males and females aged from 18 to 79 years
• Body mass index (BMI) from 18 to 30 kg/m2
• HbA1c less than 5.7%
• Fasting plasma glucose less than 5.6 mmol/L
Minimum age
18 Years
Maximum age
79 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
• Habitual use of more than one serve of any food or beverage containing a low-calorie (LCS) per day during the past 3 months, ascertained using a LCS frequency questionnaire
• Evidence of drug abuse, consumption of more than 20 g alcohol or 10 cigarettes on a daily basis
• 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)
• History of difficulty passing urine
• Other significant illness, including epilepsy, cardiovascular or respiratory disease
• Impaired renal or liver function (as assessed by calculated creatinine clearance less than 60 mL/min or abnormal liver function tests (> 2 times upper limit of normal range))
• Haemoglobin below the lower limit of the normal range (ie. less than 135 g/L for men and 115 g/L for women), and ferritin below the lower limit of normal (ie. less than 30 ng/mL for men and 20 mg/mL for women)
• Female participants who are pregnant or planning for pregnancy, or are lactating
• Donation of blood within the previous 3 months
• Participation in any other research studies within the previous 3 months
• Inability to give informed consent
• Vegetarians/Vegans

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)
Simple randomisation using a randomisation table created by computer 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
Safety/efficacy
Statistical methods / analysis
Based on our recent observations that an acute dose of Ace-K led to an acute ~50% reduction in urinary glucose excretion after a 50g oral glucose drink in healthy humans, we anticipate that 20 participants (male : female, 1:1) in each intervention arm will provide at least 90% power (a = 0.025 to allow for subgroup comparisons) to detect ~50% difference in the excretion of urinary glucose between interventions. 70 participants will be recruited in each group (health and type 2 diabetes) to allow for drop-outs.
Data will be analysed using standardised, non-parametric or parametric statistical methods where appropriate (e.g. paired student t-test, repeated measures ANOVA).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
3/02/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
140
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 318012 0
Government body
Name [1] 318012 0
Department of Health and Aged Care - Medical Research Future Fund (MRFF)
Country [1] 318012 0
Australia
Primary sponsor type
University
Name
The University of Adelaide
Address
Country
Australia
Secondary sponsor category [1] 320358 0
None
Name [1] 320358 0
N/A
Address [1] 320358 0
Country [1] 320358 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 316672 0
Central Adelaide Local Health Network HREC
Ethics committee address [1] 316672 0
Ethics committee country [1] 316672 0
Australia
Date submitted for ethics approval [1] 316672 0
25/10/2024
Approval date [1] 316672 0
Ethics approval number [1] 316672 0

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

Contacts
Principal investigator
Name 138610 0
A/Prof Tongzhi Wu
Address 138610 0
Level 6 AHMS Building, The University of Adelaide, North Terrace, Adelaide, SA 5000
Country 138610 0
Australia
Phone 138610 0
+61 8 8313 6535
Fax 138610 0
Email 138610 0
[email protected]
Contact person for public queries
Name 138611 0
Tongzhi Wu
Address 138611 0
Level 6 AHMS Building, The University of Adelaide, North Terrace, Adelaide, SA 5000
Country 138611 0
Australia
Phone 138611 0
+61 8 8313 6535
Fax 138611 0
Email 138611 0
[email protected]
Contact person for scientific queries
Name 138612 0
Tongzhi Wu
Address 138612 0
Level 6 AHMS Building, The University of Adelaide, North Terrace, Adelaide, SA 5000
Country 138612 0
Australia
Phone 138612 0
+61 8 8313 6535
Fax 138612 0
Email 138612 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
No
No 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.