Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000570583
Ethics application status
Approved
Date submitted
10/04/2024
Date registered
6/05/2024
Date last updated
6/05/2024
Date data sharing statement initially provided
6/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of Ozempic on stomach emptying, blood sugar levels and blood pressure after a high carbohydrate meal in people with type 2 diabetes
Scientific title
Effect of subcutaneous (sc) semaglutide on gastric emptying of, and the postprandial glycaemic and cardiovascular responses to, a carbohydrate meal in people with type 2 diabetes.
Secondary ID [1] 311918 0
Nil known
Universal Trial Number (UTN)
Trial acronym
SAGE-T2D
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Type 2 diabetes 333506 0
Condition category
Condition code
Metabolic and Endocrine 330182 330182 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Semaglutide 0.25-1mg or matching placebo once weekly sc for 12 weeks. Semaglutide will be uptitrated from 0.25mg for 4 weeks, followed by 0.5mg for 4 weeks and then 1mg for 4 weeks. The injection is administered by one of the investigators to remove any issues relating to compliance and adherence to the intervention.

A gastric emptying study using the gold standard technique (scintigraphy) will be performed by a qualified nuclear medicine technologist, at baseline (ie before treatment), at 12 weeks after commencing semaglutide, and 1 week and 4 weeks post cessation of semaglutide. Following an overnight fast (14h solids, 12h liquids), participants will consume a carbohydrate mashed potato meal (369 kcal) comprising 65 g powdered potato and 20 g glucose reconstituted with 250 ml boiling water and labelled with 20 MBq 99mTc-calcium phytate to measure gastric emptying using scintigraphy. The meal will include 3g 3-O-methylglucose (3-OMG, Sigma Aldrich, USA) and 1000mg of paracetamol. Fasting requirements will be confirmed prior to administration of the test meal. Paracetamol 1000mg will not be added to the test meal during gastric emptying studies at 1 and 4 weeks post drug cessation.
Intervention code [1] 328384 0
Treatment: Drugs
Comparator / control treatment
Placebo will be sc saline (0.9%)
Control group
Placebo

Outcomes
Primary outcome [1] 337936 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on gastric emptying in type 2 diabetes.
Timepoint [1] 337936 0
Gastric emptying will be assessed at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug.

On each day, gastric emptying will be assessed immediately after ingestion of the mashed potato meal (t=0 minutes) in dynamic mode i.e. in 1 min frames for the first 60 minutes and in 3-minute frames thereafter until t=180 minutes.

The primary outcome measure will be AUC0-180min.
Secondary outcome [1] 433802 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on postprandial glycaemia in response to a standardised mashed potato meal.
Timepoint [1] 433802 0
Blood glucose (pre- and postprandial) will be assessed during the gastric emptying studies at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug.

Venous blood (15ml) will be sampled immediately before ingesting the test meal and at t = 30, 60, 90, 120, 150, 180 min. Blood glucose concentrations will be measured immediately using a glucose oxidase analyser (Yellow Springs Institute, USA).

The outcome measure will be AUC0-180min.
Secondary outcome [2] 433803 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on postprandial BP and HR.
Timepoint [2] 433803 0
BP and HR will be assessed immediately prior to meal ingestion (3 3-min measurements will be taken and the average used as the baseline value) and following the meal at 5-min intervals until 120 min and at 15 min intervals until 180 min (23).

The outcome measure will be AUC0-60min.
Secondary outcome [3] 433804 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on insulin, C-peptide, and glucagon concentrations before and after a standardised meal.
Timepoint [3] 433804 0
In each of the study days, at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug, venous blood (15ml) will be sampled immediately before ingesting the test meal and at t = 30, 60, 90, 120, 150, 180 min. Blood glucose concentrations will be measured immediately using a glucose oxidase analyser (Yellow Springs Institute, USA). Plasma and serum will be separated from the remainder of each sample and stored at – 80 degree Celsius for subsequent measurements of plasma insulin, C-peptide, and glucagon, serum 3-OMG and paracetamol concentrations.

The outcome measure will be AUC0-180min.
Secondary outcome [4] 433805 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on the rate of absorption of the glucose analogue, 3-O-methylglucose (3-OMG, a marker of glucose absorption).
Timepoint [4] 433805 0
Rate of absorption will be assessed at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug.

The outcome measure will be AUC0-180min.
Secondary outcome [5] 433806 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on gastrointestinal symptoms.
Timepoint [5] 433806 0
In each of the study days, at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug, subjects will complete standardised visual analogue questionnaires to score gastrointestinal symptoms immediately before the test meal and at t = 30, 60, 90, 120, 150, 180 min.

The outcome measure will be AUC0-180min.
Secondary outcome [6] 433807 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on appetite..
Timepoint [6] 433807 0
In each of the study days, at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug, subjects will complete standardised visual analogue questionnaires to score sensations of hunger, fullness and desire to eat at immediately before the test mealt = 30, 60, 90, 120, 150, 180 min.
Secondary outcome [7] 433875 0
To compare the effect of 12 weeks treatment with semaglutide QW (once weekly) versus placebo on energy intake.
Timepoint [7] 433875 0
In each of the study days, at baseline (before drug), 12 weeks after drug and 1 and 4 weeks after cessation of the study drug, subjects will be presented with a standardised buffet style meal at t=180 that they will eat over 30 min ie until t=210 min

Eligibility
Key inclusion criteria
• Male or female participants aged 40 – 80 years
• Female subjects who are post-menopausal; or pre-menopausal with surgical contraception (such as tubal ligation) or an intrauterine device. Pre-menopausal women will require a confirmed negative urine ß-hCG pregnancy test at screening visit.
• T2DM (World Health Organisation (WHO) criteria) managed by diet alone or on metformin
• Glycated haemoglobin (HbA1c) greater than or equal to 6.0% and less than or equal to 8.5%, in the last 4 months prior to enrolment in the study
• Body mass index (BMI) 25 – 40 kg/m2
• Haemoglobin and ferritin in the normal range for gender and age.
• Participant has provided written informed consent.
Minimum age
40 Years
Maximum age
80 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Evidence of renal disease (i.e. a creatinine clearance cut-off of < 50 ml/min. Calculated creatinine clearance will be determined as follows using the Cockcroft-Gault equation: Cr clearance = [140 - age (years) x weight (kg)] / [0.814 x serum creatinine (µmol/L)] (For female subjects, multiply Cr clearance x 0.85)(24)
• Iron stores, or liver function tests outside the following ranges:
Alanine aminotransferase (ALT) < 55 U/L
Alkaline phosphatase (ALP) 30 - 110 U/L
Aspartate transaminase (AST) < 45 U/L
Total bilirubin 6 - 24 µmol/L
Haemoglobin 115 – 155 g/L (Females)
135 – 172 g/L (Males)
Ferritin 15 – 200 µg/L (Females)
30 – 300 µg/L (Males)
• Hepatic or cardiovascular disease, pancreatitis (subjects with past history of acute or chronic pancreatitis, gastric surgery, or known gastroparesis on history or screening biochemistry tests.
• Participants with any history of cancer, except for basal cell carcinoma or in situ carcinoma of the cervix treated with apparent success with curative therapy = 12 months prior to screening or other malignancies treated with apparent success with curative therapy = 5 years prior to screening will be excluded.
• History of any clinically significant disease or disorder which may either put the volunteer at risk because of participation in the study, or influence the results or the volunteer’s ability to participate in the study.
• Personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• History of hyperthyroidism or uncontrolled hypothyroidism.
• Chronic gastrointestinal symptoms as assessed by questionnaire.
• Use of drugs potentially affecting gastrointestinal motility (corticosteroids; anti-emetics (dopamine antagonists, 5HT-3 receptor antagonists), laxatives, prokinetic agents, anticholinergic agents, cholinergic agents, opioid medications, erythromycin).
• Current use of anticoagulants.
• Inability to abstain from smoking for 12 hours prior to the gastric emptying tests.
• Consumption of greater than 2 units alcohol daily on a regular basis.
• Known or suspected history of alcohol or drug abuse, as judged by the Investigator.
• History of severe allergy/hypersensitivity or ongoing allergy/hypersensitivity, or history of hypersensitivity to semaglutide or drugs with a similar chemical structure or its components.
• Known hypersensitivity to IV infusion equipment, plastics, adhesive or silicone, or know history of hypotension or infusion site reactions with IV administration of other medicines
• Participation in any research studies involving exposure to ionising radiation exceeding 2.5mSv in the previous 12 months
• Donated blood in the past 3 months
• Vegetarian

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)
Randomisation will be carried out by the Pharmacy at the Royal Adelaide Hospital. Allocation will involve contacting the holder of the allocation schedule (RAH Pharmacy) who is at a separate site to provide the medication (so that this is blinded to both the participant and study investigator).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be carried out by the Pharmacy at the Royal Adelaide Hospital using simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis
The two analysis sets include the ‘intervention’ group and the ‘control/placebo’ group. Analysis will be undertaken on a per-protocol basis. Analysis of covariance (ANCOVA) will be used to compare changes in gastric emptying in each group at 12 weeks, adjusting for baseline values. Secondary endpoints will be analysed in similar fashion, using ANCOVA and mixed models. Data will be performed in consultation with our biostatistician, Kylie Lange, who is an investigator in this study. The data will be prepared for publication in a peer-reviewed journal. All records will be kept for a minimum of 15 years in the Discipline of Medicine and the study will maintain the anonymity of the participants. No medical records will be required for this project. Only the investigators will have access to the research data and results. The Adelaide Medical School, University of Adelaide, will own all data from this study.
The study follows a pre-post design with independent groups of subjects studied under different conditions (parallel design) and treatment administration will be double-blind. Sample size requirements have been based on power calculations alpha = 0.05 and beta = 0.8, performed with gastric emptying as the outcome variable based on our previous data (8). 32 patients with T2DM (16 in each group) are required to detect a difference of 15% intragastric retention at 120 min after sc semaglutide compared to placebo, allowing for all possible post hoc tests between the study days. Based on our experience, we have estimated an overall ‘dropout rate’ of ~10%.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
6/05/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
32
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA

Funding & Sponsors
Funding source category [1] 316264 0
Charities/Societies/Foundations
Name [1] 316264 0
Diabetes Australia Research Trust
Country [1] 316264 0
Australia
Primary sponsor type
University
Name
University of Adelaide
Address
Country
Australia
Secondary sponsor category [1] 318453 0
None
Name [1] 318453 0
Address [1] 318453 0
Country [1] 318453 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315084 0
Central Adelaide Local Health Network (CALHN) HREC
Ethics committee address [1] 315084 0
Ethics committee country [1] 315084 0
Australia
Date submitted for ethics approval [1] 315084 0
02/11/2023
Approval date [1] 315084 0
17/01/2024
Ethics approval number [1] 315084 0
2023HRE00226

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

Contacts
Principal investigator
Name 133626 0
Prof Karen Jones
Address 133626 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 133626 0
Australia
Phone 133626 0
+61 8 8313 7821
Fax 133626 0
Email 133626 0
[email protected]
Contact person for public queries
Name 133627 0
Seva Hatzinikolas
Address 133627 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 133627 0
Australia
Phone 133627 0
+61 8 8313 7804
Fax 133627 0
Email 133627 0
[email protected]
Contact person for scientific queries
Name 133628 0
Karen Jones
Address 133628 0
Level 5, Adelaide Health and Medical Sciences (AHMS) Building, University of Adelaide, North Terrace & George St, Adelaide SA 5000
Country 133628 0
Australia
Phone 133628 0
+61 8 8313 7821
Fax 133628 0
Email 133628 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
Data are to remain confidential to maintain participant anonymity


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.