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Trial registered on ANZCTR


Registration number
ACTRN12624001253594
Ethics application status
Approved
Date submitted
17/09/2024
Date registered
14/10/2024
Date last updated
14/10/2024
Date data sharing statement initially provided
14/10/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
DIVINE – Pilot Trial: A phase 2 multicentre, randomised interventional trial in women with a history of gestational diabetes and evidence of pre-diabetes.
Scientific title
DIVINE – Pilot Trial: A phase 2 multicentre, randomised interventional trial in overweight or obese women with a history of gestational diabetes and evidence of pre-diabetes.
Secondary ID [1] 312944 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes 335114 0
Condition category
Condition code
Metabolic and Endocrine 331617 331617 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A 6-months multi-centre, randomised, interventional trial in women with a history of Gestational Diabetes Mellitus (GDM) with persisting dysglycaemia who are overweight or obese, with a further 6 months follow-up (12-month total study duration – 6 months active intervention, 6 months additional follow-up).

This is a 2x2 factorial design with an active metformin run-in.

For the active pharmacotherapy intervention, participants will be randomised (1:1) to metformin up to 1000mg/day and semaglutide (up to 1.0mg/week) or metformin up to 1000mg/day and no semaglutide for 6 months.

The patient will start with 0.25mg of semaglutide, given once per week through a prefilled self-injection pen. The pen is injected under the skin (subcutaneously) weekly, and will be up-titrated 0.25mg weekly, to a maximum of 1mg by week 4. Face-to-face meetings between trial staff and participants once per week within 4 weeks of first randomisation.

A second randomisation will occur for the physical activity intervention (1:1) to a physical activity intervention or no physical activity intervention. The participants and Accredited Exercise Physiologist will meet once only. Instruction of how to use the Garmin (monitoring device) will be given by an Accredited Exercise Physiologist.

There will be a 2-week active run in:
• 500 mg daily metformin sustained release (SR) for 1 week
• 1000 mg daily metformin sustained release (SR) for 1 week
The patient will start with a 250 mg sustained release weekly, drug to be taken orally daily. The dose will be up-titrated to 500 mg metformin sustained release will be given daily for 7 days. If the patient can tolerate the 500 mg dosage, then 1000 mg metformin sustained release will be given daily for 7 days.

If the patient cannot tolerate the 1000 mg metformin sustained release daily, down-titration to 500 mg dosage daily is allowed. Mode of administration of metformin: oral.

Following active run-in, all participants who can tolerate and are compliant with 80% or above of the study drug will be eligible for study entry. They will continue metformin (maximum tolerated dose up to 1000g daily), and randomised 1:1:1:1 into each of the following intervention groups:
• ARM1 (metformin up to 1000mg/day and no semaglutide + physical activity intervention)
• ARM2 (metformin up to 1000mg/day and no semaglutide + physical activity control)
• ARM3 (metformin up to 1000mg/day and semaglutide up to 1.0mg/week + physical activity intervention)
• ARM4 (metformin up to 1000mg/day and semaglutide up to 1.0mg/week + physical activity control)

All participants will wear an activity monitor (Garmin) throughout the intervention. The physical activity intervention group will have consistent activity feedback via the activity monitor. Feedback will include steps, minutes of activity, calories burnt, etc. The trial is requesting participants full time, throughout the intervention. The physical activity control group will not receive activity feedback and the monitor will be set to only show time.

All participants will be provided with one individual session with an Accredited Exercise Physiologist (AEP) within 2 weeks of randomisation. During this session, they will be provided with individualised support to increase physical activity and reduce sedentary behaviour. They will be advised to increase their physical activity by 10% each week until they meet the National Health and Medical Research Council guidelines on physical activity in adults (150 minutes of moderate-intensity exercise or equivalent). These sessions will be held only once either face to face or via Zoom/MS Teams and will last approximately 2 hours.

The feedbacks that the patient will receive: number of steps per day taken by the subject, minutes of physical activity taken daily.

The participant will be asked to wear the Garmin Connect device continuously throughout the intervention period which is 6 months.

All participants will also be provided with nutritional information from Diabetes Australia in written and verbal form from research study staff for the prevention of type 2 diabetes. Information will be provided to the participants verbally face-to-face.

All participants will be followed up at 6 months at the end of intervention phase and again at 12 months. Throughout the trial, participants will be monitored by study sites and the Medical Monitor will conduct ongoing monitoring as appropriate for the trial. Device analytics can be sought if needed to ensure adherence to wearing the activity tracking device.
Intervention code [1] 329486 0
Treatment: Devices
Intervention code [2] 329487 0
Treatment: Drugs
Intervention code [3] 329638 0
Lifestyle
Comparator / control treatment
ARM 2 (metformin up to 1000mg/day and no semaglutide + physical activity control)
Control group
Active

Outcomes
Primary outcome [1] 339360 0
Absolute body weight in kilograms
Timepoint [1] 339360 0
Baseline to 6 months post-baseline in Metformin vs. Metformin and Semaglutide study arms.
Primary outcome [2] 339361 0
Mean activity levels
Timepoint [2] 339361 0
Baseline to 6 months post-baseline in physical activity intervention vs physical activity control arms
Secondary outcome [1] 440296 0
Fasting Plasma Glucose
Timepoint [1] 440296 0
Baseline to 6 months post-baseline, and at 12 months post-baseline.
Secondary outcome [2] 440297 0
Systolic/Diastolic Blood Pressure (whole blood pressure reading), to be assessed as a composite outcome.
Timepoint [2] 440297 0
Baseline to 6 months post-baseline and at 12 months post-baseline.

Eligibility
Key inclusion criteria
The trial will include women with a history of GDM (within the last 5 years) with persisting dysglycaemia who are overweight or obese.

The main inclusion criteria are:
1. Aged 18 years or above;
2. At least 3 months post-partum;
3. Biochemical evidence of persisting post-partum dysglycaemia in the last 12 months as defined by:
a. Fasting plasma glucose 6.1 to 6.9 mmol/L; and/or
b. 2-hour blood glucose 7.8 to 11.0 mmol/L on 75g oral glucose tolerance test (OGTT); and/or
c. HbA1c 6.0 to 6.4% (HbA1c performed at least 3 months post-partum).
4. Body mass index greater than or equal to 25 kg/m2;
5. eGFR greater than or equal to 45 ml/min/1.73m2;
6. Willing to take a pregnancy test prior to starting treatment and during follow-up;
7. Willing to wear an activity monitor (Garmin) for the duration of the study;
8. Have access to smart mobile phone or tablet to enable Garmin Connect App;
9. Able to provide written informed consent by signing the consent form.

Women who are currently treated with metformin for dysglycaemia will be eligible to participate in the study.
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
Women will be ineligible if:
1. They are currently pregnant, breast-feeding or actively planning pregnancy;
2. They have known Type 2 Diabetes (T2D), type 1 diabetes or any other forms of current diabetes;
3. They have a history of bariatric surgery (e.g., gastric bypass, gastric sleeve, gastric banding)
4. There is known intolerance to metformin or there is current absolute contraindication for metformin therapy, absolute contraindications to metformin are as follows
a. Severe renal impairment defined as eGFR less than 30 ml/minute/1.73m2,
b. Known hypersensitivity to metformin,
c. Acute or chronic metabolic acidosis, including diabetes ketoacidosis, with or without coma;
5. There is known intolerance or allergy to semaglutide, current use of a semaglutide or another Glucagon-like peptide-1 receptor (GLP1-RA) or known personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 gene;.
6. They have received treatment with any other medication for the indication of overweight or obesity within the last 90 days including phentermine (Duromine and Metermine), orlistat (Xenical) and naltrexone-burpronorphone (Contrave);
7. They have previous or planned (during the trial period) obesity treatment with surgery or weight loss device;
8. They are unwilling to use the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)-defined “highly effective” contraception;
9. They are unable to engage in physical activity;
10. There is known inability to give informed consent to participate due to severe active mental health issues or major developmental disability as identified through the maternity database.

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 to intervention will occur via a password-protected web-based system into one of four arms. Randomisation will be concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be performed by a blinded statistician using web-based software and concealed from the participants and study staff until allocation of intervention arm.
There will be a 2-week active run in:
• 500 mg daily metformin SR for 1 week
• 1000 mg daily metformin SR for 1 week

Following active run-in, all participants who can tolerate and are compliant with greater than or equal to 80% of the study drug will be eligible for study entry. They will continue metformin (maximum tolerated dose up to 1000g daily), and randomised 1:1:1:1 into each of the following intervention groups:
• ARM1 (metformin up to 1000mg/day and no semaglutide + physical activity intervention)
• ARM2 (metformin up to 1000mg/day and no semaglutide + physical activity control)
• ARM3 (metformin up to 1000mg/day and semaglutide up to 1.0mg/week + physical activity intervention)
• ARM4 (metformin up to 1000mg/day and semaglutide up to 1.0mg/week + physical activity control.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
13/01/2025
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 27090 0
Royal Hospital for Women - Randwick
Recruitment hospital [2] 27091 0
St George Hospital - Kogarah
Recruitment postcode(s) [1] 43164 0
2031 - Randwick
Recruitment postcode(s) [2] 43165 0
2217 - Kogarah

Funding & Sponsors
Funding source category [1] 317379 0
Government body
Name [1] 317379 0
National Health and Medical Research Council
Country [1] 317379 0
Australia
Primary sponsor type
Other
Name
The George Institute for Global Health
Address
Country
Australia
Secondary sponsor category [1] 319669 0
None
Name [1] 319669 0
Address [1] 319669 0
Country [1] 319669 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316108 0
Eastern Health Human Research Ethics Committee
Ethics committee address [1] 316108 0
https://www.easternhealth.org.au/site/item/34-research-ethics
Ethics committee country [1] 316108 0
Australia
Date submitted for ethics approval [1] 316108 0
17/05/2024
Approval date [1] 316108 0
11/07/2024
Ethics approval number [1] 316108 0

Summary
Brief summary
The primary aim is to assess the effect of metformin versus metformin and semaglutide on absolute change in body weight over 6 months with women with a recent history of Gestational Diabetes Mellitus with persisting dysglycaemia who are overweight or obese. We also assess the efficacy of a physical activity intervention of wearable activity monitors on increasing activity levels (minutes per week) in these women. Secondary aims include assessing the acceptability, tolerability and safety of metformin with/without semaglutide. In addition, we will examine changes in outcomes at 12 months.
Hypothesis
Among women with persistent dysglycaemia and Body Mass Index (BMI) is greater than or equal to 25kg/m2 within 5 years of a Gestational Diabetes Mellitus (GDM)-affected pregnancy:
1. 6 months treatment with metformin and semaglutide will result in greater persistent weight loss compared to treatment with metformin alone.
2. A monitor-based physical activity intervention will result in higher mean activity levels at 6 months, compared to no physical activity intervention.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136810 0
Prof Amanda Henry
Address 136810 0
The George Institute for Global Health/UNSW and RHW and St George Hospitals, SESLHD The George Institute for Global Health: Level 18, International Towers 3, Barangaroo Ave, Sydney NSW 2000 Australia, PO Box M201, Missenden Rd, NSW 2050 Australia
Country 136810 0
Australia
Phone 136810 0
+61 2 8052 4599
Fax 136810 0
Email 136810 0
[email protected]
Contact person for public queries
Name 136811 0
Amanda Henry
Address 136811 0
The George Institute for Global Health/UNSW and RHW and St George Hospitals, SESLHD The George Institute for Global Health: Level 18, International Towers 3, Barangaroo Ave, Sydney NSW 2000 Australia, PO Box M201, Missenden Rd, NSW 2050 Australia
Country 136811 0
Australia
Phone 136811 0
+61 2 8052 4599
Fax 136811 0
Email 136811 0
[email protected]
Contact person for scientific queries
Name 136812 0
Amanda Henry
Address 136812 0
The George Institute for Global Health/UNSW and RHW and St George Hospitals, SESLHD The George Institute for Global Health: Level 18, International Towers 3, Barangaroo Ave, Sydney NSW 2000 Australia, PO Box M201, Missenden Rd, NSW 2050 Australia
Country 136812 0
Australia
Phone 136812 0
+61 2 8052 4599
Fax 136812 0
Email 136812 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


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.