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Trial registered on ANZCTR


Registration number
ACTRN12619001440112
Ethics application status
Approved
Date submitted
12/09/2019
Date registered
17/10/2019
Date last updated
17/10/2019
Date data sharing statement initially provided
17/10/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
INTIMET: INsulin Resistance in Type 1 Diabetes Managed with METformin
Scientific title
Effect of metformin on hepatic and peripheral insulin resistance in adults with type 1 diabetes: protocol of a double-blind placebo controlled, randomised trial
Secondary ID [1] 299047 0
Nil known.
Universal Trial Number (UTN)
U1111-1238-8090
Trial acronym
INTIMET
Linked study record
N/A

Health condition
Health condition(s) or problem(s) studied:
Type 1 Diabetes 314063 0
Condition category
Condition code
Metabolic and Endocrine 312449 312449 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Active arm:
oral metformin 1500mg extended release daily (as 500mg extended release tablets three times a day) titrated from initial dose 500mg to target 1500mg over 3 weeks (or maximum tolerated up to 1500mg) for 26 weeks post initiation of treatment.

Adherence will be monitored with drug tablet return.


Intervention code [1] 315319 0
Treatment: Drugs
Comparator / control treatment
Comparator arm: oral placebo 3 tablets daily (as 1 tablets three times a day) titrated from 1 tablet daily up to target 3 tablets daily over 3 weeks (or maximum tolerated up to 3 tablets) for 26 weeks post initiation of treatment. Placebo tablets appear identical to metformin tablets.

Composition of placebo tablet: 95-98% microcellulose (Prosolv Easy Tab Powder)
Control group
Placebo

Outcomes
Primary outcome [1] 321195 0
Change in hepatic insulin resistance, assessed by hyperinsulinaemic euglycaemic clamp (with deuterated glucose tracers).
Timepoint [1] 321195 0
26 weeks post initiation of treatment
Secondary outcome [1] 374276 0
Change in peripheral insulin resistance, as determined by hyperinsulinaemic euglycaemic clamp assessment.
Timepoint [1] 374276 0
26 weeks post initiation of treatment
Secondary outcome [2] 374277 0
Change in HbA1c, assessed by serum assay
Timepoint [2] 374277 0
13 and 26 weeks post initiation of treatment
Secondary outcome [3] 374281 0
Change in blood pressure (assessed by digital sphygmomanometer)
Timepoint [3] 374281 0
26 weeks post initiation of treatment
Secondary outcome [4] 374285 0
Change in growth/differentiation factor 15 (GDF15) (assessed by serum assay)
Timepoint [4] 374285 0
26 weeks post initiation of treatment
Secondary outcome [5] 374289 0
Change in gastrointestinal microbiota (assessed by faecal sampling)
Timepoint [5] 374289 0
26 weeks post initiation of treatment
Secondary outcome [6] 375582 0
Change in glycaemic variability (assessed by continuous glucose monitoring)
Timepoint [6] 375582 0
26 weeks post initiation of treatment
Secondary outcome [7] 375583 0
Change in time in range (4-10mmol/L, assessed by continuous glucose monitoring)
Timepoint [7] 375583 0
26 weeks post initiation of treatment
Secondary outcome [8] 375584 0
Change in time in hypoglycaemia (assessed by continuous glucose monitoring)
Timepoint [8] 375584 0
26 weeks post initiation of treatment
Secondary outcome [9] 375585 0
Change in total daily insulin dose (assessed by insulin pump download, or participant diary)
Timepoint [9] 375585 0
26 weeks post initiation of treatment
Secondary outcome [10] 375586 0
Change in daily basal insulin dose (assessed by insulin pump download, or participant diary)
Timepoint [10] 375586 0
26 weeks post initiation of treatment
Secondary outcome [11] 375587 0
Change in total daily bolus insulin (assessed by insulin pump download or participant dairy)
Timepoint [11] 375587 0
26 weeks post initiation of treatment
Secondary outcome [12] 375588 0
Change in weight (assessed by digital scales)
Timepoint [12] 375588 0
26 weeks post initiation of treatment
Secondary outcome [13] 375589 0
Change in waist circumference (assessed by tape measure)
Timepoint [13] 375589 0
26 weeks post initiation of treatment
Secondary outcome [14] 375590 0
Change in waist/hip ratio (assessed by tape measure)
Timepoint [14] 375590 0
26 weeks post initiation of treatment
Secondary outcome [15] 375591 0
Change in adiponectin (as deterimined by serum assay)
Timepoint [15] 375591 0
26 weeks post initiation of treatment
Secondary outcome [16] 375592 0
Change in sex hormone binding globulin (SHBG) (assessed by serum assay)
Timepoint [16] 375592 0
26 weeks post initiation of treatment
Secondary outcome [17] 375593 0
Change in liver stiffness (assessed by fibroscan)
Timepoint [17] 375593 0
26 weeks post initiation of treatment
Secondary outcome [18] 375594 0
Change in liver fat (assessed by fibroscan)
Timepoint [18] 375594 0
26 weeks post initiation of treatment
Secondary outcome [19] 375595 0
Change in LDL cholesterol (assessed by serum assay)
Timepoint [19] 375595 0
26 weeks post initiation of treatment
Secondary outcome [20] 375596 0
Change in HDL cholesterol (assessed by serum assay)
Timepoint [20] 375596 0
26 weeks post initiation of treatment
Secondary outcome [21] 375597 0
Change in triglyceride level (assessed by serum assay)
Timepoint [21] 375597 0
26 weeks post initiation of treatment

Secondary outcome [22] 375673 0
Change in total fat mass (assessed by whole body DXA)
Timepoint [22] 375673 0
26 weeks post initiation of treatment
Secondary outcome [23] 375674 0
Change in free-fat mass (assessed by whole body DXA)
Timepoint [23] 375674 0
26 weeks post initiation of treatment
Secondary outcome [24] 375675 0
Change in visceral fat (assessed by whole body DXA)
Timepoint [24] 375675 0
26 weeks post initiation of treatment
Secondary outcome [25] 375678 0
Change in arterial stiffness (determined by radial artery applanation tonometry)
Timepoint [25] 375678 0
26 weeks post initiation of treatment

Eligibility
Key inclusion criteria
T1D and controls without diabetes:
1. Age: adult (ages 20-50)
2. Premenopausal (if female)

T1D:
1. < 10 years since diagnosis of diabetes
2. Fasting c-peptide < 0.3nmol/L)
3. HbA1c less than or equal to 9.5%

Minimum age
20 Years
Maximum age
50 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Current smoking
2. Current or planned prescription of medications that affect glucose metabolism (glucocorticoids, antipsychotics, immunosuppressants).
3. Exposure to metformin within the last 30 days
4. Alcohol intake > 20g/day in women or > 40g/day in men
5. Weight change > 5% in last 3 months or history of bariatric surgery
6. Pregnancy, breastfeeding, or childbearing potential not willing to avoid pregnancy during the study
7. Known major organ dysfunction (eGFR < 60, liver disease transaminases > 3 times the upper limit of normal, cardiac event within the last 6 months, current cancer or uncontrolled thyroid dysfunction).
8. Diabetic ketoacidosis or severe hypoglycaemia (hypoglycaemia requiring third-party assistance) in the last 6 months.
9. A history of a psychological illness or condition that would interfere with the patient’s ability to understand the requirements of the study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis

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)
NSW
Recruitment hospital [1] 14651 0
St Vincent's Hospital (Darlinghurst) - Darlinghurst
Recruitment hospital [2] 14652 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 27676 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 27677 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 303583 0
Charities/Societies/Foundations
Name [1] 303583 0
Diabetes Australia
Address [1] 303583 0
PO Box 3156 Canberra ACT 2601
Country [1] 303583 0
Australia
Primary sponsor type
Other
Name
Garvan Institute of Medical Research
Address
384 Victoria Street Darlinghurst, NSW 2010
Country
Australia
Secondary sponsor category [1] 303792 0
None
Name [1] 303792 0
Address [1] 303792 0
Country [1] 303792 0
Other collaborator category [1] 280928 0
Hospital
Name [1] 280928 0
St Vincent's Hospital Sydney
Address [1] 280928 0
390 Victoria St, Darlinghurst, NSW 2010
Country [1] 280928 0
Australia
Other collaborator category [2] 280929 0
Hospital
Name [2] 280929 0
Westmead Hospital, Sydney
Address [2] 280929 0
Cnr Hawkesbury and Darcy Rd, Westmead NSW 2145
Country [2] 280929 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 304111 0
St Vincent's Hospital HREC
Ethics committee address [1] 304111 0
St Vincent’s Hospital Translational Research Centre
97-105 Boundary Street Darlinghurst NSW 2010
Ethics committee country [1] 304111 0
Australia
Date submitted for ethics approval [1] 304111 0
Approval date [1] 304111 0
06/05/2019
Ethics approval number [1] 304111 0
2019/ETH00379

Summary
Brief summary
This is a detailed study of liver and muscle insulin resistance in adults with type 1 diabetes. The investigators will study the efficacy of adjunctive metformin in reversing insulin resistance and improve glucometabolic status, endothelial health and other parameters. Predictors of response to metformin will be assessed.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 95846 0
Prof Jerry R Greenfield
Address 95846 0
Garvan Institute of Medical Research
384 Victoria St Darlinghurst NSW 2010
Country 95846 0
Australia
Phone 95846 0
+61 2 9295 8482
Fax 95846 0
Email 95846 0
j.greenfield@garvan.org.au
Contact person for public queries
Name 95847 0
Dr Jennifer Snaith
Address 95847 0
Garvan Institute of Medical Research
384 Victoria St Darlinghurst NSW 2010
Country 95847 0
Australia
Phone 95847 0
+61 2 9295 8490
Fax 95847 0
Email 95847 0
j.snaith@garvan.org.au
Contact person for scientific queries
Name 95848 0
Dr Jennifer Snaith
Address 95848 0
Garvan Institute of Medical Research
384 Victoria St Darlinghurst NSW 2010
Country 95848 0
Australia
Phone 95848 0
+61 2 9295 8490
Fax 95848 0
Email 95848 0
j.snaith@garvan.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
all individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Immediately following publication (ending 5 years following main results publication)
Available to whom?
case-by-case basis at the discretion of the primary sponsor and pending ethics committee approval, investigators whose proposed use of the data has been approved by an independent review committee (“learned intermediary”) identified for this purpose.
Available for what types of analyses?
only to achieve the aims in the approved proposal
How or where can data be obtained?
Access subject to approvals by the Principal Investigator (Professor Jerry Greenfield). Enquiries should be directed to j.greenfield@garvan.org.au
What supporting documents are/will be available?
No other documents available
Summary results
No Results