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Trial registered on ANZCTR


Registration number
ACTRN12617000480381
Ethics application status
Approved
Date submitted
30/03/2017
Date registered
3/04/2017
Date last updated
19/03/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Improving Glucose Outcomes Using a Novel Treatment Strategy in Young Adult Onset Type 2 Diabetes
Scientific title
Improving Glycaemic Outcomes Using a Rapid Titration Treatment Strategy in Young Adult Onset Type 2 Diabetes
Secondary ID [1] 291545 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Young Adult Onset Type 2 Diabetes Mellitus 302636 0
Condition category
Condition code
Metabolic and Endocrine 302153 302153 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
After baseline tests are performed, subjects will be randomised to either a continuous glucose monitoring (CGM) guided, rapid titration of treatment strategy or a currently accepted standard of care type 2 diabetes treatment strategy. Treatment strategies (both rapid titration and standard of care) will be managed by experienced Endocrinologists for the duration of the study period.

Rapid Titration Treatment Strategy:

During the initial (six week) phase of the study, participants randomised to the rapid titration treatment strategy will be seen weekly for assessment and possible intensification of treatment. Weekly CGM recordings will be used to guide treatment decisions and assessments will be made on the basis of the mean blood glucose level (MBG). A MBG of 7.56 mmol/l has been found to correlate with an HbA1c of 6.5% (Nathan DM et al. Diabetologia 2007; 50: 2239-2244). If the MBG during the final 48 hours of the weekly recording is >7.56 mmol/l, treatment will be intensified. Treatment will begin with metformin (titrated from 1 g daily to 2 g daily) followed by the addition of an SGLT2 inhibitor (empagliflozin - 10 mg daily titrated to 25 mg daily) and then GLP-1 receptor agonist (liraglutide - 0.6 mg daily titrated to a maximum of 1.8 mg daily) in sequential addition. In the event that a participant is intolerant of metformin, treatment will progress to the next agent in the algorithm, empaglifozin. If treatment with the GLP-1 receptor agonist is required it will be commenced at the starting dose as per product information. The dose will be up-titrated according to recommendations within the product information provided by the manufacturer. If a higher dose of medication is not tolerated then reversion will be to the maximum tolerated dose. At the end of the rapid titration period, participants should be at the target MBG level and/or on the maximum tolerated combination of metformin, empagliflozin and liraglutide. Participants continue on their treatment regimen established by week 6 and are seen again after 3 months of treatment. From this point on, further treatment intensification will be based on achieving an HbA1c target of <6.5%. The active treatment phase of this trial will last twelve months. In addition to the assessment performed after 3 months, participants will also seen after 6 months and 9 months and treatment will be intensified if the HbA1c is not at the target level (<6.5%). If the HbA1c target of <6.5% is not achieved or maintained on combination therapy with metformin, empagliflozin and liraglutide, insulin can be commenced. An on insulin HbA1c target of <7% without hypoglycaemia will be applied. This is consistent with the current Australian Diabetes Society endorsed clinical guidelines.

To ensure treatment fidelity, primary care physicians will be contacted by the investigator team prior to randomisation requesting that on-study treatment be left unchanged except in the case of a severe adverse event. A 24 hour emergency contact number will be provided to assist. In addition all participants will be provided with a trial summary card including the emergency contact number. Treatment retention will be facilitated by the provision of a flexible appointment schedule and provisions will be made to ensure ease of access to Royal Prince Alfred Hospital on an individual basis.
Intervention code [1] 297612 0
Treatment: Drugs
Comparator / control treatment
Standard of Care Treatment Strategy:

This is based on the Australian Diabetes Society treatment “usual care” algorithm for type 2 diabetes. Treatment options include metformin, sulfonylurea or DPP-IV inhibitor and insulin or GLP-1 receptor agonist in sequential addition. Intensification will be by three monthly HbA1c assessments; hence participants are seen 3, 6, 9 and 12 months after entering the study. Similarly to Treatment Strategy A, the pre-insulin treatment target HbA1c level for Treatment Strategy B is 6.5% without hypoglycaemia. If a study participant assigned treatment strategy B is deemed to require insulin therapy, the HbA1c target level will be <7.0% without hypoglycaemia.
Control group
Active

Outcomes
Primary outcome [1] 301578 0
Glycaemic control assessed by HbA1c. HbA1c will be measured on a sample of whole blood using an IFCC standardised method.
Timepoint [1] 301578 0
12 months
Secondary outcome [1] 333178 0
Change in beta-cell function. Beta-cell function will be primarily assessed indirectly from the results obtained during oral glucose tolerance testing and will include the derivation of the oral disposition index (ODI).
Timepoint [1] 333178 0
12 months (with reference point being beta-cell function at baseline)
Secondary outcome [2] 333179 0
Markers of renal function (including serum creatinine, eGFR, urinary albumin to creatinine ratio plus additional novel serum and urinary biomarkers)
Timepoint [2] 333179 0
12 months (with reference point being the baseline assessment)

Eligibility
Key inclusion criteria
Recent diagnosis of type 2 diabetes (< 6 months since diagnosis)
Age range: 18 to 40 years of age
Diabetes management at time of recruitment: diet alone or metformin monotherapy
Minimum age
18 Years
Maximum age
40 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Type 1 diabetes / GAD or IA2 positive diabetes
Current pregnancy
HbA1c <6.5% at time of screening
Contraindication to metformin, SGLT2 inhibitor or GLP-1 receptor agonist treatment
History of diabetic ketoacidosis

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)
Allocation will be concealed via the use of a central computer program.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Treatment allocation will take place via the process of minimisation (with weighted randomisation) using open source software.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The intervention groups will be compared for the primary outcome and secondary outcome measures at 12 months, adjusted for the baseline value of each outcome. The analyses for each of the treatment protocols will be conducted separately and ANCOVA analysis will use all available clinical data for baseline adjustments. Secondary analysis will be for outcome changes at 6 months. Significance will be set at a probability of 0.05. As secondary measures are largely exploratory no adjustment for multiple comparisons are planned.

Recruitment
Recruitment status
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

Funding & Sponsors
Funding source category [1] 296034 0
Hospital
Name [1] 296034 0
Royal Prince Alfred Hospital, Department of Endocrinology
Address [1] 296034 0
Level 6 West, Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country [1] 296034 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Hospital
Address
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 294973 0
None
Name [1] 294973 0
Address [1] 294973 0
Country [1] 294973 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297293 0
SLHD Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 297293 0
Research Ethics and Governance Office
Royal Prince Alfred Hospital
Camperdown NSW 2050
Ethics committee country [1] 297293 0
Australia
Date submitted for ethics approval [1] 297293 0
10/08/2016
Approval date [1] 297293 0
15/11/2016
Ethics approval number [1] 297293 0
X16-0339 & HREC/16/RPAH/465

Summary
Brief summary
Guidelines for the treatment of type 2 diabetes direct clinicians to individualise therapy in diabetes however there is little evidence to guide successful treatment in Young Adults with Type 2 Diabetes (YT2DM). This study will provide much needed evidence on which to base treatment decisions for YT2DM, a growing problem in our clinics. The outcomes of a physiologically sensible, innovative continuous glucose monitoring-guided rapid titration strategy which differs from usual care will provide new knowledge on the treatment for this high risk group. Further the fundamental physiologic effects of this strategy on beta cell function and early renal decline in YT2DM will provide further insights to guide therapeutic decisions for this high risk patient group. If positive, the results can be translated into wider practice and guide individualised therapy in addition to evidence based clinical practice guidelines for YT2DM. The global nature of the problem of YT2DM will ensure international interest and the investigators are well placed to facilitate dissemination of results to wider stakeholders and translation.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 73610 0
Dr Timothy Middleton
Address 73610 0
Diabetes Centre, Level 6 West
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 73610 0
Australia
Phone 73610 0
+61 2 9515 5888
Fax 73610 0
+61 2 9515 5820
Email 73610 0
timothy.middleton@sswahs.nsw.gov.au
Contact person for public queries
Name 73611 0
Dr Timothy Middleton
Address 73611 0
Diabetes Centre, Level 6 West
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 73611 0
Australia
Phone 73611 0
+61 2 9515 5888
Fax 73611 0
+ 61 2 9515 5820
Email 73611 0
timothy.middleton@sswahs.nsw.gov.au
Contact person for scientific queries
Name 73612 0
Dr Timothy Middleton
Address 73612 0
Diabetes Centre, Level 6 West
Royal Prince Alfred Hospital
Missenden Road
Camperdown NSW 2050
Country 73612 0
Australia
Phone 73612 0
+61 2 9515 5888
Fax 73612 0
+61 2 9515 5820
Email 73612 0
timothy.middleton@sswahs.nsw.gov.au

No data has been provided for results reporting
Summary results
Not applicable