ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12617000789369

Ethics application status

Approved

Date submitted

7/06/2016

Date registered

30/05/2017

Date last updated

4/05/2018

Type of registration

Retrospectively registered

Titles & IDs

Public title

Triple therapy for new onset Type 2 Diabetes Mellitus (T2DM)

Scientific title

A randomised controlled study aimed to normalise glycaemia using triple therapy in newly diagnosed patients with type 2 diabetes

Secondary ID [1]

Nil known

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

type 2 diabetes mellitus

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Metformin XR - 7 days at 500mg followed by 7 days at 1000mg, followed by 7 days at 1500mg and then to a total daily dose of 2000mg for a duration of 12 months.
Saxagliptin - oral tablet at a total daily dose of 5mg for a duration of 12 months.
Dapagliflozin - oral tablet at a total daily dose of 10mg for a duration of 12 months.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Patients randomized to usual care (sequential/control) arm will initially receive metformin alone (increased to a total daily dose of 2000mg daily). Saxagliptin (5mg once daily) followed by dapagliflozin 10mg daily will be offered to the patients if HbA1c remains above 7.5% throughout the study period.
Treating endocrinologist will make the decision to begin saxagliptin if HbA1c remains above 7.5% for the first three months, then begin dapagliflozin if HbA1c remains above 7.5% for another three months (i.e. at the 6 month timepoint).

Control group

Active

Outcomes

Primary outcome [1]

Beta cell function assessed using a mixed-meal challenge test (MMCT).

Timepoint [1]

The MMCT will be undertaken using high-protein boost concentrate of 1 g/kg carbohydrate equivalent, at baseline and at 12-month post randomization. Patients will fast for 12 hours before the test, and all hypoglycaemic agents will be withheld for 24 hours before each testing. Glucose and C-peptide will be measured from blood samples at baseline (before the ingestion of the mixed meal) and then 8 times over the 4-hour test (15, 30, 60, 90, 120, 150, 180 and 240 minutes).

Insulin secretion will be estimated using the area under the curve (AUC) for glucose and C-peptide (total, incremental, 0- 30 minutes and 0-maximal production) and then determining C- peptide to glucose ratio to estimate insulin production. Insulin sensitivity will be calculated using the C-peptide based Matsuda index.

Secondary outcome [1]

Markers of glycation will be measured using serum samples the following markers will be assessed: TNF receptors 1 and 2, soluble advanced glycation end product receptor (sRAGE), pigment epithelium-derived factor,

Timepoint [1]

At baseline and 12 months post commencement of intervention

Secondary outcome [2]

Markers of oxidative stress will be measured using serum samples: IL-6R, IL-2R. We will also be exploring new markers of oxidative stress.

Timepoint [2]

At baseline and 12 months post commencement of intervention

Secondary outcome [3]

Known markers of endothelial function will be measured using serum samples such as fibroblast growth factor 23. We will also be exploring new markers of endothelial function.

Timepoint [3]

at baseline and 12 months post commencement of intervention

Secondary outcome [4]

HbA1c will be measured using serum samples.

Timepoint [4]

at baseline and 12 months post commencement of intervention

Secondary outcome [5]

electrolytes will be measured using the Roche method using serum samples

Timepoint [5]

At baseline and 12 months post commencement of intervention

Secondary outcome [6]

albumin excretion (24 hour urine collection) will be measured using the Roche system

Timepoint [6]

At baseline and 12 months post commencement of intervention

Secondary outcome [7]

renal function will be measured using the Roche system using 24 hour urine collection to estimate glomerular filtration.

Timepoint [7]

At baseline and 12 months post commencement of intervention

Eligibility

Key inclusion criteria

- newly diagnosed patients with type 2 diabetes and HbA1c > 6.5%.
- age between 40 and 75 years
- BMI > 25
- community dwelling
- able to visit the Repatriation Hospital
- has a general practitioner

Minimum age

40 Years

Maximum age

75 Years

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- estimated glomerular filtration rate (eGFR) < 60ml/min/1.73m2
- active drug or heavy alcohol use
- type 1 diabetes
- pregnancy or breastfeeding
- BMI<25
- previous history of bladder cancer
excluded because of unacceptable risk of adverse events from study treatment

- active malignancy
- use of warfarin, alpha – glucosidase inhibitors, gliptins, orlistat, opioids, corticosteroids
excluded because confounding factors would make outcomes difficult to interpret

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)

Participants and investigators will not be blinded to treatment allocation. Allocation will not be concealed.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomly allocated to treatment groups in a 1:1 ratio using a computer-generated randomization method.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 1

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

All statistical analyses will be based on the intent-to-treat population.
This is a pilot study and the data from this study will be used to determine the sample size calculation for a larger multicenter study. Data will be analysed using descriptive statistics.
Demographic, medical history, and baseline data will be summarised by treatment group and analysed for comparability across groups using Student’s t-tests or Wilcoxon rank sum tests for pairwise comparisons. A p-value of 0.05 or less will be considered statistically significant.
Unpaired student t tests will be undertaken to determine differences in the change in HbA1c from baseline until the end of the study between the two groups of patients.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

Actual

6/02/2017

Date of last participant enrolment

Anticipated

29/03/2019

Actual

Date of last data collection

Anticipated

11/03/2019

Actual

Sample size

Target

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

VIC

Recruitment hospital [1]

Austin Health - Heidelberg Repatriation Hospital - Heidelberg West

Recruitment postcode(s) [1]

3081 - Heidelberg Heights

Recruitment postcode(s) [2]

3081 - Heidelberg West

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Melbourne

Address [1]

The University of Melbourne
300 Waterdale Road
Level 2, Boronia Building, Heidelberg Repatriation Hospital
Heidelberg Heights, VIC 3081

Country [1]

Australia

Primary sponsor type

Hospital

Name

Austin Health

Address

Austin Hospital
145 Studley Road
PO Box 5555
Heidelberg
Victoria
Australia 3084

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Austin Health Human Research Ethics Committee

Ethics committee address [1]

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

05/04/2016

Approval date [1]

05/05/2016

Ethics approval number [1]

HREC/16/Austin/10

Summary

Brief summary

In the majority of people with newly-diagnosed type 2 diabetes, the standard medical treatment starts with metformin, followed by the addition of other medications if blood glucose levels remain elevated.  The purpose of this study is to evaluate the possible risks and the effectiveness of using three different tablets together to normalise blood glucose levels in adults with newly-diagnosed type 2 diabetes, compared with starting treatment with one tablet, and adding the other two tablets sequentially if blood glucose levels remain above normal.  All of the tablets are already available for the treatment of type 2 diabetes, but the use of all 3 together in newly diagnosed diabetes has not been studied.
Participants will be randomly assigned by a computer to receive treatment with metformin, saxagliptin and dapagliflozin together at the onset of the study, or to commence treatment with metformin, and add saxagliptin and dapagliflozin sequentially if their blood glucose levels remain above normal. 
Approximately 20 volunteers will be recruited to participate in the study. Participants’ involvement in the study will last 12 months, and include 5 study visits at the research site.  Participants will have an initial medical assessment, and receive information about blood glucose self-monitoring, diet and lifestyle habits. They will then be randomly assigned to receive metformin 2000mg daily, saxagliptin 5mg daily and dapagliflozin 10mg daily either concurrently, or sequentially over 12 months.
Participants will visit the research site every 4 months during the treatment period for monitoring. During these visits, participants will be weighed, have their blood pressure checked and blood glucose readings reviewed, and have a fasting blood and a urine test.  At the beginning and end of the 12 month treatment period, participants will be also be asked to undergo testing of their blood glucose levels in response to a meal.
Once all participants have completed the study, the study results will be analysed and released.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Elif Ekinci

Address

Department of Endocrinology
Level 2, Centaur Building
Heidelberg Repatriation Hospital
300 Waterdale Road
Heidelberg West
Victoria
Australia, 3081

Country

Australia

Phone

+61394965489

Fax

elif.ekinci@unimelb.edu.au

Contact person for public queries

Name

Elif Ekinci

Address

Department of Endocrinology
Level 2, Centaur Building
Heidelberg Repatriation Hospital
300 Waterdale Road
Heidelberg West
Victoria
Australia, 3081

Country

Australia

Phone

+61394965489

Fax

elif.ekinci@unimelb.edu.au

Contact person for scientific queries

Name

Elif Ekinci

Address

Department of Endocrinology
Level 2, Centaur Building
Heidelberg Repatriation Hospital
300 Waterdale Road
Heidelberg West
Victoria
Australia, 3081

Country

Australia

Phone

+61394965489

Fax

elif.ekinci@unimelb.edu.au

No information has been provided regarding IPD 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.

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