ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12615000732583

Ethics application status

Approved

Date submitted

4/07/2015

Date registered

16/07/2015

Date last updated

16/07/2015

Type of registration

Prospectively registered

Titles & IDs

Public title

Stop or Replace: Effect of stopping sulfonylureas or replacing sulfonylureas with a dipeptidyl peptidase 4 (DPP-IV) inhibitor in Type 2 diabetes patients on pre-mix insulin.

Scientific title

STop Or REplace – STORE: Patients with type 2 diabetes on pre-mix insulin: Impact of stopping sulfonylureas or of replacing sulfonylureas with a DPP-IV Inhibitor on glycaemic control, hypoglycaemia and body weight.

Secondary ID [1]

NIL

Universal Trial Number (UTN)

Trial acronym

STORE

Linked study record

Health condition

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

type 2 diabetes

Condition category

Condition code

Metabolic and Endocrine

Diabetes

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Prospective, randomised, open label, controlled trial with three arms
1.) Patients continue Sulfonylurea (oral tablet, no change in product, dose or frequency)
2.) Patients stop Sulfonylurea
3.) Patients replace Sulfonylurea with the DPP4 inhibitor Linagliptin (oral tablet, 5mg/day)
Study duration: 6 months
Other medications (for diabetes or other conditions) will be continued.
Adherence will be monitored by pill count of returned tablets at follow-up visits

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Patients randomised to continue sulfonylureas will act as the control arm. They will take at least one sulfonylurea class drug at the dose that they would normally take for diabetes management under standard care.

Control group

Active

Outcomes

Primary outcome [1]

To measure the change in glycaemic control when stopping SU or replacing SU with a DPP-4 inhibitor in patients on pre-mix insulin. This will be assessed by:
a) HbA1c
b) 4-point capillary blood glucose measurements done by patients at home, at least 7 continuous days preceding the appointment.

Timepoint [1]

Outcomes will be assessed at 3 and 6 months and compared to baseline measures.

Secondary outcome [1]

Changes in body weight (weight gain is a common side side effects of sulfonylureas).
This will be assessed by measuring body weight by the same calibrated hospital scale at the time of each study visit.

Timepoint [1]

These outcomes will be assessed at 3 and 6 months and compared to baseline measures.

Secondary outcome [2]

Frequency and severity of hypoglycaemic episodes.
This will be assessed by standard questions to the patients as well as review of the patient's blood glucose diary at the time of study visit.

Timepoint [2]

These outcomes will be assessed at 3 and 6 months and compared to baseline measures.

Eligibility

Key inclusion criteria

- Diagnosed with type 2 diabetes
- Taking sulfonylurea since > 4 years
- Taking NovoMix30 or HumalogMix25 at least twice daily since more than 6 months
- Stable dose of current regular medication in last 4 weeks

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- HbA1c > 8.5%
- Already on DPP-4 inhibitor
- Intolerance or contraindication to DPP-4 inhibitors
- Unstable micro- or macrovascular complications within last 3 months
- Non-adherence to medications or glucose monitoring
- Type 1 diabetes

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

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Parallel

Other design features

Phase

Phase 4

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

27/07/2015

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]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

St Vincent's Hospital Sydney

Address [1]

390 Victoria Street, Darlinghurst NSW 2010

Country [1]

Australia

Funding source category [2]

Commercial sector/Industry

Name [2]

Competitive Grant from Regional Diabetes Support Scheme, Novo Nordisk

Address [2]

Novo Nordisk Pharmaceuticals Pty. Ltd.
PO Box 7586
Baulkham Hills Business Centre NSW 2153
Australia

Country [2]

Australia

Primary sponsor type

Hospital

Name

St Vincent's Hospital Sydney

Address

390 Victoria Street, Darlinghurst NSW 2010

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

St Vincent's Hospital HREC

Ethics committee address [1]

St Vincent's Hospital
Research Office
L6 De Lacey Building
390 Victoria Street
Darlinghurst NSW 2010

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

02/02/2015

Approval date [1]

05/06/2015

Ethics approval number [1]

HREC/15/SVH/34

Summary

Brief summary

The emerging epidemic of type 2 diabetes, coupled with finite health resources, requires the treatment of hyperglycaemia to be simple and efficiently managed. Type 2 diabetes is a progressive disease and eventually most patients will require insulin at a certain stage to maintain good glycaemic control. 
The key to when to start insulin is to identify the appropriate glycated haemoglobin (HbA1c) target for an individual patient.  If target A1C is not achieved with metformin combined with sulfonylurea, the most commonly used 2nd line oral hypoglycaemic agents, insulin therapy is usually started. In patients on sulfonylureas and metformin who are starting insulin therapy, metformin is usually continued. Part of the rationale for combination oral hypoglycaemic agents and insulin therapy is that by suppressing hepatic glucose production, the patient can retain the convenience of oral agents while minimizing total insulin requirements and, therefore, the degree of hyperinsulinemia. GLP-1 agonists, DPP-4 inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors can also be continued when insulin is added, however, they are currently not PBS listed for being combined with insulin. There are no clear guidelines as to whether and at what time point SU are to be discontinued or continued when insulin is introduced. Data from the UKPDS and meta-analyses of several randomized placebo-controlled trials report modest but consistent benefits of a combination of sulfonylurea and metformin with insulin therapy compared with insulin monotherapy. However, the combination of sulfonylurea and insulin is less efficacious and results in more weight gain than metformin and insulin. Furthermore, insulin and sulfonylureas have similar effects of increasing circulating insulin levels, and the same glucose-lowering effect can usually be achieved, and at a lower cost and better prediction, with a modestly higher dose of insulin alone. Furthermore, a recent retrospective Danish study has found that patients with a combination with SU and insulin had an increased mortality compared to metformin and insulin. Studies also report increased risks of weight gain and hypoglycaemia when left on SU while starting basal or pre-mixed insulins.
Based on this recent literature review, it is a concern that many patients with Type 2 Diabetes are continuing their SU together with their pre-mix insulin, with limited evidence for an added benefit, but a growing evidence of increased risk of hypoglycaemia, weight gain and possibly increased mortality. The outcome of this study will give as important information which could lead to a change in current practice guidelines.
The aim of our study is to assess whether SU should be stopped, continued or replaced with a DPP4 Inhibitor once pre-mixed insulin therapy has been started.  
We hypothesise that SU will not have a significant additive effect on glycaemic control in patients on pre-mix insulin, but contribute significantly to increased risk of hypoglycaemia and weight gain. A similar glycaemic control can be achieved by a dose adjustment of the insulin dose, or by adding a DPP-IV inhibitor without the side effects of SU, such as hypoglycaemia and weight gain.
Results of this study could have an important impact on how type 2 diabetes patients are treated safely and effectively.

PRIMARY OUTCOMES:
To measure the change in glycaemic control when stopping SU or replacing SU with a DPP-4 inhibitor in patients on pre-mix insulin. 
SECONDARY OUTCOMES
To compare the side effects (weight gain) and safety (hypoglycaemia) of stopping SU or replacing SU with a DPP-4 inhibitor in patients with pre-mix insulin.
This is a prospective, randomised, open label controlled single centre trial with three arms: 
a)	Patients continue SU
b)	Patients stop SU
c)	Patients replace SU with the DPP4 inhibitor Linagliptin (5mg/day)

Patient characteristics: Patients with Type 2 Diabetes treated with pre-mix insulin (NovoMix30 or HumalogMix25), at least twice daily for at least 6 months, and also treated with SU since at least 4 years. 99 patients in total (33 patients per arm) will be recruited at St Vincent’s Hospital, Sydney.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Alexander Viardot

Address

Diabetes Service, Department of Endocrinology
St Vincent's Hospital
Level 4, Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010

Country

Australia

Phone

+61 2 8382 2622

Fax

a.viardot@garvan.org.au

Contact person for public queries

Name

Alexander Viardot

Address

Diabetes Service, Department of Endocrinology
St Vincent's Hospital
Level 4, Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010

Country

Australia

Phone

+61 2 8382 2622

Fax

a.viardot@garvan.org.au

Contact person for scientific queries

Name

Alexander Viardot

Address

Diabetes Service, Department of Endocrinology
St Vincent's Hospital
Level 4, Garvan Institute of Medical Research
384 Victoria Street
Darlinghurst NSW 2010

Country

Australia

Phone

+61 2 8382 2622

Fax

a.viardot@garvan.org.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

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