Condition category
Nutritional, Metabolic, Endocrine
Date applied
02/11/2016
Date assigned
30/11/2016
Last edited
30/11/2016
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Type 2 Diabetes is a common health condition where the sufferer has difficulty controlling their blood sugar (glucose) as they do not produce enough insulin to function properly (insulin deficiency), or that the body’s cells don’t react to insulin as they should do (insulin resistance). Over 4% of the population has Type 2 diabetes. It is a major cause of illness and accounts for around 10% of the money spent in the NHS. Good control of blood sugar with appropriate life style and medication makes patients feel better and reduces the risks of complications of diabetes. The current guidelines for treatment of patients with Type 2 diabetes list a large number of drugs without giving clear guidance on which patients should have which drugs. This makes it difficult for patients and their health care professionals to know which drugs are likely to suit them best. In type 2 diabetes, it is common for additional treatments to be added over time to maintain, or lower, blood sugar levels. Responses to this change of treatment can vary between individuals, but little is known about why this happens. If it was possible to predict which medicine is likely to work for a person, the most effective treatment could be chosen from the start, avoiding ineffective medicines and unnecessary side effects. This study is looking at three standard diabetes treatments which can be added when two existing medicines stop maintaining good blood sugar levels. The aim of this study is to compare how patients with different blood sugar levels, weight and kidney function respond, and which treatment each patient prefers.

Who can participate?
Adults aged between 30 and 80 who have Type 2 Diabetes and are currently taking two oral diabetes medications but whose blood sugar levels mean they need an additional (third) medication.

What does the study involve?
Participants are assigned to undergo treatment with three different study drugs in a random order for 16 weeks. Before each medicine cycle, participants attend a study visit with a research nurse, where they undergo repeated blood sampling after drinking a ‘meal’ drink (like a milkshake) to test the pattern of their blood sugar levels. At the end of visit the participants are given their first pot of study medication. All of the medications are in the form of a plain capsule to be taken once a day in addition to existing diabetes medications. The participant is also be given them a card to carry with them in case a doctor needs to know which treatment they are taking in an emergency. While they are taking the medications, participants are asked to keep a note of any new symptoms they. At the end of all three medicine cycles, participants are interviewed to find out which medication they preferred. In addition, their blood sugar tests before and after each cycle are compared to see which medication was most effective for them.

What are the possible benefits and risks of participating?
The main benefit for research participants is that future care could be informed and improved by results from the study which show which patients may do best on which treatment. In addition, we are recruiting patients who need another (third) therapy to maintain good blood sugar levels. These participants will be able to ‘test’ the 3 available drugs that their doctor could prescribe, in a trial setting, with support from the research team. At the end of their study involvement, participants and their clinicians will receive un-blinded results of blood sugar tests, weight, and frequency of side effects. Clinicians will be able to use this data alongside the participant's medical history, their own clinical judgement and the patient's preference to make an informed decision about recommended future treatment. The main risk to participants is the risk of low blood sugar (hypoglycaemia) and other side effects from the study drugs. If a participant has a very good response to a study drug they could be at some risk of low blood sugar. Long term hypoglycaemia can lead to complications but the brief period which would be possible in the study is of very low risk. By taking a standard diabetes drug in a trial setting participants will receive equal if not better care and support than if this was prescribed by their usual doctor. We will take steps to make sure participants are closely monitored and have instructions for what to do should they experience low blood sugar. Participants may also experience some side effects whilst taking the study drugs. These drugs are all licensed, well-established medications recommended by NICE for these patients. They will be prescribed as per usual clinical care guidelines in a standard dose. All medications can result in side effects and participants will be provided with a list of common, uncommon and serious potential side effects and what to do should they occur before they choose to take part.

Where is the study run from?
Royal Devon and Exeter Hospital (lead centre) and 19 other hosptials in England, Scotland and Wales (UK)

When is the study starting and how long is it expected to run for?
August 2016 to January 2020

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Ms Catherine Angwin
c.angwin@exeter.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Ms Catherine Angwin

ORCID ID

Contact details

University of Exeter Medical School and NIHR Exeter CRF
RILD
L3 Rm 2.15
Royal Devon and Exeter Hospital (Wonford)
Barrack Road
Exeter
EX2 5DW
United Kingdom
+44 1392 408181
c.angwin@exeter.ac.uk

Additional identifiers

EudraCT number

2015-002790-38

ClinicalTrials.gov number

Protocol/serial number

31613

Study information

Scientific title

TriMaster: Randomised Double-Blind Crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione as third line therapy in patients with type 2 diabetes who have suboptimal glycaemic control on dual therapy with metformin and a sulphonylurea

Acronym

TriMaster

Study hypothesis

Hypotheses:
1. Patients with insulin resistance, characterised clinically by a raised BMI (>30 kg/m2), compared to non-obese patients, will:
1.1. Respond well to pioglitazone, a thiazolidinedione that works as an insulin sensitiser
1.2. Respond less well to sitagliptin, a DPP4i, which works through stimulating endogenous insulin secretion post-prandially.
2. Patients with modestly reduced estimated glomerular filtration rate (eGFR 60-90 mls/min/1.73m2), compared to those with eGFR >90 mls/min/1.73m2, will:
2.1. Respond poorly to canagliflozin, a SGLT2 inhibitor, which works through inhibiting the active reabsorption of glucose in the proximal tubule, as the reduced eGFR will reduce the glucose-lowering efficacy
2.2. Respond well to sitagliptin, a DPP4i that is renally cleared, as the reduced eGFR will increase plasma DPP4i concentrations

Ethics approval

South Central - Oxford A Research Ethics Committee, 09/05/2016, ref: 16/SC/0147

Study design

Randomised; Interventional; Design type: Treatment, Drug

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Diabetes, Primary sub-specialty: Type 2; UKCRC code/ Disease: Metabolic and Endocrine/ Diabetes mellitus

Intervention

All participants receive all three treatments in random order, according to one of six possible treatment order ABC, ACA, BAC, BCA, CAB, CBA.

The treatment study drugs are over-encaspulated capsules taken once a day for 16 weeks (16-18 week window).
1. Pioglitazone 30mg
2. Sitagliptin 100mg
3. Canagliflozin 100mg

Following screening and confirmation of eligibility, participants are randomises by the trial database and allocated a treatment order. They then receive the three treatments for 16-18 weeks at a time, with no washouts between treatment periods.

At the end of each treatment period participants attend a research visit for sample and data collection. A final follow-up visit is conducted 2-4 weeks after all study treatments have concluded.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Glycated haemoglobin (HbA1c) is measured using a HbA1c test on blood samples collected at baseline, 8 and 16 weeks of each treatment cycle.

Secondary outcome measures

Patient treatment preference will be recorded through participant interviews at the end of the study.

Overall trial start date

01/08/2016

Overall trial end date

31/01/2020

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Clinical diagnosis of Type 2 diabetes
2. Age ≥30 and ≤80
3. Currently treated with two classes of oral glucose-lowering therapy (given either as separate or combined medications), that do not include a DPP4-inhibitor, a SGLT2-inhibitor or a thiazolidinedione. This is likely to be metformin and sulphonylurea but may include prandial glucose regulators nateglinide or repaglinide.
4. No change in diabetes treatment (new treatments or dose change) within previous 3 months
5. HbA1c > 58mmol/mol (7.5%) – confirmed at screening visit
6. eGFR ≥ 60mls/min/1.73m² - confirmed at screening visit
7. Able and willing to give informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 600; UK Sample Size: 600

Participant exclusion criteria

1. Changes in glucose-lowering therapy or dose within last 3 months
2. HbA1c ≤ 58mmol/mol (7.5%)
3. eGFR 2.5 x upper limit of the assay normal range or known liver disease, specifically >30 μmol/L that is associated with other evidence of liver failure.
4. Currently treated with corticosteroids
5. Active infection (any infection requiring antibiotics at present)
6. Active foot ulcer
7. Recent (within 3 months) significant surgery or planned surgery (excluding minor procedures)
8. Acute cardiovascular episode (angina, myocardial infarction, stroke, transient ischemic episode) occurring within the previous 3 months
9. History of heart failure or current use of loop diuretic therapy (Furosemide or Bumetanide)
10. History of bladder carcinoma or current/ongoing investigation for macroscopic haematuria
11. History of Diabetic Ketoacidosis or pancreatitis
12. Pregnant, breastfeeding or planning a pregnancy over the study period
13. Concurrent Participation on another Clinical Trial of an Investigational Medicinal Product
14. Unable or unwilling to give informed consent

Recruitment start date

01/11/2016

Recruitment end date

31/07/2019

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Devon and Exeter Hospital
Royal Devon and Exeter NHS Foundation Trust Barrack Road
Exeter
EX2 5DW
United Kingdom

Trial participating centre

Ninewells Hospital & Medical School
NHS Tayside
Dundee
DD1 9SY
United Kingdom

Trial participating centre

BHF Glasgow Cardiovascular Research Centre
Greater Glasgow & Clyde Health Board - BHF CGRC Institute of Cardiovascular & Medical Sciences University of Glasgow 126 University Place
Glasgow
G12 8TA
United Kingdom

Trial participating centre

Musgrove Park Hospital
Taunton and Somerset NHS Foundation Trust
Taunton
TA1 5DA
United Kingdom

Trial participating centre

Royal Sussex County Hospital
Brighton and Sussex University Hospitals NHS Trust Eastern Road
Brighton
BN2 5BE
United Kingdom

Trial participating centre

Manchester Royal Infirmary
Central Manchester University Hospitals NHS Foundation Trust Oxford Road
Manchester
M13 9WL
United Kingdom

Trial participating centre

Churchill Hospital
Oxford University Hospitals Old Road Headington
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Northern General Hospital
Sheffield Teaching Hospitals NHS Foundation Trust Herries Road
Sheffield
S5 7AU
United Kingdom

Trial participating centre

Freeman Hospital
The Newcastle Upon Tyne Hospitals NHS Foundation Trust Freeman Road High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom

Trial participating centre

Queen Alexandra Hospital
Portsmouth Hospitals NHS Trust Southwick Hill Road
Portsmouth
PO6 3LY
United Kingdom

Trial participating centre

Southmead Hospital
North Bristol NHS Trust Southmead Road Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom

Trial participating centre

Derriford Hospital
Plymouth Hospitals NHS Trust Derriford Road
Plymouth
PL6 8DH
United Kingdom

Trial participating centre

Prince Philip Hospital
Hywel Dda University Health Board Bryngwyn Mawr
Dafen
SA14 8QF
United Kingdom

Trial participating centre

Morriston Hospital
Abertawe Bro Morgannwg University Health Board Heol Maes Eglwys Morriston
Swansea
SA6 6NL
United Kingdom

Trial participating centre

Royal Cornwall Hospital
Royal Cornwall Hospitals NHS Trust Treliske
Truro
TR1 3LJ
United Kingdom

Trial participating centre

University Hospital of Wales
Cardiff and Vale University Health Board Heath Park
Cardiff
CF14 4XW
United Kingdom

Trial participating centre

Guy's Hospital
Guy's and St Thomas' NHS Foundation Trust Great Maze Pond
London
SE1 9RT
United Kingdom

Trial participating centre

East Surrey Hospital
Surrey and Sussex Health NHS Trust Canada Avenue
Redhill
RH1 5RH
United Kingdom

Trial participating centre

Queen Elizabeth The Queen Mother Hospital
East Kent Hospitals University NHS Foundation Trust St Peters Road
Margate
CT9 4AN
United Kingdom

Sponsor information

Organisation

Royal Devon and Exeter NHS Foundation Trust

Sponsor details

Royal Devon and Exeter Hospital
Research & Development Office
3rd Floor
Noy Scott House
Barrack Road
Exeter
EX2 5DW
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Research council

Funder name

Medical Research Council

Alternative name(s)

MRC

Funding Body Type

government organisation

Funding Body Subtype

Federal/National Government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

Data and results related to protocol-derived outcomes will be published by the MASTERMIND consortium. A lay summary of results will be provided to all participants. Analysis will be conducted from recruitment end with results intended for publication from early 2020 onwards.

IPD Sharing plan:
The datasets generated during and/or analysed during the current study are/will be available upon request from the Chief Investigator Andrew Hattersley (A.T.Hattersley@exeter.ac.uk)

Intention to publish date

31/03/2020

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes