TriMaster - a research study to help improve treatment of type 2 diabetes, by learning how individuals respond to different blood sugar-lowering drugs
| ISRCTN | ISRCTN12039221 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12039221 |
| EudraCT/CTIS number | 2015-002790-38 |
| IRAS number | 183044 |
| ClinicalTrials.gov number | NCT02653209 |
| Secondary identifying numbers | 31613, IRAS 183044 |
- Submission date
- 02/11/2016
- Registration date
- 30/11/2016
- Last edited
- 12/12/2022
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nutritional, Metabolic, Endocrine
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 December 2021
Who is funding the study?
Medical Research Council (UK)
Who is the main contact?
Ms Catherine Angwin
c.angwin@exeter.ac.uk
Contact information
Public
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
 ORCID ID |
0000-0002-0935-5284 |
|---|---|
| Phone | +44 1392 408181 |
| c.angwin@exeter.ac.uk |
Study information
| Study design | Randomised; Interventional; Design type: Treatment, Drug |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use the contact details below to request a patient information sheet |
| 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 |
| Study 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(s) | South Central - Oxford A Research Ethics Committee, 09/05/2016, ref: 16/SC/0147 |
| Condition | Type 2 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 |
| 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 study start date | 01/08/2016 |
| Overall study end date | 14/12/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Sex | Both |
| Target number of participants | Planned Sample Size: 600; UK Sample Size: 600 |
| Total final enrolment | 525 |
| 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 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 | 31/01/2020 |
Locations
Countries of recruitment
- England
- Scotland
- United Kingdom
- Wales
Study participating centres
Barrack Road
Exeter
EX2 5DW
United Kingdom
Dundee
DD1 9SY
United Kingdom
Institute of Cardiovascular & Medical Sciences
University of Glasgow
126 University Place
Glasgow
G12 8TA
United Kingdom
Taunton
TA1 5DA
United Kingdom
Eastern Road
Brighton
BN2 5BE
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Old Road
Headington
Oxford
OX3 7LE
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
Freeman Road
High Heaton
Newcastle Upon Tyne
NE7 7DN
United Kingdom
Southwick Hill Road
Portsmouth
PO6 3LY
United Kingdom
Southmead Road
Westbury-on-Trym
Bristol
BS10 5NB
United Kingdom
Derriford Road
Plymouth
PL6 8DH
United Kingdom
Bryngwyn Mawr
Dafen
SA14 8QF
United Kingdom
Heol Maes Eglwys
Morriston
Swansea
SA6 6NL
United Kingdom
Treliske
Truro
TR1 3LJ
United Kingdom
Heath Park
Cardiff
CF14 4XW
United Kingdom
Great Maze Pond
London
SE1 9RT
United Kingdom
Canada Avenue
Redhill
RH1 5RH
United Kingdom
St Peters Road
Margate
CT9 4AN
United Kingdom
Sponsor information
Hospital/treatment centre
Royal Devon and Exeter Hospital
Research & Development Office
3rd Floor, Noy Scott House
Barrack Road
Exeter
EX2 5DW
England
United Kingdom
"ROR" |
https://ror.org/03085z545 |
|---|
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/06/2022 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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) |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol article | protocol | 01/12/2020 | Yes | No | |
| Statistical Analysis Plan | version 9 | 11/03/2021 | 24/03/2021 | No | No |
| Results article | prespecified secondary endpoint data | 07/12/2022 | 12/12/2022 | Yes | No |
| Results article | primary endpoint results | 07/12/2022 | 12/12/2022 | Yes | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
- ISRCTN12039221_SAP_V9_11Mar2021.pdf
- uploaded 24/03/2021
Editorial Notes
12/12/2022: Two publication references added.
23/02/2022: The following changes have been made:
1. The overall trial end date has been changed from 31/01/2021 to 14/12/2021 and the plain English summary has been updated to reflect this change.
2. The intention to publish date has been changed from 31/12/2021 to 30/06/2022.
21/05/2021: The intention to publish date has been changed from 31/05/2021 to 31/12/2021.
24/03/2021: The statistical analysis plan was uploaded as an additional file.
19/01/2021: The following changes were made to the trial record:
1. The trial website was added.
2. Publication reference added.
24/02/2020: The following changes have been made:
1. The total final enrolment number has been added.
2. The IRAS number has been added.
16/01/2020: ClinicalTrials.gov number added.
28/03/2019: The condition has been changed from "Specialty: Diabetes, Primary sub-specialty: Type 2; UKCRC code/ Disease: Metabolic and Endocrine/ Diabetes mellitus" to "Type 2 diabetes mellitus" following a request from the NIHR.
30/11/2018: The intention to publish date was changed from 31/03/2020 to 31/05/2021.
22/11/2018: The following changes were made:
1. The recruitment end date was changed from 31/07/2019 to 31/01/2020.
2. The overall trial end date was changed from 31/01/2020 to 31/01/2021.
