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Type 2 DiabetesPhase 4TriMasterNCT02653209

TriMaster: Study of a DPP4 Inhibitor, SGLT2 Inhibitor and Thiazolidinedione as Third Line Therapy in Patients With Type 2 Diabetes.

A Phase 4 study testing Sitagliptin - DPP4i, Canagliflozin - SGLT2i and Pioglitazone - TZD in people with Type 2 Diabetes, run by Royal Devon and Exeter NHS Foundation Trust at 1 site in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The aim of this project is to identify subgroups of patients with type 2 diabetes that respond well or poorly to particular drugs based on particular clinical characteristics such as their weight or kidney function, to enable better targeting of treatment for a particular individual. Read more about this study

Who is it for?
Ages 30 to 80 years
Conditions the study is for
Type 2 Diabetes
What is being tested?
Sitagliptin - DPP4i, Canagliflozin - SGLT2i and Pioglitazone - TZD
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
525 participants
Where
1 siteUnited Kingdom
Study dates
1 Nov 2016to Jan 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 30 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Clinical diagnosis of Type 2 diabetes
  • Age ≥30 and ≤80
  • 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.
  • Diabetes duration ≥12months
  • No change in diabetes treatment (new treatments or dose change) within previous 3 months
  • HbA1c > 58mmol/mol (7.5%) and ≤110mmol/mol (12.2%) - confirmed at screening visit
  • eGFR ≥ 60mls/min/1.73m² - confirmed at screening visit
  • Able and willing to give informed consent

Who cannot join

  • Changes in glucose-lowering therapy or dose within last 3 months
  • HbA1c ≤ 58mmol/mol (7.5%) or >110mmol/mol (12.2%)
  • eGFR <60mls/min/1.73m².
  • Diabetes duration <12 months
  • ALT >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.
  • Insulin treated within the last 12 months
Show all 23Show fewer
  • Limb ischaemia shown by absence of both pulses in one or both feet.
  • Currently treated with corticosteroids
  • Currently treated with rifampicin, gemfibrozil, phenytoin and carbamazepine
  • Active infection (any infection requiring antibiotics at present)
  • Foot ulcer requiring antibiotics within previous three months
  • Recent (within 3 months) significant surgery or planned surgery (excluding minor procedures)
  • Acute cardiovascular episode (angina, myocardial infarction, stroke, transient ischemic episode) occurring within the previous 3 months
  • History of heart failure
  • Current use of loop diuretic therapy (Furosemide or Bumetanide)
  • History of bladder carcinoma
  • Current/ongoing investigation for macroscopic haematuria
  • History of Diabetic Ketoacidosis
  • History of pancreatitis
  • Pregnant, breastfeeding or planning a pregnancy over the study period
  • Concurrent Participation on another Clinical Trial of an Investigational Medicinal Product, where the IMP is currently being taken, or without sufficient washout period* and without consultation with the CTIMP research team.
  • Unable or unwilling to give informed consent
  • Sufficient washout period = five times the half-life of the IMP / potential IMP if involving a placebo / longest half-life if a trial includes more than one drug

Trial locations and contacts

1 site in 1 country.

United Kingdom1 site
  • Exeter Clinical Research Facility

    Exeter, EX2 5DW

Other trials in United Kingdom

About this study

Official 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

The aim of this project is to identify subgroups of patients with type 2 diabetes that respond well or poorly to particular drugs based on particular clinical characteristics such as their weight or kidney function, to enable better targeting of treatment for a particular individual.

This study will test 2 hypotheses of drug response supported by routine clinical and trial data. 600 patients with type 2 diabetes who have suboptimal glycaemic control on dual oral therapy will be recruited to a randomised double-blind crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione. Each patient will take each study drug in addition to their existing treatment for four months at a time. At the end of each treatment the patient's glucose control will be measured and information about their experience of the drug will be collected.

Read the detailed description

The study is a phase 4 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.

600 patients aged 30-80 who have been on stable doses of 2 classes of therapy (not including the trial IMPs or GLP1-agonist) for at least 3 months with HbA1c >58mmol/mol (7.5%) will receive three double-blinded third-line non-injectable therapies. On recruitment into the study participants will have underlying pathophysiology assessed in a mixed-meal tolerance test (MMTT) and samples will be collected for baseline analysis and storage for future biomarker analysis and discovery. Participants will then receive 16 weeks of each over-encapsulated blinded therapy in random order.

At the end of each treatment period, fasting blood will be taken to measure glycaemic response (HbA1c), fasting glucose and insulin concentrations trough drug levels and to confirm continued eligibility. Weight, blood pressure and. data about patient experience will also be collected including perceived side effects, preparedness to remain on therapy, psychological health and health related quality of life.

At the end of the study, patient treatment preference will be recorded after feeding back to the patient for each of the 3 therapies their HbA1c, weight change, frequency of hypoglycaemias, any patient reported side effects and the patient's verdict on each therapy will be recorded. Each participant will be asked which treatments they would take long term and the reason for their preference.

Conditions
Type 2 Diabetes
Being tested
Sitagliptin - DPP4i, Canagliflozin - SGLT2i, Pioglitazone - TZD
Keywords
Type 2 diabetes, Stratification, Biomarkers, Pharmacogenetics, SGLT2 inhibitors, Thiazolidinediones, DPP4 inhibitors
Medical subject headings
Diabetes Mellitus, Type 2

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Sitagliptin - DPP4iDrug

    Also called Januvia

    DPP4 inhibitor 100mg supplied as over-encapsulated hard capsule shell to be taken orally, once a day for 16 weeks in addition to existing prescribed oral diabetes therapy.

  • Canagliflozin - SGLT2iDrug

    Also called Invokana

    SGLT2 inhibitor 100mg supplied as over-encapsulated hard capsule shell to be taken orally, once a day for 16 weeks in addition to existing prescribed oral diabetes therapy.

  • Pioglitazone - TZDDrug

    Also called Actos

    Thiazolidinedione 30mg supplied as over-encapsulated hard capsule shell to be taken orally, once a day for 16 weeks in addition to existing prescribed oral diabetes therapy.

Study groups in NCT02653209
Study groupRoleWhat they receive
Sitagliptin - DPP4iExperimentalNot described
Receives: Drug: Sitagliptin - DPP4i
Canagliflozin - SGLT2iExperimentalNot described
Receives: Drug: Canagliflozin - SGLT2i
Pioglitazone - TZDExperimentalNot described
Receives: Drug: Pioglitazone - TZD

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients

    Outcome measure will test hypothesis that patients with insulin resistance, characterised clinically by a raised BMI (>30 kg/m2), compared to non-obese patients, will:

    1. Respond well to pioglitazone, a thiazolidinedione that works as an insulin sensitiser.
    2. Respond less well to sitagliptin, a DPP4i, which works through stimulating endogenous insulin secretion post-prandially.

    Measured: 16 weeks

  2. On treatment HbA1c in patients with an eGFR <90 mls/min/1.73m2 compared to patients with an eGFR >90 mls/min/1.73m2.

    Outcome measure will test hypothesis that 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:

    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. Respond well to sitagliptin, a DPP4i that is renally cleared, as the reduced eGFR will increase plasma DPP4i concentrations.

    Measured: 16 weeks

Secondary outcomes (3)
  1. Patient preference

    Patient treatment preference of study drug within hypothesised strata and overall

    Measured: 48-54 weeks (3 x 16 weeks of therapy)

  2. Prevalence of side effects

    Prevalence of side effects within hypothesised strata and for specific drugs, to include: weight gain, hypoglycaemia, oedema, genital tract infection and discontinuation of therapy

    Measured: 48-54 weeks (3 x 16 weeks of therapy)

  3. HbA1c on therapy against predefined test of gender heterogeneity

    Predefined test of gender heterogeneity with pilot data suggesting females are likely to show an improved response relative to males for pioglitazone.

    Measured: 16 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jan 2016 (estimated)
  2. Study start1 Nov 2016
  3. Primary completionJan 2021
  4. Study completionJan 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
525 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02653209
Sponsor's protocol ID
1603221
Other IDs
2015-002790-38, 12039221, MR/N00633X/1, 2015
Acronym
TriMaster
Status last verified
Mar 2021
First submitted
8 Jan 2016
Last updated
1 Apr 2021
Results posted
No
Data monitoring committee
Yes

Publications

  • Shields BM, Angwin CD, Shepherd MH, Britten N, Jones AG, Sattar N, Holman R, Pearson ER, Hattersley AT. Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study. Nat Med. 2023 Feb;29(2):384-391. doi: 10.1038/s41591-022-02121-6. Epub 2022 Dec 7.

    PubMed 36477734
  • Shields BM, Dennis JM, Angwin CD, Warren F, Henley WE, Farmer AJ, Sattar N, Holman RR, Jones AG, Pearson ER, Hattersley AT; TriMaster Study group. Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study. Nat Med. 2023 Feb;29(2):376-383. doi: 10.1038/s41591-022-02120-7. Epub 2022 Dec 7.

    PubMed 36477733
  • Angwin C, Jenkinson C, Jones A, Jennison C, Henley W, Farmer A, Sattar N, Holman RR, Pearson E, Shields B, Hattersley A; MASTERMIND consortium. TriMaster: randomised double-blind crossover study of a DPP4 inhibitor, SGLT2 inhibitor and thiazolidinedione as second-line or third-line therapy in patients with type 2 diabetes who have suboptimal glycaemic control on metformin treatment with or without a sulfonylurea-a MASTERMIND study protocol. BMJ Open. 2020 Dec 21;10(12):e042784. doi: 10.1136/bmjopen-2020-042784.

    PubMed 33371044

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Sitagliptin - DPP4i, Canagliflozin - SGLT2i and Pioglitazone - TZD in people with Type 2 Diabetes, run by Royal Devon and Exeter NHS Foundation Trust at 1 site in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 8 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients (time frame: 16 weeks). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02653209, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Apr 2021.

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