Clinical trial NCT02653209: TriMaster: Study of a DPP4 Inhibitor, SGLT2 Inhibitor and Thiazolidinedione as Third Line Therapy in Patients With Type 2 Diabetes.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Type 2 Diabetes
Keywords: Type 2 diabetes
Stratification
Biomarkers
Pharmacogenetics
SGLT2 inhibitors
Thiazolidinediones
DPP4 inhibitors
Lead sponsor: Royal Devon and Exeter NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Exeter
name: NHS Tayside
name: University of Dundee
name: University of Glasgow
name: Newcastle University
name: King's College London
First posted: 2016-01-12
Enrollment: 525
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

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.

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.

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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
* 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

Primary outcomes:
measure: On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients
timeFrame: 16 weeks
measure: On treatment HbA1c in patients with an eGFR <90 mls/min/1.73m2 compared to patients with an eGFR >90 mls/min/1.73m2.
timeFrame: 16 weeks
Secondary outcomes:
measure: Patient preference
timeFrame: 48-54 weeks (3 x 16 weeks of therapy)
measure: Prevalence of side effects
timeFrame: 48-54 weeks (3 x 16 weeks of therapy)
measure: HbA1c on therapy against predefined test of gender heterogeneity
timeFrame: 16 weeks
Other outcomes:
Locations:
city: Exeter
country: United Kingdom
facility: Exeter Clinical Research Facility
Study officials:
affiliation: University of Exeter / Royal Devon & Exeter NHS Trust
name: Andrew Hattersley
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.