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

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.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes
• Intervention / Treatment: Drug: Sitagliptin - DPP4i; Drug: Canagliflozin - SGLT2i; Drug: Pioglitazone - TZD

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.

• Study Type: Interventional
• Enrollment (Actual): 525
• Phase: Phase 4

Contacts and Locations

Study Locations

• United Kingdom
  • Exeter, United Kingdom, EX2 5DW
    • Exeter Clinical Research Facility

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin - DPP4i	Drug: Sitagliptin - DPP4i; 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.; Other Names: Januvia
Experimental: Canagliflozin - SGLT2i	Drug: Canagliflozin - SGLT2i; 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.; Other Names: Invokana
Experimental: Pioglitazone - TZD	Drug: Pioglitazone - TZD; 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.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: Respond well to pioglitazone, a thiazolidinedione that works as an insulin sensitiser.; Respond less well to sitagliptin, a DPP4i, which works through stimulating endogenous insulin secretion post-prandially.	16 weeks
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: 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.; Respond well to sitagliptin, a DPP4i that is renally cleared, as the reduced eGFR will increase plasma DPP4i concentrations.	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient preference	Patient treatment preference of study drug within hypothesised strata and overall	48-54 weeks (3 x 16 weeks of therapy)
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	48-54 weeks (3 x 16 weeks of therapy)
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.	16 weeks

Collaborators and Investigators

• Sponsor: Royal Devon and Exeter NHS Foundation Trust
• Collaborators: King's College London; Newcastle University; NHS Tayside; University of Dundee; University of Exeter; University of Glasgow
• Investigators: Principal Investigator: Andrew Hattersley, University of Exeter / Royal Devon & Exeter NHS Trust

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2016
• Primary Completion (Actual): January 1, 2021
• Study Completion (Actual): January 1, 2021

Study Registration Dates

• First Submitted: January 8, 2016
• First Submitted That Met QC Criteria: January 8, 2016
• First Posted (Estimate): January 12, 2016

Study Record Updates

• Last Update Posted (Actual): April 1, 2021
• Last Update Submitted That Met QC Criteria: March 30, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Type 2 diabetes; Biomarkers; Pharmacogenetics; SGLT2 inhibitors; Stratification; Thiazolidinediones; DPP4 inhibitors
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Pioglitazone; Sitagliptin Phosphate; Canagliflozin
• Other Study ID Numbers: 1603221; 2015-002790-38 (EudraCT Number); 12039221 (Registry Identifier: ISRCTN); MR/N00633X/1 (Other Grant/Funding Number: Medical Research Council, UK)