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

Sponsor

Royal Devon and Exeter NHS Foundation Trust (Other)

Overall Status

Completed

CT.gov ID

NCT02653209

Collaborator

University of Exeter (Other), NHS Tayside (Other), University of Dundee (Other), University of Glasgow (Other), Newcastle University (Other), King's College London (Other)

525

Enrollment

Location

Arms

Actual Duration (Months)

10.5

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes	Drug: Sitagliptin - DPP4i Drug: Canagliflozin - SGLT2i Drug: Pioglitazone - TZD	Phase 4

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 Design

Study Type:

Interventional

Actual Enrollment :

525 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Nov 1, 2016

Actual Primary Completion Date :

Jan 1, 2021

Actual Study Completion Date :

Jan 1, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients [16 weeks]
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.
On treatment HbA1c in patients with an eGFR <90 mls/min/1.73m2 compared to patients with an eGFR >90 mls/min/1.73m2. [16 weeks]
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.

Secondary Outcome Measures

Patient preference [48-54 weeks (3 x 16 weeks of therapy)]
Patient treatment preference of study drug within hypothesised strata and overall
Prevalence of side effects [48-54 weeks (3 x 16 weeks of therapy)]
Prevalence of side effects within hypothesised strata and for specific drugs, to include: weight gain, hypoglycaemia, oedema, genital tract infection and discontinuation of therapy
HbA1c on therapy against predefined test of gender heterogeneity [16 weeks]
Predefined test of gender heterogeneity with pilot data suggesting females are likely to show an improved response relative to males for pioglitazone.

Eligibility Criteria

Criteria

Ages Eligible for Study:

30 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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