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

Primary Purpose

Type 2 Diabetes

Status
Completed
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Sitagliptin - DPP4i
Canagliflozin - SGLT2i
Pioglitazone - TZD
Sponsored by
Royal Devon and Exeter NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Type 2 Diabetes focused on measuring Type 2 diabetes, Stratification, Biomarkers, Pharmacogenetics, SGLT2 inhibitors, Thiazolidinediones, DPP4 inhibitors

Eligibility Criteria

30 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Exeter Clinical Research Facility

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Sitagliptin - DPP4i

Canagliflozin - SGLT2i

Pioglitazone - TZD

Arm Description

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Patient preference
Patient treatment preference of study drug within hypothesised strata and overall
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
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.

Full Information

First Posted
January 8, 2016
Last Updated
March 30, 2021
Sponsor
Royal Devon and Exeter NHS Foundation Trust
Collaborators
University of Exeter, NHS Tayside, University of Dundee, University of Glasgow, Newcastle University, King's College London
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1. Study Identification

Unique Protocol Identification Number
NCT02653209
Brief Title
TriMaster: Study of a DPP4 Inhibitor, SGLT2 Inhibitor and Thiazolidinedione as Third Line Therapy in Patients With Type 2 Diabetes.
Acronym
TriMaster
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

2. Study Status

Record Verification Date
March 2021
Overall Recruitment Status
Completed
Study Start Date
November 1, 2016 (Actual)
Primary Completion Date
January 2021 (Actual)
Study Completion Date
January 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Royal Devon and Exeter NHS Foundation Trust
Collaborators
University of Exeter, NHS Tayside, University of Dundee, University of Glasgow, Newcastle University, King's College London

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Type 2 Diabetes
Keywords
Type 2 diabetes, Stratification, Biomarkers, Pharmacogenetics, SGLT2 inhibitors, Thiazolidinediones, DPP4 inhibitors

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
525 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Sitagliptin - DPP4i
Arm Type
Experimental
Arm Title
Canagliflozin - SGLT2i
Arm Type
Experimental
Arm Title
Pioglitazone - TZD
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Sitagliptin - DPP4i
Other Intervention Name(s)
Januvia
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Canagliflozin - SGLT2i
Other Intervention Name(s)
Invokana
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Pioglitazone - TZD
Other Intervention Name(s)
Actos
Intervention Description
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.
Primary Outcome Measure Information:
Title
On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients
Description
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.
Time Frame
16 weeks
Title
On treatment HbA1c in patients with an eGFR <90 mls/min/1.73m2 compared to patients with an eGFR >90 mls/min/1.73m2.
Description
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.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Patient preference
Description
Patient treatment preference of study drug within hypothesised strata and overall
Time Frame
48-54 weeks (3 x 16 weeks of therapy)
Title
Prevalence of side effects
Description
Prevalence of side effects within hypothesised strata and for specific drugs, to include: weight gain, hypoglycaemia, oedema, genital tract infection and discontinuation of therapy
Time Frame
48-54 weeks (3 x 16 weeks of therapy)
Title
HbA1c on therapy against predefined test of gender heterogeneity
Description
Predefined test of gender heterogeneity with pilot data suggesting females are likely to show an improved response relative to males for pioglitazone.
Time Frame
16 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
30 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Andrew Hattersley
Organizational Affiliation
University of Exeter / Royal Devon & Exeter NHS Trust
Official's Role
Principal Investigator
Facility Information:
Facility Name
Exeter Clinical Research Facility
City
Exeter
ZIP/Postal Code
EX2 5DW
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
33371044
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.
Results Reference
derived

Learn more about this trial

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

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