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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)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02653209
Recruitment Status : Completed
First Posted : January 12, 2016
Last Update Posted : April 1, 2021
Sponsor:
Collaborators:
University of Exeter
NHS Tayside
University of Dundee
University of Glasgow
Newcastle University
King's College London
Information provided by (Responsible Party):
Royal Devon and Exeter NHS Foundation Trust

Tracking Information
First Submitted Date  ICMJE January 8, 2016
First Posted Date  ICMJE January 12, 2016
Last Update Posted Date April 1, 2021
Actual Study Start Date  ICMJE November 1, 2016
Actual Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 8, 2016)
  • On treatment HbA1c in obese patients (BMI >30kgm-2), compared to non-obese patients [ Time Frame: 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:
    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.
  • On treatment HbA1c in patients with an eGFR <90 mls/min/1.73m2 compared to patients with an eGFR >90 mls/min/1.73m2. [ Time Frame: 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:
    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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 8, 2016)
  • Patient preference [ Time Frame: 48-54 weeks (3 x 16 weeks of therapy) ]
    Patient treatment preference of study drug within hypothesised strata and overall
  • Prevalence of side effects [ Time Frame: 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 [ Time Frame: 16 weeks ]
    Predefined test of gender heterogeneity with pilot data suggesting females are likely to show an improved response relative to males for pioglitazone.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE TriMaster: Study of a DPP4 Inhibitor, SGLT2 Inhibitor and Thiazolidinedione as Third Line Therapy in Patients With Type 2 Diabetes.
Official Title  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Type 2 Diabetes
Intervention  ICMJE
  • 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 Name: Januvia
  • 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 Name: Invokana
  • 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 Name: Actos
Study Arms  ICMJE
  • Experimental: Sitagliptin - DPP4i
    Intervention: Drug: Sitagliptin - DPP4i
  • Experimental: Canagliflozin - SGLT2i
    Intervention: Drug: Canagliflozin - SGLT2i
  • Experimental: Pioglitazone - TZD
    Intervention: Drug: Pioglitazone - TZD
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 8, 2020)
525
Original Estimated Enrollment  ICMJE
 (submitted: January 8, 2016)
600
Actual Study Completion Date  ICMJE January 2021
Actual Primary Completion Date January 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02653209
Other Study ID Numbers  ICMJE 1603221
2015-002790-38 ( EudraCT Number )
12039221 ( Registry Identifier: ISRCTN )
MR/N00633X/1 ( Other Grant/Funding Number: Medical Research Council, UK )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party Royal Devon and Exeter NHS Foundation Trust
Original Responsible Party NIHR Exeter Clinical Research Facility
Current Study Sponsor  ICMJE Royal Devon and Exeter NHS Foundation Trust
Original Study Sponsor  ICMJE NIHR Exeter Clinical Research Facility
Collaborators  ICMJE
  • University of Exeter
  • NHS Tayside
  • University of Dundee
  • University of Glasgow
  • Newcastle University
  • King's College London
Investigators  ICMJE
Principal Investigator: Andrew Hattersley University of Exeter / Royal Devon & Exeter NHS Trust
PRS Account Royal Devon and Exeter NHS Foundation Trust
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP