NCT02653209

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
525

participants targeted

Target at P75+ for phase_4 type-2-diabetes

Timeline
Completed

Started Nov 2016

Longer than P75 for phase_4 type-2-diabetes

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

First Submitted

Initial submission to the registry

January 8, 2016

Completed
4 days until next milestone

First Posted

Study publicly available on registry

January 12, 2016

Completed
10 months until next milestone

Study Start

First participant enrolled

November 1, 2016

Completed
4.2 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

January 1, 2021

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

January 1, 2021

Completed
Last Updated

April 1, 2021

Status Verified

March 1, 2021

Enrollment Period

4.2 years

First QC Date

January 8, 2016

Last Update Submit

March 30, 2021

Conditions

Type 2 Diabetes

Keywords

Type 2 diabetesStratificationBiomarkersPharmacogeneticsSGLT2 inhibitorsThiazolidinedionesDPP4 inhibitors

Outcome Measures

Primary Outcomes (2)

  • 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: 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.

    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: 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.

    16 weeks

Secondary Outcomes (3)

  • Patient preference

    48-54 weeks (3 x 16 weeks of therapy)

  • Prevalence of side effects

    48-54 weeks (3 x 16 weeks of therapy)

  • HbA1c on therapy against predefined test of gender heterogeneity

    16 weeks

Study Arms (3)

Sitagliptin - DPP4i

EXPERIMENTAL
Drug: Sitagliptin - DPP4i

Canagliflozin - SGLT2i

EXPERIMENTAL
Drug: Canagliflozin - SGLT2i

Pioglitazone - TZD

EXPERIMENTAL
Drug: Pioglitazone - TZD

Interventions

Sitagliptin - DPP4iDRUG

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.

Also known as: Januvia
Sitagliptin - DPP4i
Canagliflozin - SGLT2iDRUG

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.

Also known as: Invokana
Canagliflozin - SGLT2i
Pioglitazone - TZDDRUG

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.

Also known as: Actos
Pioglitazone - TZD

Eligibility Criteria

Age30 Years - 80 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • 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

You may not qualify if:

  • 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)
  • +8 more criteria

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

Exeter Clinical Research Facility

Exeter, EX2 5DW, United Kingdom

Location

Related Publications (3)

  • Shields BM, Angwin CD, Shepherd MH, Britten N, Jones AG, Sattar N, Holman R, Pearson ER, Hattersley AT. Patient preference for second- and third-line therapies in type 2 diabetes: a prespecified secondary endpoint of the TriMaster study. Nat Med. 2023 Feb;29(2):384-391. doi: 10.1038/s41591-022-02121-6. Epub 2022 Dec 7.

    PMID: 36477734DERIVED

  • Shields BM, Dennis JM, Angwin CD, Warren F, Henley WE, Farmer AJ, Sattar N, Holman RR, Jones AG, Pearson ER, Hattersley AT; TriMaster Study group. Patient stratification for determining optimal second-line and third-line therapy for type 2 diabetes: the TriMaster study. Nat Med. 2023 Feb;29(2):376-383. doi: 10.1038/s41591-022-02120-7. Epub 2022 Dec 7.

    PMID: 36477733DERIVED

  • 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.

    PMID: 33371044DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Sitagliptin PhosphateCanagliflozinPioglitazone

Condition Hierarchy (Ancestors)

Diabetes MellitusGlucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System Diseases

Intervention Hierarchy (Ancestors)

TriazolesAzolesHeterocyclic Compounds, 1-RingHeterocyclic CompoundsPyrazinesThiophenesSulfur CompoundsOrganic ChemicalsGlucosidesGlycosidesCarbohydratesThiazolidinedionesThiazoles

Study Officials

  • Andrew Hattersley

    University of Exeter / Royal Devon & Exeter NHS Trust

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 4
Allocation
RANDOMIZED
Masking
DOUBLE
Who Masked
PARTICIPANT, INVESTIGATOR
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

January 8, 2016

First Posted

January 12, 2016

Study Start

November 1, 2016

Primary Completion

January 1, 2021

Study Completion

January 1, 2021

Last Updated

April 1, 2021

Record last verified: 2021-03

Locations

GB(1)