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    Summary
    EudraCT Number:2015-002790-38
    Sponsor's Protocol Code Number:1603221
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2017-08-23
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-002790-38
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    TriMaster: Study of a DPP4 Inhibitor, SGLT2 Inhibitor and Thiazolidinedione as Third Line Therapy in Patients With Type 2 Diabetes.
    A.3.2Name or abbreviated title of the trial where available
    TriMaster v1
    A.4.1Sponsor's protocol code number1603221
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberISRCTN12039221
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02653209
    A.5.4Other Identifiers
    Name:RECNumber:16/SC/0147
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRoyal Devon & Exeter NHS Foundation Trust
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Exeter Medical School
    B.5.2Functional name of contact pointChief Investigator
    B.5.3 Address:
    B.5.3.1Street AddressBarrack Road
    B.5.3.2Town/ cityExeter
    B.5.3.3Post codeEX2 5DW
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number01392408260
    B.5.6E-maila.t.hattersley@exeter.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Pioglitazone
    D.2.1.1.2Name of the Marketing Authorisation holderTeva Pharma B.V.
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePioglitazone
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPioglitazone Hydrochloride
    D.3.9.1CAS number 111025-46-8
    D.3.9.2Current sponsor codePioglitazone 30mg
    D.3.9.3Other descriptive namePioglitazone Hydrochloride
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Januvia
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSitagliptin
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSitagliptin
    D.3.9.1CAS number 654671-78-0
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Invokana
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen-Cilag
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCanaglifozin
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCanagliflozin Hemihydrate
    D.3.9.1CAS number 928672-86-0
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type 2 Diabetes
    Patients with type 2 diabetes who have suboptimal glycaemic control (HbA1c >58mmol/mol, 58%) on one or two oral therapies, not including a thiazolidinedione, a DPP4 inhibitor or a SGLT2 inhibitor
    E.1.1.1Medical condition in easily understood language
    Type 2 Diabetes - patients who currently take one or two glucose-lowering tablets and whose blood glucose remains above 58mmol/mol (7.5%)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10067585
    E.1.2Term Type 2 diabetes mellitus
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    This study aims to test 2 hypotheses of how well or poorly different subgroups of patients respond to particular drugs based on particular clinical characteristics such as their weight or blood test results.

    Hypothesis 1:
    Patients with insulin resistance (characterised by a raised BMI >30 kg/m2), compared to non-obese patients (BMI ≤30) will:
    a) respond well to pioglitazone
    b) respond less well to sitagliptin

    Hypothesis 2:
    Patients with modestly reduced renal function, compared to those with normal renal function will:
    a) respond poorly to canagliflozin
    b) respond well to sitagliptin


    Therefore the study’s primary research question:
    a) Do obese patients (BMI >30kgm-2), compared to non-obese patients, achieve a lower HbA1c when given pioglitazone rather than sitagliptin?

    b) Do patients with an eGFR <90 mls/min/1.73m2 achieve a lower HbA1c, compared to patients with an eGFR>90 mls/min/1.73m2, when givena sitagliptin rather than canagliflozin.
    E.2.2Secondary objectives of the trial
    The study's secondary research objectives are to look at:

    a) Which treatment patients prefer, both within the different subgroups (BMI above/below 30 and reduced/normal renal function) and overall.

    b) The number of side effects experienced, both within the different subgroups and for the different drugs. These will specifically include weight gain, hypoglycaemia, oedema, genital tract infection and discontinuation of therapy.

    c) Whether there is a gender difference in response to pioglitazone therapy
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Clinical diagnosis of Type 2 diabetes
    • Age ≥30 and ≤80
    • Currently treated with either metformin alone, or 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%) & ≤ 110mmol/mol (12.2%) – confirmed at screening visit
    • eGFR ≥ 60mls/min/1.73m² - confirmed at screening visit
    • Able and willing to give informed consent
    E.4Principal exclusion criteria
    • Changes in glucose-lowering therapy or dose within last 3 months
    • HbA1c ≤ 58mmol/mol (7.5%) & >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
    • Treatment with study dugs within the last 3 months
    • Limb ischaemia shown by absence of both pulses in one or both feet
    • Currently treated with corticosteroids
    • Active infection (any infection requiring antibiotics at present)
    • Active foot ulcer
    • 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 or current use of loop diuretic therapy (Furosemide or Bumetanide)
    • History of bladder carcinoma or current/ongoing investigation for macroscopic haematuria
    • History of Diabetic Ketoacidosis or pancreatitis
    • Pregnant, breastfeeding or planning a pregnancy over the study period
    • Concurrent Participation on another Clinical Trial of an Investigational Medicinal Product
    • Unable or unwilling to give informed consent
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome of this crossover study is HbA1c on treatment after 16 weeks. When a subject withdraws from a treatment arm before 16 weeks an HbA1c will be taken and used if the subject has been taking the medication at least 8 weeks. If a subject has taken the medication for less than 8 weeks their HbA1c measure will not be used in primary analysis.

    The HbA1c primary outcome measure will be that achieved after 16 weeks on therapy and not the percentage or absolute HbA1c change between either study or therapy baseline and end of treatment arm.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary outcome measurement will be taken at the end of each of the three 16 week on-treatment periods.
    E.5.2Secondary end point(s)
    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 and ask them which treatments they would take long term and the reason for their preference.

    Frequency and severity of side effects will be recorded throughout the study. Participants that routinely self-monitor their blood glucose levels with devices issued by their clinician will be asked to record their glucose values immediately following hypoglycaemias.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary end points will be evaluated at the end of each of the three 16 week on-treatment periods.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned19
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS plus 6 months to enable follow-up
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days31
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days31
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 260
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 260
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state520
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 520
    F.4.2.2In the whole clinical trial 520
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Any change from pre-study therapy and prescription of additional/changed treatments would be at the discretion of the participant's usual clinician.

    Individual participant's unblinded data will be provided to inform ongoing care but the research team will not provide continuing treatment and will not propose a specific therapy as we consider this decision will be best made by the patient with their usual medical team.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation NIHR CRN
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-05-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-07
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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