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    Summary
    EudraCT Number:2009-013157-15
    Sponsor's Protocol Code Number:1218.74
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2010-10-06
    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 ConcernedIreland - HPRA
    A.2EudraCT number2009-013157-15
    A.3Full title of the trial
    A multicentre, international, randomised, parallel group, double blind study to evaluate Cardiovascular safety of linagliptin versus glimepiride in patients with type 2 diabetes mellitus at high cardiovascular risk. The CAROLINA Trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CAROLINA: Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients With Type 2 Diabetes
    A.3.2Name or abbreviated title of the trial where available
    CAROLINA
    A.4.1Sponsor's protocol code number1218.74
    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 SponsorBoehringer Ingelheim Limited
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBoehringer Ingelheim
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBoehringer Ingelheim Pharma GmbH & Co. KG
    B.5.2Functional name of contact pointQRPE PSC CT Information Disclosure
    B.5.3 Address:
    B.5.3.1Street AddressBingerStrasse 173
    B.5.3.2Town/ cityIngelheim am Rhein
    B.5.3.3Post code55216
    B.5.3.4CountryGermany
    B.5.4Telephone number+18002430127
    B.5.5Fax number+18008217119
    B.5.6E-mailclintriage.rdg@boehringer-ingelheim.com
    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 Trajenta
    D.2.1.1.2Name of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 namelinagliptin
    D.3.2Product code BI1356
    D.3.4Pharmaceutical form Film-coated tablet
    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 INNlinagliptin
    D.3.9.1CAS number 668270-12-0
    D.3.9.2Current sponsor codeBI 1356
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5.0
    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 RoleComparator
    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 Amaryl
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAmaryl
    D.3.4Pharmaceutical form Tablet
    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 INNGLIMEPIRIDE
    D.3.9.1CAS number 93479971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 RoleComparator
    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 Amaryl
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAmaryl
    D.3.4Pharmaceutical form Tablet
    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 INNGLIMEPIRIDE
    D.3.9.1CAS number 93479971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Information not present in EudraCT
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Amaryl
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAmaryl
    D.3.4Pharmaceutical form Tablet
    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 INNGLIMEPIRIDE
    D.3.9.1CAS number 93479971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Amaryl
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi-Aventis Deutschland GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameAmaryl
    D.3.4Pharmaceutical form Tablet
    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 INNGLIMEPIRIDE
    D.3.9.1CAS number 93479971
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule, hard
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients with documented diagnosis of T2DM with insufficient glycaemic control and at high risk of CV events prior to informed consent can be enrolled in the study.
    E.1.1.1Medical condition in easily understood language
    Patients with type 2 diabetes with insufficient glycaemic control and at high risk of CV events can be enrolled in the study.
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10045242
    E.1.2Term Type II diabetes mellitus
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate non-inferiority (by means of comparing the upper limit of a two-sided 95% confidence interval with the non-inferiority margin of 1.3) of treatment with linagliptin in comparison to glimepiride (as monotherapy or as add-on therapy) with respect to time to first occurrence of any of the adjudicated components of the primary composite endpoint (i.e. cardiovascular [CV] death, non-fatal stroke or non-fatal myocardial infarction [MI] (excluding silent MI) in patients with type 2 diabetes mellitus [T2DM]. If the non-inferiority hypothesis with margin 1.3 has revealed a significant result, then secondly, the primary composite endpoint will be tested with a superiority hypothesis.
    E.2.2Secondary objectives of the trial
    If the superiority test has revealed a significant result, then thirdly the first key secondary endpoint will be tested hierarchically with a superiority hypothesis. If the test of the first key secondary hypothesis has revealed a significant result, then fourthly the second key secondary endpoint will be tested hierarchically. If the test of the second key secondary hypothesis has revealed a significant result, then fifthly the third key secondary endpoint will be tested hierarchically.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Sub-studies are planned that could further advance our understanding of important issues in the management of patients with T2DM related to oral DPP-IV inhibition. The sub-studies currently planned are three: one addressing glycaemic variability and its importance; one addressing cognitive function and factors associated with its decline; and one addressing long term β-cell function associated with the two different treatment strategies. The sub-studies are described in separate protocols, which were reviewed separately by the relevant IECs/IRBs and HAs.
    E.3Principal inclusion criteria
    1) Documented diagnosis of T2DM and concurrently 2) insufficient glycaemic control and a high risk of CV events 3) prior to informed consent

    2) Insufficient glycaemic control (at Visit 1a) defined as:
    a) HbA1c 6.5 - 8.5% (48 - 69 mmol/mol) while patient is treatment naïve (if intolerant or contra-indicated to first line anti-diabetic treatment) or treated with:
    - metformin monotherapy, or
    - alpha-glucosidase inhibitor monotherapy (e.g. acarbose, voglibose), or
    - metformin + alpha-glucosidase inhibitor (e.g. acarbose, voglibose), or
    b) HbA1c 6.5 - 7.5% (48 - 58 mmol/mol) while patient is treated with
    - sulphonylurea (SU) monotherapy, or
    - glinide monotherapy (e.g. repaglinide, nateglinide), or
    - metformin + sulphonylurea (combination maximal up to 5 years), or
    - metformin + glinide (combination maximal up to 5 years), or
    - SU + alpha-glucosidase inhibitor (combination maximal up to five years), or
    - glinide + alpha-glucosidase inhibitor (combination maximal up to five years)

    3) High risk of CV events defined as any one (or more) of A), B), C) or D):

    A) Previous Vascular Disease:
    - Myocardial infarction (> 6 weeks prior to informed consent)
    - Documented coronary artery disease (≥50% luminal diameter narrowing of left main coronary artery or ≥50% in at least two major coronary arteries in angiogram)
    - Percutaneous Coronary Intervention (PCI) > 6 weeks prior informed consent
    - Coronary Artery By-pass Grafting (CABG) > 4 years prior to informed consent or with recurrent angina following surgery
    - Ischemic or hemorrhagic stroke (> 3 months prior to informed consent)
    - Peripheral occlusive arterial disease (previous limb bypass surgery, stenting or percutaneous transluminal angioplasty; previous limb or foot amputation due to circulatory insufficiency, angiographic or ultrasound detected significant vessel stenosis (>50%) of major limb arteries (common iliac artery, internal iliac artery, external iliac artery, femoral artery, popliteal artery), history of intermittent claudication, with an ankle: arm blood pressure ratio < 0.90 on at least one side).

    B) Evidence of vascular related end-organ damage:
    - Moderately impaired renal function (as defined by modified diet of renal disease (MDRD) formula) with estimated glomerular filtration rate [eGFRF]) 30-59 mL/min/1.73 m2
    - Random spot urinary albumin:creatinine ratio ≥ 30 μg/mg (≥ 3.4 mg/mmol) in two of three unrelated specimens in previous 12 months prior Visit 1a
    - Proliferative retinopathy defined as retinal neovascularisation or previous retinal laser coagulation therapy.

    C) Age ≥ 70 years (at Visit 1a)

    D) At least two of the following CV risk factors:
    - Type 2 diabetes mellitus duration > 10 years at Visit 1a.
    - Current* Systolic blood pressure (SBP) > 140 mmHg (or on at least one blood pressure lowering treatment at Visit 1a)
    - Current daily cigarette smoking
    - Current* LDL cholesterol ≥ 135 mg/dL (3.5 mmol/l) (or specific current treatment for this lipid abnormality) at Visit 1a

    * Current = measurement < 6 months prior V1a.

    4) Body Mass Index (BMI) ≤ 45 kg/m2 at Visit 1b

    5) Age ≥ 40 and ≤ 85 years at Visit 1a

    6) Signed and dated written informed consent at the latest by the date of Visit 1a, in accordance with GCP and local legislation

    7) Stable anti-diabetic background medication (unchanged daily dose) for at least 8 weeks prior V1a and without short term use of insulin. Background medication should be stable during screening/run-in phase to allow randomisation.

    Treatment compliance in the placebo run-in should be between 80% and 120% to be eligible for randomisation.
    E.4Principal exclusion criteria
    • Type 1 diabetes mellitus
    • Any history and/or current treatment with other antidiabetic drugs (e.g. rosiglitazone, pioglitazone, GLP-1 analogue/agonists, DPP-IV inhibitors or any insulin) prior to informed consent. Note: previous short term use of any insulin (up to two consecutive weeks) is allowed (e.g. during hospitalisation) if taken at least 8 weeks prior informed consent.
    • Treatment with anti-obesity drugs 3 months prior to informed consent
    • Uncontrolled hyperglycaemia with a glucose level > 240 mg/dl (>13.3 mmol/L) after an overnight fast during placebo run-in and confirmed by a second measurement (not on the same day)
    • Any previous (or planned within next 12 months) bariatric surgery (open or laparascopic) or intervention (gastric sleeve)
    • Current treatment with systemic corticosteroids at time of informed consent or pre-planned initiation of such therapy. Note: inhaled use of steriods (e.g. for asthma/COPD) is no exclusion criterion, as this does not cause systemic steriod action
    • Change in dose of thyroid hormones within 6 weeks prior informed consent
    • Active liver disease or impaired hepatic function, defined by serum levels of either ALT (SGPT), AST (SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at visit 1a
    • Pre-planned coronary artery re-vascularization (PCI, CABG) within next 6 months after V1a or any previous PCI and/or CABG ≤ 6 weeks prior informed consent
    • Known hypersensitivity or allergy to the investigational product or its excipients, or glimepriride (or the SU class)
    • Inappropriateness of glimepiride treatment for renal safety issues or other issues (e.g. allergy) according to local prescribing information
    • Congestive heart failure of NYHA class III or IV
    • Acute or chronic metabolic acidosis (present condition in patient history)
    • Hereditary galactose intolerance
    • Alcohol or drug abuse within the 3 months prior to informed consent
    that would interfere with trial participation
    • Participation in another trial with an investigational drug given within 2
    months prior to informed consent
    • Pre-menopausal women (last menstruation ≤ 1 year prior to informed
    consent) who are nursing or pregnant,or are of child-bearing potential
    and are not practicing an acceptable method of birth control (acceptable
    methods of birth control include tubal ligation, transdermal patch, intra
    uterine devices/systems (IUDs/IUSs), oral, implantable or injectable
    contraceptives, sexual abstinence (if allowed by local authorities), double
    barrier method and vasectomised partner) or do not plan to continue
    using acceptable method of birth control throughout the study and do
    not agree to submit to periodic pregnancy testing during participation in
    the trial.
    • Patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration, has a life expectancy less than 5 years for non-CV causes, or has cancer other than non-melanoma skin cancer within last 3 years, or has any other condition than mentioned which in the opinion of the investigator, would not allow safe participation in the study
    • Acute coronary syndrome ≤ 6 weeks prior to informed consent
    • Stroke or TIA ≤ 3 months prior to informed consent

    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoint: time to first occurrence of any of the following adjudicated components of the primary composite endpoint: CV death (including fatal stroke and fatal MI), non-fatal stroke or non-fatal MI (excluding silent MI).
    E.5.1.1Timepoint(s) of evaluation of this end point
    The number of confirmed adjudicated primary endpoint events will be continuously monitored during the trial. Based on the available number of events the projected number of expected future events will be calculated. As soon as the projection reliably suggests that the total number of patients with a by adjudication confirmed primary endpoint event will reach 631, the trial team will perform respective actions to stop the trial.
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints are:
    • time to first occurrence of any of the following adjudicated components of the composite endpoint:
    CV death (including fatal stroke and fatal MI), non-fatal stroke, non-fatal MI (excluding silent MI) or hospitalisation for unstable angina pectoris.

    • composite endpoint of (treatment sustainability defined as the proportion of patients that are on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication (between end of titration [Visit 6] and Final Visit) and patients without any moderate/severe hypoglycaemic episodes (between Visit 6 and Final Visit) and without > 2% weight gain at Final Visit (between Visit 6 and Final Visit))
    • composite endpoint of (treatment sustainability defined as the proportion of patients that are on study treatment at study end, that at Final Visit maintain glycaemic control (HbA1c ≤ 7.0%) without need for rescue medication (between Visit 6 and Final Visit) and patients without > 2% weight gain at Final Visit (between Visit 6 and Final Visit))
    E.5.2.1Timepoint(s) of evaluation of this end point
    Every 16 weeks the secondary endpoints will be evaluated (up to an estimated 432 weeks).
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.4Therapeutic use (Phase IV) No
    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 Yes
    E.8.1.6Cross over No
    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 trial2
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA200
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Belgium
    Brazil
    Bulgaria
    Canada
    Chile
    Colombia
    Czech Republic
    Finland
    France
    Georgia
    Germany
    Greece
    Hong Kong
    Hungary
    India
    Ireland
    Israel
    Italy
    Japan
    Korea, Republic of
    Malaysia
    Mexico
    Netherlands
    New Zealand
    Norway
    Peru
    Philippines
    Portugal
    Romania
    Russian Federation
    Serbia
    Slovakia
    South Africa
    Spain
    Sweden
    Switzerland
    Taiwan
    Tunisia
    Ukraine
    United Kingdom
    United States
    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
    An independent Data Monitoring Committee (DMC) will review safety and efficacy data and make recommendations whether to continue the study, continue the study with modifications, or terminate the study. See for further details the trial protocol.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months4
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 4000
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2000
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 2200
    F.4.2.2In the whole clinical trial 6000
    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)
    The attending doctor will speak to the patient about further treatment options and may administer the orignal medication.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2010-12-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-12-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-21
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