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    Summary
    EudraCT Number:2011-001254-29
    Sponsor's Protocol Code Number:I2R-MC-BIAM
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-11-28
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2011-001254-29
    A.3Full title of the trial
    Protocol I2R-MC-BIAM
    The Impact of LY2605541 versus Insulin Glargine for Patients with Type 2 Diabetes Mellitus Advanced to Multiple Injection Bolus Insulin with Insulin Lispro: a Double-Blind, Randomized, 26-week Study
    The IMAGINE 4 Study
    Impacto de LY2605541 versus insulina glargina en pacientes con diabetes mellitus tipo 2 que progresan a un tratamiento con múltiples bolos de insulina con insulina lispro preprandial: estudio doble ciego, aleatorizado, de 26 semanas de duración- IMAGINE 4
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study in Type 2 Diabetes
    Estudio de diabetes Mellitus tipo 2
    A.3.2Name or abbreviated title of the trial where available
    IMAGINE 4
    IMAGINE 4
    A.4.1Sponsor's protocol code numberI2R-MC-BIAM
    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 SponsorLilly S.A.
    B.1.3.4CountrySpain
    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 International GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationEli Lilly
    B.5.2Functional name of contact pointClinical Trial Information
    B.5.3 Address:
    B.5.3.1Street Addressavda de la industria 30
    B.5.3.2Town/ cityAlcobendas Madrdi
    B.5.3.3Post code28108
    B.5.3.4CountrySpain
    B.5.4Telephone number34916633485
    B.5.5Fax number34916633481
    B.5.6E-mailEU_Lilly_Clinical_Trials@lilly.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 No
    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 nameLY2605541
    D.3.2Product code LY2605541
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.2Current sponsor codeLY2605541
    D.3.9.3Other descriptive nameLY2605541
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Lantus
    D.2.1.1.2Name of the Marketing Authorisation holderSanofi Aventis
    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.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINSULIN GLARGINE
    D.3.9.1CAS number 160337-95-1
    D.3.9.4EV Substance CodeSUB08196MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Humalog
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly Nederland B.V.
    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.3.4Pharmaceutical form Solution for injection in pre-filled pen
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNINSULIN LISPRO
    D.3.9.1CAS number 133107-64-9
    D.3.9.4EV Substance CodeSUB08198MIG
    D.3.10 Strength
    D.3.10.1Concentration unit U/ml unit(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Type 2 Diabetes Mellitus
    Diabetes Mellitus tipo 2
    E.1.1.1Medical condition in easily understood language
    Diabetes
    Diabetes
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10049746
    E.1.2Term Insulin-requiring type II 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
    The primary objective is to demonstrate that glycemic control as measured by change in HbA1c from baseline to 26 weeks for LY2605541 is non-inferior compared with insulin glargine when each is combined with preprandial insulin lispro with or without metformin in patients with type 2 diabetes mellitus (T2DM) who have not achieved adequate glycemic control with at least 1 injection of insulin daily with or without OAMs.
    El objetivo principal del estudio es demostrar la no inferioridad de LY2605541 frente a insulina glargina, cuando cada uno de dichos fármacos se administra con insulina lispro preprandial (con o sin la administración conjunta de metformina), en relación con el control glucémico observado (determinado por el cambio al cabo de 26 semanas respecto a la concentración basal de HbA1c), en pacientes con DMT2 que no presenten un control glucémico adecuado cuando se les administra al menos 1 inyección diaria de insulina (con o sin ADO). El margen de no inferioridad es del 0,4%.
    E.2.2Secondary objectives of the trial
    The gated secondary objectives are to demonstrate that LY2605541 is superior to insulin
    glargine (each in combination with preprandial insulin lispro) for:
    1. Nocturnal hypoglycemia rate
    2. Proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia
    3. HbA1c change from baseline
    4. Proportion of patients with HbA1c < 7.0%
    5. Fasting serum glucose (FSG) by laboratory measurement
    6. Total hypoglycemia rate

    The non-gated secondary objectives are to compare the efficacy and safety of LY2605541 versus insulin glargine (each in combination with preprandial insulin lispro) for:
    ? Total and nocturnal hypoglycemia rates
    ? Total and nocturnal hypoglycemia incidences
    ? Proportion of patients with HbA1c ?6.5%
    ? FBG (as measured by self-monitored blood glucose [SMBG])
    ? FBG intra-patient variability (SMBG) as measured by standard deviation (SD)
    ? Weight change from baseline
    ? SMBG 9-point profiles
    ? HbA1c
    ? Basal, bolus, and total insulin dose (units and units/kg)
    Demostrar que LY2605541 es superior a insulina glargina (administrada con insulina lispro preprandial) al cabo de 52 semanas, en relación a:
    - Tasa de hipoglucemia nocturna, HbA1c, % con HbA1c < 7,0% , GA, Tasa de hipoglucemia global.
    También se comparará la eficacia y seguridad de LY2605541 e insulina glargina (administrada con insulina lispro preprandial) al cabo de 26 y 52 semanas, en relación a:
    - Tasa de hipoglucemia global y nocturna; Incidencia de hipoglucemia global y nocturna; Cambio respecto al peso basal; Perfiles de glucemia de 9 puntos; % de pacientes con HbA1c < 7,0%, con HbA1c ? 6,5%; con HbA1c < 7,0% y sin hipoglucemia nocturna; Cambio respecto a la concentración basal de HbA1c; HbA1c a las 26 semanas; Dosis de insulina basal, total y en bolo; TG, CE total, LDL, HDL; Anticuerpos frente a LY2605541; Criterios de seguridad; CSGA: GA; Variabilidad de la GA; Fluctuación de glucemia; Cuestionarios ITSQ,LBSS, EuroQoL (EQ)-5,RAPA.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Protocol Addendum I2R-MC-BIAM (1) - 21-Sep-11
    The Impact of LY2605541 versus Insulin Glargine for Patients with Type 2 Diabetes Mellitus Advanced to Multiple Injection Bolus Insulin with Insulin Lispro: a Double-Blind, Randomized, 26 Week Study - The IMAGINE 4 Study: Continuous Glucose Monitoring Addendum

    Continuous glucose monitoring (CGM) will be performed in a subpopulation of approximately 148 patients enrolled in study I2R-MC-BIAM.


    Pharmacogenetic Evaluations ? 15-Sep-11
    Where local regulations allow, a blood sample will be collected for pharmacogenetic analysis. It is a onetime collection, as noted in the Study Schedule. Samples will be stored and analysis may be performed on genetic variants thought to play a role in glucose and insulin regulation, beta cell function, characterization of patients? responsiveness to LY2605541, or diabetes- related metabolic abnormalities.

    Nonpharmacogenetic/Biomarker Evaluation -15-Sep-11
    Samples will be collected for nonpharmacogenetic biomarker research where local regulations allow. Blood and/or urine samples will be collected at the times specified in the Study Schedule. Samples may be used for research on diabetes progression and/or complications, mechanism of action of LY2605541, patients? response to LY2605541, in case future analyses are warranted with regard to safety, or in validating diagnostic tools or assay(s) related to diabetes or related metabolic abnormalities or biomarker response to LY2605541.
    Addendum al protocolo I2R-MC-BIAM (1) - 21-Sep-11
    Impacto de LY2605541 versus insulina glargina en pacientes con diabetes mellitus tipo 2 que progresan a un tratamiento con múltiples bolos de insulina con insulina lispro preprandial: estudio doble ciego, aleatorizado, de 26 semanas de duración- IMAGINE 4- subestudio de la monitorizacion continua de glucosa- CGM
    E.3Principal inclusion criteria
    [1]Have T2DM based on the World Health Organization (WHO) classification
    [2] Are at least 18 years of age
    [3] Duration of diabetes ?1 year
    [4] Have an HbA1c value ?7.0% and <12.0% according to the central laboratory
    at screening
    [5] BMI ?45.0 kg/m2
    [6] Patients on any glucose lowering regimen that contains at least 1 injection of
    insulin per day. Patients will take their last dose of antidiabetic medication with the exception of metformin the day prior to randomization.
    [7] This inclusion criterion applies ONLY to women of childbearing potential.
    ? Are not breastfeeding.
    ? Test negative for pregnancy at the time of screening and time of randomization based on a serum pregnancy test.
    ? Do not intend to become pregnant during the study.
    ? Have practiced a reliable method of birth control (eg, use of oral contraceptives or levonorgestrel; diaphragms with contraceptive jelly; cervical caps with contraceptive jelly; condoms with contraceptive foam; intrauterine devices; partner with vasectomy; or abstinence) for at least 6 weeks prior to screening.
    ? Agree to continue to use a reliable method of birth control during the study, as determined by the investigator (and for 2 weeks following the last dose of study drug).
    [8] Have access to a method of communication with the site
    [9] Have refrigeration in the home
    [10] Capable of, and willing to do the following: adhere to a multiple daily
    injection regimen, inject insulin with a covered vial and syringe and prefilled
    pen, attend some patient visits in the fasting state, and perform self blood
    glucose monitoring and record keeping as required by this protocol, as
    determined by the investigator. Caregiver may be responsible for all of the
    above.
    [11] Have given written informed consent to participate in this study in accordance with local regulations.
    [1] Diagnóstico de DMT2, de acuerdo con la clasificación de la Organización Mundial de la Salud (OMS)
    [2] Tener al menos 18 años de edad.
    [3] Duración de la diabetes ? 1 año.
    [4] Presentar en la visita 1 un valor de HbA1c ? 7,0% y < 12,0%, de acuerdo con los resultados de las pruebas realizadas en el laboratorio central
    [5] IMC ? 45,0 kg/m2.
    [6] Estar recibiendo un tratamiento con hipoglucemiantes, que incluya la administración de al menos 1 inyección de insulina al día. Los pacientes deberán tomar la última dosis de antidiabéticos el día previo a la visita 3 (con la excepción de metformina) ?véanse los criterios de exclusión 12-15?.
    [7] Este criterio de inclusión se aplica ÚNICAMENTE a las mujeres en edad fértil.
    ? No encontrarse en período de lactancia.
    ? Presentar, en las visitas 1 y 3, un resultado negativo en una prueba de embarazo en suero.
    ? No tener intención de quedarse embarazada durante el estudio.
    ? Utilizar un método anticonceptivo fiable (por ejemplo, anticonceptivos orales o levonorgestrel; diafragmas con gel anticonceptivo; capuchones cervicales con gel anticonceptivo; preservativos con espuma anticonceptiva; dispositivos intrauterinos, vasectomía de la pareja o abstinencia) al menos durante las 6 semanas previas al cribado.
    ? Estar de acuerdo en continuar utilizando un método anticonceptivo fiable, durante el estudio (así como durante las 2 semanas posteriores a la última dosis del fármaco del estudio), según determine el investigador.
    [8] Disponer de un método de comunicación con el centro de investigación.
    [9] Disponer de un frigorífico en el domicilio.
    [10] Ser capaz y estar dispuesto a (de acuerdo con el criterio del investigador): recibir un tratamiento que comprenda la administración de múltiples inyecciones diarias, inyectarse la insulina con el material que se le proporcione (vial, jeringuilla y pluma precargada [enmascaradas]), realizar las determinaciones de glucemia y mantener los correspondientes registros, de acuerdo con el protocolo. El cuidador podrá encargarse de realizar todas las anteriores actividades.
    [11] Haber proporcionado el consentimiento informado para participar en este estudio, de acuerdo con la regulación local
    E.4Principal exclusion criteria
    [12] Insulin pump therapy: Continuous subcutaneous insulin infusion therapy prior to screening.
    [13] Twice daily insulin glargine: Are using twice daily insulin glargine prior to screening.
    [14] Excessive insulin resistance: Defined as having received a daily dose of insulin ? 2.0 units/kg at the time of pre-randomization.
    [15] Concomitant medications: glucagon-like peptide-1 (GLP-1) receptor agonist (eg, exenatide, exenatide once weekly, or liraglutide), thiazolidinedione (rosiglitazone, pioglitazone), or pramlintide, used concurrently or within 90 days prior to screening.
    [16] Lipid-lowering medications: are using niacin preparations as a lipid lowering medication and bile acid
    sequestrants within 90 days prior to screening; or, are using lipid-lowering medication at a dose that has not been stable for ?90 days prior to screening. If a patient has not been on a stable dose of lipid-lowering medication for ?90 days prior to screening, the site should wait to screen the patient. If the results of the screening laboratory tests require a change to the patient's current lipid-lowering medication or initiation of lipid-lowering medication, it is acceptable to change the lipid-lowering medication for the patient and have the patient return ?90 days
    later to complete some of the screening procedures again.
    [17] Triglycerides: Have fasting hypertriglyceridemia (defined as >4.5 mmol/L, >400 mg/dL) at screening, as determined by the central laboratory.
    [18] Weight loss medications: Are currently taking, or have taken within the 90 days preceding screening, prescription or over-the-counter medications to promote weight loss.
    [19] Severe hypoglycemia history: Have had any episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia) within 6 months prior to entry into the study.
    [20] Glycemic control: Have had 2 or more emergency room visits or hospitalizations due to poor glucose control within the 6 months prior to screening.
    [21] Diabetic ketoacidosis: Have had 1 or more episodes of ketoacidosis or hyperosmolar state/coma requiring hospitalization within 6 months prior to screening.
    [22] Cardiovascular: Have cardiac disease with functional status that is New York Heart Association Class III or IV (per New York Heart Association [NYHA] Cardiac Disease Classification).
    [23] Renal: Are currently receiving renal dialysis or have a serum creatinine ?2.0 mg/dL, except for patients taking metformin who will be required to follow local labeling restrictions regarding metformin use and serum creatinine.
    [24] Hepatic: Have obvious clinical signs or symptoms of liver disease (excluding non-alcoholic fatty liver disease [NAFLD]), acute or chronic hepatitis, non-alcoholic steatohepatitis (NASH), or elevated liver enzyme measurements as indicated below:
    ? total bilirubin ?2X the upper limit of normal (ULN) as defined by the central laboratory, or
    ? alanine aminotransferase (ALT)/(serum glutamic pyruvic transaminase (SGPT) >2.5X ULN as defined by the central laboratory, or
    ? aspartate aminotransferase (AST)/(serum glutamic oxaloacetic transaminase (SGOT) >2.5X ULN as defined by the central laboratory.
    [25] Malignancy: Have active or untreated malignancy, have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or are at increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator.
    [26] Allergic: Have known or develop hypersensitivity or allergy to any of the study insulins or their excipients.
    [27] Hematologic: Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia, or any other traits of hemoglobin abnormalities known to interfere with the HbA1c measurement.
    [28] Glucocorticoid therapy: Receiving chronic (lasting longer than 14 consecutive days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, and inhaled preparations) or have received such therapy within 8 weeks immediately before screening with the exception of replacement therapy for adrenal insufficiency.
    [29] Diabetic neuropathy: Diagnosed clinically significant diabetic autonomic neuropathy, in the opinion of the investigator.
    [30] Transplant: Have had an organ transplant.
    [31] Adherence to protocol: Have any other condition (including known drug or alcohol abuse or psychiatric disorder including eating disorder) that precludes the patient from following and completing the protocol.
    [12] Terapia con bomba de insulina.
    [13] Insulina glargina (administrada dos veces al día).
    [14] Resistencia excesiva a insulina.
    [15] Medicaciones concomitantes: agonistas del receptor del péptido 1 similar al glucagón (GLP-1), tiazolidinediona, o pramlintida, 90 días previos a la visita 1.
    [16] Hipolipemiantes:
    ? preparados de niacina o,
    ? No estar recibiendo una dosis estable de hipolipemiantes durante ? 90 días antes de la visita 1.
    [17] Triglicéridos: Presentar en la visita 1 hipertrigliceridemia en ayunas
    18] Medicaciones que promuevan la pérdida de peso.
    [19] Antecedentes de hipoglucemia grave.
    [20] Haber acudido a urgencias o haber sido hospitalizados 2 o más veces por haber presentado un mal control glucémico, en el transcurso de los 6 meses previos a la visita 1.
    [21] Cetoacidosis diabética
    [22] Presentar una enfermedad cardiaca con un estado funcional de clase III o IV.
    [23] Estar recibiendo actualmente diálisis renal o presentar una concentración sérica de creatinina > 2,0 mg/dl, excepto en el caso de los pacientes que estén recibiendo metformina, que deberán seguir las restricciones a nivel local, relativas al uso de metformina y la concentración sérica de creatinina.
    [24] Presentar claros signos o síntomas clínicos de enfermedad hepática (excepto los casos de enfermedad del hígado graso no inducida por el alcohol [NAFLD]), hepatitis aguda o crónica, esteatohepatitis no alcohólica (NASH) o una elevación de las enzimas hepáticas, según se describe en el protocolo:
    [25] Presentar una neoplasia activa o sin tratar, o haber estado en remisión de una neoplasia clínicamente significativa (excepto los casos de carcinomas basocelulares o escamosos de la piel), durante un período inferior a 5 años, o presentar, de acuerdo con la opinión del investigador, un mayor riesgo de experimentar cáncer o una recidiva de cáncer.
    [26] Presentar o que se desarrolle hipersensibilidad o alergia a cualquiera de las insulinas del estudio, o a sus excipientes.
    [27] Haber recibido una transfusión de sangre o haber sufrido una hemorragia grave en el transcurso de los 3 meses previos a la visita 1, o presentar hemoglobinopatía, anemia hemolítica o anemia drepanocítica conocidas, o algún otro tipo de alteraciones de la hemoglobina que puedan interferir con la metodología para evaluar la HbA1c.
    [28] Estar recibiendo tratamiento sistémico y crónico (durante más de 14 días consecutivos) con glucocorticoides, o haber recibido dicho tratamiento en el transcurso de las 8 semanas inmediatamente previas a la visita 1, con la excepción de la terapia restitutiva en caso de insuficiencia suprarrenal.
    [29] Presentar neuropatía diabética neurovegetativa clínicamente significativa, de acuerdo con la opinión del investigador.
    [30] Haber recibido un trasplante de órgano.
    [31] Padecer cualquier otra enfermedad que impida que el paciente siga y complete el protocolo.
    [32] Empleados de Lilly o Boehringer Ingelheim
    [33] Personal del centro
    [34] Fármacos no aprobados
    [35] Participación previa en estudios clínicos: Estar participando en la actualidad o haber abandonado en el transcurso de los 30 días previos un ensayo clínico.
    [36] Haber finalizado o haber sido retirado previamente de este estudio (después de haber firmado el ICF) o de cualquier otro estudio en el que se investigue LY2605541, después de haber recibido al menos 1 dosis del producto en fase de investigación.
    [37] Restricciones generales: No poder y/o no estar dispuesto a proporcionar el consentimiento informado, no estar disponible durante la duración del estudio o no atenerse a los procedimientos o requerimientos del estudio, incluido el uso de un dispositivo de recogida de datos.
    E.5 End points
    E.5.1Primary end point(s)
    A change of HbA1c from baseline that is non-inferior to insulin glargine injected once a day each in combination with preprandial insulin lispro with or without metformin
    Demostrar la no inferioridad de LY2605541 frente a insulina glargina, cuando cada uno de dichos fármacos se administra con insulina lispro preprandial (con o sin la administración conjunta de metformina).
    E.5.1.1Timepoint(s) of evaluation of this end point
    26 weeks
    26 semanas
    E.5.2Secondary end point(s)
    Nocturnal hypoglycemia rate; proportion of patients with HbA1c <7.0% and no nocturnal hypoglycemia; HbA1c change from baseline; proportion of patients with HbA1c < 7.0%; fasting serum glucose (FSG) by laboratory measurement; total hypoglycemia rate.

    Total and nocturnal hypoglycemia rates;
    total and nocturnal hypoglycemia incidences; proportion of patients with HbA1c ?6.5%; FBG (as measured by self-monitored blood glucose [SMBG]); FBG intra-patient variability (SMBG) as measured by standard deviation (SD);
    weight change from baseline; SMBG 9-point profiles; HbA1c; basal, bolus, and total insulin dose (units and units/kg).
    Tasa de hipoglucemia nocturna, % con HbA1c < 7,0% y sin hipoglucemia nocturna, Cambio en la HbA1c desde el inicio, GA, Tasa de hipoglucemia global.
    Tasa de hipoglucemia global y nocturna; Incidencia de hipoglucemia global y nocturna; Cambio respecto al peso basal; Perfiles de glucemia de 9 puntos; % de pacientes con HbA1c < 7,0%, con HbA1c ? 6,5%; con HbA1c < 7,0% y sin hipoglucemia nocturna; Cambio respecto a la concentración basal de HbA1c; HbA1c a las 26 semanas; Dosis de insulina basal, total y en bolo; Variabilidad de la GA intra-paciente.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All gated objective endpoints are at 26 weeks of treatment. Total and nocturnal hypoglycemia rates and incidences have various timepoints such as 0 to 2 weeks, 0 to 12 weeks, 0 to 26 weeks, 2 to 12 weeks, 2 to 26 weeks, 12 to 26 weeks, at 26 weeks for all other objectives.
    26 semanas de tratamiento.
    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 Yes
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA82
    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
    Australia
    Austria
    Brazil
    Croatia
    Czech Republic
    Denmark
    Germany
    Greece
    Hungary
    Israel
    Italy
    Japan
    Lithuania
    Mexico
    Netherlands
    Poland
    Romania
    Russian Federation
    Slovakia
    Slovenia
    Spain
    Taiwan
    Turkey
    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
    last visit of the last subject undergoing the trial
    Ultima visita del ultimo paceintes del estudio
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days2
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months7
    E.8.9.2In all countries concerned by the trial days2
    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: 994
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 331
    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 state38
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 575
    F.4.2.2In the whole clinical trial 1325
    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 Sponsor will not provide patients with ongoing supplies of study medication after they have completed the study treatment period because LY2605541 is experimental, while insulin glargine is readily available.
    El sponsor no suministrara a los pacientes del estudio de la medicacion despues de la finalizacion del estudio ya que el tratamiento con LY2605541 es experimenta, los pacientes podran seguir con el tratamiento con glargina que esta disponible en el mercado.
    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 Decision2012-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2013-08-13
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