| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes Mellitus |
| Diabetes Mellitus tipo 2 |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049746 |
| E.1.2 | Term | Insulin-requiring type II diabetes mellitus |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main 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.2.2 | Secondary 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.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full 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.3 | Principal 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.4 | Principal 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.5.1 | Primary 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.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary 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.5.2.1 | Timepoint(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.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 82 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If 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.8.7 | Trial 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.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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