E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 1 Diabetes Mellitus |
Diabetes Mellitus Tipo 1 |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 10045228 |
E.1.2 | Term | Type I diabetes mellitus |
E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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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 |
To demonstrate that glycemic control as measured by HbA1c at 52 weeks for LY2605541 is non-inferior compared with insulin glargine when each is combined with pre-prandial insulin lispro in patients with T1DM. |
El objetivo principal es demostrar que el control glucémico que se alcanza con LY2605541 al cabo de 52 semanas, de acuerdo con la concentración de hemoglobina A1c [HbA1c], no es inferior al obtenido con insulina glargina, cuando cada uno de dichos fármacos se administra con insulina lispro preprandial, en pacientes con diabetes mellitus tipo 1 (DMT1). El margen de no inferioridad es del 0,4%. |
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E.2.2 | Secondary objectives of the trial |
Gated:To demonstrate that LY2605541 is superior to insulin glargine (each in combination with pre-prandial insulin lispro) for: ? Nocturnal hypoglycemia rate ? HbA1c ? Proportion of patients with HbA1c <7.0% ? Fasting serum glucose (FSG) by laboratory measurement ? Total hypoglycemia rate Non-Gated: To compare the efficacy and safety of LY2605541 versus insulin glargine (each in combination with pre-prandial insulin lispro): ? Total and nocturnal hypoglycemia rates and incidence ? Weight change ? SMBG 9-point profiles ? Proportion of patients with HbA1c <7.0% and HbA1c ? 6.5% ? Proportion of patients with HbA1c <7% without nocturnal hypoglycemia ? HbA1c change from baseline ? HbA1c endpoint ? Basal, mealtime, and total insulin dose ?Triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol ? Antibodies to LY2605541 ? Additional safety endpoints ? FSG by laboratory ? FBG (measured by SMBG) ? FBG (SMBG) intra-subject variability |
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. |
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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 |
Continuous Glucose Monitoring Addendum (21 September 2011) In order to better understand the impact of LY2605541 on glucose metabolism as well as within- and between-patient variability, especially during the nocturnal time period, in patients with type 1 diabetes, continuous glucose monitoring (CGM) will be performed in a subpopulation of approximately 180 patients enrolled in study I2R-MC-BIAO. The primary objective of this addendum is to compare the duration (in minutes) spent with a blood glucose ?70 mg/dL (in a hypoglycemic state) during the nocturnal period defined as midnight to 06:00 in patients taking LY2605541 versus insulin glargine at 52 weeks.
Pharmacogenetic Evaluations (10 September 2011) 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 (10 September 2011) 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. |
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E.3 | Principal inclusion criteria |
[1] Have T1DM based on the World Health Organization (WHO) classification [2] Are at least 18 years of age [3] Have had diabetes for at least 1 year [4] Have an HbA1c value < 12% according to the central laboratory at screening [5] Body mass index ? 35.0 kg/m2 [6] Have been treated for at least 90 days prior to screening with: ? insulin detemir, insulin glargine, or NPH insulin in combination with pre-meal insulin, or ? self mixed or pre-mixed insulin regimens with any basal and bolus insulin combination administered at least twice daily, or ? continuous subcutaneous insulin infusion therapy. [7] This inclusion criterion applies to all females only. ? Are not breastfeeding. ? Test negative for pregnancy at the time of screening and time of randomization based on a serum pregnancy test. ? Intend not to become pregnant during the study. ? Have practiced a reliable method of birth control (for example, 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 telephone [9] Have refrigeration in the home [10] Capable of, willing and desirous to do the following: adhere to a multiple daily injection regimen, inject insulin with a vial and syringe and prefilled pen and perform self blood glucose monitoring and record keeping as required by this protocol. Caregiver may do all of the above. [11] Have given written informed consent to participate in this study in accordance with local regulations. |
[1] Diagnóstico de DMT1, de acuerdo con la clasificación de la Organización Mundial de la Salud (OMS) (Anexo 4). [2] Tener al menos 18 años de edad. [3] Haber padecido diabetes al menos durante 1 año. [4] Presentar en la visita 1 una concentración de HbA1c < 12%, de acuerdo con los resultados de la prueba realizada en el laboratorio central. [5] Presentar un índice de masa corporal ? 35,0 kg/m2. [6] Haber recibido tratamiento, al menos durante 90 días antes de la visita 1, con: o Insulina detemir, insulina glargina o insulina NPH, conjuntamente con la administración de insulina preprandial, o o Terapias insulínicas premezcladas o mezcladas por el paciente, con cualquier combinación de insulina basal e insulina en bolo, administradas al menos dos veces al día, o o Terapia insulínica mediante infusión subcutánea continua. [7] Este criterio de inclusión aplica a todas las pacientes. o No encontrarse en período de lactancia. o Presentar en las visitas 1 y 3 un resultado negativo en una prueba de embarazo en suero. o No tener intención de quedarse embarazada durante el estudio. o 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. o 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] Tener acceso a un teléfono. [9] Disponer de un frigorífico en el domicilio. [10] Estar dispuesto y mostrar la capacidad y voluntad de: 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), 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. |
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E.4 | Principal exclusion criteria |
[12] Are using twice daily insulin glargine having been inadequately controlled on single daily dosed glargine prior to screening [13] Excessive insulin resistance defined as having received a total daily dose of insulin > 1.5 U/kg at the time of randomization. [14] Receiving any oral or injectable medication (other than insulins or metformin for treatment of polycystic ovarian disease) intended for the treatment of diabetes mellitus other than insulins in the 90 days prior to screening. Note: for subjects on metformin, the following exclusion criteria will apply: have serum creatinine concentration that contraindicates metformin use per the country-specific product labeling. [15] lipid lowering medication: are using niacin preparations as lipid lowering medication or 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. [16] Have fasting hypertriglyceridemia (defined as >4.5 mmol/L, >400 mg/dl) at screening, as determined by the central laboratory. [17] Have had more than 1 episode of severe hypoglycemia (defined as requiring assistance due to neurologically disabling hypoglycemia) within 6 months prior to screening. [18] Have had 2 or more emergency room visits or hospitalizations due to poor glucose control (hyperglycemia or diabetic ketoacidosis [DKA]) within 6 months prior to screening. [19] 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). [20] Renal: Have a history of renal transplantation or are currently receiving renal dialysis or have serum creatinine > 2.5 mg/dL. [21] Hepatic: have obvious clinical signs or symptoms of liver disease (excluding non-alcoholic fatty liver disease), acute or chronic hepatitis, non-alcoholic steatohepatitis (NASH), or elevated liver enzyme measurements as indicated below: ? total bilirubin ?2 x the upper limit of normal (ULN) as defined by the central laboratory, or ? ALT/serum glutamic pyruvic transaminase (SGPT) >2.5 x ULN as defined by the central laboratory, or ? AST/serum glutamic oxaloacetic transaminase (SGOT) >2.5 x ULN as defined by the central laboratory. [22] 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. [23] Allergy: Have known or develop hypersensitivity or allergy to any of the study insulins or their excipients. [24] 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. [25] 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. [26] Diagnosed clinically significant diabetic autonomic neuropathy, in the opinion of the investigator. [27] 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. |
[1] Estar recibiendo insulina glargina dos veces al día, tras haber presentado un control glucémico inadecuado con una única administración diaria de insulina glargina. [2] Haber recibido una dosis diaria total de insulina > 1,5 U/kg en el momento de la aleatorización. [3] Haber recibido cualquier medicación oral o inyectable para tratar la diabetes mellitus en el transcurso de los 90 días previos a la visita 1. [4] Hipolipemiantes: ? Estar recibiendo preparados de niacina como hipolipemiantes y secuestradores de ácidos biliares, en el transcurso de los 90 días previos a la visita 1; o, ? No estar recibiendo una dosis estable de hipolipemiantes durante ? 90 días antes de la visita 1. [5] Presentar en la visita 1 hipertrigliceridemia en ayunas de acuerdo con los análisis llevados a cabo en el laboratorio central. [6] Haber experimentado más de 1 episodio de hipoglucemia grave en el transcurso de los 6 meses previos a la visita 1. [7] Haber acudido a urgencias o haber sido hospitalizado 2 o más veces por haber presentado un mal control glucémico, en el transcurso de los 6 meses previos a la visita 1. [8] Cardiovascular: Presentar una enfermedad cardiaca con un estado funcional de clase III o IV (de acuerdo con la[NYHA]). [9] Haber recibido un trasplante renal, o estar recibiendo actualmente diálisis renal o presentar una concentración sérica de creatinina > 2,5 mg/dl. [10] Presentar claros signos o síntomas clínicos de enfermedad hepática (excepto los casos de enfermedad del hígado graso no inducida por el alcohol, hepatitis aguda o crónica, esteatohepatitis no alcohólica (NASH) o una elevación de las enzimas hepáticas, según se muestra a continuación: o Concentración de bilirrubina total ? 2 veces el límite superior de la normalidad (LSN), de acuerdo con los análisis llevados a cabo en el laboratorio central. o Concentración de ALT / transaminasa glutámico pirúvica sérica (SGPT) > 2,5 veces el LSN, de acuerdo con los análisis llevados a cabo en el laboratorio central. o Concentración de AST / transaminasa glutámica oxalacética sérica (SGOT) > 2,5 veces el LSN, de acuerdo con los análisis llevados a cabo en el laboratorio central. [11] Presentar una neoplasia activa o sin tratar, o haber estado en remisión de una neoplasia clínicamente significativa, o presentar, de acuerdo con la opinión del investigador, un mayor riesgo de experimentar cáncer o una recidiva de cáncer. [12] Presentar o que se desarrolle hipersensibilidad o alergia a cualquiera de las insulinas del estudio, o a sus excipientes. [13] 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. [14] Estar recibiendo tratamiento sistémico y crónico con glucocorticoides, o haber recibido dicho tratamiento en el transcurso de las 8 semanas previas a la visita 1. [15] Presentar neuropatía diabética neurovegetativa clínicamente significativa. [16] Padecer cualquier otra enfermedad que impida que el paciente siga y complete el protocolo. [17] Empleados de Lilly o Boehringer Ingelheim: [18] Personal del centro [19] Fármacos no aprobados: Haber recibido tratamiento, en el transcurso de los 30 días previos a la inclusión en el estudio [20] Participación previa en estudios clínicos: Estar participando en la actualidad o haber abandonado en el transcurso de los 30 días previos un ensayo clínico, en el que se administre un fármaco en fase de investigación. [21] Estudios previos con LY2605541: 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. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
A change of HbA1c from baseline to 52 weeks that is not inferior to glargine when combined with pre-prandial insulin lispro. |
Cambio en la HbA1c desde el inicio a 52 semanas, no es inferior al obtenido con insulina glargina, cuando cada uno de dichos fármacos se administra con insulina lispro preprandial. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
52 weeks of treatment |
52 semanas de tratamiento |
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E.5.2 | Secondary end point(s) |
Total and nocturnal hypoglycemia rates and incidence; weight change from baseline by visit; SMBG 9-pt profiles; proportion of patients with HbA1c <7.0% without nocturnal hypoglycemia; HbA1c change from baseline; proportion of patients with HbA1c <7%; proportion of patients with HbA1c ?6.5%; HbA1c endpoint by visit; basal, mealtime, and total insulin dose by visit; triglycerides, total cholesterol, LDL-cholesterol, HDL-cholesterol; antibodies to LY2600541; additional safety endpoints (treatment-emergent adverse events, serious adverse events, vital signs, treatment exposure, other laboratory measures, etc); FSG by laboratory, FBG (measured by SMBG), FBG (SMBG) intra-subject patient variability, 0300-hour BG to fasting FBG excursion, ITSQ, LBSS, EQ-5D, and RAPA. |
Tasa de hipoglucemia nocturna, HbA1c, % con HbA1c < 7,0% , 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; 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. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
All gated objective endpoints are at 52 weeks of treatment. Nocturnal and total hypoglycemia rates and incidence have various timepoints such as 0-2 weeks, 0-12 weeks, 0-26 weeks, 0-52 weeks, 2-12 weeks, 2-26 weeks, 12-26 weeks, 26-52 weeks; proportion of patients with HbA1c <7.0%, HbA1c, and FSG by laboratory at 26 weeks; ITSQ and EQ-5D at 52 weeks; all other endpoints at 26 and 52 weeks. |
52 semanas de tratamiento |
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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 | 8 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Belgium |
Brazil |
Canada |
Croatia |
Denmark |
France |
Greece |
Ireland |
Israel |
Lithuania |
Netherlands |
Poland |
South Africa |
Spain |
Sweden |
Turkey |
United Kingdom |
United States |
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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
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last visit of the last subject undergoing the trial |
Ultima visita del ultimo paciente en el estudio |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |