E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type II Diabetes Mellitus |
Diabetes Mellitus tipo 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type II Diabetes Mellitus |
Diabetes Mellitus tipo 2 |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 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 the superiority of the insulin glargine/lixisenatide fixed ratio combination to insulin glargine in HbA1c change from baseline to week 30. |
Demostrar la superioridad de la combinación de insulina glargina/lixisenatida en proporción fija con respecto a la insulina glargina en el cambio producido en la HbA1c a la semana 30 con respecto al momento basal. |
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E.2.2 | Secondary objectives of the trial |
To compare the overall efficacy and safety of insulin glargine/lixisenatide fixed ratio combination to insulin glargine (with or without metformin) over a 30 week treatment period in patients with type 2 diabetes |
Comparar la eficacia y la seguridad global de la combinación de insulina glargina/lixisenatida en proporción fija en comparación con la insulina glargina (con o sin metformina) al cabo de 30 semanas de tratamiento en pacientes con diabetes tipo 2. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
? Type 2 diabetes mellitus diagnosed at least 1 year before the screening visit. ?Treatment with basal insulin for at least 6 months before the screening visit. ? Stable basal insulin regimen (i.e. type of insulin and time/frequency of the injection) for at least 3 months before the screening visit. ? Stable (plus/minus 20 percent) total daily basal insulin dose between 15 and 40U/day for at least 2 months prior to the screening visit. ? For patients receiving basal insulin AND 1 or 2 oral anti-diabetic drugs (OADs): the OAD dose(s) must be stable during the 3 months before the screening visit. The OADs can be 1 to 2 out of: - metformin (more than or equal to1500mg/day or maximal tolerated dose), - a sulfonylurea - a glinide, - a dipeptidyl-peptidase-4 inhibitor - a sodium glucose co-transporter 2 inhibitor ? Fasting plasma glucose (FPG) less than or equal to 180 mg/dL(10.0 mmol/L) at screening visit for patients receiving basal insulin in combination with 2 OADs or with 1 OAD other than metformin; FPG less than or equal to 200 mg/dL (11.1 mmol/L) at screening visit for patients on basal insulin only or basal insulin plus metformin at screening visit, ? Signed written informed consent. |
? Pacientes con diabetes mellitus tipo 2 (DMT2) diagnosticada desde al menos 1 año antes de la visita de selección, ? Pacientes tratados con una insulina basal durante al menos 6 meses antes de la visita de selección, ? Pacientes tratados con un régimen estable de insulina basal (es decir, en cuanto al tipo de insulina y al momento/frecuencia de las inyecciones) durante al menos 3 meses antes de la visita de selección, ? Dosis estable de insulina basal total diaria (±20 %) de entre 15 y 40 U/día durante al menos 2 meses antes de la visita de selección, ? En el caso de los pacientes que reciban insulina basal Y 1 o 2 antidiabéticos orales (ADO): la(s) dosis de ADO debe(n) haber sido estable(s) durante los 3 meses previos a la visita de selección. Los ADO pueden ser 1 o 2 de los siguientes: - una metformina (dosis mayor o igual a 1500 mg/día o dosis máxima tolerada), - una sulfonilurea (SU), - una glinida, - un inhibidor de la dipeptidil-peptidasa 4 (inhibidor de la DPP-4) o - un inhibidor de la proteína cotransportadora de sodio y glucosa de tipo 2 (inhibidor de la SGLT-2). ? GPA ?180 mg/dl (10,0 mmol/l) en la visita de selección para los pacientes que reciban insulina basal en combinación con 2 ADO o con 1 ADO distinto de la metformina; GPA ?200 mg/dl (11,1 mmol/l) en la visita de selección para los pacientes tratados con insulina basal sola o con insulina basal más metformina en la visita de selección, ? Consentimiento informado por escrito firmado. |
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E.4 | Principal exclusion criteria |
? Age under legal age of adulthood at screening visit ? HbA1c at screening visit less than 7.5% or above 10%. ? Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. ? Use of other oral or injectable glucose-lowering agents than stated in the inclusion criteria in a period of 3 months prior to screening. ? Previous use of insulin regimen other than basal insulin e.g. prandial or pre-mixed insulin. (short term treatment due to intercurrent illness including gestational diabetes is allowed at the discretion of the investigator). ? History discontinuation of a previous treatment with Glucagon Like Peptide -1 Receptor Agonists for safety/tolerability or lack of efficacy. ? Patient who has previously participated in any clinical trial with lixisenatide or the insulin glargine/lixisenatide fixed ratio combination or has previously received lixisenatide. ? Use of weight loss drugs within 3 months prior to screening visit. ? Within the last 6 months prior to screening visit: history of stroke, myocardial infarction, unstable angina, or heart failure requiring hospitalization. Planned coronary, carotid or peripheral artery revascularisation procedures to be performed during the study period. ? History of pancreatitis (unless pancreatitis was related to gallstones and cholecystectomy was already performed), chronic pancreatitis, pancreatitis during a previous treatment with incretin therapies, pancreatectomy, stomach/gastric surgery. ? Personal or immediate family history of medullary thyroid cancer (MTC) or genetic conditions that predispose to MTC (eg, multiple endocrine neoplasia syndromes). ? Uncontrolled or inadequately controlled hypertension (systolic blood pressure above 180 mmHg or diastolic blood pressure above 95 mmHg) at screening visit ? At screening visit, Body Mass Index (BMI) less than or equal to 20 or above 40 kg/m² ? At screening visit amylase and/or lipase more than 3 times the upper limit of the normal (ULN) laboratory range, ? At screening visit ALT or AST more than 3 ULN ? At screening visit calcitonin above or equal to 20 pg/mL (5.9 pmol/L) ? Any contraindication to metformin use, according to local labeling, if the patient is taking metformin. ? Patient who has a renal function impairment with creatinine clearance less than 30 mL/min (using the Cockroft and Gault formula) or end-stage renal disease for patients, not treated with metformin. Exclusion criteria for randomization: ? HbA1c less than 7% or above 10% . ? Mean fasting Self Measured Plasma Glucose (SMPG) calculated from the self-measurements for 7 days the week before randomization visit is above 140 mg/dL (7.8 mmol/L). ? Average insulin glargine daily dose less than 20U or above 50U ( in the week before randomization visit). ? Amylase and/or lipase more than 3 ULN |
Criterios de exclusión: ? En la visita de selección, edad inferior a la de la edad adulta legal, ? HbA1c en la visita de selección <7,5 % o >10 %, ? Embarazo o lactancia, ? Mujeres con capacidad para procrear no protegidas con un método anticonceptivo de eficacia elevada para el control de la natalidad, ? Uso de hipoglucemiantes orales o inyectables distintos de los mencionados en los criterios de inclusión durante los 3 meses previos a la selección, ? Uso previo de un régimen de insulina distinto de la insulina basal, p. ej., insulina prandial o premezclada, Nota: Se permitirán tratamientos a corto plazo por enfermedades intercurrentes, incluida la diabetes gestacional, según criterio del investigador. ? Antecedentes de suspensión de un tratamiento previo con un agonista del receptor de péptido 1 similar al glucagón (GLP-1) por motivos de seguridad/tolerabilidad o por falta de eficacia, ? Los siguientes resultados de laboratorio en la visita de selección: - Amilasa y/o lipasa >3 veces el límite superior de la normalidad (LSN) del intervalo del laboratorio, - ALT o AST >3 veces el LSN, - Calcitonina ?20 pg/ml (5,9 pmol/l), - Prueba de embarazo en suero positiva. ? Cualquier contraindicación para el uso de metformina, según la ficha técnica (p. ej., deterioro renal definido como creatinina >1,4 mg/dl en mujeres, >1,5 mg/dl en hombres o aclaramiento de la creatinina <60 ml/min, etc.) si el paciente está tomando metformina, ? Paciente con deterioro de la función renal con un aclaramiento de la creatinina <30 ml/min (según la fórmula de Cockroft y Gault) o insuficiencia renal terminal en el caso de los pacientes no tratados con metformina, ? Antecedentes previos de reacción alérgica a cualquier agonista del receptor de la GLP-1 o al metacresol, ? Contraindicación del uso de insulina glargina según la ficha técnica. Historial previo de hipersensibilidad a la insulina glargina o a cualquiera de los excipientes, ? Antecedentes personales o familiares directos de carcinoma medular tiroideo (CMT) o afecciones genéticas que predispongan al CMT (p. ej., síndromes de neoplasia endocrina múltiple), ? Antecedentes previos de pancreatitis (a menos que haya estado relacionada con colelitiasis y ya se haya practicado unacolecistectomía), pancreatitis crónica, pancreatitis durante un tratamiento previo con incretinas, pancreatectomía, intervenciones quirúrgicas estomacales/gástricas. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from baseline |
Cambio en la HbA1c desde la basal |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- Percentage of patients reaching HbA1c targets - Change in 2-hour Post Prandial Glucose and in blood glucose excursion during standardized meal test from baseline to week 30 - Change in body weight from baseline - Change in 7-point Self-Monitoring Plasma Glucose profiles from baseline - Change in daily dose of insulin glargine from baseline - Change in Fasting Plasma Glucose from baseline - Documented (plasma glucose less than or equal to 70 mg/dl) symptomatic hypoglycemia - Severe symptomatic hypoglycemia |
? Porcentaje de pacientes que alcancen una HbA1c <7 % o ?6,5 % en la semana 30, ? Cambio en la GPP a las 2 horas y oscilaciones de la glucosa en sangre durante la prueba de comida estandarizada desde el momento basal hasta la semana 30, ? Cambio en el peso corporal desde el momento basal hasta la semana 30, ? Cambio en los perfiles del autocontrol de la glucosa plasmática (SMPG) de 7 puntos con respecto al momento basal hasta la semana 30 (en cada punto temporal y en el valor medio diario), ? Porcentaje de pacientes que alcancen una HbA1c <7 % sin ganancia de peso corporal en la semana 30, ? Cambio producido en la dosis diaria de insulina glargina desde el momento basal hasta la semana 30, ? Porcentaje de pacientes que alcancen una HbA1c <7 % sin ganancia de peso corporal en la semana 30 y sin ninguna hipoglucemia sintomática documentada (GP ?70 mg/dl [3,9 mmol/l]) durante el período de tratamiento aleatorizado de 30 semanas, ? Cambio en la GPA desde el momento basal hasta la semana 30, ? Porcentaje de pacientes que alcancen una HbA1c <7 % a la semana 30 sin ninguna hipoglucemia sintomática documentada (GP ?70 mg/dl [3,9 mmol/l]) durante el período de tratamiento aleatorizado de 30 semanas, ? Cambio producido en la GPP a los 30 minutos y al cabo de 1 hora y oscilaciones de la glucosa en sangre durante la prueba de comida estandarizada desde el momento basal hasta la semana 30, ? Porcentaje de pacientes que requieren terapia de rescate durante el período de tratamiento abierto de 30 semanas |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 30/ 30 weeks |
Semana 30 |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 63 |
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 |
Canada |
Denmark |
Netherlands |
Romania |
Slovakia |
Sweden |
Australia |
Chile |
Czech Republic |
Estonia |
Hungary |
Lithuania |
Spain |
Mexico |
Poland |
Russian Federation |
Ukraine |
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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LVLS |
Última visita del último paciente |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 0 |