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 compare the insulin glargine/lixisenatide fixed ratio combination to lixisenatide alone and to insulin glargine alone (on top of metformin treatment) in HbA1c change from baseline to week 30 |
Comparar la combinación en proporción fija de insulina glargina/lixisenatida respecto a lixisenatida y la insulina glargina solas (en combinación con metformina) en el cambio de HbA1c desde el momento basal a la semana 30 |
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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 alone and to lixisenatide alone (on top of metformin treatment) over a 30 week treatment period in patients with type 2 diabetes |
Comparar la eficacia y la seguridad global de la combinación en proporción fija de insulina glargina/lixisenatida respecto a lixisenatida y la insulina glargina solas (en combinación con metformina) a la semana 30 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 |
? Patients with type 2 diabetes mellitus diagnosed for at least 1 year before the screening visit, treated for at least 3 months prior to visit 1 with metformin alone or metformin and a second oral anti-diabetic treatment that can be a sulfonylurea, or a glinide, or a sodium glucose co-transporter 2 inhibitor, and who are not adequately controlled with this treatment; ? Signed written informed consent |
? Pacientes con diabetes mellitus tipo 2 diagnosticada al menos 1 año antes de la visita de selección, tratados durante al menos 3 meses antes de la visita 1 con metformina sola o con metformina y un segundo tratamiento antidiabético oral que puede ser una sulfonilurea (SU), una glinida, o un inhibidor del SGLT-2 que no estén debidamente controlados con este tratamiento; ? Consentimiento informado por escrito firmado. |
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E.4 | Principal exclusion criteria |
? HbA1c at screening visit: - less than 7.5% or more than 10% for patients previously treated with metformin alone, - less than 7.0% or more than 9 % for patients previously treated with metformin and a second oral anti-diabetic treatment; ? Pregnancy or lactation, women of childbearing potential with no effective contraceptive method; ? Use of oral glucose-lowering agents other than those stated in the inclusion criteria or any injectable glucose-lowering agents during the 3 months before screening. ? Previous Treatment with insulin (except for short-term treatment due to intercurrent illness including gestational diabetes, at the discretion of the trial physician) ? History of discontinuation of a previous treatment with a GLP-1 receptor agonist (GLP-1 RA) due to safety/tolerability issue 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. ? Any contraindication to metformin use, according to local labeling ? 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) Exclusion Criteria for randomization at the end of the screening period: ? HbA1c less than 7% or above 10%; ? Fasting Plasma glucose above 250mg/dL (13.9 mmol/L); ? Metformin maximal tolerated dose less than 1500 mg/day; ? Amylase and/or lipase more than 3 ULN; |
? Menor de edad en la visita de selección ? HbA1c en la visita de selección: - < 7,5 % y > 10 % para pacientes previamente tratados solo con metformina, - < 7,0 % y > 9 % para pacientes previamente tratados con metformina y un segundo tratamiento antidiabético oral; ? Embarazo o lactancia, mujeres en edad fértil sin un método anticonceptivo eficaz; ? Uso de agentes hipoglucemiantes orales distintos de los indicados en los criterios de inclusión o cualquier agente hipoglucemiante inyectable durante los 3 meses previos a la selección. ? Tratamiento previo con insulina (excepto tratamiento a corto plazo debido a enfermedad concomitante, incluida diabetes gestacional, a discreción del médico del ensayo) ? Antecedentes de interrupción de un tratamiento previo con un agonista del receptor de péptido 1 similar al glucagón GLP-1 (GLP-1 RA) por motivos de seguridad/tolerancia, o falta de eficacia; ? Resultados de laboratorio en el momento de la selección: - Amilasa y/o lipasa > 3 veces el límite superior del intervalo normal del laboratorio (Límite superior del intervalo normal LSN), - ALT o AST > 3 LSN, - Calcitonina ? 20 pg/ml (5,9 pmol/l) - Prueba de embarazo positiva; ? Cualquier contraindicación para el uso de metformina, según la ficha técnica local, (p. ej. deterioro de la función renal definida como creatinina > 1,4 mg/dl en mujeres, > 1,5 mg/dl en hombres, o aclaramiento de creatinina < 60 ml/min); ? Contraindicación para el uso de insulina glargina o lixisenatida según la ficha técnica local. Antecedentes de hipersensibilidad a la insulina glargina o a cualquiera de los excipientes; ? Antecedentes de reacción alérgica a cualquier agonista del receptor de GLP-1 o a metacresol; ? Antecedentes personales o familiares directos de cáncer medular tiroideo (CMT) o afecciones genéticas que predispongan al CMT (p. ej., síndromes de neoplasia endocrina múltiple) ? Antecedentes de pancreatitis (a menos que la pancreatitis estuviera relacionada con cálculos biliares y ya se hubiera realizado una colecistectomía), pancreatitis crónica, pancreatitis durante un tratamiento previo con terapias de incretinas, pancreatectomía, cirugía de estómago/gástrica. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change in HbA1c from baseline |
Cambios en la HbA1c desde el momento 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 - Change in body weight from baseline - Change in 7-point Self Measured Plasma Glucose profiles from baseline - Daily dose of insulin glargine - 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 alcanzan objetivos de HbA1c; - Control glucémico en relación con una comida evaluado mediante la glucosa postprandial plasmática (GPP) a las 2 horas y la oscilación glucémica durante una prueba de comida estandarizada; - Glucosa plasmática en ayunas (GPA) - Peso corporal; - Perfil de autocontrol de la glucosa plasmática (Self-Monitored Plasma Glucose, SMPG) con 7 puntos - Porcentaje de pacientes que alcanzan objetivos de HbA1c sin aumento de peso y/o hipoglucemia sintomática documentada; - Dosis de insulina glargina (en los grupos de la combinación y de insulina glargina). Evaluar la seguridad y la tolerancia en cada grupo de tratamiento. Evaluar el desarrollo de anticuerpos anti-lixisenatida y/o anti-insulina (dependiendo del grupo de tratamiento). Evaluar la concentración plasmática total y activa de lixisenatida antes y después de la inyección (en los grupos de combinación enproporción fija y de lixisenatida). Evaluar los efectos del tratamiento en cada grupo de tratamiento sobre los resultados percibidos por el paciente (Patient Reported Outcomes, PRO) medidos en los siguientes cuestionarios: ? Medición del impacto relacionado con el tratamiento para la diabetes (Treatment related impact measure ? diabetes, TRIM-D); ? Cuestionario sobre la calidad de vida EuroQol-5D (EQ-5D); ? Impacto del peso sobre la calidad de vida (Impact of Weight on Quality of Life-Lite, IWQoL-Lite). Evaluar la respuesta global de los pacientes al tratamiento utilizando una escala de evaluación sobre la eficacia global valorada por el paciente y por el médico para cada grupo de tratamiento. |
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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 | 3 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 |
Belgium |
Denmark |
France |
Italy |
Romania |
Sweden |
Australia |
Chile |
Czech Republic |
Estonia |
Germany |
Hungary |
Latvia |
Lithuania |
Spain |
Mexico |
Poland |
Russian Federation |
South Africa |
Ukraine |
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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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 | 5 |
E.8.9.1 | In the Member State concerned days | 14 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 14 |