E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 Diabetes Mellitus |
Diabetes Mellitus Tipo 2 |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 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 | 19.0 |
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 (FRC) versus GLP-1 receptor agonist (GLP-1 RA) in hemoglobin A1c (HbA1c) change. |
Demostrar la superioridad de la combinación en proporción fija (CPF) de insulina glargina/lixisenatida frente al agonista del receptor del péptido 1 similar al glucagón (AR de GLP-1) en el cambio de la hemoglobina A1c (HbA1c) |
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E.2.2 | Secondary objectives of the trial |
To compare the overall efficacy and safety of the insulin glargine/lixisenatide fixed ratio combination (FRC) to GLP-1 receptor agonist (GLP-1 RA) on top of metformin (with or without pioglitazone) in patients with type 2 diabètes. |
Comparar la eficacia global y la seguridad de la insulina glargina / lixisenatida en combinación fija (FRC) para los agonistas de los receptores GLP-1 (GLP-1 RA) más metformina (con o sin pioglitazona) 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 at least 1 year prior to screening visit. -Patients who have been treated with one of the following glucagon-like peptide 1 (GLP-1) receptor agonists for at least 4 months prior to screening visit (V1), and with stable dose for at least 3 months prior to screening visit (V1): -Liraglutide (Victoza®) 1.8 mg QD or 1.2 mg QD, if the 1.8 mg QD dose is not well tolerated according to the Investigator's judgment or -Exenatide (Byetta®) 10 ?g BID or of 5 ?g BID, if 10 ?g BID dose is not well tolerated according to the Investigator's judgment in combination with metformin (daily dose ?1500 mg/day or maximum tolerated dose [MTD]), with or without pioglitazone, both at stable dose for at least 3 months prior to screening. or Patients who have been treated with stable dose of one of the following GLP-1 receptor agonists for at least 6 months prior to screening visit (V1): -Exenatide extended-release (Bydureon®) 2 mg once weekly (QW), if well tolerated according to Investigator?s judgment, -Albiglutide (Tanzeum®, Eperzan®) 50 mg QW or 30 mg QW, if 50 mg QW is not well tolerated according to Investigator?s judgment, -Dulaglutide (Trulicity®) 1.5 mg QW or 0.75 mg QW, if 1.5 mg QW is not well tolerated according to Investigator?s judgment in combination with metformin (daily dose ?1500 mg/day or MTD), with or without pioglitazone, both at stable dose for at least 3 months prior to screening; -Signed written informed consent. |
-Pacientes con diabetes mellitus tipo 2 diagnosticada al menos un año antes de la visita de selección (V1); -Pacientes que han recibido tratamiento con uno de los siguientes agonistas del receptor de GLP-1 durante al menos 4 meses antes de la visita de selección (V1), y que están recibiendo una dosis estable desde al menos los 3 meses anteriores a la visita de selección (V1): - Liraglutida (Victoza®) 1,8 mg una vez al día (1 v/d), o 1,2 mg 1 v/d cuando, según el criterio del Investigador, no se tolere bien la dosis de 1,8 mg 1 v/d - o exenatida dos veces al día (2 v/d), (Byetta®) 10 μg 2 v/d o 5 μg 2 v/d cuando, según el criterio del Investigador, no se tolere bien la dosis de 10 μg 2 v/d en combinación con metformina (dosis diaria ≥1500 mg/día o Dosis Máxima Tolerada (DMT)), con o sin pioglitazona, los dos fármacos administrados a una dosis estable como mínimo en los 3 meses anteriores a la selección; o Pacientes que han recibido tratamiento con una dosis estable de uno de los siguientes agonistas del receptor de GLP-1 durante al menos 6 meses antes de la visita de selección (V1): - Exenatida de liberación prolongada (Bydureon®) 2 mg una vez a la semana (1 v/s), cuando, según el criterio del Investigador, se tolere bien - Albiglutida (Tanzeum®, Eperzan®) 50 mg 1 v/s o 30 mg 1 v/s cuando, según el criterio del Investigador, no se tolere bien 50 mg 1 v/s - Dulaglutida (Trulicity®) 1,5 mg 1 v/s o 0,75 mg 1 v/s cuando, según el criterio del Investigador, no se tolere bien 1,5 mg 1 v/s en combinación con metformina (dosis diaria ≥1500 mg/día o DMT), con o sin pioglitazona, los dos fármacos administrados a una dosis estable como mínimo en los 3 meses anteriores a la selección; Consentimiento informado por escrito y firmado. |
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E.4 | Principal exclusion criteria |
-At screening visit, age <18. -Screening HbA1c <7% and >9%. -Pregnancy or lactation, women of childbearing potential with no effective contraceptive method. -Any use of oral antidiabetic drugs within 3 months prior to the screening visit other than those described in the inclusion criteria. -Previous treatment with insulin in the year prior to screening visit (note: short-term treatment with insulin [?10 days] due to intercurrent illness including gestational diabetes is allowed at the discretion of the study physician). -Laboratory findings at the time of screening, including: -Fasting plasma glucose (FPG) >250 mg/dL (13.9 mmol/L), -Amylase and/or lipase >3 times the upper limit of the normal laboratory range (ULN), -Alanine transaminase or aspartate transaminase >3 ULN, -Calcitonin ?20 pg/mL (5.9 pmol/L), -Positive pregnancy test. -Patient who has renal function impairment with estimated glomerular filtration rate <30 mL/min (using the Modification of Diet in Renal Disease formula) or end-stage renal disease. -Contraindication to use of insulin glargine, or lixisenatide or GLP-1 receptor agonist (Victoza®, Byetta®, Bydureon®, Tanzeum®/Eperzan® or Trulicity®) according to local labeling. -Any contraindication to metformin or pioglitazone use, according to local labeling. -History of hypersensitivity to insulin glargine, or to any of the excipients. -History of allergic reaction to any GLP-1 receptor agonist or to meta-cresol. -Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (eg, multiple endocrine neoplasia type 2 syndromes). -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. -Body mass index ?20 or >40 kg/m^2. |
-En la visita de selección (V1), no haber alcanzado la mayoría de edad; -HbA1c en la selección <7 % (53 mmol/mol) y >9 % (75 mmol/mol); -Embarazo o lactancia, mujeres con posibilidad de quedar embarazadas que no usan un método anticonceptivo eficaz; -Cualquier uso de antidiabéticos orales (ADO) en los 3 meses anteriores a la visita de selección (V1), diferentes a los mencionados en los criterios de inclusión; -Tratamiento anterior con insulina en el año anterior a la visita de selección (V1) (nota: está permitido, según el criterio del médico del estudio, el tratamiento a corto plazo con insulina (≤10 días) como consecuencia de una enfermedad intercurrente, entre otras la diabetes gestacional); Resultados de laboratorio en el momento de la selección, entre otros: - Glucosa plasmática en ayunas (GPA) >250 mg/dl (13,9 mmol/l); - Amilasa y/o lipasa >3 veces el límite superior de la normalidad del intervalo analítico (LSN); - Alanina aminotransferasa (ALT) o aspartato aminotransferasa (AST) >3 LSN; - Calcitonina >20 pg/ml (5,9 pmol/l); - Prueba de embarazo en suero positiva. Paciente con deterioro de la función renal con una tasa de filtración glomerular (TFG) <30 ml/min (según la fórmula MDRD) o enfermedad renal en estadío terminal; Contraindicación al uso de insulina glargina, o lixisenatida o un agonista del receptor de GLP-1 (Victoza®, Byetta®, Bydureon®, Tanzeum®/Eperzan® o Trulicity®) de acuerdo a la ficha técnica local; Cualquier contraindicación al uso de metformina o pioglitazona (cuando sea aplicable), de acuerdo a la ficha técnica local; Antecedentes de hipersensibilidad a la insulina glargina o a cualquiera de los excipientes; Antecedentes de reacción alérgica con cualquier agonista del receptor de GLP-1 o con Metacresol; Antecedentes personales o familiares inmediatos de cáncer medular tiroideo (CMT) o afecciones genéticas que predisponen al CMT (p. ej., síndromes de neoplasia endocrina múltiple de tipo 2); Antecedentes de pancreatitis (a menos que la pancreatitis se relacione con litiasis biliar y se haya realizado una colecistectomía), pancreatitis crónica, pancreatitis durante tratamiento previo con incretinas, pancreatectomía, cirugía gástrica; Índice de Masa Corporal (IMC) ≤20 o >40 kg/m2. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in HbA1c |
Cambio en la HbA1c |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline to 26 weeks |
desde el momento basal hasta la Semana 26. |
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E.5.2 | Secondary end point(s) |
1- Percentage of participants reaching HbA1c targets 2- Change from baseline in FPG 3- Change from baseline in 7-point self-monitored plasma glucose (SMPG) profiles 4- Change from baseline in 2-hour postprandial glucose (PPG) during standardized meal test 5- Change from baseline in blood glucose excursion during standardized meal test 6- Change from baseline in body weight 7- Percentage of participants with symptomatic hypoglycemia 8- Number of adverse events |
1 -Porcentaje de pacientes que alcanzan valores de HbA1c <7 % (53 mmol/mol) o ≤6,5 % (48 mmol/mol) 2 -Cambio en la GPA 3 -Cambio en el perfil de SMPG de 7 puntos 4 -Cambio en la GPP a las 2 horas 5 -Cambio en la oscilación glucémica durante una prueba de comida estandarizada 6 -Cambio en el peso corporal 7- Porcentaje de participantes con hipoglucemia sintomática 8- Número de eventos adversos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1- 26 weeks 2-3-4-5-6 Baseline to 26 weeks 7-8 26 weeks |
1- en la Semana 26; 2-3-4-5-6 desde el momento basal hasta la Semana 26; 7-8 en la Semana 26; |
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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 | No |
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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 53 |
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 |
Estonia |
France |
Germany |
Hungary |
Israel |
Italy |
Portugal |
Romania |
Slovakia |
Spain |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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
|
Date of database lock (database is planned to be locked approximately 4 weeks after last patient last visit) |
Fecha del cierre de la base de datos (la base de datos está previsto que se cierre aproximadamente 4 semanas después de la 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 | |
E.8.9.1 | In the Member State concerned months | 18 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 18 |