| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Type 2 Diabetes |
| Diabetes tipo 2 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Type 2 Diabetes |
| Diabetes tipo 2 |
|
| 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 | 18.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012601 |
| E.1.2 | Term | 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 |
To demonstrate that once-weekly dulaglutide (1.5 mg and/or 0.75 mg) is superior to placebo as measured by HbA1c at 24 weeks (change from baseline) in patients
with inadequately controlled T2D on concomitant SGLT2 inhibitor therapy. |
| Demostrar que la administración de dulaglutida una vez a la semana (1,5 mg o 0,75 mg) es superior a placebo, de acuerdo con la concentración de HbA1c a las 24 semanas (variación respecto a los valores basales), en pacientes con DT2 que presentan un control insuficiente con un tratamiento concomitante con un inhibidor del SGLT2. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary efficacy objectives (controlled for type 1 error) are to compare dulaglutide 1.5 mg and 0.75 mg to placebo at 24 weeks
Other secondary efficacy objectives are to compare
dulaglutide 1.5 mg and 0.75 mg to placebo at 24 weeks
Secondary safety objectives are to compare dulaglutide
1.5 mg and 0.75 mg to placebo at 24 weeks |
Los objetivos secundarios fundamentales relacionados con la eficacia (en los que se controlará el error de tipo 1), son comparar la administración de 1,5 mg o 0,75 mg de dulaglutida con placebo al cabo de 24 semanas.
Otros objetivos secundarios relacionados con la eficacia son comparar las dosis de 1,5 mg y 0,75 mg de dulaglutida con el placebo al cabo de 24 semanas
Los objetivos secundarios relacionados con la seguridad son comparar las dosis de 1,5 mg y 0,75 mg de dulaglutida con el placebo al cabo de 24 semanas |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
[1] are men or non-pregnant women aged ?18 years at screening
[2] have T2D
[3] have been treated with an SGLT2 inhibitor, with or without metformin, for at least 3 months prior to study entry
[4] daily doses of all allowed OAMs must have been stable for at least 12 weeks (± 3 days) prior to randomization
[5] have HbA1c ?7.0% and ?9.5% at study entry
[6] have body mass index (BMI) ?45 kg/m2 and agree to not initiate a diet and/or exercise program during the study with the intent of reducing body weight;
[7] are able and willing to administer once-weekly injections;
[8] in the investigator?s opinion, are well motivated, capable, and willing to:
a) perform finger-stick plasma glucose monitoring including scheduled daily PG profile with up to 6 measurements in 1 day;
b) learn how to self-inject treatment, as required for this protocol
c) maintain a study diary, as required for this protocol;
[9] Women of childbearing potential participating must agree to remain abstinent, use 1 highly effective method of contraception (eg, combined oral contraceptive pill and mini-pill, NuvaRing, implantable contraceptives, injectable contraceptives, intrauterine devices or use a combination of 2 effective methods (eg, male condom with spermicide, female condom with spermicide, diaphragm with spermicide, cervical sponge, cervical cap with spermicide) for the entirety of the study. Abstinence or contraception must continue following completion of study drug administration until 4 weeks after the last dose of study drug.
[10] have given written and informed consent to participate in this study in accordance with local regulations and the Ethical Review board (ERB) governing the study site. |
[1] Varones y mujeres que no estén embarazadas que tengan ? 18 años en el momento de la selección;
[2] Presentar DT2
[3] Haber recibido tratamiento con un inhibidor del SGLT2, con o sin metformina, al menos durante los 3 meses previos a la inclusión en el estudio
[4] Las dosis diarias de todos los AHO permitidos deben haberse mantenido estables al menos durante las 12 semanas (± 3 días) previas a la aleatorización
[5] Presentar una concentración de HbA1c ? 7,0 % y ? 9,5 % en el momento de la inclusión en el estudio
[6] Tener un índice de masa corporal (IMC) ? 45 kg/m2 y estar de acuerdo en no iniciar una dieta o un programa de ejercicio durante el estudio
[7] Ser capaz y estar dispuesto a administrarse inyecciones una vez a la semana
[8] De acuerdo con el criterio del investigador, estar motivado, ser capaz y estar dispuesto a:
[a] Realizar seguimiento de los valores de glucosa plasmática, incluido un perfil diario programado de la GP, con hasta 6 mediciones en 1 día
[b] Aprender cómo inyectarse el tratamiento, de acuerdo con el protocolo
[c] Completar el diario del estudio, según se especifica en el protocolo
[9] Las mujeres fértiles que participen en el estudio deben estar de acuerdo en practicar la abstinencia, utilizar 1 método anticonceptivo muy eficaz o 2 métodos eficaces de forma combinada, durante la totalidad del estudio. La abstinencia o el uso de métodos anticonceptivos deben continuar con posterioridad a la finalización de la administración del fármaco del estudio (hasta 4 semanas después de la última dosis del fármaco del estudio).
[10] Haber proporcionado el consentimiento informado para participar en este estudio, de acuerdo con la normativa local y el comité ético (CEIC) del centro del estudio. |
|
| E.4 | Principal exclusion criteria |
[11] have type 1 diabetes mellitus;
[12] have been treated with ANY other OAMs (other than SGLT2s and metformin), GLP-1 receptor agonist or insulin 3 months prior to study entry, or between study entry and randomization; or initiate metformin between study entry and randomization; short-term use of insulin for acute care (?14 days) during the 3-month period prior to entry is not exclusionary;
[13] have any condition that is a contraindication for use of the GLP-1 analog class or the SGLT2 inhibitor class (per country-specific labels) at study entry or develop such condition between study entry and randomization
[14] for patients using metformin, if a condition that is a contraindication for its use develops between stabilization and randomization;
[15] discontinue therapy with SGLT2 inhibitors any time prior to randomization and/or metformin, if used, between stabilization and randomization based on the Exclusion Criteria described under [13] and [14] above, or any other reason;
[16] have a history of ?1 episode of ketoacidosis or hyperosmolar state/coma prior to study entry;
[17] have a history of hypoglycemia unawareness within the 6 months prior to study entry;
[18] have been treated with drugs that promote weight loss or have received a diet and/or exercise program with the intent of reducing body weight within 3 months prior to study entry or between study entry and randomization
[19] are receiving chronic (>14 days) systemic glucocorticoid therapy (excluding topical, intraocular, intranasal, intra-articular, or inhaled preparations) any time between entry and randomization or have received such therapy within 4 weeks prior to study entry;
[20] have had any of the following cardiovascular (CV) conditions within 2 months prior to study entry: acute myocardial infarction, New York Heart Association (NYHA) Class III or Class IV heart failure, or cerebrovascular accident (stroke);
[21] have a known clinically significant gastric emptying abnormality at study entry, or have undergone bariatric surgery in the past;
[22] have acute or chronic hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (NAFLD), or alanine transaminase (ALT) level >2.5 times the upper limit of the reference range, as determined by the central laboratory at study entry; patients with NAFLD are eligible for participation in this trial;
[23] had chronic or acute pancreatitis any time prior to study entry;
[24] have an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2, calculated by the Chronic Kidney Disease-Epidemiology (CKD-EPI) equation, as determined by the central laboratory at study entry and confirmed at lead in;
[25] have evidence of a significant, uncontrolled endocrine abnormality at study entry, in the opinion of the investigator;
[26] have any self or family history of type 2A or type 2B multiple endocrine neoplasia (MEN 2A or 2B) in the absence of known C-cell hyperplasia
[27] have any self or family history of medullary C-cell hyperplasia, focal hyperplasia, carcinoma (including sporadic, familial or part of MEN 2A or 2B syndrome);
[28] have a serum calcitonin ?20 pg/mL as determined by the central laboratory at study entry;
[29] have evidence of a significant, active autoimmune abnormality (eg, lupus, rheumatoid arthritis) at study entry;
[30] have a history of transplanted organ (corneal transplants [keratoplasty] are allowed);
[31] have a history of an active or untreated malignancy, or are in remission from a clinically significant malignancy (other than basal or squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostate cancer) during the last 5 years prior to study entry;
[32] have a history of any other condition (eg, known drug or alcohol abuse or psychiatric disorder) at study entry, that, in the opinion of the investigator, may preclude the patient from following and completing the protocol;
[33] have any hematologic condition that may interfere with HbA1c measurement (eg, hemolytic anemias, sickle-cell disease) at study entry;
[34] are investigator-site personnel directly affiliated with this study and/or their immediate families; immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted;
[35] are Lilly employees;
[36] are currently enrolled in, or discontinued within the last 30 days from a clinical trial involving an off-label use of an investigational drug or device (other than the study drug/device used in this study);
[37] are currently enrolled in any other clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study;
[38] have previously screen failed, withdrawn, discontinued or completed this study or been randomized in any other study investigating dulaglutide. |
[11] Presentar diabetes mellitus de tipo 1.
[12]Haber recibido tratamiento con CUALQUIER otro AHO (distinto a los inhibidores del SGLT2 y a metformina), AR GLP-1, pramlintida o insulina en el transcurso de los 3 meses previos a la inclusión en el estudio, o en el período comprendido entre la inclusión en el estudio y la randomización. el tratamiento a corto plazo (? 14 días) con insulina durante el período de 3 meses previos a la inclusión no es excluyente
[13]Tener cualquier enfermedad que haga que esté contraindicada la administración de fármacos de la clase de AR GLP-1 o de inhibidores del SGLT2 (de acuerdo con la ficha técnica del país), bien en el momento de inclusión en el estudio o en el período comprendido entre la inclusión en el estudio y la randomización
[14]En relación con los pacientes que reciban metformina, si se desarrolla una enfermedad entre la estabilización y randomización
[15]Haber interrumpido el tratamiento con inhibidores del SGLT2 , o en caso de estar recibiendo metformina, en cualquier momento previo a la estabilización y randomización, de acuerdo con los criterios de exclusión [13] y [14] descritos anteriormente o por cualquier otra razón
[16]Haber experimentado ? 1 episodio de cetoacidosis o de un estado/coma hiperosmolar antes de la inclusión en el estudio
[17]Presentar antecedentes de insensibilidad a la hipoglucemia en el transcurso de los 6 meses previos a la inclusión en el estudio;
[18]Haber recibido tratamiento con fármacos que favorezcan la pérdida de peso o haber seguido una dieta o un programa de ejercicio con la intención de reducir el peso corporal en el transcurso de los 3 meses previos a la inclusión en el estudio o en el período comprendido entre la inclusión y randomización
[19] Estar recibiendo tratamiento sistémico con glucocorticoides (excluidos medicamentos tópicos, intraoculares, intranasales, intraarticulares o inhalados) de forma prolongada (> 14 días) en cualquier momento del período comprendido entre la inclusión en el estudio y randomización o haber recibido dicho tratamiento en el transcurso del mes previo a la inclusión en el estudio
[20]Haber experimentado alguna de las siguientes enfermedades cardiovasculares (CV) en el transcurso de los 2 meses previos a la inclusión en el estudio: infarto de miocardio (IM) agudo, insuficiencia cardiaca de clase III o IV de acuerdo con los criterios de la New York Heart Association o accidente cerebrovascular
[21]Presentar en el momento de inclusión un vaciamiento gástrico anormal, clínicamente significativo o haberse sometido anteriormente a cirugía bariátrica
[22]Presentar hepatitis aguda o crónica, signos o síntomas de cualquier otra enfermedad hepática (distinta a esteatosis hepática no alcohólica), o una concentración de alanina aminotransferasa > 2,5 veces el límite superior del intervalo de referencia, de acuerdo con un análisis llevado a cabo en el laboratorio central en el momento de inclusión en el estudio. Los pacientes con EHNA se considerarán idóneos para participar en este ensayo;
[23]Tener pancreatitis aguda o crónica en cualquier momento previo a la inclusión en el estudio
[24) Presentar una tasa de filtración glomerular estimada (TFGe) < 45 ml/min/1,73 m2,y de acuerdo con los resultados obtenidos en el laboratorio central en el momento de inclusión en el estudio y confirmados en al preinclusión
[25]Presentar indicios de una alteración endocrina significativa sin controlar, a criterio del investigador
[26]Presentar antecedentes (bien personales o familiares) de neoplasia endocrina múltiple de tipo 2A o 2B (NEM 2A o 2B), en ausencia de hiperplasia de células C del tiroides
[27]Tener antecedentes de hiperplasia medular de células C del tiroides, hiperplasia focal, carcinoma
[28]Presentar en el momento de inclusión en el estudio una concentración sérica de calcitonina ? 20 pg/ml
[29]Mostrar en el momento de inclusión en el estudio indicios de una alteración autoinmunitaria activa y significativa
[30]Haberse sometido a un trasplante de órgano (se permiten los trasplantes de córnea)
[31]Presentar antecedentes de neoplasia maligna activa o sin tratar, o haber estado en remisión de una neoplasia maligna clínicamente significativa, en el transcurso de los 5 años previos a la inclusión en el estudio;
[32]Presentar en el momento de inclusión en el estudio antecedentes de cualquier otra enfermedad que impidan que el paciente siga y complete el protocolo;
[33]Padecer en el momento de inclusión en el estudio cualquier enfermedad hematológica que pueda interferir en la medición de la concentración de HbA1c
[34]Ser personal del centro del estudio directamente relacionado con el estudio o familiares cercanos
[36]Haber participado en el transcurso de los 30 últimos días en un ensayo clínico con un producto en fase de investigación.
[37]Estar participando en la actualidad en cualquier otro ensayo clínico en el que se administre un producto en fase de investigación |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change in HbA1c from baseline to 24 weeks |
| Variación en HbA1c al cabo de 24 semanas respecto al valor basal. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Last patient visit week 24 |
| visita del ultimo paciente en la semana 24 |
|
| E.5.2 | Secondary end point(s) |
Proportion of patients with HbA1c target values of <7.0% at 24 weeks
The change in FBG (central laboratory) from baseline to 24 weeks
The change in body weight from baseline to 24 weeks
Proportion of patients with HbA1c target values of ?6.5% at 24 weeks
The change in 6-point SMPG profile from baseline to 24 weeks
The change in fasting glucagon from baseline to 24 weeks
Incidence of:
Treatment-emergent adverse events (TEAEs)
Early discontinuations due to AEs
Adjudicated cardiovascular and pancreatic AEs
Thyroid neoplasms AEs
AEs related to kidney failure, eGFR
Systemic hypersensitivity AEs
Local injection site reactions
The change in systolic and diastolic blood pressure, heart rate, and lipids from baseline to 24 weeks
Incidence and rate of hypoglycemic episodes
Ketoacidosis, and initiation of rescue therapy for severe persistent hyperglycemia |
? Porcentaje de pacientes que alcancen el valor de HbA1c deseado (< 7,0 %) al cabo de 24 semanas.
? Variación en los valores de glucemia en ayunas (GA) (laboratorio central) al cabo de 24 semanas respecto al valor basal.
? Variación en el peso corporal al cabo de 24 semanas respecto al valor basal. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Last patient visit week 24 |
| visita del ultimo paciente en la semana 24 |
|
| 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 | Yes |
| 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| 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 | 21 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| 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 |
| Austria |
| Czech Republic |
| Germany |
| Hungary |
| Israel |
| Mexico |
| Spain |
|
| 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
|
| LVLS |
| Ultima visita del ultimo paciente |
|
| 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 |
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