E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
major cardiovascular events in type 2 diabetes mellitus patients |
Acontecimientos Cardiovasculares mayores en pacientes con diabetes mellitus tipo 2 |
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E.1.1.1 | Medical condition in easily understood language |
cardiovascular death, myocardial infarction and stroke |
muerte cardiovascular, infarto de miocardio o ictus |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10042244 |
E.1.2 | Term | Stroke |
E.1.2 | System Organ Class | 100000004852 |
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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 | 10028596 |
E.1.2 | Term | Myocardial infarction |
E.1.2 | System Organ Class | 10007541 - Cardiac 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 |
The primary objective of the study is to compare the effect of long-term treatment with ticagrelor 90 mg twice daily (bd) vs. placebo for the prevention of major cardiovascular (CV) events (composite of CV death, myocardial infarction [MI] or stroke) in patients with Type 2 Diabetes Mellitus (T2DM) at high risk for CV events, but without a previous medical history of MI or stroke. The primary efficacy variable is time from randomisation to first occurrence of any event from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown etiology). |
El objetivo principal del ensayo es comparar el efecto del tratamiento a largo plazo con ticagrelor 90 mg administrado dos veces al día (BID) en comparación con placebo para la prevención de los acontecimientos cardiovasculares (CV) mayores (combinación de muerte CV, infarto de miocardio [IM] o ictus) en pacientes con diabetes mellitus tipo 2 (DMT2) con alto riesgo de sufrir acontecimientos CV, pero sin antecedentes médicos de IM o ictus previos. La variable principal de eficacia es el tiempo transcurrido desde la aleatorización hasta que ocurra por primera vez algún episodio de la combinación de muerte CV, IM o ictus (de etiología isquémica, hemorrágica o desconocida). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study (presented in hierarchical order) are to compare the effect of long-term treatment with ticagrelor vs. placebo for: 1. Prevention of the composite of all-cause death, MI or stroke. The efficacy variable is time from randomisation to first occurrence of any event from the composite of all-cause death, MI or stroke. 2. Prevention of CV death. The efficacy variable is time from randomisation to death of CV cause. 3. Prevention of all-cause death. The efficacy variable is time from randomisation to death of any cause. |
Los objetivos secundarios del ensayo (presentados en orden jerárquico) son comparar el efecto del tratamiento a largo plazo con ticagrelor frente a placebo para: 1. La prevención de la combinación de muerte por cualquier causa, IM o ictus. La variable de eficacia es el tiempo transcurrido desde la aleatorización hasta que ocurra por primera vez cualquier episodio del criterio de valoración compuesto de muerte por cualquier causa, IM o ictus. 2. La prevención de la muerte CV. La variable de eficacia es el tiempo transcurrido desde la aleatorización hasta la muerte por causas CV. 3. La prevención de la muerte por cualquier causa. La variable de eficacia es el tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Men or women > or = 50 years of age Diagnosed with T2DM defined by ongoing glucose lowering drug treatment prescribed by a physician for treatment of T2DM since at least 6 months prior to Visit 1 At high risk of CV events, defined as history of percutaneous coronary intervention or coronary artery bypass graft or angiographic evidence of > or = 50% lumen stenosis of at least 1 coronary artery |
Hombres o mujeres > ó = 50 años. Diagnóstico de DMT2, definida por el uso actual de un tratamiento farmacológico para la diminución de los niveles de glucosa recetado por un médico para el tratamiento de la DMT2, desde al menos 6 meses antes de la Visita 1. Riesgo alto de acontecimientos CV, definido como antecedentes de intervención coronaria percutánea, cirugía de revascularización coronaria o pruebas angiográficas de estenosis del lumen > ó = 50% de 1 arteria coronaria como mínimo. |
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E.4 | Principal exclusion criteria |
1.Previous MI (with the exception of definite secondary MI [e.g., due to coronary revascularization procedure, profound hypotension, hypertensive emergency, tachycardia, or profound anaemia]) 2. Previous stroke (transient ischaemic attacks [TIA] is not included in the stroke definition) 3. Planned use of ADP receptor antagonists (e.g., clopidogrel, ticlopidine, prasugrel), dipyridamole, or cilostazol. Planned use of ASA treatment at doses >150 mg od. 4. Planned coronary, cerebrovascular, or peripheral arterial revascularization. 5. Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices that cannot be stopped for the course of the study: - Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir. - CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 mg daily or lovastatin at doses >40 mg daily 6. Need for chronic oral anticoagulant therapy or chronic low-molecular-weight heparin (at venous thrombosis treatment not prophylaxis doses) 7. Patients with known bleeding diathesis or coagulation disorder, or with uncontrolled hypertension (defined as a systolic BP > or = 180 mmHg and/or diastolic BP > or = 100 mmHg) 8. History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed within the past 6 months, or major surgery within 30 days. 9. Increased risk of bradycardic events (e.g., known sick sinus syndrome, second or third degree AV block or previous documented syncope suspected to be due to bradycardia) unless treated with a pacemaker. 10. Known severe liver disease (e.g., ascites and/or clinical signs of coagulopathy) 11. Renal failure requiring dialysis. |
1. IM previo (con excepción de IM secundario evidente [p.ej., debido a un procedimiento de revascularización coronaria, hipotensión intensa, urgencia hipertensiva, taquicardia o anemia grave]) 2. Ictus previo (el ataque isquémico transitorio [AIT] no se incluye dentro de la definición de ictus) 3. Uso programado de antagonistas del receptor de ADP (p.ej., clopidogrel, ticlopidina, prasugrel), dipiridamol o cilostazol. Uso programado de tratamiento con AAS a dosis >150 mg OD. 4. Revascularización coronaria, cerebrovascular o arterial periférica programada. 5. Uso programado de tratamiento concomitante, oral o intravenoso, con inhibidores potentes del citocromo P450 3A4 (CYP3A4) o sustratos del CYP3A4 con índices terapéuticos estrechos, que no se puede suspender durante el transcurso del ensayo: - Inhibidores potentes: ketoconazol, itraconazol, voriconazol, telitromicina, claritromicina (pero no eritromicina o azitromicina), nefazadona, ritonavir, saquinavir, nelfinavir, indinavir y atanazavir. - Sustratos del CYP3A4 con índice terapéutico estrecho: quinidina y simvastatina a dosis diarias >40 mg o lovastatina a dosis diarias >40 mg. 6. Necesidad de terapia crónica con anticoagulante oral o con heparina de bajo peso molecular (a dosis no profilácticas para el tratamiento de la trombosis venosa) 7. Pacientes con diátesis hemorrágica conocida, trastornos de la coagulación o hipertensión no controlada (definida como una PA sistólica > ó = 180 mmHg y/o PA diastólica > ó = 100 mmHg) 8. Antecedentes de hemorragia intracerebral previa en cualquier momento, hemorragia gastrointestinal (GI) en los 6 meses previos a la aleatorización o cirugía mayor en los 30 días previos a la aleatorización. 9. Aumento del riesgo de experimentar acontecimientos bradicárdicos (p.ej., síndrome de disfunción sinusal conocido, bloqueo AV de segundo o tercer grado o síncope previo documentado que se sospecha que se debió a la bradicardia), a no ser que esté tratado con un marcapasos. 10. Enfermedad hepática grave conocida (p. ej., ascitis y/o signos clínicos de coagulopatía) 11. Insuficiencia renal que precisa diálisis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time from randomisation to first occurrence of any event from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown etiology). |
Tiempo transcurrido desde la aleatorización hasta que ocurra por primera vez algún episodio de la combinación de muerte CV, IM o ictus (de etiología isquémica, hemorrágica o desconocida). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 35 months. |
Hasta aproximadamente 35 meses. |
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E.5.2 | Secondary end point(s) |
Time from randomisation to first occurrence of any event from the composite of all-cause death, MI or stroke. Time from randomisation to death of CV cause. Time from randomisation to death of any cause. |
Tiempo transcurrido desde la aleatorización hasta que ocurra por primera vez algún episodio de la combinación de todas las causas de muerte, IM o ictus. Tiempo transcurrido desde la aleatorización hasta la muerte por causas CV. Tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to approximately 35 months. |
Hasta aproximadamente 35 meses. |
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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 | Yes |
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 | 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 | 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 | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 300 |
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 |
Bulgaria |
Canada |
China |
France |
Italy |
Japan |
Netherlands |
Romania |
Slovakia |
Sweden |
Argentina |
Australia |
Brazil |
Chile |
Czech Republic |
Germany |
Hong Kong |
Hungary |
India |
Korea, Republic of |
Spain |
Thailand |
Israel |
Mexico |
Peru |
Philippines |
Poland |
Russian Federation |
South Africa |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
Vietnam |
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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 subject last visit. |
La última visita del último paciente incluido en el ensayo. |
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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 | 35 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 35 |