| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| atherosclerosis in Type 2 Diabetes Mellitus patients with cardiovascular disease |
| Aterosclerosis en pacientes con Diabetes Mellitus Tipo 2 con enfermedad cardiovascular |
|
| E.1.1.1 | Medical condition in easily understood language |
| atherosclerosis in Type 2 Diabetes Mellitus patients with cardiovascular disease |
| Aterosclerosis en pacientes con Diabetes Mellitus Tipo 2 con enfermedad cardiovascular |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003601 |
| E.1.2 | Term | Atherosclerosis |
| E.1.2 | System Organ Class | 10047065 - Vascular 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 compare RSG versus GLP on the progression of atherosclerosis as measured by IVUS-derived change in percent atheroma volume from baseline to 18 months in non-intervened coronary arteries of subjects with T2DM and CVD undergoing coronary angiography or percutaneous coronary intervention (PCI). |
| ? Comparar RSG frente a GLP en la progresión de la aterosclerosis medida por el cambio, a través de IVUS, en el porcentaje del volumen de ateroma desde la evaluación basal hasta los 18 meses, en arterias coronarias sin intervención de sujetos con DMT2 y ECV sometidos a angiografía coronaria o a intervención coronaria percutánea (ICP). |
|
| E.2.2 | Secondary objectives of the trial |
? To assess the effects of RSG on other IVUS-derived atherosclerotic endpoints in non-intervened coronary arteries
? To assess the effects of RSG on IVUS-derived atherosclerotic endpoints in the proximal segment of intervened coronary arteries
? To assess the effects of RSG on the time to first occurrence of composite adjudicated major adverse cardiovascular events (MACE)
? To assess the effects of RSG on glycemia-related parameters
? To assess the effects of RSG on CV biomarkers and lipids
? To assess the safety and tolerability of RSG in subjects with T2DM and CVD. |
? Evaluar los efectos de RSG sobre otras variables ateroscleróticas derivadas del IVUS en arterias coronarias sin intervención.
? Evaluar los efectos de RSG sobre variables ateroscleróticas derivadas del IVUS en el segmento proximal de las arterias coronarias con intervención.
? Evaluar los efectos de RSG sobre el tiempo hasta la primera aparición de acontecimientos cardiovasculares adversos mayores (ACAM) adjudicados compuestos.
? Evaluar los efectos de RSG sobre parámetros relacionados con la glucemia.
? Evaluar los efectos de RSG sobre biomarcadores CV y lípidos.
? Evaluar la seguridad y tolerabilidad de RSG en sujetos con DMT2 y ECV. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study if ALL of the following criteria apply:
1. Male or female between 30 to 80 years of age, inclusive.
2. Established diagnosis of T2DM (based on diagnostic criteria of the American Diabetes Association (ADA), WHO guidelines or local national guidelines).
3. Subjects who are undergoing coronary angiography for evaluation of suspected or previously diagnosed coronary artery disease or who are undergoing PCI.
4. Subjects' prior anti-hyperglycemic diabetic therapy:
? Diet and exercise only (drug naïve), with HbA1c >7.0 and ? 10.0%.
? OAD monotherapy or low dose dual combination OAD therapy with
HbA1c > 6.5 and ? 8.5%.
5. Left ventricular ejection fraction (EF) ? 40% as assessed by contrast ventriculography (or previously documented in medical notes within one month prior to index procedure by other methods e.g. echocardiography or nuclear study)
6. Female subjects must be postmenopausal (i.e., >6 months without menstrual period), surgically sterile, or using effective contraceptive measures (oral contraceptives, Norplant, Depo-Provera, an intra-uterine device (IUD), a diaphragm with spermicide or a condom with spermicide). Women of childbearing potential must use effective contraceptive measures for at least 1 month prior to visit 1a, and should continue to use the same contraceptive method during the study and for 30 days after discontinuing study medication.
7. Willingness and ability to give informed consent prior to entering the study and available to complete the study. |
1. Hombres o mujeres de 30 a 80 años de edad, inclusive.
2. Sujetos con diagnóstico establecido de DMT2 (según los criterios diagnósticos de la American Diabetes Association (ADA), las directrices de la OMS o las directrices de cada país).
3. Sujetos que vayan a ser sometidos a angiografía coronaria por sospecha de enfermedad coronaria o diagnóstico previo de la misma, o que vayan a ser sometidos a ICP.
4. Sujetos con tratamiento antidiabético previo:
- Sólo dieta y ejercicio (nunca han recibido fármacos), con HbA1c >7% y <=10%.
- Monoterapia con MADO o dosis baja de una combinación doble de MADO con HbA1c >6,5% y ?8,5%.
5. Fracción de eyección (FE) ventricular izquierda ?40%, evaluada mediante ventriculografía de contraste (o previamente documentada en informes médicos del el mes anterior al procedimiento inicial por otros métodos, p.ej. ecocardiografía o estudio nuclear).
6. Las mujeres deben ser postmenopáusicas (es decir, >6 meses sin periodo menstrual), quirúrgicamente estériles, o utilizar métodos anticonceptivos efectivos (anticonceptivos orales, Norplant, Depo-Provera, dispositivo intrauterino (DIU), diafragma con espermicida o preservativo con espermicida). Las mujeres en edad fértil deben utilizar métodos anticonceptivos como mínimo durante el mes anterior a la visita 1a y deben seguir utilizando el mismo método durante todo el estudio y durante los 30 días siguientes a la interrupción de la medicación del estudio.
7. Sujetos que estén dispuestos y sean capaces de dar su consentimiento informado para participar en el estudio. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for this study if ANY of the following criteria apply:
1. Type 1 diabetes and/or history of diabetic ketoacidosis.
2. Exposure to a TZD or other PPAR-gamma agonist within the 6 months prior to screening visit.
3. Subjects treated with triple OAD therapy or high dose dual combination OAD therapy .
4. Subjects who have required chronic insulin use in the last 6 months (except during pregnancy or acute episodes such as hospitalization, trauma or infection).
5. ST segment elevation myocardial infarction in the last 30 days.
6. Subjects who have a history or are scheduled to receive coronary artery bypass graft surgery (CABG), valve repair or replacement, aneurysmectomy or planned major non-cardiac surgery during the study period.
7. Subjects who have severe cardiac valvular disease.
8. Stroke or resuscitated in the past 6 months.
9. History of congestive heart failure (NYHA class I ? IV).
10. History of significant hypersensitivity or reaction (e.g., difficulty swallowing, difficulty breathing, tachycardia or skin reaction) to any TZD, SU, biguanide or insulin.
11. Prior history of severe edema or edema requiring medical treatment.
12. Chronic disease requiring chronic or intermittent treatment with oral, intravenous, or injected corticosteroids (use of topical, inhaled, or nasal corticosteroids is permissible).
13. Recent history or suspicion of current drug abuse or alcohol abuse within the last 6 months.
14. Untreated hypo- or hyperthyroidism.
15. A diagnosis of cancer (other than superficial squamous, basal cell skin cancer, or adequately treated cervical carcinoma in situ) in the past 3 years or current treatment for the active cancer.
16. Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgement of the Investigator, would preclude safe completion of the study.
17. Blood pressure: SBP >170 or DBP > 100 mmHg.
18. Significant anemia (Hemoglobin < 11 g/dL for males and < 10 g/dL for females).
19. Significant renal disease manifested by serum creatinine (>= 1.5mg/dL for males or >= 1.4mg/dL for females), or where the use of metformin is contra-indicated.
20. Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (ALT or AST > 2.5 times upper limit of normal (ULN) or bilirubin >2x ULN).
21. History of myopathy or history of elevated creatine kinase (CK) > 3 times upper normal limit.
22. Use of an investigational drug within 30 days or 5 half-lives (whichever is the longer).
23. Women who are lactating, pregnant or planning to become pregnant during the course of the study.
24. Unwillingness or inability to comply with the procedures described in this protocol. |
1. Sujetos con diabetes tipo 1 y/o antecedentes de cetoacidosis diabética.
2. Sujetos expuestos a TZD o a otro agonista PPAR-gamma en los 6 meses anteriores a la visita de selección.
3. Sujetos tratados con MADO triple o dosis alta de una combinación doble.
4. Sujetos que hayan necesitado un uso crónico de insulina en los 6 últimos meses (excepto durante el embarazo o episodios agudos como hospitalización, trauma o infección).
5. Sujetos con infarto de miocardio con elevación del segmento ST en los 30 últimos días.
6. Sujetos con antecedentes o que estén programados para una intervención de bypass arterial coronario (CBAC), reparación o sustitución valvular, resección de aneurisma o cirugía mayor extracardiaca durante el periodo de estudio.
7. Sujetos con una enfermedad valvular cardiaca grave.
8. Sujetos que hayan sufrido un ictus o hayan sido reanimados en los 6 últimos meses.
9. Sujetos con antecedentes de insuficiencia cardiaca congestiva (clase I-IV de la NYHA).
10. Sujetos con historia de hipersensibilidad o reacción significativa (p.ej. dificultad para tragar, dificultad para respirar, taquicardia o reacción cutánea) a cualquier TZD, SU, biguanida o insulina.
11. Sujetos con antecedentes de edema grave o que requiere tratamiento médico.
12. Sujetos con enfermedad crónica que requiera tratamiento crónico o intermitente con corticosteroides orales, intravenosos o inyectados (la administración tópica, nasal o inhalatoria está permitida).
13. Sujetos con historia reciente o sospecha de abuso actual de drogas o de abuso de alcohol en los 6 últimos meses.
14. Sujetos con hipotiroidismo o hipertiroidismo no tratado.
15. Sujetos con diagnóstico de cáncer (distinto del superficial de células escamosas, el basalioma o el carcinoma in situ de cuello de útero adecuadamente tratado) en los 3 últimos años o en tratamiento actual para un cáncer activo.
16. Sujetos con cualquier anomalía clínicamente significativa identificada en la visita de selección, la exploración física, las pruebas de laboratorio o el electrocardiograma y que, a juicio del investigador, impida que el estudio pueda completarse con seguridad.
17. Sujetos con PAS >170 mmHg o PAD >100 mmHg.
18. Sujetos con anemia significativa (hemoglobina <11g/dl en los hombres y <10g/dl en las mujeres).
19. Sujetos con nefropatía significativa manifestada por valores de creatinina sérica >=1,5mg/dl en los hombres o
>=1,4mg/dl en las mujeres, o en la que el uso de metformina esté contraindicado.
20. Sujetos con hepatopatía u obstrucción de las vías biliares o elevación significativa de las enzimas hepáticas (ALT o AST >2,5 veces por encima del límite superior normal (LSN) o bilirrubina >2 x LSN).
21. Sujetos con historia de miopatía o de valores de creatina quinasa (CK) >3 veces por encima del límite normal.
22. Sujetos que hayan recibido un fármaco en investigación durante lo 30 días o 5 semividas (lo que sea más largo) anteriores.
23. Mujeres en estado de gestación, lactancia o que planeen quedarse embarazadas durante el estudio.
24. Sujetos que no estén dispuestos o sean incapaces de cumplir los procedimientos que se describen en el protocolo. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The change in percent atheroma volume (defined as total atheroma volume divided by total vessel volume x 100) within a 40mm segment in non-intervened coronary arteries from baseline to 18-months, based upon IVUS assessment. |
| ? Cambio a los 18 meses respecto al valor basal en el porcentaje del volumen de ateroma (definido como el volumen total de ateroma dividido por el volumen total del vaso x 100) dentro de un segmento de 40mm en arterias coronarias sin intervención, basado en una evaluación con IVUS. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Information not present in EudraCT |
|
| E.5.2 | Secondary end point(s) |
| Information not present in EudraCT |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Information not present in EudraCT |
|
| 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | No |
| 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 | 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 81 |
| 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 |
| Argentina |
| Brazil |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| Hong Kong |
| India |
| Italy |
| Korea, Republic of |
| Latvia |
| Mexico |
| Netherlands |
| Poland |
| Russian Federation |
| Spain |
| Sweden |
| Thailand |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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