E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe sepsis or septic shock. |
Sepsis grave o shock séptico |
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E.1.1.1 | Medical condition in easily understood language |
Severe sepsis or septic shock. |
Sepsis grave o shock séptico |
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E.1.1.2 | Therapeutic area | Diseases [C] - Bacterial Infections and Mycoses [C01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040070 |
E.1.2 | Term | Septic shock |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 assess the therapeutic efficacy of Melatonin in adult patients with severe sepsis and septic shock. |
Establecer la eficacia terapéutica de la melatonina en la evolución de los pacientes adultos con sepsis grave y shock séptico.
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E.2.2 | Secondary objectives of the trial |
a)To assess severe sepsis and septic shock under the influence of Melatonin treatment:
b)Analytical parameters related to sepsis.
c)Behavior from the circulating levels of pro- and anti-inflammatory cytokines.
d)Oxidative and Nitrosative Stress.
e)Acute phase response as a marker of the intensity of the systemic inflammatory response. Mainly interested in assessing the dynamic response of ITIH4 protein (Inter-Alpha-Trypsin Inhibitor Heavy Chain 4), a positive acute phase protein IL-6 dependent, as a pioneer study, in severe sepsis treated with Melatonin.
f)Celular and humoral immune response.
g)Endocrine response.
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a)Evaluar en la sepsis grave y shock séptico bajo la influencia del tratamiento con melatonina:
b)Los parámetros analíticos relativos a la sepsis .
c)El comportamiento de los niveles circulantes de citoquinas pro y antiinflamatorias.
d)El estrés oxidativo y nitrosativo.
e)La respuesta de fase aguda como marcador de la intensidad de la respuesta inflamatoria sistémica. Interesa sobre todo evaluar la respuesta dinámica de la proteína ITIH4 (Inter-Alpha-Trypsin Inhibitor Heavy Chain 4), proteína de fase aguda positiva dependiente de la IL-6, como estudio pionero, en la sepsis grave y en la sepsis grave en tratamiento con melatonina.
f)La respuesta inmune celular y humoral.
g)La respuesta endocrina.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
a) Patient admitted to the Intensive Care Unit (ICU),
b) Aged 18 years or over.
c) Fulfils the diagnostic criteria of severe sepsis or septic shock secondary to extrahospital or intrahospital pneumonia and/or intraabdominal infection.
d) More than 24 hours has passed after recording the first organ dysfunction.
e) To be receiving the standard treatments for these conditions according to universally accepted guidelines* (Dellinger RP et al, 2008) and with the antibiotherapy protocol of our ICU.
f) Signed informed consent.
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a) Paciente ingresado en la Unidad de Cuidados Intensivos (UCI),
b) Edad igual o superior a 18 años
c) Cumplimiento de los criterios diagnósticos de sepsis grave o shock séptico secundarios a neumonía extrahospitalaria o intrahopitalaria y/o infección intraabdominal.
d) Que hayan transcurrido menos de 24 horas de la documentación de la primera disfunción de órganos.
e) Recibir el tratamiento intensivo estándar de estos padecimientos de acuerdo con las directrices universalmente aceptadas y con los protocolos de antibioterapia de nuestra UCI.
f) Consentimiento informado firmado. |
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E.4 | Principal exclusion criteria |
a) Absence of informed consent.
b) Patient identified as being very close to death.
c) Patient expected to die within 28 days from a medical condition that cannot be cured, such as a poorly controlled neoplasm or other terminal illness.
d) History of organ transplant.
e) Absence of concomitant intensive treatment.
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a) Ausencia de consentimiento informado.
b) Estado moribundo en el que se percibe que la muerte es inminente.
c) Paciente que no se espera que sobreviva 28 días debido a una condición médica que no se puede corregir, tal como una neoplasia mal controlada u otra enfermedad en fase terminal.
d) Historia de trasplante de un órgano.
e) Ausencia de tratamiento intensivo concomitante. |
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E.5 End points |
E.5.1 | Primary end point(s) |
-Mortality (any cause) within 28 days of inclusion in the study. The primary cause of death will be defined: multi-organic failure induced by sepsis, respiratory failure, refractory septic shock and other causes.
-Clinical parameters: number of days with assisted mechanical ventilation, number of days with vasoactive drugs, need of hemodyalisis or hemofiltration and number of days, other organs infection that are not the initial cause of the septic symptoms and development of failure of other organs after starting treatment.
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-Mortalidad de cualquier causa a los 28 días de inclusión en el estudio. Se determinará la causa primaria de muerte: fracaso multiorgánico inducido por la sepsis, fracaso respiratorio, shock séptico refractario y otras causas.
-Parámetros clínicos evolutivos: días de ventilación mecánica asistida, días con drogas vasoactivas, necesidad de hemodiálisis o hemofiltración y días de la misma, sobreinfección de otros órganos distintos al causante inicial del cuadro séptico y evolución hacia el fallo de otros órganos después de iniciar el tratamiento.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Mortality: 28 days after patient inclusion in the study.
- Clinical parameters of patient evolution: continously within the 28 days of patient follow-up. |
- Mortalidad: a los 28 días de la inclusión de los pacientes en el estudio.
- Parámetros evolutivos clínicos: de forma continuada durante los 28 días de seguimiento de los pacientes. |
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E.5.2 | Secondary end point(s) |
Evaluated by the response rate of:
-patient clinical parameters: temperature; heart and respiratory rate; blood pressure; diuresis.
-Blood parameters related to sepsis: leucocytes; platelets; bilirubinemia; glycemia; creatinine; lactacemia; arterial gasometry; coagulation study: prothrombine activity, INR (International Normalized Ratio), partial thromboplastine time, fibrinogen, Oxidative and Nitrosative Stress markers: malonaldehyde and hydroxyl-alkenals, proteins carbonyls, antioxidant serum total activity, superoxide dismutase activity, catalase, glutathione reductase and glutathione peroxidase, nitrites concentration, erythrocytes membrane fluidity and plasmatic leveles of melatonin
-citokines : interleukines (IL)-1β; IL-2; IL-4; IL-5; IL-6; IL-7; IL-8; IL-10; IL-12p70; IL-13 ; intereferon alpha; tumor necrosis factor (TNF)-α and granulocyte-macrophage colony stimulating factor (GM-CSF).
-acute phase proteins: C reactive protein (CRP), haptoglobin, apolipoprotein A1 (Apo A1) and acid alpha 1-glycoprotein (α1-GPA) and Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4).
-humoral and cellular immune response: linfocytes T, B, NK, TCD4, y TCD8 and immunoglobulins.
-hormone profile: cortisol, aldosterone, ACTH, ADH, insuline, glucagon and 25-hydroxyvitamin D3 (25-OHD3).
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Serán la evolución de la respuesta de:
-parámetros del estado clínico del paciente: temperatura; frecuencia cardiaca y respiratoria; tensión arterial; diuresis.
-parámetros sanguíneos relativos a la sepsis: leucocitos; plaquetas; bilirrubinemia; glucemia; creatinina; lactacidemia; gasometría arterial; estudio de coagulación: actividad de protrombina, INR (International Normalized Ratio), tiempo de tromboplastina parcial, fibrinógeno. marcadores de estrés oxidativo y nitrosativo: malonildialdehido y 4-hidroxialquenales, restos carbonilo de las proteínas, actividad total antioxidante sérica, actividad de la superóxido dismutasa, catalasa, glutation reductasa y glutation peroxidasa, concentración de nitritos, fluidez de membrana eritrocitaria y niveles plasmáticos de melatonina.
-citoquinas: interleucina (IL)-1β; IL-2; IL-4; IL-5; IL-6; IL-7; IL-8; IL-10; IL-12p70; IL-13; interferon (IFN)-alfa; factor de necrosis tumoral (TNF)-α y factor estimulante de colonias de granulocitos-macrófagos (GM-CSF)
-proteínas de fase aguda: proteína C reactiva (PCR), haptoglobina, apolipoproteína A-1 (Apo A-I) y alfa1-glicoproteína ácida (α1-GPA) e Inter-Alpha-Trypsin Inhibitor Heavy Chain 4 (ITIH4).
-inmunidad celular y humoral: linfocitos T, B, NK, TCD4, y TCD8 e inmunoglobulinas.
-perfil endocrino: cortisol, aldosterona, ACTH, ADH, insulina, glucagón y 25-hidroxivitamina D3 (25-OH-D3).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Dentro de los 28 días de seguimiento de los pacientes, las variables secundarias se recogen en distintos momentos temporales. |
Within the 28 days follow-up period of patients, the different secondary endpoints will be measured at different timepoints. |
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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 | No |
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 | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
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End of study is defined as 28 days after study inclusion (considering study inclusion as the first day of melatonin or placebo administration). |
Se define el final del estudio cuando hayan transcurrido 28 días desde la inclusión en el estudio (que coincide con el primer día de administración de melatonina o placebo). |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |