- ICH GCP
- Registro de ensayos clínicos de EE. UU.
- Ensayo clínico NCT01486524
Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis
A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]
Descripción general del estudio
Estado
Condiciones
Descripción detallada
This will be a multicenter, "prospective-retrospective", controlled, matched-patients study. Retrospective phenotypic data and DNA samples will be obtained from patient registries and clinical trials where the study hypotheses were not related to DrotAA treatment. The prospective aspect of this study will be the statistical testing of prespecified hypotheses regarding the IRP genotype as a predictive biomarker for differential DrotAA treatment effects.
To control for differences in standard of care in different countries and medical centers, the selection of matched control patients will be performed within each cohort. Control patients will be selected to match the DrotAA-treated patients using an algorithm that matches on baseline demographic and disease characteristics that may have influenced the decision to give DrotAA or that may impact survival. A propensity score (the likelihood for having received DrotAA treatment) will be derived using the matching variables that are common in all cohorts. The number of matched control patients for each treated patient will be variable, up to a maximum of 3.
The selection of the control patients via the matching algorithm will be conducted by an independent clinical research organization (CRO) in a blinded manner - specifically without knowledge of survival outcome, other outcome data, and genotype. A two-phase transfer of data from each center will be implemented to ensure that the selection of matched control patients is implemented in a blinded manner. The first step will involve the transfer of the baseline data for all variables needed to conduct the matching. Once the control patients have been identified for each cohort, the outcomes data will be transferred to the CRO in the second phase of data transfer.
Centralized genotyping using a validated Taqman®-based analytical method will be conducted on the DNA samples for all matched patients. The genotyping laboratory will be blinded to treatment and outcome.
The total number of patients in the available cohorts is >23,000, with approximately 800 who have received DrotAA as part of their standard ICU-based care. After applying eligibility criteria to all patients and selecting the matched control patients, it is expected that the final analysis will include approximately 3000 patients.
Tipo de estudio
Inscripción (Anticipado)
Contactos y Ubicaciones
Ubicaciones de estudio
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British Columbia
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Vancouver, British Columbia, Canadá, V6Z 1Y6
- University of British Columbia and Providence Health Care, St. Paul's Hospital
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Georgia
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Atlanta, Georgia, Estados Unidos, 30322
- Emory University School of Medicine
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Maryland
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Baltimore, Maryland, Estados Unidos, 21224
- Johns Hopkins University, Bayview Medical Center
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Massachusetts
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Boston, Massachusetts, Estados Unidos, 02115
- Harvard University School of Public Health
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Tennessee
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Nashville, Tennessee, Estados Unidos, 73232-2650
- Vanderbilt University Schoo of Medicine
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Garches, Francia, 92380
- University of Versailles, Hospital Raymond Poincaré (AP-HP)
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Paris, Francia, 75014
- Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital
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London, Reino Unido, W6 8RF
- Imperial College London, Charing Cross Hospital
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Método de muestreo
Población de estudio
Descripción
Inclusion Criteria for INDICATED population:
- Age ≥ 18 years
Severe sepsis (must meet a, b, and c below)
- Suspected or proven infection
Systemic Inflammatory Response Syndrome (SIRS)(must meet 2 of 4 criteria)
- Temperature < 36°C or > 38°C
- Heart rate > 90 beats/minute
- Respiratory rate > 20 breaths/minute or PaC02 < 32 mm Hg) or on mechanical ventilation
- White blood cell count < 4,000/mm3 or > 12,000/mm3
At least one organ dysfunction due to sepsis based on definitions of clinically significant organ dysfunction
Cardiovascular dysfunction [must meet one of (1), (2), or (3) below]:
- Systolic blood pressure ≤ 90 mmHg and pH ≤ 7.3
- Mean arterial pressure ≤ 70 mmHg and pH ≤ 7.3
- Reported use of a vasopressor alone is sufficient evidence of shock
- Pulmonary dysfunction: PaO2/FiO2 ≤ 300 mmHg
- Central Nervous System dysfunction: Glasgow Coma Scale ≤ 12
- Coagulation dysfunction: platelets ≤ 80,000/mm3
- Renal dysfunction: creatinine ≥ 2.0 mg/dL
- Hepatic dysfunction: bilirubin ≥ 2.0 mg/dL
High risk of death (one of a, b, or c below)
- APACHE II ≥ 25
- SAPS II ≥ 54
- Multiple organ dysfunction - two or more clinically significant organ dysfunctions (as defined above), which have occurred within 2 days of each other
- Platelet counts ≥ 30,000/mm3
- DrotAA status known
Exclusion Criteria:
- Patients with no DNA
- Patients enrolled in local cohort more than 2 years before Xigris [drotrecogin alfa activated)] was commercially available
A secondary analysis population with severe sepsis will be defined by Inclusion Criteria 1, 2, 4, and 5 above, and the Exclusion Criteria. This will be referred to as the SEVSEP population.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
Cohortes e Intervenciones
Grupo / Cohorte |
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DrotAA Treatment Group
Patients with severe sepsis at high risk of death (INDICATED patients) who received treatment with drotrecogin alfa (activated (DrotAA) as part of standard care in ICU.
The standard dosing regimen for DrotAA is 96 hours of continuous infusion at a dose of 24 ug/kg/hour.
DrotAA is also known as recombinant human activated protein C.
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Control Group (non-DrotAA treated)
Patients with severe sepsis at high risk of death (INDICATED patients) who did not receive DrotAA treatment as part of their standard care in an ICU.
The Control group patients will be selected to match the DrotAA-treated patients based on numerous clinical covariates, including propensity score (for DrotAA treatment).
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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In-hospital mortality through Day 28
Periodo de tiempo: Through Day 28.
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All cause in-hospital mortality up to Day 28 or discharge, whichever comes first.
Day 1 is the day when patient meets eligibility criteria for this study.
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Through Day 28.
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Time to death in hospital
Periodo de tiempo: Through Day 28
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Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital
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Through Day 28
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Time to death
Periodo de tiempo: Through Day 60
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Time to death (any cause), censored at Day 60 or last evaluation.
Will be evaluated using data from centers where follow-up extended beyond hospital discharge.
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Through Day 60
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Mechanical ventilator-free days through Day 28
Periodo de tiempo: Through Day 28
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Number of days alive and free of mechanical ventilation from Day 1 through Day 28.
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Through Day 28
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ICU-free days through Day 28
Periodo de tiempo: Through Day 28
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Number of days alive and free of ICU from Day 1 through Day 28.
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Through Day 28
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Hospital-free days through Day 28
Periodo de tiempo: Through Day 28
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Number of days alive and free of hospitalization from Day 1 through Day 28.
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Through Day 28
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ICU length of stay
Periodo de tiempo: Through Day 180
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Through Day 180
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Hospital length of stay
Periodo de tiempo: Through Day 180
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Through Day 180
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Investigador principal: Djillali Annane, MD, PhD, University of Versailles
- Director de estudio: Alexandra DJ Mancini, MSc, Sirius Genomics Inc.
Publicaciones y enlaces útiles
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Anticipado)
Finalización del estudio (Anticipado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
Otros números de identificación del estudio
- SGX301
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