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Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis

5 décembre 2011 mis à jour par: Sirius Genomics Inc.

A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]

The overall purpose of the study is to determine whether either of the Improved Response Polymorphisms (IRPs) individually predicts a differential DrotAA treatment effect in patients with severe sepsis and high risk of death. This will be an international, multicenter, "prospective-retrospective", nonrandomized, controlled, outcome-blinded, genotype-blinded, matched-patients study. No prospective enrollment or treatment of patients will occur under this protocol. Retrospectively collected clinical data and DNA samples will be analyzed for existing cohorts of patients with severe sepsis who were previously treated with DrotAA (treatment group) or not (control group) as part of their standard care in an ICU.

Aperçu de l'étude

Statut

Inconnue

Les conditions

Description détaillée

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.

Type d'étude

Observationnel

Inscription (Anticipé)

3000

Contacts et emplacements

Cette section fournit les coordonnées de ceux qui mènent l'étude et des informations sur le lieu où cette étude est menée.

Lieux d'étude

Canada
- British Columbia
  - Vancouver, British Columbia, Canada, V6Z 1Y6
    - University of British Columbia and Providence Health Care, St. Paul's Hospital
France
- - Garches, France, 92380
    - University of Versailles, Hospital Raymond Poincaré (AP-HP)
  - Paris, France, 75014
    - Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital
Royaume-Uni
- - London, Royaume-Uni, W6 8RF
    - Imperial College London, Charing Cross Hospital
États-Unis
- Georgia
  - Atlanta, Georgia, États-Unis, 30322
    - Emory University School of Medicine
- Maryland
  - Baltimore, Maryland, États-Unis, 21224
    - Johns Hopkins University, Bayview Medical Center
- Massachusetts
  - Boston, Massachusetts, États-Unis, 02115
    - Harvard University School of Public Health
- Tennessee
  - Nashville, Tennessee, États-Unis, 73232-2650
    - Vanderbilt University Schoo of Medicine

Critères de participation

Les chercheurs recherchent des personnes qui correspondent à une certaine description, appelée critères d'éligibilité. Certains exemples de ces critères sont l'état de santé général d'une personne ou des traitements antérieurs.

Critère d'éligibilité

Âges éligibles pour étudier

18 ans et plus (Adulte, Adulte plus âgé)

Accepte les volontaires sains

Non

Sexes éligibles pour l'étude

Tout

Méthode d'échantillonnage

Échantillon non probabiliste

Population étudiée

The indicated-patients population (INDICATED) population will be the primary population for this study and it will include those DrotAA-treated patients who have documented severe sepsis and high risk of death, defined in keeping with the regulatory approvals in the EU and US, and their matched controls. Documented organ dysfunction will be defined according to published criteria. A secondary severe sepsis population (SEVSEP) will have had documented severe sepsis, but not necessarily a high risk of death. The INDICATED population will be a subset within the broader SEVSEP population.The SEVSEP population will be analyzed only if at least 10% larger than the INDICATED population.

La description

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 d'étude

Cette section fournit des détails sur le plan d'étude, y compris la façon dont l'étude est conçue et ce que l'étude mesure.

Comment l'étude est-elle conçue ?

Détails de conception

Nombre de groupes / cohortes

Cohortes et interventions

Groupe / Cohorte
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.
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).

Que mesure l'étude ?

Principaux critères de jugement

Mesure des résultats	Description de la mesure	Délai
In-hospital mortality through Day 28 Délai: Through Day 28.	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.	Through Day 28.

Mesures de résultats secondaires

Mesure des résultats	Description de la mesure	Délai
Time to death in hospital Délai: Through Day 28	Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital	Through Day 28
Time to death Délai: Through Day 60	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.	Through Day 60
Mechanical ventilator-free days through Day 28 Délai: Through Day 28	Number of days alive and free of mechanical ventilation from Day 1 through Day 28.	Through Day 28
ICU-free days through Day 28 Délai: Through Day 28	Number of days alive and free of ICU from Day 1 through Day 28.	Through Day 28
Hospital-free days through Day 28 Délai: Through Day 28	Number of days alive and free of hospitalization from Day 1 through Day 28.	Through Day 28
ICU length of stay Délai: Through Day 180		Through Day 180
Hospital length of stay Délai: Through Day 180		Through Day 180

Collaborateurs et enquêteurs

C'est ici que vous trouverez les personnes et les organisations impliquées dans cette étude.

Parrainer

Sirius Genomics Inc.

Les enquêteurs

Chercheur principal: Djillali Annane, MD, PhD, University of Versailles
Directeur d'études: Alexandra DJ Mancini, MSc, Sirius Genomics Inc.

Publications et liens utiles

La personne responsable de la saisie des informations sur l'étude fournit volontairement ces publications. Il peut s'agir de tout ce qui concerne l'étude.

Publications générales

Annane D, Mira JP, Ware LB, Gordon AC, Hinds CJ, Christiani DC, Sevransky J, Barnes K, Buchman TG, Heagerty PJ, Balshaw R, Lesnikova N, de Nobrega K, Wellman HF, Neira M, Mancini ADJ, Walley KR, Russell JA. Pharmacogenomic biomarkers do not predict response to drotrecogin alfa in patients with severe sepsis. Ann Intensive Care. 2018 Jan 31;8(1):16. doi: 10.1186/s13613-018-0353-2.

Dates d'enregistrement des études

Ces dates suivent la progression des dossiers d'étude et des soumissions de résultats sommaires à ClinicalTrials.gov. Les dossiers d'étude et les résultats rapportés sont examinés par la Bibliothèque nationale de médecine (NLM) pour s'assurer qu'ils répondent à des normes de contrôle de qualité spécifiques avant d'être publiés sur le site Web public.

Dates principales de l'étude

Début de l'étude

1 octobre 2011

Achèvement primaire (Anticipé)

1 avril 2012

Achèvement de l'étude (Anticipé)

1 avril 2012

Dates d'inscription aux études

Première soumission

2 décembre 2011

Première soumission répondant aux critères de contrôle qualité

5 décembre 2011

Première publication (Estimation)

6 décembre 2011

Mises à jour des dossiers d'étude

Dernière mise à jour publiée (Estimation)

6 décembre 2011

Dernière mise à jour soumise répondant aux critères de contrôle qualité