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

5 dicembre 2011 aggiornato da: 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.

Panoramica dello studio

Stato

Sconosciuto

Condizioni

Descrizione dettagliata

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 di studio

Osservativo

Iscrizione (Anticipato)

3000

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

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

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

18 anni e precedenti (Adulto, Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Metodo di campionamento

Campione non probabilistico

Popolazione di studio

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.

Descrizione

Inclusion Criteria for INDICATED population:

  1. Age ≥ 18 years

  2. 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

  3. 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
  4. Platelet counts ≥ 30,000/mm3
  5. DrotAA status known

Exclusion Criteria:

  1. Patients with no DNA
  2. 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.

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

Coorti e interventi

Gruppo / Coorte
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).

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
In-hospital mortality through Day 28
Lasso di tempo: 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.

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Time to death in hospital
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: 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
Lasso di tempo: Through Day 28
Number of days alive and free of hospitalization from Day 1 through Day 28.
Through Day 28
ICU length of stay
Lasso di tempo: Through Day 180
Through Day 180
Hospital length of stay
Lasso di tempo: Through Day 180
Through Day 180

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

Sirius Genomics Inc.

Investigatori

  • Investigatore principale: Djillali Annane, MD, PhD, University of Versailles
  • Direttore dello studio: Alexandra DJ Mancini, MSc, Sirius Genomics Inc.

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio

1 ottobre 2011

Completamento primario (Anticipato)

1 aprile 2012

Completamento dello studio (Anticipato)

1 aprile 2012

Date di iscrizione allo studio

Primo inviato

2 dicembre 2011

Primo inviato che soddisfa i criteri di controllo qualità

5 dicembre 2011

Primo Inserito (Stima)

6 dicembre 2011

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Stima)

6 dicembre 2011

Ultimo aggiornamento inviato che soddisfa i criteri QC

5 dicembre 2011

Ultimo verificato

1 dicembre 2011

Maggiori informazioni

Termini relativi a questo studio

Parole chiave

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • SGX301

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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