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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01486524
Recruitment Status : Unknown
Verified December 2011 by Sirius Genomics Inc..
Recruitment status was:  Active, not recruiting
First Posted : December 6, 2011
Last Update Posted : December 6, 2011
Information provided by (Responsible Party):
Sirius Genomics Inc.

Brief Summary:
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.

Condition or disease
Severe Sepsis Septic Shock

Detailed Description:

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.

Study Type : Observational
Estimated Enrollment : 3000 participants
Time Perspective: Retrospective
Official Title: A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]
Study Start Date : October 2011
Estimated Primary Completion Date : April 2012
Estimated Study Completion Date : April 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Sepsis

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).

Primary Outcome Measures :
  1. In-hospital mortality through Day 28 [ Time Frame: 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.

Secondary Outcome Measures :
  1. Time to death in hospital [ Time Frame: Through Day 28 ]
    Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital

  2. Time to death [ Time Frame: 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.

  3. Mechanical ventilator-free days through Day 28 [ Time Frame: Through Day 28 ]
    Number of days alive and free of mechanical ventilation from Day 1 through Day 28.

  4. ICU-free days through Day 28 [ Time Frame: Through Day 28 ]
    Number of days alive and free of ICU from Day 1 through Day 28.

  5. Hospital-free days through Day 28 [ Time Frame: Through Day 28 ]
    Number of days alive and free of hospitalization from Day 1 through Day 28.

  6. ICU length of stay [ Time Frame: Through Day 180 ]
  7. Hospital length of stay [ Time Frame: Through Day 180 ]

Biospecimen Retention:   Samples With DNA
Minimum 700 ng DNA required, extracted from blood samples. Two Improved Response Polymorphisms (IRPs) will be tested in this study. IRP A is comprised of two single nucleotide polymorphisms (SNPs), RYR2 (ryanodine receptor 2 gene) rs684923 and ACIN1 (apoptotic chromatin condensation inducer 1 gene)rs3751501. IRP B is comprised of two SNPs, SPATA7 (spermatogenesis associated 7 gene) rs3179969 and FLI1 (Friend leukemia virus integration 1 gene) rs640098. An individual patient will be considered to be biomarker positive if they have the responsive genotype for either of the SNPs or for both of the SNPs in the IRP.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01486524

United States, Georgia
Emory University School of Medicine
Atlanta, Georgia, United States, 30322
United States, Maryland
Johns Hopkins University, Bayview Medical Center
Baltimore, Maryland, United States, 21224
United States, Massachusetts
Harvard University School of Public Health
Boston, Massachusetts, United States, 02115
United States, Tennessee
Vanderbilt University Schoo of Medicine
Nashville, Tennessee, United States, 73232-2650
Canada, British Columbia
University of British Columbia and Providence Health Care, St. Paul's Hospital
Vancouver, British Columbia, Canada, V6Z 1Y6
University of Versailles, Hospital Raymond Poincaré (AP-HP)
Garches, France, 92380
Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital
Paris, France, 75014
United Kingdom
Imperial College London, Charing Cross Hospital
London, United Kingdom, W6 8RF
Sponsors and Collaborators
Sirius Genomics Inc.
Principal Investigator: Djillali Annane, MD, PhD University of Versailles
Study Director: Alexandra DJ Mancini, MSc Sirius Genomics Inc.

Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: Sirius Genomics Inc. Identifier: NCT01486524     History of Changes
Other Study ID Numbers: SGX301
First Posted: December 6, 2011    Key Record Dates
Last Update Posted: December 6, 2011
Last Verified: December 2011

Keywords provided by Sirius Genomics Inc.:
pharmacogenomic biomarker
predictive marker
propensity score
matched-patients trial

Additional relevant MeSH terms:
Shock, Septic
Systemic Inflammatory Response Syndrome
Pathologic Processes
Protein C
Drotrecogin alfa activated
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents