Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis
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.
|Study Design:||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)]|
- In-hospital mortality through Day 28 [ Time Frame: Through Day 28. ] [ Designated as safety issue: No ]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.
- Time to death in hospital [ Time Frame: Through Day 28 ] [ Designated as safety issue: No ]Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital
- Time to death [ Time Frame: Through Day 60 ] [ Designated as safety issue: No ]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.
- Mechanical ventilator-free days through Day 28 [ Time Frame: Through Day 28 ] [ Designated as safety issue: No ]Number of days alive and free of mechanical ventilation from Day 1 through Day 28.
- ICU-free days through Day 28 [ Time Frame: Through Day 28 ] [ Designated as safety issue: No ]Number of days alive and free of ICU from Day 1 through Day 28.
- Hospital-free days through Day 28 [ Time Frame: Through Day 28 ] [ Designated as safety issue: No ]Number of days alive and free of hospitalization from Day 1 through Day 28.
- ICU length of stay [ Time Frame: Through Day 180 ] [ Designated as safety issue: No ]
- Hospital length of stay [ Time Frame: Through Day 180 ] [ Designated as safety issue: No ]
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.
|Study Start Date:||October 2011|
|Estimated Study Completion Date:||April 2012|
|Estimated Primary Completion Date:||April 2012 (Final data collection date for primary outcome measure)|
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).
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.
|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|
|Imperial College London, Charing Cross Hospital|
|London, United Kingdom, W6 8RF|
|Principal Investigator:||Djillali Annane, MD, PhD||University of Versailles|
|Study Director:||Alexandra DJ Mancini, MSc||Sirius Genomics Inc.|