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

NCT01486524 | Unknown

• 1 other identifier: SGX301
• Study Type: observational
• Target: 3,000
• Locations: 4 countries
• Sites: 8

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.

Conditions

Severe Sepsis; Septic Shock

Keywords

pharmacogenomic biomarker; predictive marker; prospective-retrospective; propensity score; matched-patients trial

Outcome Measures

Primary Outcomes (1)

• In-hospital mortality 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.

Secondary Outcomes (7)

• Time to death in hospital

  Through Day 28

• Time to death

  Through Day 60

• Mechanical ventilator-free days through Day 28

  Through Day 28

• ICU-free days through Day 28

  Through Day 28

• Hospital-free days through Day 28

  Through Day 28

Study Arms (2)

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).

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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

You may not qualify if:

• Patients with no DNA
• Patients enrolled in local cohort more than 2 years before Xigris \[drotrecogin alfa activated)\] was commercially available

Sponsors & Collaborators

• Sirius Genomics Inc.: lead

Study Sites (8)

Emory University School of Medicine

Atlanta, Georgia, 30322, United States

Location

Johns Hopkins University, Bayview Medical Center

Baltimore, Maryland, 21224, United States

Location

Harvard University School of Public Health

Boston, Massachusetts, 02115, United States

Location

Vanderbilt University Schoo of Medicine

Nashville, Tennessee, 73232-2650, United States

Location

University of British Columbia and Providence Health Care, St. Paul's Hospital

Vancouver, British Columbia, V6Z 1Y6, Canada

Location

University of Versailles, Hospital Raymond Poincaré (AP-HP)

Garches, 92380, France

Location

Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital

Paris, 75014, France

Location

Imperial College London, Charing Cross Hospital

London, W6 8RF, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 29388048 DERIVED

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.

MeSH Terms

Conditions

Sepsis; Shock, Septic

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Shock

Study Officials

• Djillali Annane, MD, PhD

  University of Versailles

  PRINCIPAL INVESTIGATOR

• Alexandra DJ Mancini, MSc

  Sirius Genomics Inc.

  STUDY DIRECTOR

Study Design

• Study Type: observational
• Time Perspective: RETROSPECTIVE
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 2, 2011
• First Posted: December 6, 2011
• Study Start: October 1, 2011
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: December 6, 2011

Record last verified: 2011-12

Locations

FR (2); GB (1); US (4); CA (1)