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

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.

Study Overview

• Status: Unknown
• Conditions: Septic Shock; Severe Sepsis

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
• Enrollment (Anticipated): 3000

Contacts and Locations

Study Locations

• 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
• United Kingdom
  • London, United Kingdom, W6 8RF
    • Imperial College London, Charing Cross Hospital
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University, Bayview Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Harvard University School of Public Health
  • Tennessee
    • Nashville, Tennessee, United States, 73232-2650
      • Vanderbilt University Schoo of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• 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.

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to death in hospital	Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital	Through Day 28
Time to death	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	Number of days alive and free of mechanical ventilation from Day 1 through Day 28.	Through Day 28
ICU-free days 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	Number of days alive and free of hospitalization from Day 1 through Day 28.	Through Day 28
ICU length of stay		Through Day 180
Hospital length of stay		Through Day 180

Collaborators and Investigators

• Sponsor: Sirius Genomics Inc.
• Investigators: Principal Investigator: Djillali Annane, MD, PhD, University of Versailles; Study Director: Alexandra DJ Mancini, MSc, Sirius Genomics Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2011
• Primary Completion (Anticipated): April 1, 2012
• Study Completion (Anticipated): April 1, 2012

Study Registration Dates

• First Submitted: December 2, 2011
• First Submitted That Met QC Criteria: December 5, 2011
• First Posted (Estimate): December 6, 2011

Study Record Updates

• Last Update Posted (Estimate): December 6, 2011
• Last Update Submitted That Met QC Criteria: December 5, 2011
• Last Verified: December 1, 2011

More Information

Terms related to this study

• Keywords: propensity score; predictive marker; pharmacogenomic biomarker; prospective-retrospective; matched-patients trial
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Sepsis; Toxemia
• Other Study ID Numbers: SGX301