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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Multicenter Pharmacogenomic Biomarker Study in Matched Patients With Severe Sepsis Treated With or Without Recombinant Human Activated Protein C [Xigris®, Drotrecogin Alfa (Activated)]

Conditions
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Severe Sepsis, Septic Shock

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for INDICATED population: 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 Coagulation dysfunction: platelets ≤ 80,000/mm3 Renal dysfunction: creatinine ≥ 2.0 mg/dL Hepatic dysfunction: bilirubin ≥ 2.0 mg/dL 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 Platelet counts ≥ 30,000/mm3 DrotAA status known Exclusion Criteria: Patients with no DNA 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DrotAA Treatment Group<br>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)<br>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?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pharmacogenomic biomarker, predictive marker, prospective-retrospective, propensity score, matched-patients trial