Clinical trial NCT01486524: Pharmacogenomic Biomarker Study for Recombinant Human Activated Protein C Treatment in Severe Sepsis
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 type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Severe Sepsis
Septic Shock
Keywords: pharmacogenomic biomarker
predictive marker
prospective-retrospective
propensity score
matched-patients trial
Lead sponsor: Sirius Genomics Inc.
Sponsor class: INDUSTRY
First posted: 2011-12-06
Enrollment: 3000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Time perspective: RETROSPECTIVE
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.

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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: In-hospital mortality through Day 28
timeFrame: Through Day 28.
Secondary outcomes:
measure: Time to death in hospital
timeFrame: Through Day 28
measure: Time to death
timeFrame: Through Day 60
measure: Mechanical ventilator-free days through Day 28
timeFrame: Through Day 28
measure: ICU-free days through Day 28
timeFrame: Through Day 28
measure: Hospital-free days through Day 28
timeFrame: Through Day 28
measure: ICU length of stay
timeFrame: Through Day 180
measure: Hospital length of stay
timeFrame: Through Day 180
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory University School of Medicine
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University, Bayview Medical Center
state: Maryland
city: Boston
country: United States
facility: Harvard University School of Public Health
state: Massachusetts
city: Nashville
country: United States
facility: Vanderbilt University Schoo of Medicine
state: Tennessee
city: Vancouver
country: Canada
facility: University of British Columbia and Providence Health Care, St. Paul's Hospital
state: British Columbia
city: Garches
country: France
facility: University of Versailles, Hospital Raymond Poincaré (AP-HP)
city: Paris
country: France
facility: Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital
city: London
country: United Kingdom
facility: Imperial College London, Charing Cross Hospital
Study officials:
affiliation: University of Versailles
name: Djillali Annane, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sirius Genomics Inc.
name: Alexandra DJ Mancini, MSc
role: STUDY_DIRECTOR
References:
citation: 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.