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Severe SepsisNCT01486524

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

An observational study of Severe Sepsis and Septic Shock, run by Sirius Genomics Inc. at 8 sites in 4 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Severe Sepsis, Septic Shock
Type of treatment
Injection or infusion
How many people
3,000 participants
Where
8 sitesin 4 countries
Study dates
Oct 2011to Apr 2012
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

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.

Who may be able to join

  • 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
Show all 24Show fewer
  • 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

Who cannot join

  • 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.

Trial locations and contacts

8 sites in 4 countries.

8 sites in 4 countries

United States4 sites

  • Emory University School of Medicine

    Atlanta, Georgia, 30322

  • Johns Hopkins University, Bayview Medical Center

    Baltimore, Maryland, 21224

  • Harvard University School of Public Health

    Boston, Massachusetts, 02115

  • Vanderbilt University Schoo of Medicine

    Nashville, Tennessee, 73232-2650

Other trials in United States

France2 sites

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

    Garches, 92380

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

    Paris, 75014

Other trials in France

Canada1 site

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

    Vancouver, British Columbia, V6Z 1Y6

Other trials in Canada

United Kingdom1 site

  • Imperial College London, Charing Cross Hospital

    London, W6 8RF

Other trials in United Kingdom

About this study

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)]

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.

Read the 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.

Keywords
pharmacogenomic biomarker, predictive marker, prospective-retrospective, propensity score, matched-patients trial
Medical subject headings
Sepsis, Shock, Septic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT01486524
Study groupRoleWhat they receive
DrotAA Treatment GroupPatients 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 being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: Through Day 28.

Secondary outcomes (7)

  1. Time to death in hospital

    Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital

    Measured: Through Day 28

  2. 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.

    Measured: Through Day 60

  3. Mechanical ventilator-free days through Day 28

    Number of days alive and free of mechanical ventilation from Day 1 through Day 28.

    Measured: Through Day 28

  4. ICU-free days through Day 28

    Number of days alive and free of ICU from Day 1 through Day 28.

    Measured: Through Day 28

  5. Hospital-free days through Day 28

    Number of days alive and free of hospitalization from Day 1 through Day 28.

    Measured: Through Day 28

  6. ICU length of stay

    Measured: Through Day 180

  7. Hospital length of stay

    Measured: Through Day 180

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Dec 2011 (estimated)
  2. Study startOct 2011
  3. Primary completionApr 2012 (estimated)
  4. Study completionApr 2012 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Time perspective
Retrospective
Enrolment
3,000 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01486524
Sponsor's protocol ID
SGX301
Status last verified
Dec 2011
First submitted
2 Dec 2011
Last updated
6 Dec 2011
Results posted
No
Data monitoring committee
No

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.

    PubMed 29388048

Questions about this trial

What is this clinical trial studying?

An observational study of Severe Sepsis and Septic Shock, run by Sirius Genomics Inc. at 8 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 6 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States, France, Canada, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

In-hospital mortality through Day 28 (time frame: Through Day 28.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01486524, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Dec 2011.

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