このページは自動翻訳されたものであり、翻訳の正確性は保証されていません。を参照してください。英語版ソーステキスト用。

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

2011年12月5日更新者：Sirius Genomics Inc.

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.

調査の概要

状態

わからない

条件

詳細な説明

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.

研究の種類

観察的

入学 (予想される)

3000

連絡先と場所

このセクションには、調査を実施する担当者の連絡先の詳細と、この調査が実施されている場所に関する情報が記載されています。

研究場所

アメリカ
- Georgia
  - Atlanta、Georgia、アメリカ、30322
    - Emory University School of Medicine
- Maryland
  - Baltimore、Maryland、アメリカ、21224
    - Johns Hopkins University, Bayview Medical Center
- Massachusetts
  - Boston、Massachusetts、アメリカ、02115
    - Harvard University School of Public Health
- Tennessee
  - Nashville、Tennessee、アメリカ、73232-2650
    - Vanderbilt University Schoo of Medicine
イギリス
- - London、イギリス、W6 8RF
    - Imperial College London, Charing Cross Hospital
カナダ
- British Columbia
  - Vancouver、British Columbia、カナダ、V6Z 1Y6
    - University of British Columbia and Providence Health Care, St. Paul's Hospital
フランス
- - Garches、フランス、92380
    - University of Versailles, Hospital Raymond Poincaré (AP-HP)
  - Paris、フランス、75014
    - Université Paris Descartes, Sorbonne Paris Cité, Cochin Hotel-Dieu University Hospital

参加基準

研究者は、適格基準と呼ばれる特定の説明に適合する人を探します。これらの基準のいくつかの例は、人の一般的な健康状態または以前の治療です。

適格基準

就学可能な年齢

18年歳以上 (大人、高齢者)

健康ボランティアの受け入れ

いいえ

受講資格のある性別

全て

サンプリング方法

非確率サンプル

調査対象母集団

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.

説明

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.

研究計画

このセクションでは、研究がどのように設計され、研究が何を測定しているかなど、研究計画の詳細を提供します。

研究はどのように設計されていますか？

デザインの詳細

グループ/コホートの数

コホートと介入

グループ/コホート
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).

この研究は何を測定していますか？

主要な結果の測定

結果測定	メジャーの説明	時間枠
In-hospital mortality through Day 28 時間枠：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.

二次結果の測定

結果測定	メジャーの説明	時間枠
Time to death in hospital 時間枠：Through Day 28	Time to death (any cause) in hospital, censored by the competing risk of discharge from hospital	Through Day 28
Time to death 時間枠：Through Day 60	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 時間枠：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 時間枠：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 時間枠：Through Day 28	Number of days alive and free of hospitalization from Day 1 through Day 28.	Through Day 28
ICU length of stay 時間枠：Through Day 180		Through Day 180
Hospital length of stay 時間枠：Through Day 180		Through Day 180

協力者と研究者

ここでは、この調査に関係する人々や組織を見つけることができます。

スポンサー

Sirius Genomics Inc.

捜査官

主任研究者：Djillali Annane, MD, PhD、University of Versailles
スタディディレクター：Alexandra DJ Mancini, MSc、Sirius Genomics Inc.

出版物と役立つリンク

研究に関する情報を入力する責任者は、自発的にこれらの出版物を提供します。これらは、研究に関連するあらゆるものに関するものである可能性があります。

一般刊行物

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.

研究記録日

これらの日付は、ClinicalTrials.gov への研究記録と要約結果の提出の進捗状況を追跡します。研究記録と報告された結果は、国立医学図書館 (NLM) によって審査され、公開 Web サイトに掲載される前に、特定の品質管理基準を満たしていることが確認されます。

主要日程の研究

研究開始

2011年10月1日

一次修了 (予想される)

2012年4月1日

研究の完了 (予想される)