Validation of Molecular and Protein Biomarkers in Sepsis

NCT04289506 | Unknown

• 1 other identifier: VAMp-Sepsis 1.1
• Study Type: observational
• Target: 270
• Locations: 1 country
• Sites: 3

Brief Summary

Background: Sepsis (blood poisoning) is a clinical syndrome characterised by a dysregulated host response to infection causing life-threatening organ dysfunction which results in admission to an intensive care unit. It typically shows an initial harmful inflammation resulting from the immune system's overreaction to a severe infection. It is a major healthcare problem, affecting millions of people worldwide. In the UK, it kills over 37,000 people/year, costing the NHS £2.5 billion a year, and is increasing in incidence. Despite extensive efforts to tackle this burden, at present, however, there are no specific and effective therapies for this illness. Sepsis is a potentially life-threatening condition caused by a severe infection. When someone develops sepsis, inflammation occurs not just at the site of the infection but throughout the whole body. This widespread inflammation can be very harmful. It is known that similar responses occur in other conditions, not relating to infection. The investigators are recruiting patients with severe infections causing organ failure (also known as severe sepsis/ septicaemia and septic shock) and also patients where widespread inflammation, not related to infection, causes organ failure. In this study the investigators hope to find out whether certain groups of genetic and blood based protein markers of sepsis can forewarn the clinicians to this condition and also highlight patients who are responding well to the treatment. Although it is known that the majority of the patients suffering from sepsis will survive their ICU stay and leave the hospital alive, there is insufficient data how these patients do on a longer term, i.e. after some time at home. To date there is little information on the ability of the observed genetic and blood based protein markers to predict the functional status of the patients surviving these conditions.

Conditions

Sepsis; Cardiac Arrest; Pneumonia; Abdominal Sepsis; SIRS

Outcome Measures

Primary Outcomes (1)

• mRNA expression levels

  mRNA expression levels from peripheral blood cells

  Day 1 ICU/Hospital admission

Secondary Outcomes (3)

• Mortality

  30 days

• Mortality

  90 days

• Health related quality of life

  6 months

Study Arms (5)

Community-acquired pneumonia (Sepsis)

Community-acquired pneumonia with organ dysfunction

Diagnostic Test: mRNA expression

Abdominal sepsis

Abdominal infection due to peritoneal soiling, biliary infection, urinary tract infection leading to organ dysfunction

Diagnostic Test: mRNA expression

Infection of unknown origin (Sepsis)

Infection of unknown origin of less than 72 hours duration, including bacteraemia with organ dysfunction

Diagnostic Test: mRNA expression

Organ dysfunction related to non-infectious cause (SIRS)

Patients admitted to the ICU following out-of hospital cardiac arrest OR Patients admitted to the ICU following major trauma (ISS\>12) OR Patients admitted to the ICU following pancreatitis with organ dysfunction

Diagnostic Test: mRNA expression

Healthy volunteers

Healthy volunteers

Diagnostic Test: mRNA expression

Interventions

mRNA expression DIAGNOSTIC_TEST

The primary objective is the external validation of our filed patent-claims panels of mRNA biomarkers, which in the inflammatory and SIRS/Sepsis panels have better discriminatory properties than any other published biomarker panel for detecting individuals with severe inflammation and differentiating infectious and non-infectious origin of organ failure (Sepsis/SIRS).

Abdominal sepsis; Community-acquired pneumonia (Sepsis); Healthy volunteers; Infection of unknown origin (Sepsis); Organ dysfunction related to non-infectious cause (SIRS)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with organ dysfunction due to infection and no-infectious causes.

You may qualify if:

• Age =\> 18
• Admission to hospital within 72 hours of symptoms onset and development of clinical signs of sepsis
• Diagnosis of sepsis
• SEPSIS is defined as a (1) DEFINED FOCUS OF INFECTION AND (2) SOFA\>2, with at least ONE organ specific SOFA subscore =2.
• (1) DEFINED FOCUS OF INFECTION is indicated by either i. An organism grown in blood or sterile site OR ii. An abscess or infected tissue (e.g. pneumonia, peritonitis, urinary tract, vascular line infection, soft tissue, etc).
• (2) The SOFA score criteria are described in the Appendix \[7\]
• SEPTIC SHOCK is defined as SEPSIS plus the presence of hypotension requiring the use of vasopressors to maintain mean arterial pressure of 65 mmHg or greater and having a serum lactate level greater than 2 mmol/L persisting after adequate fluid resuscitation \[8\]
• Patients admitted to the ICU following out-of hospital cardiac arrest OR Patients admitted to the ICU following major trauma (ISS\>12) OR Patients admitted to the ICU following pancreatitis
• Have multiorgan failure as defined by SOFA\>2, with at least ONE organ specific SOFA subscore =2.
• Patients must not be receiving antibiotics for treatment of known or suspected infection
• patient already has or will require arterial cannulation as part of standard treatment

You may not qualify if:

• \. Patients who are on immune-modulating therapy (e.g., methotrexate, prednisolone \>5mg/day, or other immunosuppressants) for any length of time within 6 months of index admission 2. Patients with acquired cellular immune deficiency (E.g. active HIV infection or AIDS); 3. Patients with concurrent blood-borne viral infections (E.g. Hepatitis B or C) 4. Patients with any haematological malignancy in their past medical history; 5. Patients who are on chronic haemodialysis; 6. Solid organ transplant recipients; 7. Patients who have biopsy, image or endoscopy proven liver cirrhosis; 8. Patients who are not expected to survive beyond 90 days due to the advancement of their underlying disease.

Sponsors & Collaborators

• Public Health England: lead
• Aneurin Bevan University Health Board: collaborator
• Cardiff University: collaborator

Study Sites (3)

Aneurin Bevan University Health Board

Newport, Gwent, NP20 3UB, United Kingdom

NOT YET RECRUITING

Hampshire Hospitals NHS Foundation Trust

Basingstoke, United Kingdom

NOT YET RECRUITING

Public Health England

London, SE1, United Kingdom

RECRUITING

Related Publications (7)

• Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing Sepsis as a Global Health Priority - A WHO Resolution. N Engl J Med. 2017 Aug 3;377(5):414-417. doi: 10.1056/NEJMp1707170. Epub 2017 Jun 28. No abstract available.

  PMID: 28658587 BACKGROUND

• Cohen J, Vincent JL, Adhikari NK, Machado FR, Angus DC, Calandra T, Jaton K, Giulieri S, Delaloye J, Opal S, Tracey K, van der Poll T, Pelfrene E. Sepsis: a roadmap for future research. Lancet Infect Dis. 2015 May;15(5):581-614. doi: 10.1016/S1473-3099(15)70112-X. Epub 2015 Apr 19.

  PMID: 25932591 BACKGROUND

• Sweeney TE, Shidham A, Wong HR, Khatri P. A comprehensive time-course-based multicohort analysis of sepsis and sterile inflammation reveals a robust diagnostic gene set. Sci Transl Med. 2015 May 13;7(287):287ra71. doi: 10.1126/scitranslmed.aaa5993.

  PMID: 25972003 BACKGROUND

• Sweeney TE, Thomas NJ, Howrylak JA, Wong HR, Rogers AJ, Khatri P. Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome. Crit Care Med. 2018 Feb;46(2):244-251. doi: 10.1097/CCM.0000000000002839.

  PMID: 29337789 BACKGROUND

• Kempsell KE, Ball G, Szakmany T. Issues in biomarker identification, validation and development for disease diagnostics in Public Health. Expert Rev Mol Diagn. 2016;16(4):383-6. doi: 10.1586/14737159.2016.1133300. Epub 2016 Jan 22. No abstract available.

  PMID: 26680111 BACKGROUND

• Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-10. doi: 10.1001/jama.2016.0287.

  PMID: 26903338 BACKGROUND

• Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, Angus DC, Rubenfeld GD, Singer M; Sepsis Definitions Task Force. Developing a New Definition and Assessing New Clinical Criteria for Septic Shock: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):775-87. doi: 10.1001/jama.2016.0289.

  PMID: 26903336 BACKGROUND

Related Links

• Patent description of mRNA marker sets validated

Biospecimen

Retention: SAMPLES WITH DNA

2.5 mL x2 blood will be collected in PAXgenes tube for mRNA extraction as well as 30mL blood for isolation of peripheral white cells (PMBC). In centres where routine clinical practice is to discard up to 5 mL blood during arterial blood gas analysis, this otherwise wasted sample will be collected in EDTA tubes for cytokine analysis (max 10 mL/day). Samples will be anonymised and processed for storage or frozen as required, within 30 minutes. Blood samples will be sent to the research consortium's approved and appointed laboratories for further analysis. All samples will be stored for a maximum of ten years after study closure, in order to enable validation of results with new methodology and to develop methods for detecting new biomarkers (protein and mRNA).

MeSH Terms

Conditions

Sepsis; Heart Arrest; Pneumonia; Intraabdominal Infections

Interventions

Gene Expression

Condition Hierarchy (Ancestors)

Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Heart Diseases; Cardiovascular Diseases; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Genetic Phenomena

Central Study Contacts

Tamas Szakmany, MD, PhD

CONTACT

01633234165; szakmanyt1@cardiff.ac.uk

Karen Kempsell, PhD

CONTACT

karen.kempsell@phe.gov.uk

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2020
• First Posted: February 28, 2020
• Study Start: February 25, 2020
• Primary Completion: November 1, 2021
• Study Completion: November 1, 2021
• Last Updated: March 5, 2020

Record last verified: 2020-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (3)