Clinical trial NCT00131196: Functional Genomic Influences on Disease Progression and Outcome in Sepsis
Official title: Functional Genomic Influences on Disease Progression and Outcome in Sepsis Due to Pneumonia or Peritonitis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Pneumonia
Peritonitis
Keywords: pneumonia
peritonitis
sepsis
outcome
genomics
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Sainsbury Family Charitable Trusts
name: Wellcome Trust
name: Queen Mary University of London
name: Barts and the London School of Medicine and Dentistry
First posted: 2005-08-17
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients admitted to Intensive Care Units or High Dependency Units in the UK with faecal peritonitis or community acquired pneumonia

Brief summary: The proposal is aimed at identifying genetic factors that determine the incidence and severity of, and the outcome from life-threatening infections (severe sepsis/septic shock) in patients admitted to High Dependency Units (HDUs) or Intensive Care Units (ICUs) with pneumonia which developed outside the hospital (community acquired pneumonia - CAP) or contamination of the abdominal cavity with faeces due to a leak in the bowel (faecal peritonitis). This will require the acquisition of a large, high quality resource of genetic material (DNA), plasma, urine, white blood cells and clinical information from well characterized groups of similar patients with, or at risk for, severe sepsis/septic shock. The principal objective is to perform studies which are sufficiently large to establish beyond doubt the influence of a series of selected "candidate" genes on the development, progress and outcome of sepsis.

Detailed description: The investigators plan to recruit 2,000 cases of community acquired pneumonia (CAP) and 2,000 cases of faecal peritonitis (FP) from 30 UK ICUs and HDUs (members of the UK Critical Care Genomics group - UKCCG). The large number of patients is required to satisfy the power calculations based upon the predicted allele frequencies of candidate genes and the level of functional expression of the gene polymorphisms.

If a patient is eligible, written, informed consent will be obtained either from the patient or, if the patient is incompetent via the patient's legal representative. Patients will be characterized clinically in terms of admission diagnosis, severity of illness (APACHE II), organ failures (SOFA) and final outcome (ICU and hospital mortality, death or survival 6 months following ICU admission. Date of death will be recorded when appropriate). Clinical status will be assessed daily for days 1, 2, 3, 5 and 7 of ICU admission using the Sepsis criteria, SOFA score, microbiological culture results and antibiotic therapy.

Selected ICUs will, following consent, also undertake blood and urine sampling on days 1, 3 and 5 for genomic, proteomic and metabolomic studies. Information will be recorded on a bar-coded paper clinical report form (CRF) at the bedside. The CRFs will be securely stored locally and copied to the research coordinator, where they will be archived. The data will be entered independently by the research coordinator and one of the investigators into a secure, central web-based electronic database for storage of clinical data and the calculation of derived values. The patient codes for genetic analysis will be derived directly from the clinical database. Those undertaking genotyping will be blinded to the clinical details and these two databases will be brought together at the time of analysis only under the direct supervision of one of the principal investigators.

Eligibility criteria: Inclusion Criteria:

* Patient, or legal representative, is able to give informed consent
* Male or female of 18 years or more
* Patient admitted to ICU/HDU with faecal peritonitis or community acquired pneumonia

Exclusion Criteria:

* Patient or legal representative is unwilling to consent
* Patient is under the age of 18 years
* Patient is already enrolled in an interventional study
* Patient is immunocompromised
* Patient is pregnant
* There is an advance directive to withhold or withdraw life-sustaining treatment or patient is admitted for palliative care only.

Primary outcomes:
measure: ICU and hospital Mortality
timeFrame: ICU discharge, hospital discharge and 6 month. The date of death will be recorded, as appropriate, for each patient.
Secondary outcomes:
measure: Severity of illness, duration of organ support, shock reversal, duration of ICU and hospital stay
timeFrame: From ICU admission to discharge
Other outcomes:
Locations:
city: Bristol
country: United Kingdom
facility: Southmead Hospital
state: Avon
city: Reading
country: United Kingdom
facility: Royal Berkshire Hospital
state: Berkshire
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: Cambridgeshire
city: Middlesborough
country: United Kingdom
facility: James Cook University Hospital
state: Cleveland
city: Antrim
country: United Kingdom
facility: Antrim Hospital
state: County Antrim
city: Cottingham
country: United Kingdom
facility: Castle Hill Hospital
state: East Riding of Yorkshire
city: Chelmsford
country: United Kingdom
facility: Broomfield Hospital
state: Essex
city: Colchester
country: United Kingdom
facility: Colchester General Hospital
state: Essex
city: Southend
country: United Kingdom
facility: Southend General Hospital
state: Essex
city: Bristol
country: United Kingdom
facility: Bristol Royal Infirmary
state: Gloucestershire
city: Cheltenham
country: United Kingdom
facility: Cheltenham General Hospital
state: Gloucestershire
city: Manchester
country: United Kingdom
facility: Withington Hospital
state: Greater Manchester
city: Manchester
country: United Kingdom
facility: Wythenshawe Hospital
state: Greater Manchester
city: Manchester
country: United Kingdom
facility: Hope Hospital
state: Greater Manchester
city: Blackburn
country: United Kingdom
facility: Royal Blackburn Hospital
state: Lancashire
city: Blackpool
country: United Kingdom
facility: Blackpool Victoria Hospital
state: Lancashire
city: Preston
country: United Kingdom
facility: Royal Preston Hospital
state: Lancashire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: Leicestershire
city: Lewisham
country: United Kingdom
facility: University Hospital Lewisham
state: London
city: King's Lynn
country: United Kingdom
facility: Queen Elizabeth Hospital
state: Norfolk
city: Norwich
country: United Kingdom
facility: Norfolk and Norwich University Hospitals
state: Norfolk
city: Kettering
country: United Kingdom
facility: Kettering General Hospital
state: Northants
city: Oxford
country: United Kingdom
facility: John Radcliffe Hospital
state: Oxon
city: Cardiff
country: United Kingdom
facility: University Hospital of Wales
state: South Glamorgan
city: Bristol
country: United Kingdom
facility: Frenchay Hospital
state: South Gloucestershire
city: Ipswich
country: United Kingdom
facility: The Ipswich Hospital
state: Suffolk
city: Frimley
country: United Kingdom
facility: Frimley Park Hospital
state: Surrey
city: Brighton
country: United Kingdom
facility: Royal Sussex County Hospital
state: Sussex
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Royal Victoria Infirmary
state: Tyne and Wear
city: Coventry
country: United Kingdom
facility: University Hospital
state: Warwickshire
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
state: West Midlands
city: Walsall
country: United Kingdom
facility: Walsall Manor Hospital
state: West Midlands
city: Worthing
country: United Kingdom
facility: Worthing and Southlands Hospitals NHS Trust
state: West Sussex
city: Halifax
country: United Kingdom
facility: Calderdale Royal Hospital
state: West Yorkshire
city: Huddersfield
country: United Kingdom
facility: Huddersfield Royal Infirmary
state: West Yorkshire
city: Leeds
country: United Kingdom
facility: St James's University Hospital
state: West Yorkshire
city: Hull
country: United Kingdom
facility: Hull Royal Infirmary
state: Yorkshire
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Leicester
country: United Kingdom
facility: Glenfield Hospital
city: Leicester
country: United Kingdom
facility: Leicester General Hospital
city: London
country: United Kingdom
facility: Homerton Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: London
country: United Kingdom
facility: North Middlesex University Hospital
city: London
country: United Kingdom
facility: Chelsea and Westminster Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: London
country: United Kingdom
facility: UCLH Middlesex Hospital
city: London
country: United Kingdom
facility: St Mary's Hospital
city: London
country: United Kingdom
facility: Charing Cross Hospital
city: Sheffield
country: United Kingdom
facility: Royal Halamshire Hospital
city: Swindon
country: United Kingdom
facility: The Great Western Hospital
Study officials:
affiliation: University of Oxford, UK
name: Christopher S Garrard, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Queen Mary College, University of London, UK
name: Charles J Hinds, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Victoria Infirmary and Freeman Hospital, Newcastle, UK
name: Simon Baudouin, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Southend General Hospital, Southend, UK.
name: David Higgins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Worthing and Southlands Hospitals NHS Trust, Worthing, UK.
name: Richard Venn, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Homerton University Hospital, London, UK.
name: David Watson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Berkshire Hospital, Reading, UK.
name: Atul Kapila, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Norfolk and Norwich University Hospitals, Norwich, UK.
name: Simon Fletcher, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Addenbrooke's Hospital, Cambridge, UK.
name: Andrew Johnston, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Queen Elizabeth Hospital, Birmingham, UK.
name: Julian Bion, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Halamshire Hospital, Sheffield, UK.
name: Gary Mills, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: James Cook University Hospital, Middlesborough, UK.
name: Stephen Bonner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The Ipswich Hospital, Ipswich, UK.
name: Mark Garfield, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Antrim Hospital, Antrim, Northern Ireland.
name: Ronald Baillie, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital of Wales, Cardiff,UK.
name: George Findlay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: UCLH Middlesex Hospital, London, UK.
name: Geoffrey Bellingan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Charing Cross Hospital, London, UK.
name: Tony Gordon, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Chelsea and Westminster Hospital, London, UK.
name: Michelle Hayes, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Broomfield Hospital, Chelmsford, UK.
name: Dilshan Arawwawala, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wythenshawe Hospital, Manchester, UK.
name: Andrew Bentley, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hope Hospital, Manchester, UK.
name: Gareth Thomas, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wellcome Trust
name: Julian Knight, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospitals, Leicester
name: Jonathan Thompson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Frenchay Hospital and Southmead Hospital, Bristol
name: Jasmeet Soar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Kettering General Hospital
name: Phil Watt, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Blackburn Hospital
name: Anton Krige, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Castle Hill Hospital and Hull Royal Infirmary
name: Ian Smith, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Blackpool Victoria Hospital
name: Achyut Guleri, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Preston Hospital
name: Shond Laha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hammersmith Hospitals NHS Trust
name: Stephen Brett, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: North Middlesex University Hospital
name: Jeronimo Moreno Cuesta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Coventry University Hospital
name: Pyda Venkatesh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Huddersfield Royal Infirmary and Calderdale Royal Hospital
name: Peter Hall, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The WhittingtonHospital, London. UK
name: Martin Kuper, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Manor Hospital, Walsall. UK
name: Sia Pesian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Colchester Hospital, Colchester . UK
name: Andrew Timmins, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Royal Sussex County Hospital
name: Stephen Drage, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Mary's Hospital, London, UK
name: Martin Stotz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Queen Elizabeth Hospital, King's Lynn. UK
name: Mark Blunt, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Aberdeen Royal Infirmary
name: Nigel Webster, Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: St James Hospital, Leeds. UK
name: Jane Minton, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Cheltenham General Hospital, Cheltenham. UK
name: Matt Oram, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Lewisham Hospital
name: Ingrid Krupe, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Leeds General Infirmary, Leeds. UK
name: Abhiram Mallick, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Frimley Park Hospital, Frimley. UK
name: Samuel Pambakian, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Great Western Hospital, Swindon. UK
name: Malcolm Watters, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vincent JL, Angus D, Annane D, Bernard G, Faist E, Giroir B, Reinhart K. Clinical expert round table discussion (session 5) at the Margaux Conference on Critical Illness: outcomes of clinical trials in sepsis: lessons learned. Crit Care Med. 2001 Jul;29(7 Suppl):S136-7. doi: 10.1097/00003246-200107001-00040. No abstract available.
citation: Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Regnier B. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. JAMA. 1995 Sep 27;274(12):968-74.
citation: File TM. Community-acquired pneumonia. Lancet. 2003 Dec 13;362(9400):1991-2001. doi: 10.1016/S0140-6736(03)15021-0.
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citation: Roy S, Knox K, Segal S, Griffiths D, Moore CE, Welsh KI, Smarason A, Day NP, McPheat WL, Crook DW, Hill AV; Oxford Pneumoccocal Surveillance Group. MBL genotype and risk of invasive pneumococcal disease: a case-control study. Lancet. 2002 May 4;359(9317):1569-73. doi: 10.1016/S0140-6736(02)08516-1.