Functional Genomic Influences on Disease Progression and Outcome in Sepsis

Pneumonia Clinical Trial

— GAinS  

Official title:

Functional Genomic Influences on Disease Progression and Outcome in Sepsis Due to Pneumonia or Peritonitis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00131196
• Other study ID #: N8518
• Status: Recruiting
• Phase: N/A
• First received: August 15, 2005
• Last updated: May 13, 2016
• Start date: September 2005
• Est. completion date: December 2017

Study information

• Verified date: May 2016
• Source: University of Oxford
• Contact: Charles J Hinds, MD
• Phone: +44 20346 57294
• Email: c.j.hinds[@]qmul.ac.uk
• Is FDA regulated: No
• Health authority: United Kingdom: National Health Service
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4000
• Est. completion date: December 2017
• Est. primary completion date: December 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Observational Model: Cohort, Time Perspective: Prospective

Related Conditions & MeSH terms

• Disease Progression
• Peritonitis
• Pneumonia

Locations

Country	Name	City	State
United Kingdom	Aberdeen Royal Infirmary	Aberdeen
United Kingdom	Antrim Hospital	Antrim	County Antrim
United Kingdom	Queen Elizabeth Hospital	Birmingham	West Midlands
United Kingdom	Royal Blackburn Hospital	Blackburn	Lancashire
United Kingdom	Blackpool Victoria Hospital	Blackpool	Lancashire
United Kingdom	Royal Sussex County Hospital	Brighton	Sussex
United Kingdom	Bristol Royal Infirmary	Bristol	Gloucestershire
United Kingdom	Frenchay Hospital	Bristol	South Gloucestershire
United Kingdom	Southmead Hospital	Bristol	Avon
United Kingdom	Addenbrooke's Hospital	Cambridge	Cambridgeshire
United Kingdom	University Hospital of Wales	Cardiff	South Glamorgan
United Kingdom	Broomfield Hospital	Chelmsford	Essex
United Kingdom	Cheltenham General Hospital	Cheltenham	Gloucestershire
United Kingdom	Colchester General Hospital	Colchester	Essex
United Kingdom	Castle Hill Hospital	Cottingham	East Riding of Yorkshire
United Kingdom	University Hospital	Coventry	Warwickshire
United Kingdom	Frimley Park Hospital	Frimley	Surrey
United Kingdom	Calderdale Royal Hospital	Halifax	West Yorkshire
United Kingdom	Huddersfield Royal Infirmary	Huddersfield	West Yorkshire
United Kingdom	Hull Royal Infirmary	Hull	Yorkshire
United Kingdom	The Ipswich Hospital	Ipswich	Suffolk
United Kingdom	Kettering General Hospital	Kettering	Northants
United Kingdom	Queen Elizabeth Hospital	King's Lynn	Norfolk
United Kingdom	St James's University Hospital	Leeds	West Yorkshire
United Kingdom	Glenfield Hospital	Leicester
United Kingdom	Leicester General Hospital	Leicester
United Kingdom	Leicester Royal Infirmary	Leicester	Leicestershire
United Kingdom	University Hospital Lewisham	Lewisham	London
United Kingdom	Charing Cross Hospital	London
United Kingdom	Chelsea and Westminster Hospital	London
United Kingdom	Hammersmith Hospital	London
United Kingdom	Homerton Hospital	London
United Kingdom	North Middlesex University Hospital	London
United Kingdom	St Bartholomew's Hospital	London
United Kingdom	St Mary's Hospital	London
United Kingdom	UCLH Middlesex Hospital	London
United Kingdom	Hope Hospital	Manchester	Greater Manchester
United Kingdom	Withington Hospital	Manchester	Greater Manchester
United Kingdom	Wythenshawe Hospital	Manchester	Greater Manchester
United Kingdom	James Cook University Hospital	Middlesborough	Cleveland
United Kingdom	Royal Victoria Infirmary	Newcastle-Upon-Tyne	Tyne and Wear
United Kingdom	Norfolk and Norwich University Hospitals	Norwich	Norfolk
United Kingdom	John Radcliffe Hospital	Oxford	Oxon
United Kingdom	Royal Preston Hospital	Preston	Lancashire
United Kingdom	Royal Berkshire Hospital	Reading	Berkshire
United Kingdom	Royal Halamshire Hospital	Sheffield
United Kingdom	Southend General Hospital	Southend	Essex
United Kingdom	The Great Western Hospital	Swindon
United Kingdom	Walsall Manor Hospital	Walsall	West Midlands
United Kingdom	Worthing and Southlands Hospitals NHS Trust	Worthing	West Sussex

Sponsors (5)

Lead Sponsor	Collaborator
University of Oxford	Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Sainsbury Family Charitable Trusts, Wellcome Trust Centre for Human Genetics, Oxford

Country where clinical trial is conducted

United Kingdom, 

References & Publications (8)

Brun-Buisson C, Doyon F, Carlet J, Dellamonica P, Gouin F, Lepoutre A, Mercier JC, Offenstadt G, Régnier 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. — View Citation

File TM. Community-acquired pneumonia. Lancet. 2003 Dec 13;362(9400):1991-2001. Review. — View Citation

Gordon AC, Lagan AL, Aganna E, Cheung L, Peters CJ, McDermott MF, Millo JL, Welsh KI, Holloway P, Hitman GA, Piper RD, Garrard CS, Hinds CJ. TNF and TNFR polymorphisms in severe sepsis and septic shock: a prospective multicentre study. Genes Immun. 2004 Dec;5(8):631-40. — View Citation

Mira JP, Cariou A, Grall F, Delclaux C, Losser MR, Heshmati F, Cheval C, Monchi M, Teboul JL, Riché F, Leleu G, Arbibe L, Mignon A, Delpech M, Dhainaut JF. Association of TNF2, a TNF-alpha promoter polymorphism, with septic shock susceptibility and mortality: a multicenter study. JAMA. 1999 Aug 11;282(6):561-8. — View 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. — View Citation

Sands KE, Bates DW, Lanken PN, Graman PS, Hibberd PL, Kahn KL, Parsonnet J, Panzer R, Orav EJ, Snydman DR, Black E, Schwartz JS, Moore R, Johnson BL Jr, Platt R; Academic Medical Center Consortium Sepsis Project Working Group. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA. 1997 Jul 16;278(3):234-40. — View Citation

Sørensen TI, Nielsen GG, Andersen PK, Teasdale TW. Genetic and environmental influences on premature death in adult adoptees. N Engl J Med. 1988 Mar 24;318(12):727-32. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ICU and hospital Mortality		ICU discharge, hospital discharge and 6 month. The date of death will be recorded, as appropriate, for each patient.	No
Secondary	Severity of illness, duration of organ support, shock reversal, duration of ICU and hospital stay		From ICU admission to discharge	No

External Links

•   GAinS Website (Genomic Advances in Sepsis)