Condition category
Infections and Infestations
Date applied
26/10/2020
Date assigned
28/10/2020
Last edited
02/11/2020
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting
Publication status
Results overdue

Plain English Summary

Background and study aims
We are trying to develop a blood test which would allow us to predict whether (and when) patients will go on to develop the severe complications of infection. We call severe infection “sepsis”, which can cause people to become very ill and need intensive care.

Who can participate?
Adults aged between 18 and 80 who are undergoing elective surgery.

What does the study involve?
- Taking blood samples (15 ml) and urine samples from participants before their operation and each day afterwards for a week or until they leave hospital or develop an infection.
· Noting details of medical background
· Noting details such as pulse and blood pressure, each day
- Use of blood and urine to measure various things including which genes are activated in any response to infection
- Collection of some follow up details from hospital records
- Use of these data in this study and possibly use of the data and samples in future studies

What are the benefits and risks of participating?
Developing a blood test to predict the onset of these problems would allow us to start treatment very early and early treatment is more effective and saves lives. The study may have major implications for patients in the future, though it will not be of immediate benefit to the participant. There are no risks involved in the study. The only inconvenience is that of having a daily blood test over and above the normal blood tests normally needed. We will try to ensure these samples are taken together to minimize the inconvenience to the participant.

Where is the study run from?
1. Defence Science and Technology Laboratory (Dstl) Porton Down (UK)
2. Centre for Intensive Care Medicine, Department of Medicine & Wolfson Institute for Biomedical Research, University College London (UK)

When is the study starting and how long is it expected to run for?


Who Is funding the study?
1. Ministry of Defence (UK)
2. Defense Threat Reduction Agency (USA)

Who is the main contact?
Prof. Mervin Singer, m.singer@ucl.ac.uk

Trial website

Contact information

Type

Scientific

Primary contact

Dr Mervyn Singer

ORCID ID

Contact details

University College London
Cruciform Building
Gower St
London
WC1E 6BT
United Kingdom
+44 (0)207 6796714
m.singer@ucl.ac.uk

Type

Public

Additional contact

Dr Roman Lukaszewski

ORCID ID

http://orcid.org/0000-0003-1774-5335

Contact details

DSTL
Porton Down
Salisbury
SP4 0JQ
United Kingdom
+44 (0)1980 957424
ralukaszewski@dstl.gov.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

S167-01

Study information

Scientific title

A multi-centre study to investigate immune modulators for the early diagnosis of sepsis in patients undergoing major elective surgery

Acronym

MASH

Study hypothesis

Patterns of host biomarker expression in the blood of patients undergoing high-risk elective surgery predict which patients will and will not go onto develop sepsis before the onset of clinical symptoms of infection.

Ethics approval

Approved 22/02/2007, Southampton & South West Hampshire Research Ethics Committee (A) (1st Floor Regents Park Surgery, Park Street, Shirley, Southampton, Hampshire, SO16 4RJ, UK; +44 203 8036 2466; hampshirea.rec@hra.nhs.uk), ref: 06/Q1702/152

Study design

Observational case control

Primary study design

Observational

Secondary study design

Case-control study

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet

Condition

Prediction of sepsis in elective surgery patents

Intervention

Demographic and clinical data will be gathered daily along with blood samples for immune modulators and urine samples. Some patients will have a straightforward perioperative course (non-septic group) and some will develop sepsis (sepsis group). Blood and urine samples will be taken daily for up to 7 days in all patients (or until discharge for the non-sepsis group and until the time of development of sepsis in the sepsis group). Standard blood biochemistry and haematology assays will be run. Appropriate microbiological analysis of a variety of clinical matrices (e.g. blood, urine, swab and sputum) will be undertaken when there is a clinical suspicion of infection.

Expression of host genes in the transcriptomes of patients that go on to develop sepsis that differentiates patient groups who do and do not go onto develop sepsis. Gene expression will be measured using microarray and reverse transcriptase quantitative polymerase chain. Gene expression (RT-qPCR) will be analysed in blood samples taken before surgery and then on each day following surgery for 7 days or until the patient developed sepsis, or until the patient is discharged earlier than 7 days post-surgery.

Intervention type

Other

Phase

Drug names

Primary outcome measure

Original primary outcome:
1. Development of sepsis, measured using the “sepsis 2” criteria which is a Systemic Inflammatory Response Syndrome (SIRS) characterised by 2 of the following (measured daily for 7 days after surgery):
1.1. Temperature >38 or <36°C measured by clinical observation
1.2. Respiratory rate >20/min or PCO2 <4.3 or the need for ventilation measured by clinical observation
1.3. Tachycardia >90/min after fluid resuscitation measured by clinical observation
1.4. White cell count >10 or < 4 x10(9)/l, or >10% immature forms measured by blood test
A clinical adjudication panel sifted blinded patient data (including all relevant patient observations and clinical data) to determine which patients adhered to this criteria and which did not.

The definition of the study’s primary outcome (SEPSIS) was later changed to be defined as organ dysfunction (characterised by an increase in daily Sequential Organ Failure Assessment (SOFA) score of 2 or more from one day to the next) caused by an infectious agent. Sufficient clinical data was collected during the study to enable identification of patients who achieved the new “sepsis 3” criteria. The parameters for SOFA score include (measured using standard clinical biochemistry and haematology assays, daily for up to 7 days after surgery):
1.1. Respiratory system function (PO2/FiO2 mmHg/kPa >400 to <100)
1.2. Coagulation (Platelets x 10³ >150 to <20)
1.3. Liver function (Bilirubin levels <1.2 to >12.0 mg/dl)
1.4. Cardiovascular system function (MAP or medication to maintain MAP)
1.5. Central nervous system function (Glasgow Coma Score)
1.6. Renal system function (Creatinine levels <1.2 to >5.0 mg/dl)

2. Biomarkers in whole blood samples (collected daily for 7 days) of patients who go on to develop sepsis, assessed using gene expression measured using microarray and RT-qPCR

Secondary outcome measures

1. The time point at which sepsis occurred judged by a clinical advisory panel using the information collected for the primary outcome measures
2. Identification of alternative biomarkers such as proteins and metabolomic by-products was enabled through the collection of patient sera at the same time points as whole blood. Secondary analysis of protein expression by immunoassay in serial serum samples will enable identification of biomarker signatures that do not rely on RT-qPCR

Overall trial start date

01/06/2006

Overall trial end date

28/02/2017

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

1. Patients aged between 18 and 80 years
2. Ability to give written informed consent prior to study participation
3. Patients undergoing elective high-risk surgery (e.g. aortic vascular surgery, cardio-thoracic surgery, colonic surgery, gastrectomy, oesophago-gastrectomy, Whipple’s procedure, biliary or urological procedures)
4. ASA grades 1, 2, 3

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

4,385

Total final enrolment

4385

Participant exclusion criteria

1. Pregnant patients
2. Immunosuppressed patients (e.g. HIV disease, anti-rejection medication)

Recruitment start date

01/11/2007

Recruitment end date

20/02/2017

Locations

Countries of recruitment

Germany, United Kingdom

Trial participating centre

Heartlands Hospital
Bordesley Green E
Birmingham
B9 5SS
United Kingdom

Trial participating centre

University College Hospital
University College London Hospitals NHS Foundation Trust 235 Euston Road Bloomsbury
London
NW1 2BU
United Kingdom

Trial participating centre

The Royal Liverpool University Hospital
Royal Liverpool & Broadgreen University Hospitals NHS Trust Prescot Street
Liverpool
L7 8XP
United Kingdom

Trial participating centre

St James's University Hospital
Beckett Street Harehills
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Bristol Royal Infirmary
University Hospitals Bristol and Weston NHS Foundation Trust Upper Maudlin Street
Bristol
BS2 8HW
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital Birmingham Mindelsohn Way Edgbaston
Birmingham
B15 2TH
United Kingdom

Trial participating centre

St. Thomas' Hospital
Guy's and St Thomas's NHS Foundation Trust Westminster Bridge Road
London
SE1 7EH
United Kingdom

Trial participating centre

University Hospital Frankfurt
Theodor-Stern-Kai 7
Frankfurt am Main
60590
Germany

Sponsor information

Organisation

Defence Science and Technology Laboratory

Sponsor details

Porton Down
Salisbury
SP4 0JQ
United Kingdom
+44 (0)1980 957424
ralukaszewski@dstl.gov.uk

Sponsor type

Government

Website

https://www.gov.uk/government/organisations/defence-science-and-technology-laboratory

Funders

Funder type

Government

Funder name

Ministry of Defence

Alternative name(s)

MOD

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Funder name

Defense Threat Reduction Agency

Alternative name(s)

The Defense Threat Reduction Agency, DTRA

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United States of America

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer-reviewed journal.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be stored in a publically available repository.
All raw data is derived following the anonymisation of participating patients. Transcriptomic data will be uploaded to a publicly available GEO database. Individual patient metadata will not be publicly available but will be available to individual patients on a case by case basis.

Intention to publish date

01/01/2021

Participant level data

Stored in repository

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

02/11/2020: Internal review. 27/10/2020: Trial’s existence confirmed by Southampton & South West Hampshire Research Ethics Committee (A)