Condition category
Infections and Infestations
Date applied
13/12/2019
Date assigned
19/12/2019
Last edited
19/12/2019
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Sepsis (also known as septicaemia or blood poisoning) is a common, potentially life-threatening complication of infection. The optimal treatment for sepsis includes early recognition, prompt antibiotics and fluids into a vein (intravenous/IV). Currently, clinicians assess severity in patients in the Emergency Department (ED) with a scoring system based on simple to measure observations: the National Early Warning Score (NEWS2). NEWS2 helps clinicians identify the sickest patients. It is not specific and tends to over-diagnose sepsis leading to over-prescribing of antibiotics and promoting antimicrobial resistance. It is the best we have and currently used in over 70% of English hospitals. Adults with suspected sepsis fall into one of three categories: a) those looking ill needing urgent IV antibiotics and fluids within 1 hour, b) those that are unwell, but will not come to harm if IV antibiotics are not administered within 1 hour, allowing time for further assessment prior to starting antibiotics within 3 hours, c) those not critically unwell who may or may not need IV antibiotics. Procalcitonin (PCT), a blood test not widely used in the NHS, helps to identify bacterial infection. The National Institute for Health and Care Excellence (NICE) recommended further research on PCT testing in EDs for guiding antibiotic use in people with suspected sepsis.

In this study, we will conduct a randomised controlled trial to compare PCT-supported assessment with standard care of suspected sepsis in adults presenting to the ED, and measure whether this approach reduces prescriptions of antibiotics without increasing mortality by decreasing uncertainty in the group who may not need IV antibiotics urgently within 1 hour, or not need antibiotics at all.

Who can participate?
Patients ≥16 years presenting to the ED with suspected sepsis.

What does the study involve?
Adult patients with suspected sepsis will be randomly assigned to current standard of care or PCT-supported care. In the PCT group, a bedside test (taking 20 minutes) is performed plus the NEWS2 assessment. Depending on the result of the PCT plus the NEWS2, patients will receive IV antibiotics and fluids within the current recommended time frame depending on severity. Doctors and patients will know what treatment arm they are in. An analysis will be done to understand how well clinicians follow the recommendations, ease of use of the additional test in a busy ED, and its cost effectiveness. A sample of patients interviewed at 90 days follow up will assess experiences of care.

What are the possible benefits and risks of participating?
Participants who do not have sepsis will avoid being given IV antibiotics unnecessarily and therefore might avoid side effects. Taking part in the trial will mean that participants may have to give up some of their time to complete some follow up questionnaires. There are no other disadvantages or risks in taking part in the trial.

Where is the study run from?
University of Liverpool (UK)

When is the study starting and how long is it expected to run for?
December 2019 to November 2022

Who is funding the study?
National Institute for Health Research (NIHR), UK

Who is the main contact?
Dr Joanne Euden, eudenj@cardiff.ac.uk

Trial website

Contact information

Type

Public

Primary contact

Dr Joanne Euden

ORCID ID

https://orcid.org/0000-0002-2844-6878

Contact details

Centre for trials Research
7th floor
Neaudd Meirionnydd
Cardiff University
Heath Park
Cardiff
CF14 4YS
United Kingdom
+44 (0)2922510771
eudenj@cardiff.ac.uk

Additional identifiers

EudraCT number

Nil known

ClinicalTrials.gov number

Nil known

Protocol/serial number

17/136/13, IRAS 268723

Study information

Scientific title

PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal use of antibiotics in the Emergency department.

Acronym

PRONTO

Study hypothesis

The addition of procalcitonin measurement to NEWS2 scoring will lead to a reduction in intravenous antibiotic initiation in ED patients managed as suspected sepsis, with at least no increase in 28-day mortality compared to NEWS2 scoring alone (in conjunction with local standard care pathways).

Ethics approval

Not provided at time of registration
Plan to submit to Wales REC 2 or 3 on 13th/14th February 2020.

Study design

Multi-centre parallel two-arm open-label individually randomised controlled trial with two co-primary endpoints

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Diagnostic

Patient information sheet

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

Condition

Suspected sepsis

Intervention

A procalcitonin (PCT) point-of-care test (testing equipment provided by ThermoFisher) used in combination with NEWS2 assessment of adult patients with suspected sepsis in emergency departments, using a stratification algorithm.

Individual patients will be screened for eligibility and randomised in a 1:1 ratio to either standard clinical management (control) or standard clinical management plus the Procalcitonin biomarker guided assessment (intervention). This will be implemented in a secure 24-h web-based randomisation programme controlled centrally by the Centre for Trials Research in Cardiff. In the intervention arm, levels of procalcitonin will be detected from a small blood sample which is read in a BRAHMS PCT Direct machine, taking 20 min. The result will aid in clinician's diagnosis of sepsis.

Adults in the control arm will not have the procalcitonin test performed and will simply have NEWS2 assessment for suspected sepsis as per standard care.

Intervention type

Device

Phase

Phase III

Drug names

BRAHMS PCT Direct (ThermoFisher)

Primary outcome measure

Co-primary outcomes:
1. IV antibiotics initiation at 3 hours (superiority endpoint)
2. Mortality at 28 days (non-inferiority endpoint)

Secondary outcome measures

1. Total duration of all antibiotics (IV and oral). (Number of days on any antibiotics up to day 28)
2. Type of antibiotic (defined by number of days on Access group broad spectrum IV and/or oral antibiotics during the 28 day follow up period, as defined by WHO AWaRe Classification Database). Type, dose and duration recorded in medical notes daily
3. Readmissions (number of times participant readmitted to ICU during the 28 day follow up period. Monitored daily)
4. Antibiotic associated side effects. (Recorded in medical notes and observation charts. Daily observation)
5. Health utility (EQ-5D/5L) at 90 days. (patient reported questionnaire collected at day 28 and day 90)
6. Feasibility of implementing Procalcitonin testing alongside NEWS2 scoring in Emergency Departments (EDs) (qualitative interviews with HCPs during the internal pilot phase)
7. Acceptability of implementing Procalcitonin testing alongside NEWS2 scoring in EDs, to patients, carers and clinicians, (qualitative interviews with clinicians towards the end of the trial)

Overall trial start date

01/12/2019

Overall trial end date

30/11/2022

Reason abandoned (if study stopped)

Eligibility

Participant inclusion criteria

Patients ≥ 16 years presenting to the ED with suspected sepsis

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

7,676

Participant exclusion criteria

1. Currently on intravenous antibiotics
2. Current use of any chemotherapy agent associated with myeloablation/suppression
3. History of solid organ transplantation, allogeneic bone marrow or stem cell transplantation within 3 months prior to consent
4. Patients known to require urgent surgical intervention (within the course of current admission)
5. Presence of an advance directive to withhold life-sustaining treatment (patients not wishing to receive Cardiopulmonary Resuscitation (CPR) may qualify provided they receive all other resuscitative measures e.g. respiratory support, fluid resuscitation)

Recruitment start date

01/06/2020

Recruitment end date

31/05/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Royal Liverpool University Hospital
Prescot St
Liverpool
L7 8XP
United Kingdom

Trial participating centre

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

Trial participating centre

Hull Royal Infirmary
Anlaby Rd
Hull
HU3 2JZ
United Kingdom

Trial participating centre

Royal Hampshire County Hospital
Romsey Rd
Winchester
SO22 5DG
United Kingdom

Trial participating centre

Queen Alexandra Hospital
Southwick Hill Road Cosham
Portsmouth
PO6 3LY
United Kingdom

Trial participating centre

Royal Sussex County Hospital
Eastern Rd
Brighton
BN2 5BE
United Kingdom

Sponsor information

Organisation

University of Liverpool

Sponsor details

University of Liverpool / Liverpool Joint Research Office
2nd Floor Block C Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
United Kingdom
+44 (0)151 794 8373
sponsor@liverpool.ac.uk

Sponsor type

University/education

Website

https://www.liverpool.ac.uk/

Funders

Funder type

Government

Funder name

National Institute for Health Research

Alternative name(s)

NIHR

Funding Body Type

government organisation

Funding Body Subtype

National government

Location

United Kingdom

Results and Publications

Publication and dissemination plan

All publications and presentations relating to the trial will be authorised by the Trial Management Group and will be in accordance with the trial’s publication policy.
The trial protocol will be published, and the trial will be registered with ISRCTN. At the end of the study, a final report will be published in The Health Technology Assessment Journal. The results of this study will be disseminated locally, nationally and internationally amongst scientific, clinical and lay groups. At the local level, we will interact with and promote the research findings through wider NHS Trusts (Health Boards in Wales), the NIHR Clinical Research Network: North West Coast, North West Coast CLAHRC, North West Coast AHSN (Innovation Agency). The Innovation Agency is the national lead within AHSNs for sepsis through the Patient Safety Collaborative.
Nationally, we will engage with NICE, the Royal College of Physicians, The Royal College of Emergency Medicine, The British Society for Antimicrobial Chemotherapy, The British Infection Association, NHS Improvement and the UK Sepsis Trust. Internationally, we will disseminate our findings at high impact conferences such as European Congress of Clinical Microbiology and Infectious Diseases, Federation of Infection Societies, The Interscience Conference on Antimicrobial Agents and Chemotherapy, The International Society for Pharmacoeconomics and Outcomes Research, and The European Health Economics Association. We anticipate publication outputs reporting the effectiveness and cost-effectiveness findings in high impact Journals such as The Lancet, The Journal of the American Medical Association, The British Medical Journal and Lancet Infectious Diseases. We will set up a study website and produce an annual NEWS letter for clinicians, academics and policy makers.

We will engage with patient groups and the wider public through our involvement as members of the UK Sepsis Trust, Antibiotic Action (a public awareness group of the British Society for Antimicrobial Chemotherapy), and the Meningitis Research Foundation, and publicise the study through these channels, and seek to present study updates at their annual conferences. We will use press releases and social media outlets (Facebook and Twitter) to publicise the study and disseminate findings. We will also feedback study findings to participants, their families and clinicians. We will use public engagement officers based at the University of Liverpool and participating hospital trusts to develop and disseminate public messages.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be available upon request from opendata@cardiff.ac.uk – this would be at the end of the study. The aim is to make the research data available wherever possible, subject to regulatory approvals, any terms and conditions from external providers, patient confidentiality and all laws concerning the protection of personal information. Data is generally freely available, but recipients are expected to acknowledge the original creators in any public use of the data or in publishing research results based wholly or in part upon the data – anyone requesting access to data will be asked to agree to the terms of the Creative Commons Attribution 4.0 license. The trialists may ask the requestor to cover reasonable cost for preparing and providing the data (for example physical storage and postage, where dataset size makes it impractical to provide data by electronic means).

Intention to publish date

01/08/2022

Participant level data

Available on request

Basic results (scientific)

Publication list

Publication citations

Additional files

Editorial Notes

18/12/2019: Trial's existence confirmed by the NIHR.