A point of care test to aid in diagnosis of suspected sepsis and optimal use of antibiotics in adults presenting to A & E

ISRCTN	ISRCTN54006056
DOI	https://doi.org/10.1186/ISRCTN54006056
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Integrated Research Application System (IRAS)	268723
Protocol serial number	17/136/13, IRAS 268723, UoL001520
Sponsor	University of Liverpool
Funder	National Institute for Health Research

Submission date: 13/12/2019
Registration date: 19/12/2019
Last edited: 02/04/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Infections and Infestations

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

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 April 2024

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

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

Contact information

Dr Joanne Euden
Public

Centre for trials Research
7th floor, Neaudd Meirionnydd
Cardiff University
Heath Park
Cardiff
CF14 4YS
United Kingdom

ORCID ID	0000-0002-2844-6878
Phone	+44 (0)2922510771
Email	eudenj@cardiff.ac.uk

Study information

Primary study design	Interventional
Study design	Multi-centre parallel two-arm open-label individually randomised controlled trial with two co-primary endpoints
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	PROcalcitonin and NEWS2 evaluation for Timely identification of sepsis and Optimal use of antibiotics in the Emergency department.
Study acronym	PRONTO
Study objectives	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(s)	Approved 21/07/2020, Wales Research Ethics Committee 2 Cardiff (Health and Care Research Wales Castlebridge 4 15-19 Cowbridge Road East Cardiff, CF11 9AB, UK; +44 (0)2920 785738; Wales.REC2@wales.nhs.uk), REC ref: 20/WA/0058
Health condition(s) or problem(s) studied	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 / device / biological / vaccine name(s)	BRAHMS PCT Direct (ThermoFisher)
Primary outcome measure(s)	Co-primary outcomes: 1. IV antibiotics initiation at 3 hours (superiority endpoint) 2. Mortality at 28 days (non-inferiority endpoint)
Key secondary outcome measure(s)	Current secondary outcome measures as of 03/05/2022: 1. Time until initiation of IV antibiotic therapy: time of antibiotic initiation, antibiotic type, dose and duration are taken at admission and daily as required 2. Late IV antibiotic initiation: antibiotics commenced after 3 hours, time of IV antibiotic initiation, dose and duration are taken as required) 3. Number of days on IV antibiotics: type, dose and duration of antibiotic taken during admission and total over the first 28 days as required 4. Number of days on any antibiotic: type, dose, and duration of antibiotic taken during admission and total over the first 28 days s required 5. Number of days on broad-spectrum antibiotics (IV and oral), defined by the number of days on an Access group of antibiotics as defined by the WHO AWaRe Classification Database (type, dose and duration of broad-spectrum antibiotic during admission and total over the first 28 days as required) 6. ICU admission: date and details of admission to ICU at any point during admission 7. Length of ICU stay: number of days in ICU taken from medical notes 8. Length of hospital stay: number of days of admission taken from medical notes 9. Adverse antibiotic outcomes: date and type of adverse events taken from medical notes as required 10. Readmission to hospital within 90 days: ICU re-admissions post-discharge date 11. Mortality within 90 days: date and description of death and time until death in days from admission 12. Health utility measured using EQ-5D/5L at 28 and 90 days 13. Health resource usage: patient reported medical costs and resource use collected at 28 and 90 days 14. Feasibility of implementing PCT testing alongside NEWS2 scoring in EDs assessed using qualitative interviews with HCPs throughout the duration of the trial 15. Acceptability of implementing PCT testing alongside NEWS2 scoring in EDs, to patients, carers and clinicians, assessed using qualitative interviews with HCPs throughout the duration of the trial 16. Total average cost per patient per arm and cost per gained (health-adjusted) life year, taken from patient-reported questionnaires and patient medical notes as required Previous 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 the 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 on 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)
Completion date	30/04/2024

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	16 Years
Sex	All
Target sample size at registration	7676
Total final enrolment	7676
Key inclusion criteria	Patients ≥16 years presenting to the ED with suspected sepsis
Key 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)
Date of first enrolment	01/11/2020
Date of final enrolment	01/11/2023

Locations

Countries of recruitment

United Kingdom
England

Study participating centres

Royal Liverpool University Hospital

Prescot St
Liverpool
L7 8XP
United Kingdom

St James's University Hospital

Beckett St
Leeds
LS9 7TF
United Kingdom

Hull Royal Infirmary

Anlaby Rd
Hull
HU3 2JZ
United Kingdom

Royal Hampshire County Hospital

Romsey Rd
Winchester
SO22 5DG
United Kingdom

Queen Alexandra Hospital

Southwick Hill Road
Cosham
Portsmouth
PO6 3LY
United Kingdom

Royal Sussex County Hospital

Eastern Rd
Brighton
BN2 5BE
United Kingdom

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Available on request
IPD sharing plan	The datasets generated during and/or analysed during the current study are/will be available upon request from Cardiff Centre for Trials Research by contacting the study manager (Dr Joanne Euden) at PRONTO@cardiff.ac.uk. Anonymised data will be provided upon production of the requestor’s study protocol and agreement by Centre of Trials Research and study sponsor (University of Liverpool).

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Protocol article		13/06/2022	15/06/2022	Yes	No
HRA research summary			28/06/2023	No	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Statistical Analysis Plan	version 2.0	03/12/2024	19/03/2025	No	No

Additional files

ISRCTN54006056 PRONTO SAP v2.0 signed 03Dec2024.pdf: Statistical Analysis Plan

Editorial Notes

02/04/2025: The study was officially closed on 22nd August 2024.
19/03/2025: The statistical analysis plan was uploaded as an additional file.
06/11/2023: The recruitment end date was changed from 30/11/2023 to 01/11/2023. Total final enrolment added.
07/02/2023: The participant-level data-sharing statement was updated.
08/11/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/11/2022 to 30/11/2023.
2. The overall end date was changed from 30/11/2022 to 30/04/2024.
3. The intention to publish date was changed from 01/08/2023 to 01/04/2025.
4. The plain English summary was updated to reflect these changes.
15/06/2022: Publication reference added.
10/05/2022: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/06/2020 to 01/11/2020.
2. The recruitment end date was changed from 31/05/2022 to 30/11/2022.
03/05/2022: The following changes were made to the trial record:
1. The overall trial end date was changed from 30/11/2022 to 30/11/2022.
2. The intention to publish date was changed from 01/08/2022 to 01/08/2023.
3. The secondary outcome measures were updated.
29/07/2020: Ethics approval details added.
18/12/2019: Trial's existence confirmed by the NIHR.