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 |
| IRAS number | 268723 |
| Secondary identifying numbers | 17/136/13, IRAS 268723, UoL001520 |
- 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
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 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
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 |
| eudenj@cardiff.ac.uk |
Study information
| 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 |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | Not available web format, please use contact details to request a 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 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(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 |
| 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 |
| Pharmaceutical study type(s) | |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | 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 | 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) |
| Overall study start date | 01/12/2019 |
| Overall study end date | 30/04/2024 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | 7,676 |
| Total final enrolment | 7676 |
| Participant inclusion criteria | Patients ≥16 years presenting to the ED with suspected sepsis |
| 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 | 01/11/2020 |
| Recruitment end date | 01/11/2023 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Liverpool
L7 8XP
United Kingdom
Leeds
LS9 7TF
United Kingdom
Hull
HU3 2JZ
United Kingdom
Winchester
SO22 5DG
United Kingdom
Cosham
Portsmouth
PO6 3LY
United Kingdom
Brighton
BN2 5BE
United Kingdom
Sponsor information
University/education
University of Liverpool / Liverpool Joint Research Office
2nd Floor Block C Waterhouse Building
3 Brownlow Street
Liverpool
L69 3GL
England
United Kingdom
| Phone | +44 (0)151 794 8373 |
|---|---|
| sponsor@liverpool.ac.uk | |
| Website | https://www.liverpool.ac.uk/ |
"ROR" |
https://ror.org/04xs57h96 |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/04/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| 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 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 | ||
| Statistical Analysis Plan | version 2.0 | 03/12/2024 | 19/03/2025 | No | No |
Additional files
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.
