Staphylococcus aureus Network Adaptive Platform trial (SNAP)

ISRCTN	ISRCTN17997749
DOI	https://doi.org/10.1186/ISRCTN17997749
ClinicalTrials.gov (NCT)	NCT05137119
Clinical Trials Information System (CTIS)	2022-001238-13
Integrated Research Application System (IRAS)	1005342
Central Portfolio Management System (CPMS)	58551
Protocol serial number	CT19029
Sponsor	University College London
Funder	National Institute for Health and Care Research

Submission date: 03/12/2022
Registration date: 05/09/2023
Last edited: 06/05/2026

Recruitment status: Enrolling by Invitation
Overall study status: Ongoing
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
Bacteraemia is a dangerous condition occurring when bacteria enter someone’s blood (infection in the blood). Bacteria called Staphylococcus aureus (S. aureus) can cause S. aureus bacteraemia (SAB). Up to a third of people with SAB die within 3 months, even when treated with antibiotics. The aim of the research is to find out which treatments for this illness are best and if we can reduce the number of deaths from this disease.
The sort of questions we want to answer are:
1. What is the best main antibiotic treatment for S. aureus bacteraemia? This is being explored in a part of the trial (domain) called the 'backbone' (or main) antibiotic.
2. Once patients are feeling better, do we need to continue antibiotics via a drip (usually in the hospital), or could we give patients tablet antibiotics to take at home instead? This domain is called 'early oral switch', where some people are moved to tablet antibiotic(s) early.
3. Will giving participants a PET/CT scan while they are in the hospital result in better-tailored treatment for their S. aureus↲
infection?

Who can participate?
Inpatients (by invitation only) infected with Staphylococcus aureus.

What does the study involve?
To work out which medicine is best researchers use clinical trials called a randomised controlled trial (RCT). The treatments are chosen randomly (like the flip of a coin) and one person may receive more than one treatment. Some patients then receive one or more medicines, whilst other patients receive different treatment(s). This means the same patient can be in more than one part of the trial. In this trial the drugs used are already licensed drugs used around the world to treat patients with this disease.

This is an international adaptive study so the researchers analyse the results as the study goes on rather than just at the end. If the results show any of the treatments do not work as well as others, they will be removed from the study. Similarly, new arms may be added. The initial length of the trial is 4 and a half years. Each person would be in the trial for 3 months with their data collected & stored longer.

What are the possible benefits and risks of participating?
Benefits:
Participants may or may not personally benefit from their participation in this trial. However, we hope that the trial results will contribute to the advancement of scientific knowledge in this field and help us find better treatments for patients with S. aureus.

Risks:
This trial is considered to be relatively low risk due to the fact that all of the interventions are already known treatments for S. aureus infections. No matter what arm participants are randomised to, they will be receiving treatments that are already licensed in the UK and known to be efficacious.
However, as with any medications, there are still risks, and there are a number of possible side effects in particular relation to antibiotic treatment. The PIS highlights that while risks are low with already licensed medications, these can still occur and outline some of the likely side effects. Where the combination of antibiotics may increase particular risks, this is highlighted in the PIS, and details are provided on the additional monitoring that will be undertaken as a result.
Data privacy poses another potential risk, however, this will be kept to a minimum through use of a secure database with tightly regulated access. Participant data will be pseudonymised before being entered into the study database, and this will only be viewable by the study site and the central trial and data managers. Any directly identifiable data will be restricted to the study site team, and to monitors to facilitate data checks.
Due to the severity of SAB, consent by the participant's authorised representative could also be a risk. In this situation the patient may have been consented to a study that they might not have consented to themselves. All patients will be approached to give their own consent as soon as feasibly possible in their recovery, and may withdraw their participation if they choose at any time in the trial.

Where is the study run from?
University College London Innovative Clinical Trials Unit, London (UK)

When is the study starting and how long is it expected to run for?
November 2023 to December 2029

Who is funding the study?
National Institute for Health and Care Research (NIHR) (UK).

Who is the main contact?
Professor Anna Goodman, anna.goodman@nhs.net, mrcctu.snap@ucl.ac.uk

Contact information

Prof Anna Goodman
Scientific

UCL Innovative Clinical Trials Unit
2nd Floor, 90 High Holborn
London
WC1V 6LJ
United Kingdom

Phone	+44 20 7670 4817
Email	mrcctu.snap@ucl.ac.uk

Study information

Primary study design	Interventional
Study design	Interventional randomized controlled adaptive platform trial
Secondary study design	Platform trial
Scientific title	Staphylococcus aureus Network Adaptive Platform trial (SNAP)
Study acronym	SNAP
Study objectives	The objective of SNAP is to identify the effect of a range of clinical interventions on all-cause 90-day mortality in patients with SAB
Ethics approval(s)	Approved 30/08/2023, London – Hampstead Research Ethics Committee (2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 207 104 8248; hampstead.rec@hra.nhs.uk), ref: 23/LO/0033
Health condition(s) or problem(s) studied	Staphylococcus aureus bacteraemia
Intervention	Current interventions: SNAP is a multicentre, pragmatic, multi-arm, open-label adaptive platform trial which aims to identify the effects of a range of clinical interventions on patients with Staphylococcus aureus Bacteraemia (SAB) in order to improve clinical outcomes. Participants will be randomly assigned to 1 arm within each domain for which they are eligible using a web-based module. Currently available domains: Antibiotic Backbone Domain (Adults): If the participant is deemed eligible they will be randomised within silos based on the antimicrobial susceptibility. For MRSA, they will be randomised to: 1. Combination of usual care (vancomycin or daptomycin) plus cefazolin (7 days) - In addition to standard treatment an intravenous β-lactam will be added for the first 7 calendar days following randomisation (day 1 being the day of randomisation - hence patients will receive 6-7 days of β-lactam). This β-lactam will be intravenous cefazolin 2 g every 8 h. 2. Usual care alone Antibiotic Backbone Domain (Paediatric): If the participant is deemed eligible they will be randomised within silos based on the antimicrobial susceptibility. For MSSA or PSSA, they will be randomised to: 1. Cefazolin 50mg/kg/dose up to 2g max dose every 8 hours intravenously 2. (Flu)cloxacillin 50mg/kg/dose up to 2g max dose every 6 hours intravenously For MRSA, they will be randomised to: 1. Combination of usual care (vancomycin or daptomycin) plus cefazolin (7 days) - In addition to standard treatment an intravenous β-lactam will be added for the first 7 calendar days following randomisation (day 1 being the day of randomisation - hence patients will receive 6-7 days of β-lactam). This β-lactam will be intravenous cefazolin up to 2g max dose every 8 hours intravenously. 2. Usual care alone Early Oral Switch Domain (Adult participants only) If the participant is deemed eligible, and clinically stable at Day 7 or 14, they will be randomised to receive either: 1. Oral antibiotic regimen - Switch from intravenous backbone antibiotic for MRSA or MSSA or PSSA to oral antibiotics at the treating clinicians discretion on trial Day 7 (+/- 2 days) or trial Day 14 (+/- 2 days). 2. Continued intravenous antibiotic therapy. PET/CT Domain (Adult participants only) If the participant is deemed eligible at Day 7, they will be randomised to: 1. Usual care with FDG PET/CT 2. Usual care with no PET/CT Previous interventions: SNAP is a multicentre, pragmatic, multi-arm, open-label adaptive platform trial which aims to identify the effects of a range of clinical interventions on patients with Staphylococcus aureus Bacteraemia (SAB) in order to improve clinical outcomes. Participants will be randomly assigned to 1 arm within each domain for which they are eligible using a web-based module. Currently available domains: - Adjunctive Treatment Domain: If the participant is deemed eligible they will be randomised to receive either: 1. Usual care plus clindamycin (5 days) - Intravenous clindamycin (or lincomycin) 600 mg every 8 h for 5 days. 2. Usual care alone - Antibiotic Backbone Domain: If the participant is deemed eligible they will be randomised within silos based on the antimicrobial susceptibility. For PSSA, they will be randomised to: 1. Benzylpenicillin - Intravenous benzylpenicillin 1.8 g (3 million units) every 4 or 6 h. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. 2. (Flu)cloxacillin - Either intravenous flucloxacillin/cloxacillin 2 g every 4 or 6 h. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. For MSSA, they will be randomised to: 1. Cefazolin - Intravenous cefazolin 2 g every 6 or 8 h. The minimum protocol duration of allocated study treatment is 14 days for those not allocated to early oral switch, and 5 days for those allocated to early oral switch. 2. (Flu)cloxacillin - as above For MRSA, they will be randomised to 1. Combination of usual care (vancomycin or daptomycin) plus cefazolin (7 days) - In addition to standard treatment an intravenous β-lactam will be added for the first 7 calendar days following randomisation (day 1 being the day of randomisation - hence patients will receive 6-7 days of β-lactam). This β-lactam will be intravenous cefazolin 2 g every 8 h. 2. Usual care alone - Early Oral Switch Domain: If the participant is deemed eligible, and clinically stable at Day 7 or 14, they will be randomised to receive either: 1. Oral antibiotic regimen - Switch from intravenous backbone antibiotic for MRSA or MSSA or PSSA to oral antibiotics at the treating clinicians discretion on trial Day 7 (+/- 2 days) or trial Day 14 (+/- 2 days). 2. Continued intravenous antibiotic therapy.
Intervention type	Drug
Phase	Phase IV
Drug / device / biological / vaccine name(s)	Benzylpenicillin, cefazolin, flucloxacillin, vancomycin, daptomycin, clindamycin, amoxicillin, flucloxacillin, cefalexin, linezolid, moxifloxacin, ciprofloxacin, levofloxacin, rifampicin, trimethoprim plus sulfamethoxazole (TMP+SMX), fusidic acid, clindamycin, co-amoxiclav, fludeoxyglucose (18F)
Primary outcome measure(s)	Current primary outcome as of 06/05/2026: All-cause mortality at 90 days after platform entry determined through a search of hospital databases for a record of a participant’s death, or follow-up contact with the participant’s community healthcare provider, or follow-up contact with the patient or their nominated carer, or linkage with death registries. The paediatric composite outcome will include a composite of 4 variables collected as secondary outcomes across the trial. The chosen outcomes include mortality, markers of relapse and extended hospitalisation. Previous primary outcome: All-cause mortality at 90 days after platform entry determined through a search of hospital databases for a record of a participant’s death, or follow-up contact with the participant’s community healthcare provider, or follow-up contact with the patient or their nominated carer, or linkage with death registries.
Key secondary outcome measure(s)	Current key secondary outcomes as of 06/05/2026: 1. All-cause mortality at 14, 28 and 42 days after platform entry 2. Duration of survival censored at 90 days after platform entry 3. Length of stay of acute index inpatient hospitalisation for those surviving until hospital discharge (excluding HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry. Acute index hospitalisation is defined as a continuous admission to an inpatient healthcare facility where the patient was recruited 4. Length of stay of total index hospitalisation for those surviving until hospital discharge (including HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry. Total index hospitalisation is defined as a continuous admission to any healthcare facility, including rehabilitation hospitals, and hospital-in-the-home or outpatient parenteral antimicrobial therapy services 5. Time to being discharged alive from the total index hospitalisation (including HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry (and all deaths within 90 days will be considered ’90 days’) 6. Microbiological treatment failure, defined as positive sterile site culture for S. aureus [of the same silo as the index isolate] between 14 and 90 days after platform entry. A sterile site means any sites deep to the skin and skin structures, including deep visceral and musculoskeletal abscesses that have been obtained in a sterile manner. 7. Diagnosis of new foci between 14 and 90 days after platform entry. The presence of new foci will be determined by the site investigator and can incorporate clinical, radiological, microbiological and pathological findings. 8. C. difficile diarrhoea as determined by a clinical laboratory in the 90 days following platform entry for participants ≥2 years of age. This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene. 9. Serious adverse reactions (SARs) in the 90 days following platform entry 10. Health economic costs up to 1 year, as detailed in the health economics appendix 11. Proportion of participants who have returned to their usual level of function at day 90, as determined by whether the modified functional bloodstream infection score (FBIS) remained the same or improved between baseline and 90 days after platform entry Secondary outcomes forming the paediatric composite outcome: 1. Mortality by Day 90 following platform entry 2. Microbiological treatment failure, defined as a positive sterile site culture for S. aureus (of the same silo as the index isolate) between 14 and 90 days after platform entry 3. Diagnosis of new foci between 14 and 90 days after platform entry 4. Length of total index hospitalisation of >30 days from the time of platform entry. Total index hospitalisation is defined as a continuous admission to any healthcare facility, including rehabilitation hospitals, and hospital-in-the-home or outpatient parenteral antimicrobial therapy services. (If an event is observed in any of the four above endpoints, then the composite endpoint will be considered to have been met) Previous key secondary outcomes: 1. All-cause mortality at 14, 28 and 42 days after platform entry 2. Duration of survival censored at 90 days after platform entry 3. Length of stay of acute index inpatient hospitalisation for those surviving until hospital discharge (excluding HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry. Acute index hospitalisation is defined as a continuous admission to an inpatient healthcare facility where the patient was recruited 4. Length of stay of total index hospitalisation for those surviving until hospital discharge (including HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry. Total index hospitalisation is defined as a continuous admission to any healthcare facility, including rehabilitation hospitals, and hospital-in-the-home or outpatient parenteral antimicrobial therapy services 5. Time to being discharged alive from the total index hospitalisation (including HITH/COPAT/OPAT/rehab), truncated at 90 days after platform entry (and all deaths within 90 days will be considered ’90 days’) 6. Microbiological treatment failure, defined as positive sterile site culture for S. aureus [of the same silo as the index isolate] between 14 and 90 days after platform entry. A sterile site means any sites deep to the skin and skin structures, including deep visceral and musculoskeletal abscesses that have been obtained in a sterile manner. 7. Diagnosis of new foci between 14 and 90 days after platform entry. The presence of new foci will be determined by the site investigator and can incorporate clinical, radiological, microbiological and pathological findings. 8. C. difficile diarrhoea as determined by a clinical laboratory in the 90 days following platform entry for participants ≥2 years of age. This means a stool submitted to a clinical laboratory has tested positive for C. difficile toxin or toxin gene. 9. Serious adverse reactions (SARs) in the 90 days following platform entry 10. Health economic costs up to 1 year, as detailed in the health economics appendix 11. Proportion of participants who have returned to their usual level of function at day 90, as determined by whether the modified functional bloodstream infection score (FBIS) remained the same or improved between baseline and 90 days after platform entry
Completion date	31/12/2029

Eligibility

Participant type(s)	Patient
Age group	All
Sex	All
Target sample size at registration	7000
Key inclusion criteria	1. Staphylococcus aureus complex grown from ≥1 blood culture 2. Admitted to participating hospital at anticipated time of eligibility assessment 3. Appropriate consent has been obtained for the patient’s participation in the trial
Key exclusion criteria	1. Time of anticipated platform entry is greater than 72 h post collection of the index blood culture 2. Polymicrobial bacteraemia, defined as more than one organism (at species level) in the index blood cultures, excluding those organisms judged to be contaminants by the treating clinicians 3. Patient currently being treated with a systemic antibacterial agent that cannot be ceased or substituted for interventions allocated within the platform (unless antibiotic is listed in Table 1, which specifies allowed antibiotics with limited absorption from the gastrointestinal tract or negligible antimicrobial activity against S. aureus) 4. Known previous participation in SNAP 5. Known positive blood culture for S. aureus (of the same silo: PSSA, MSSA or MRSA) between 72 h and 180 days prior to the time of eligibility assessment 6. Treating team deems enrolment in the study is not in the best interest of the patient 7. Treating clinician believes that death is imminent and inevitable 8. Patient is for end-of-life care and antibiotic treatment is considered not appropriate 9. Patient <18 years of age and paediatric recruitment not approved at recruiting site 10. Patient has died since the collection of the index blood culture
Date of first enrolment	27/11/2023
Date of final enrolment	30/06/2027

Locations

Countries of recruitment

United Kingdom
England
Scotland
Wales
Australia
Canada
Germany
Israel
Japan
Malaysia
Netherlands
New Zealand
Singapore
South Africa
Sweden
United States of America

Study participating centres

Barts Health NHS Trust

The Royal London Hospital
80 Newark Street
London
E1 2ES
England

Bristol Royal Hospital for Children

Upper Maudlin Street
Bristol
BS2 8BJ
England

University Hospitals Sussex NHS Foundation Trust

Worthing Hospital
Lyndhurst Road
Worthing
BN11 2DH
England

University Hospitals Bristol and Weston NHS Foundation Trust

Trust Headquarters
Marlborough Street
Bristol
BS1 3NU
England

Cardiff & Vale University Lhb

Woodland House
Maes-y-coed Road
Cardiff
CF14 4HH
Wales

Guy's and St Thomas' NHS Foundation Trust

St Thomas' Hospital
Westminster Bridge Road
London
SE1 7EH
England

Hull University Teaching Hospitals NHS Trust

Hull Royal Infirmary
Anlaby Road
Hull
HU3 2JZ
England

Imperial College Healthcare NHS Trust

The Bays
St Marys Hospital
South Wharf Road
London
W2 1BL
England

NHS Lothian

Waverley Gate
2-4 Waterloo Place
Edinburgh
EH1 3EG
Scotland

Leeds Teaching Hospitals NHS Trust

St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
England

Liverpool University Hospitals NHS Foundation Trust

Royal Liverpool University Hospital
Prescot Street
Liverpool
L7 8XP
England

Manchester University NHS Foundation Trust

Cobbett House
Oxford Road
Manchester
M13 9WL
England

North Bristol NHS Trust

Southmead Hospital
Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
England

The Newcastle upon Tyne Hospitals NHS Foundation Trust

Freeman Hospital
Freeman Road
High Heaton
Newcastle upon Tyne
NE7 7DN
England

Oxford University Hospitals

John Radcliffe Hospital
Headley Way
Headington
Oxford
OX3 9DU
England

Royal Free London NHS Foundation Trust

Royal Free Hospital
Pond Street
London
NW3 2QG
England

Swansea Bay Cds

One Talbot Gateway
Baglan Energy Park
Port Talbot
SA12 7BR
Wales

University College London Hospitals NHS Foundation Trust

250 Euston Road
London
NW1 2PG
England

University Hospital Southampton

Southampton University Hospital
Tremona Road
Southampton
SO16 6YD
England

University Hospitals Birmingham NHS Foundation Trust

Queen Elizabeth Hospital
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
England

Whittington Health NHS Trust

The Whittington Hospital
Magdala Avenue
London
N19 5NF
England

South Tees Hospitals NHS Foundation Trust

James Cook University Hospital
Marton Road
Middlesbrough
TS4 3BW
England

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan	Research teams may approach the SNAP leadership with a formal data sharing request detailing the specific requirement, proposed research, qualification of researchers and publication plan if they are interested in using SNAP data. The request will be reviewed by the International Trial Steering Committee. If approved and once any additional ethics has been obtained data would be shared. Any data transfer will be anonymised, and considerations will be taken if non-aggregated data is requested. All participants will be consented for future use of their data.

Individual participant data (IPD) Intention to share

Yes

IPD sharing plan

Research teams may approach the SNAP leadership with a formal data sharing request detailing the specific requirement, proposed research, qualification of researchers and publication plan if they are interested in using SNAP data. The request will be reviewed by the International Trial Steering Committee. If approved and once any additional ethics has been obtained data would be shared. Any data transfer will be anonymised, and considerations will be taken if non-aggregated data is requested. All participants will be consented for future use of their data.

Editorial Notes

06/05/2026: The following changes were made:
1. Recruitment status override was updated to "Enrolling by Invitation".
2. Interventions updated.
3. The Drug/device/biological/vaccine name(s) were updated to include fludeoxyglucose (18F).
4. Age group was changed from adult to all.
5. Date of first enrolment was changed from 18/02/2022 to 27/11/2023.
5. Germany, Japan, Malaysia, Sweden, England, Wales, Scotland and the United States of America were added to the Countries of recruitment.
6. The study contact was updated.
04/10/2023: Internal review.
05/12/2022: Trial's existence confirmed by NHS HRA.