Staphylococcus Aureus Network Adaptive Platform Trial

Staphylococcus Aureus Bacteremia Clinical Trial

— SNAP  

Official title:

Staphylococcus Aureus Network Adaptive Platform Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05137119
• Other study ID #: CT19029
• Status: Recruiting
• Phase: Phase 4
• Start date: February 16, 2022
• Est. completion date: December 1, 2025

Study information

• Verified date: March 2024
• Source: University of Melbourne
• Contact: Lauren Barina
• Phone: +61 (03) 8344 1623
• Email: lauren.barina[@]unimelb.edu.au
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is an International Multi-Centered Randomised Adaptive Platform Clinical Trial to evaluate a range of interventions to reduce mortality for patients with Staphylococcus Aureus bacteraemia (SAB).

Description:

Infection of the bloodstream with the bacterium Staphylococcus aureus (Staphylococcus aureus bacteraemia, SAB) is a serious infection that results in 15-30% of affected patients dying within three months of acquiring the infection. Treatment of this infection requires patients to be hospitalised, treated with prolonged antibiotics through an intravenous line, and carefully examined for the occurrence of complications associated with this condition. At present, there are many treatment options in current use, with no clear agreement as to which of these is best. The SNAP trial aims to identify which treatment options for SAB results in the fewest patients dying within the first 90 days after an infection. In contrast to a conventional clinical trial, the SNAP trial will examine multiple different treatment options at once. Patients will be randomly assigned to different concurrent treatment options currently considered acceptable in routine medical care, but as the trial progresses, more patients will be assigned to treatments that appear to have better outcomes than those with worse outcomes. The trial will adapt to accumulating trial evidence, on a regular basis, by removing treatment options found to be inferior, incorporating new treatment options, and ensuring that all patients in the trial receive the best treatments once they have been identified. Over time, we hope to determine the best combination of treatment options for patients with SAB.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 6000
• Est. completion date: December 1, 2025
• Est. primary completion date: December 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

PLATFORM Inclusion Criteria:

Patients must fulfil all of the following criteria to be eligible to enter the SNAP trial:

1. Staphylococcus aureus complex grown from =1 blood culture 2. Admitted to a participating hospital at the time of eligibility assessment PLATFORM Exclusion Criteria: Potentially eligible participants meeting any of the following criteria at the time of

eligibility assessment for platform entry will be excluded from the trial:

1. Time of anticipated platform entry is greater than 72 hours post collection of the index blood culture a) Where the time of culture collection is not recorded, the time of laboratory registration of the sample will be used as an alternative

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 either the microbiology laboratory or treating clinician

3. Patient currently being treated with a systemic antibacterial agent that cannot be ceased (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 hours 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 team 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 To be included in any of the following DOMAINS the participant must met eligible for the PLATFORM (as listed above) ADJUNCTIVE TREATMENT DOMAIN

Inclusion Criteria:

1. All participants that met the PLATFORM eligible are eligible to be included in this domain unless they meet any of the following exclusions listed.

2. Patients are eligible for this domain regardless of S. aureus susceptibility testing results to clindamycin.

Exclusion criteria:

1. Previous type 1 hypersensitivity reaction to lincosamides

2. Currently receiving clindamycin (lincomycin) or linezolid which cannot be ceased or substituted

3. Necrotising fasciitis

4. Current C. difficile associated diarrhoea (any severity) or severe diarrhoea from any cause

5. Known CDAD (C.Difficile Associated Diarrhoea) in the past 3 months, or CDAD relapse in the past 12 months

6. At the time of domain eligibility assessment, more than 4 hours has elapsed since platform entry

7. Treating clinician deems enrolment in this domain is not in the best interest of the patient PSSA, MSSA TREATMENT DOMAIN (backbone)

Inclusion Criteria:

1. For PSSA silo: Index blood culture is penicillin-susceptible

2. For MSSA silo: Index blood culture isolate is methicillin-susceptible but penicillin resistant

Exclusion Criteria (PSSA & MSSA):

1. >72 hours have elapsed since the collection of the index blood culture (i.e. the time of collection of the first positive blood culture from the patient during this episode) 2. History of type I hypersensitivity reaction (i.e. anaphylaxis or angioedema) to any penicillin or cephalosporin 3. History of severe delayed reaction (e.g. allergic interstitial nephritis, cutaneous vasculitis, Stevens-Johnson, DRESS, etc.) to any penicillin or cephalosporin 4. PSSA silo: Non-severe rash to any penicillin (unless patient has been subsequently de-labelled; this criteria does not include criteria 2 and 3 above), or MSSA silo: Non-severe rash to cefazolin or any penicillin (unless patient has been subsequently de-labelled)

• Nausea, diarrhoea, headache, and other non-specific symptoms are NOT allergies, they are drug intolerance, and they are not exclusion criteria. Similarly, a vague history of an allergy of unclear nature, or a family history of allergy are not exclusions.

5. Treating team deems enrolment in this domain is not in the best interest of the patient 6. Currently receiving maintenance dialysis (haemodialysis or peritoneal dialysis)

• Acute renal replacement therapy (including CRRT, haemodialysis or peritoneal dialysis) are not exclusions. Such patients are eligible as long as appropriate vascular access is available or can be arranged. MRSA TREATMENT DOMAIN (backbone)

Inclusion Criteria:

1. MRSA confirmed microbiologically

Exclusion Criteria:

1. Time to allocation reveal is >72 hours from time of index blood culture collection

2. Severe allergy to any beta-lactam (including cefazolin)

1. Immediate severe allergy: Anaphylaxis/angioedema

2. Severe delayed allergy: Severe cutaneous adverse reaction (SCAR; including Steven Johnson Syndrome, Toxic Epidermal Necrolysis, Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) and acute generalised exanthematous pustulosis (AGEP)), severe drug induced liver injury, proven allergic interstitial nephritis, immune-mediated haemolytic anaemia and other severe cytopenia.

3. Non-severe rash to cefazolin a) Nausea, diarrhoea, headache and other non-specific symptoms are NOT allergies, they are drug intolerance, and they are not exclusion criteria. Similarly, a vague history of an allergy of unclear nature, or a family history of allergy are not exclusions.

4. Severe allergy or non-severe rash to both vancomycin AND daptomycin a) Vancomycin infusion reaction (formerly known as "red man syndrome") is due to direct histamine release and is not generally an allergy, and therefore is not considered an exclusion.

5. Treating team deems enrolment in the domain is not in the best interest of the patient EARLY ORAL SWITCH DOMAIN Inclusion Criteria:

Day 7 (+/- 2 days):

1. Clearance of SAB by platform Day 2: blood cultures negative for S. aureus from platform Day 2 onwards AND no known subsequent positive blood cultures

2. Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility)

3. Primary focus is either line related (either central or peripheral IV cannula) or skin and soft tissue, AND source control achieved (for 'line-related' this means line removed; for 'skin and soft tissue' means site PI considers source control to have been achieved and any abscess more than 2cm diameter has been drained)

4. No evidence of metastatic foci (on clinical or radiological examination, but radiological imaging is not required to exclude metastatic foci if not clinically indicated)

Day 14 (+/- 2 days):

1. Clearance of SAB by platform Day 5: blood cultures negative for S. aureus from platform Day 5 (+/-1 day) AND no known subsequent positive blood cultures. If the most recent blood culture from Day 2-4 is negative for S. aureus, blood cultures do not need to be repeated on Day 5 to fulfil eligibility criteria (Day 5 blood cultures will be assumed to be negative in this situation)

2. Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility)

3. Site Principal Investigator has determined that source control is adequate Exclusion Criteria: When judging eligibility at platform Day 7 (+/- 2 days) and at Day 14 (+/- 2 days),

exclusion criteria are:

1. Adherence to oral agents unlikely (as judged by site PI in consultation with the treating team)

2. Unreliable gastrointestinal absorption (e.g. vomiting, diarrhoea, nil by mouth, anatomical reasons)

3. There are no appropriate oral antibiotics due to contraindications, drug availability, or antibiotic resistance

4. Ongoing IV therapy unsuitable e.g. no IV access

5. Clinician deems not appropriate for early oral switch

6. Patient no longer willing to participate in domain a) In the lead-up to judging eligibility, it may be helpful to discuss with the patient the potential for continued IV treatment versus oral switch, to allow hospital discharge planning

7. Clinical team deems that sufficient duration of antibiotic therapy has already been provided

Exclusions when judging eligibility for early oral switch at trial Day 7 (+/- 2 days):

1. Presence of prosthetic cardiac valve, pacemaker or other intracardiac implant

2. Known presence of intravascular clot (excluding superficial peripheral IV line-related thrombophlebitis), graft or other intravascular prosthetic material

3. Intravascular/intracardiac infections (e.g. endocarditis, mycotic aneurysm)

4. Presence of other intracardiac abnormalities felt to put patient at increased risk of endocarditis (e.g., bicuspid aortic valve)

Related Conditions & MeSH terms

• Bacteremia
• Staphylococcal Infections
• Staphylococcus Aureus Bacteremia

Intervention

Drug:
• Cefazolin
Cefazolin
• Penicillin
benzylpenicillin
• Clindamycin
Clindamycin
• Vancomycin
Vancomycin or Daptomycin

Other:
• Effectiveness of early switch to oral antibiotics
This involves testing a strategy rather than individual antibiotic agents

Locations

Country	Name	City	State
Australia	Lyell McEwin Hospital	Adelaide	South Australia
Australia	Grampians Health	Ballarat	Victoria
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Bendigo Health	Bendigo	Victoria
Australia	Sunshine Coast University Hospital	Birtinya	Queensland
Australia	Blacktown Hospital	Blacktown	New South Wales
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Cairns Hospital	Cairns	Queensland
Australia	Royal Prince Alfred Hospital	Camperdown	New South Wales
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Concord Repatriation and General Hospital	Concord	New South Wales
Australia	St Vincent's Hospital Sydney	Darlinghurst	New South Wales
Australia	Western Health- Footscray Hospital & Sunshine Hospital	Footscray	Victoria
Australia	Frankston Hospital	Frankston	Victoria
Australia	Canberra Hospital	Garran	Australia Capital Territory
Australia	Geelong Hospital	Geelong	Victoria
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Nepean Hospital	Kingswood	New South Wales
Australia	St George Hospital	Kogarah	New South Wales
Australia	Launceston Hospital	Launceston	Tasmania
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Logan Hospital	Meadowbrook	Queensland
Australia	Alfred Hospital	Melbourne	Victoria
Australia	Fiona Stanley Hospital	Murdoch	Western Australia
Australia	Perth Children's Hospital	Nedlands	Western Australia
Australia	John Hunter Hospital	New Lambton Heights	New South Wales
Australia	John Hunter Children's Hospital	Newcastle	New South Wales
Australia	Women's and Children's Hospital	North Adelaide	South Australia
Australia	Royal Children's Hospital Melbourne	Parkville	Victoria
Australia	Royal Melbourne Hospital	Parkville	Victoria
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	Goulburn Valley Health	Shepparton	Victoria
Australia	Queensland Children's Hospital	South Brisbane	Queensland
Australia	Gold Coast University Hospital	Southport	Queensland
Australia	Royal Darwin Hospital	Tiwi	Northern Territory
Australia	La Trobe Regional Hospital	Traralgon	Victoria
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	Princess Alexandra Hospital	Woolloongabba	Queensland
Canada	Peter Lougheed Centre	Calgary	Alberta
Canada	Rockyview Hospital	Calgary	Alberta
Canada	South Health Campus	Calgary	Alberta
Canada	University of Calgary - Foothills Medical Center	Calgary	Alberta
Canada	Toronto East Health Network	East York	Ontario
Canada	University Health Network	East York	Ontario
Canada	University of Alberta Hospital	Edmonton	Alberta
Canada	Hamilton Health Sciences Center	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	Jewish General Hospital	Montréal	Quebec
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Ottawa Hospital	Ottawa	Ontario
Canada	Richmond General Hospital	Richmond	British Columbia
Canada	Eastern Health - Health Sciences Centre (Memorial University)	Saint John's	Newfoundland and Labrador
Canada	Hôpital Régional de Saint Jérôme	Saint-Jérôme	Quebec
Canada	Sault Area Hospital	Sault-Sainte-Marie	Ontario
Canada	University of Sherbrooke Health Centre- USHC/CHUS	Sherbrooke	Quebec
Canada	Niagara Health - St. Catharines Site	St. Catharines	Ontario
Canada	Sinai Heath System	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Unity Health	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Health Sciences Centre Winnipeg	Winnipeg	Manitoba
Israel	Rambam Health Care Campus	Haifa
Israel	Beilinson Hospital	Petah tikva
Israel	Sheba Medical Centre	Petah tikva
Netherlands	Radboud University Medical Center	Nijmegen
Netherlands	University Medical Center Utrecht	Utrecht
New Zealand	KidzFirst	Auckland
New Zealand	Starship Hospital	Auckland
New Zealand	Hutt Valley Hospital	Boulcott	Lower Hutt
New Zealand	Christchurch Hospital	Christchurch	Canterbury
New Zealand	Dunedin Hospital	Dunedin	Otago
New Zealand	Auckland City Hospital	Grafton	Auckland
New Zealand	Waikato Hospital	Hamilton
New Zealand	Nelson Hospital	Nelson South	Nelson
New Zealand	Wellington Hospital	Newtown	Wellington
New Zealand	Middlemore Hospital	Otahuhu	Auckland
New Zealand	North Shore Hospital	Takapuna	Auckland
New Zealand	Tauranga Hospital	Tauranga
New Zealand	Whangarei Hospital	Whangarei
Singapore	National University Hospital	Singapore
Singapore	Singapore General Hospital	Singapore
Singapore	Tan Tock Seng Hospital	Singapore

Sponsors (13)

Lead Sponsor

Collaborator

University of Melbourne

Aotearoa Clinical Trials, Berry Consultants, McGill University Health Centre/Research Institute of the McGill University Health Centre, Menzies School of Health Research, Queensland University of Technology, Radboud University Medical Center, Sunnybrook Health Sciences Centre, Tan Tock Seng Hospital, Telethon Kids Institute, The Peter Doherty Institute for Infection and Immunity, The University of Queensland, UMC Utrecht

Countries where clinical trial is conducted

Australia,  Canada,  Israel,  Netherlands,  New Zealand,  Singapore, 

References & Publications (1)

Tong SYC, Mora J, Bowen AC, Cheng MP, Daneman N, Goodman AL, Heriot GS, Lee TC, Lewis RJ, Lye DC, Mahar RK, Marsh J, McGlothlin A, McQuilten Z, Morpeth SC, Paterson DL, Price DJ, Roberts JA, Robinson JO, van Hal SJ, Walls G, Webb SA, Whiteway L, Yahav D, Davis JS; Staphylococcus aureus Network Adaptive Platform (SNAP) Study Group. The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe. Clin Infect Dis. 2022 Nov 30;75(11):2027-2034. doi: 10.1093/cid/ciac476. Erratum In: Clin Infect Dis. 2023 Apr 17;76(8):1532-1533. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	All-cause mortality at 90 days after platform entry	The primary endpoint for all cells and domains will be all-cause mortality at 90 days after platform entry.; The primary endpoint will be 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.	From randomisation (day 1) until day 90
Secondary	All-cause mortality at 14, 28 and 42 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.	From randomisation (day 1) until day 14, 28, and 42
Secondary	Duration of survival censored 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.	From randomisation (day 1) until day 90
Secondary	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.	From randomisation (day 1) until day 90
Secondary	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.	From randomisation (day 1) until day 90
Secondary	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'	From randomisation (day 1) until day 90
Secondary	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.	From randomisation (day 1) until day 90
Secondary	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.	From randomisation (day 1) until day 90
Secondary	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.	From randomisation (day 1) until day 90
Secondary	Number of participants with Serious adverse reactions (SARs) in the 90 days following platform entry	SARs defined only as events that are attributable to one or more study interventions	From randomisation (day 1) until day 90
Secondary	Health economic costs as detailed in the cost utility analysis appendix.	Including hospital length of stay, readmissions, and patient employment status.	From randomisation (day 1) until day 90
Secondary	Proportion of participants who have returned to their usual level of function at day 90.	Determined by whether the modified functional bloodstream infection score (FBIS) remained the same or improved between baseline and 90 days after platform entry.	From randomisation (day 1) until day 90
Secondary	Desirability of outcome ranking 1 (modified Antibiotic Resistance Leadership Group version)	unable to insert modified ARLG table	From randomisation (day 1) until day 90
Secondary	Desirability of outcome ranking 2 (SNAP version)	unable to insert SNAP DOOR table	From randomisation (day 1) until day 90