Overview Study details Eligibility Things to know Research Study plan

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Overview Study details Eligibility Things to know Research Study plan

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Staphylococcus Aureus Network Adaptive Platform Trial

PHASE4RECRUITING

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).

Study details:

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. The SNAP Trial infrastructure will also support a number of sub-studies.

A list of all active sub-studies can be found on the SNAP website: https://www. snaptrial. com.

au/substudies.

Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Staphylococcus aureus complex grown from ≥1 blood culture
Admitted to a participating hospital at the time of eligibility assessment (OR if patient has died, they were admitted to this site anytime from the time of blood culture collection until the time of eligibility assessment)

Exclusion criteria

Time of anticipated platform entry is greater than 72 hours post collection of the index blood culture (Where the time of culture collection is not recorded, the time of laboratory registration of the sample will be used as an alternative)
Polymicrobial bacteraemia, defined as more than one organism (at species level) in the index blood cultures OR in any subsequent blood culture reported between the collection of the index blood culture and platform eligibility assessment, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician.
Known previous participation in the randomised SNAP platform
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
Treating team deems enrolment in the study is not in the best interest of the patient
Treating team believes that death is imminent and inevitable
Patient is for end-of-life care and antibiotic treatment is considered not appropriate
Patient <18 years of age and paediatric recruitment not approved at recruiting site
Patient has died since the collection of the index blood culture

Eligibility

Age eligible for study : NA

Healthy volunteers accepted : No

Gender eligible for study: ALL

Things to know

Study dates

Study start:

Primary completion:

Study completion finish:

Study type

TREATMENT

Phase

PHASE4

Study ID

NCT05137119

Intervention or treatment

DRUG: Cefazolin

DRUG: Penicillin

DRUG: Clindamycin

DRUG: Vancomycin

OTHER: Effectiveness of early switch to oral antibiotics

RADIATION: Whole body FDG PET/CT Imaging

Conditions

Staphylococcus Aureus Bacteremia

Condition: Staphylococcus Aureus Bacteremia
DRUG: Cefazolin and other drugs
Garran, Australia Capital Territory, Australia and more
Sponsor: University of Melbourne

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Research sites nearby

Closest Location:

Canberra Hospital

Select from list below to view details:

Canberra Hospital
Garran, Australia Capital Territory, Australia
Blacktown Hospital
Blacktown, New South Wales, Australia
Royal Prince Alfred Hospital
Camperdown, New South Wales, Australia
Concord Repatriation and General Hospital
Concord, New South Wales, Australia

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Who is running the clinical trial?

UoM

University of Melbourne

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/Arm	Intervention/Treatment
NO_INTERVENTION: Methicillin-resistant staphylococcus aureus (MRSA) - Standard Therapy Arm (backbone therapy) Vancomycin or Daptomycin - Standard Therapy Arm Either intravenous vancomycin dosed as per Australian Therapeutic Guidelines: This includes a loading dose of 25 mg/kg (up to 3000mg) if considered appropriate by the treating clinician, initial maintenance dosing at 15-20 mg/kg q12h, with subsequent adjustment to maintain area under the concentration-time curve (AUC) of 400 to 600 mg.hr/L OR trough levels at 10-20 mg/L, and the initial level taken 48-72 hours after the initiation of the first dose. Daptomycin 8-10mg/kg per day intravenously. The choice of vancomycin or daptomycin will be at the clinician's discretion. Dosing will be based on renal function.
EXPERIMENTAL: Methicillin-resistant staphylococcus aureus (MRSA) - Standard + B-Lactam Arm (backbone therapy) Vancomycin or Daptomycin (Standard Therapy) + Beta-Lactam (β-lactam) Arm 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 2g every 8 hours. For patients with renal impairment the intravenous cefazolin administration doses will be adjusted.	Drug: Cefazolin, Drug: Vancomycin
NO_INTERVENTION: Methicillin-susceptible staphylococcus aureus (MSSA) - Standard Therapy Arm (backbone therapy) Flucloxacillin or cloxacillin - Standard Therapy Arm Either intravenous flucloxacillin/cloxacillin 2g every 4 or 6 hours. 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 patients with renal impairment or critical illness the intravenous flucloxacillin administration dose will be adjusted.
EXPERIMENTAL: Methicillin-susceptible staphylococcus aureus (MSSA) - Interventional Arm (backbone therapy) Cefazolin - Interventional Arm Intravenous cefazolin 2g every 6 or 8 hours. 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 patients with renal impairment or critical illness the intravenous cefazolin administration dose will be adjusted.	Drug: Cefazolin
NO_INTERVENTION: Penicillin-susceptible staphylococcus aureus (PSSA) - Standard Therapy Arm (backbone therapy) Flucloxacillin or cloxacillin - Standard Therapy Arm Either intravenous flucloxacillin/cloxacillin 2g every 4 or 6 hours. 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 patients with renal impairment or critical illness the intravenous flucloxacillin administration dose will be adjusted.
EXPERIMENTAL: Penicillin-susceptible staphylococcus aureus (PSSA) - Interventional Arm (backbone therapy) Benzylpenicillin - Interventional Arm Intravenous benzylpenicillin 1.8g (3 million units) every 4 or 6 hours. 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 patients with critical illness the intravenous benzylpenicillin administration doses will be adjusted.	Drug: Penicillin
NO_INTERVENTION: No adjunctive treatment in combination with MRSA or MSSA or PSSA backbone therapy arm No adjunctive therapy + backbone therapy arm for MRSA or MSSA or PSSA Participants with either MRSA or MSSA or PSSA will have no adjunctive therapy in combination with their backbone therapy arm.
EXPERIMENTAL: Adjunctive treatment in combination with MRSA or MSSA or PSSA backbone therapy arm Adjunctive therapy + backbone therapy arm for MRSA or MSSA or PSSA Intravenous clindamycin (or lincomycin) 600mg every 8 hours from platform day 1 to day 5. No dosage adjustment is needed to renal impairment.	Drug: Clindamycin
NO_INTERVENTION: Continue intravenous antibiotic therapies (backbone +/- adjunctive therapy) - standard of care arm Backbone therapy arm for MRSA or MSSA or PSSA +/- adjunctive therapy will continue on intravenous antibiotic treatment for the length of time as per usual standard of care. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised if not eligible then eligibility will be assess again at Day 14(+/- 2 days). If eligibility is not met at day 14 then participant is excluded from this domain.
EXPERIMENTAL: Switch to oral antibiotics at trial day 7 (+/- 2 days) or Day 14 (+/- 2 days) if eligible. 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). Participants eligibility is assessed at Day 7 (+/- 2 days). If eligible will be randomised, if not eligible then eligibility will be assessed again at Day 14 (+/- 2 days). If eligibility is not met at day 14 then participant is excluded from this domain.	Other: Effectiveness of early switch to oral antibiotics
NO_INTERVENTION: No PET/CT scan - standard of care arm Participants will not receive a PET/CT scan, in addition to their allocated treatment interventions. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised. If eligibility is not met then participant is excluded from this domain.
EXPERIMENTAL: PET/CT scan at trial day 7 (+/- 2 days) if eligible Participant will receive a PET/CT scan at Day 5-12, in addition to their allocated treatment interventions. Participants eligibility is assessed at Day 7 (+/- 2 days) if eligible will be randomised. If eligibility is not met then participant is excluded from this domain.	Radiation: Whole body FDG PET/CT Imaging

What is the study measuring?

Primary Outcome

Measure	Description	Time Frame
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 Outcome

Measure	Description	Time Frame
Core1: 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
Core2: 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
Core3: Length of stay of acute index inpatient hospitalisation for those surviving until discharge from acute inpatient facilities (excluding HITH/COPAT/OPAT/rehab).	Acute index hospitalisation is defined as continuous hospital admission to one or more acute inpatient facilities for the index episode. This does not include HITH/OPAT/COPAT and stepdown inpatient rehabilitation/post-acute care. It does include admission to acute care hospitals immediately preceding and following those at the enrolling site.	From randomisation (day 1) until discharge from acute inpatient facilities, truncated at 90 days.
Core4: Length of stay of total index hospitalisation for those surviving until hospital discharge (including HITH/COPAT/OPAT/rehab)	Total index hospitalisation is defined as continuous hospital admission to one or more inpatient facilities for the index episode, including HITH/OPAT/COPAT and stepdown inpatient rehabilitation/post-acute care (if continuous with the initial inpatient admission). It includes admission to acute care hospitals immediately preceding and following those at the enrolling site.	From randomisation (day 1) to discharge from total index hospitalisation, truncated at 90 days
Core5: 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) to discharge from total index hospitalisation, truncated at 90 days
Core6: 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 day 14 until day 90
Core7: 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 day 14 until day 90
Core8: 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
Core9: Serious adverse reactions (SARs) in the 90 days following platform entry	SARs defined only as serious events that are attributable to one or more randomised study interventions	From randomisation (day 1) until day 90
Core10: Health economic costs as detailed in the health ecnomics appendix.	Including hospital length of stay, readmissions, and patient employment status.	From randomisation (day 1) until day 90
Core11: 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 where baseline=best score within the 4 weeks prior to platform entry.	From randomisation (day 1) until day 90
Core12: Desirability of outcome ranking 1 (DOOR1; modified Antibiotic Resistance Leadership Group version)	See Core Protocol; unable to insert DOOR1 table	From randomisation (day 1) until day 90
Core13: Desirability of outcome ranking 2 (DOOR2; SNAP version)	See Core Protocol; unable to insert DOOR2 table	From randomisation (day 1) until day 90
Core14: Total number of antibiotic days (IV and/or oral/enteral) in the 90 days following platform entry.	All antibiotics should be included, not only those intended for treatment of S. aureus bacteraemia. It also includes prophylactic dose antibiotics (e.g., prophylactic dose trimethoprim-sulfamethoxazole). All days on which any antibiotic dose is received should be counted - i.e. we are counting the number of whole or part days on which any antibiotics are received (not the number of defined daily doses of antibiotics). Topical, inhaled or other routes of administration besides IV or oral/enteral should not be counted.	From randomisation (day 1) until day 90
Core15: Days alive and free of antibiotics in the 90 days following platform entry.	All antibiotics should be included, not only those intended for treatment of S. aureus bacteraemia. It also includes prophylactic dose antibiotics (e.g., prophylactic dose trimethoprim-sulfamethoxazole). All days on which any antibiotic dose is received should be counted - i.e. we are counting the number of whole or part days on which any antibiotics are received (not the number of defined daily doses of antibiotics). Topical, inhaled or other routes of administration besides IV or oral/enteral should not be counted.	From randomisation (day 1) until day 90

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References

Clinical Trials Gov: Staphylococcus Aureus Network Adaptive Platform Trial

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