Staphylococcus Aureus Network Adaptive Platform Trial
试验速览
- 阶段
- 4 期
- 状态
- 招募中
- 入组人数
- 8,000
- 试验地点
- 300
- 主要终点
- All-cause mortality at 90 days after platform entry
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- None
盲法说明
This is an open-label study
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •PLATFORM Inclusion Criteria:
- •Patients must fulfil all of the following criteria to be eligible to enter the SNAP trial:
- •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)
排除标准
- •Potentially eligible participants meeting any of the following criteria at the time of eligibility assessment for platform entry will be excluded from the randomised platform (but may still participate in the registry):
- •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
- •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:
- •All participants that met the PLATFORM eligible are eligible to be included in this domain unless they meet any of the following exclusions listed.
- •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
- •Currently receiving clindamycin (lincomycin) or linezolid which cannot be ceased or substituted
- •Necrotising fasciitis
- •Current C. difficile associated diarrhoea (any severity)
- •Current severe diarrhoea from any cause (defined as Grade 3 or higher)
- •Known CDAD (C.Difficile Associated Diarrhoea) in the past 3 months, or CDAD relapse in the past 12 months
- •At the time of domain eligibility assessment, more than 4 hours has elapsed since platform entry
- •Treating clinician deems enrolment in this domain is not in the best interest of the patient
- •PSSA, MSSA TREATMENT DOMAIN (backbone)
- •Inclusion Criteria:
- •For PSSA silo: Index blood culture isolate is penicillin-susceptible as per the Microbiology Appendix. In short, this will require phenotypic disc testing with EUCAST (a P1 disc diffusion with zone >=26mm OR a P1 disc diffusion with zone >=26mm and the zone edge is NOT sharp) OR CLSI (a P10 disc diffusion) defined criteria.
- •For MSSA silo: Index blood culture isolate is methicillin-susceptible as per the Microbiology Appendix.
- •Note that where trial sites are not testing for penicillin-susceptibility, patients with MSSA/PRSA can be included in the MSSA silo, but those with MSSA/PSSA (but not confirmed with a P-disc) will be excluded from the backbone domain. The rationale for this is that patients with MSSA but not tested with a P-disc may be truly PSSA (with no blaZ). If the cefazolin inoculum effect (CIE) is a clinically relevant entity, then including patients with an organism without blaZ (and hence cannot have a CIE phenotype), will bias towards non-inferiority of cefazolin compared to (flu)cloxacillin.
- •For PSSA, the requirement for laboratories to use an accredited phenotypic test for a penicillin-susceptible phenotype, is to ensure clinical safety according to internationally accepted guidelines. The automated antimicrobial susceptibility testing, and other phenotypic tests, have poor sensitivity for detection of blaZ compared to a gold standard of blaZ PCR. Therefore, patients could be placed at risk of treatment with benzylpenicillin when the infecting isolate is actually blaZ positive, unless these guidelines are followed.
- •Exclusion Criteria (PSSA & MSSA):
- •>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)
- •History of type I hypersensitivity reaction (i.e. anaphylaxis or angioedema) to any penicillin or cephalosporin
- •History of severe delayed reaction (e.g. allergic interstitial nephritis, cutaneous vasculitis, Stevens-Johnson, DRESS, etc.) to any penicillin or cephalosporin
- •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.)
- •Treating team deems enrolment in this domain is not in the best interest of the patient
- •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.)
- •Polymicrobial bacteraemia (defined as more than one organism [at species level] in blood cultures, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician) reported between collection of the index blood culture and backbone domain eligibility assessment
- •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 of the DSA, which specifies allowed antibiotics with limited absorption from the gastrointestinal tract or negligible antimicrobial activity against S. aureus)
- •MRSA TREATMENT DOMAIN (backbone)
- •Inclusion Criteria:
- •1. MRSA confirmed microbiologically
- •Exclusion Criteria:
- •Time to allocation reveal is >72 hours from time of index blood culture collection
- •Severe allergy to any beta-lactam (including cefazolin) Immediate severe allergy: Anaphylaxis/angioedema 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.
- •Non-severe rash to cefazolin 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.)
- •3. Severe allergy or non-severe rash to both vancomycin AND daptomycin 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
- •Polymicrobial bacteraemia (defined as more than one organism [at species level] in blood cultures, excluding those organisms judged to be contaminants by either the microbiology laboratory or treating clinician) reported between collection of the index blood culture and backbone domain eligibility assessment.
- •7. 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 of the DSA, which specifies allowed antibiotics with limited absorption from the gastrointestinal tract or negligible antimicrobial activity against S. aureus)
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研究组 & 干预措施
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.
干预措施: Penicillin (Drug)
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.
干预措施: Vancomycin (Drug)
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.
干预措施: Cefazolin (Drug)
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.
干预措施: Clindamycin (Drug)
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.
干预措施: Whole body FDG PET/CT Imaging (Radiation)
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.
干预措施: Effectiveness of early switch to oral antibiotics (Other)
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.
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.
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.
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.
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.
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.
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.
干预措施: Cefazolin (Drug)
结局指标
主要结局
All-cause mortality at 90 days after platform entry
时间窗: From randomisation (day 1) until day 90
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.
次要结局
- Core1: All-cause mortality at 14, 28 and 42 days after platform entry(From randomisation (day 1) until day 14, 28, and 42)
- Core2: Duration of survival censored at 90 days after platform entry(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).(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)(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(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).(From day 14 until day 90)
- Core7: Diagnosis of new foci between 14 and 90 days after platform entry.(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.(From randomisation (day 1) until day 90)
- Core9: Serious adverse reactions (SARs) in the 90 days following platform entry(From randomisation (day 1) until day 90)
- Core10: Health economic costs as detailed in the health ecnomics appendix.(From randomisation (day 1) until day 90)
- Core11: Proportion of participants who have returned to their usual level of function at day 90.(From randomisation (day 1) until day 90)
- Core12: Desirability of outcome ranking 1 (DOOR1; modified Antibiotic Resistance Leadership Group version)(From randomisation (day 1) until day 90)
- Core13: Desirability of outcome ranking 2 (DOOR2; SNAP version)(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.(From randomisation (day 1) until day 90)
- Core15: Days alive and free of antibiotics in the 90 days following platform entry.(From randomisation (day 1) until day 90)