Staphylococcus Aureus Network Adaptive Platform Trial

Study Overview
=================
Brief 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).

Detailed 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.

Official Title
-----------------
Staphylococcus Aureus Network Adaptive Platform Trial

Conditions
-----------------
Staphylococcus Aureus Bacteremia

Intervention / Treatment
-----------------
* Drug: Cefazolin
* Drug: Penicillin
* Drug: Clindamycin
* Drug: Vancomycin
* Other: Effectiveness of early switch to oral antibiotics


Participation Criteria
=================
Eligibility Criteria
-----------------
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: 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 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 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) Known previous participation in SNAP 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 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: 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) or severe diarrhoea from any cause 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 is penicillin-susceptible 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: 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 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. 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. 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): 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 Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility) 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) 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): 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) Afebrile (<37.8°C) for the past 72 hours (at time of judging eligibility) 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: Adherence to oral agents unlikely (as judged by site PI in consultation with the treating team) Unreliable gastrointestinal absorption (e.g. vomiting, diarrhoea, nil by mouth, anatomical reasons) There are no appropriate oral antibiotics due to contraindications, drug availability, or antibiotic resistance Ongoing IV therapy unsuitable e.g. no IV access Clinician deems not appropriate for early oral switch 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 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): Presence of prosthetic cardiac valve, pacemaker or other intracardiac implant Known presence of intravascular clot (excluding superficial peripheral IV line-related thrombophlebitis), graft or other intravascular prosthetic material Intravascular/intracardiac infections (e.g. endocarditis, mycotic aneurysm) Presence of other intracardiac abnormalities felt to put patient at increased risk of endocarditis (e.g., bicuspid aortic valve)
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: Participants enrolled into the study have the option of deciding whether to be randomised in one or more (if available) treatment domains concurrently, if they meet the eligibility criteria.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Methicillin-resistant staphylococcus aureus (MRSA) - Standard Therapy Arm (backbone therapy)<br>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)<br>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<br>* Cefazolin<br>Drug: Vancomycin<br>* Vancomycin or Daptomycin<br>* Other names: Daptomycin;|
| No Intervention: Methicillin-susceptible staphylococcus aureus (MSSA) - Standard Therapy Arm (backbone therapy)<br>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)<br>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<br>* Cefazolin<br>|
| No Intervention: Penicillin-susceptible staphylococcus aureus (PSSA) - Standard Therapy Arm (backbone therapy)<br>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)<br>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<br>* benzylpenicillin<br>* Other names: Penicillin G;|
| No Intervention: No adjunctive treatment in combination with MRSA or MSSA or PSSA backbone therapy arm<br>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<br>Adjunctive therapy + backbone therapy arm for MRSA or MSSA or PSSA Intravenous clindamycin (or lincomycin) 600mg every 8 hours for 5 days. No dosage adjustment is needed to renal impairment. | Drug: Clindamycin<br>* Clindamycin<br>* Other names: Lincomycin;|
| No Intervention: Continue intravenous antibiotic therapies (backbone +/- adjunctive therapy) - standard of care arm<br>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.<br>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<br>* This involves testing a strategy rather than individual antibiotic agents<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Desirability of outcome ranking 1 (modified Antibiotic Resistance Leadership Group version) | unable to insert modified ARLG table | From randomisation (day 1) until day 90 | 
| Desirability of outcome ranking 2 (SNAP version) | unable to insert SNAP DOOR table | From randomisation (day 1) until day 90 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-susceptible Staphylococcus aureus (MSSA), Penicillin-susceptible Staphylococcus aureus (PSSA), Staphylococcus aureus, S. aureus, Staph Aureus Bacteremia (SAB)