Study setting
The CASSETTE study is an investigator-initiated, open label, parallel group, superiority, multicentre, RCT. This study will be conducted across 12 hospitals in Australia (listed in the additional file). Sites are selected based on 1) prevalence of S. aureus infection (an estimate of at least 10 potentially eligible cases per year for adults and five for children); 2) availability of a committed site principal investigator (PI); and 3) A second person available at each site to assist the PI: either a research nurse, registrar or physician colleague.
Inclusion criteria
- Age – both children and adults will be eligible. Infants must have a corrected age of ≥28 days.
- S. aureus (MSSA OR MRSA) identified in at least one clinically-relevant specimen (Including an isolation in a polymicrobial culture when the other isolates are thought to be non-significant).
A “clinically relevant specimen” refers to any specimen where the site PI judges the isolate to be contributing to the patient’s clinical syndrome. This does not have to be a sterile site. These may include blood, fluids from other normally sterile sites (such as joint fluid or cerebrospinal fluid), pus, tissue, or bone obtained surgically. The site PI may additionally make a clinical judgement on whether other specimens from non-sterile sample types yielding S. aureus, such as sputum and superficial swabs, are considered clinically relevant.
- Ability to be randomised within 72 hours of the collection of the index culture.
The index culture is the first clinically relevant specimen collected both after the participant has arrived at a hospital AND after the onset of systemic symptoms. If more than one specimen is collected within the same four-hour period, the most clinically significant specimen will count as the index specimen (sterile site isolates are prioritised over others).
- Probability of remaining as an inpatient of the study site hospital for at least 7 days following randomisation (or accessible for follow up by the site PI. e.g. hospital in the home)
- Index culture drawn no later than 48 hours after hospital admission
- Severe disease: Evidence of ≥ 2 systemic inflammatory response syndrome (SIRS) criteria within 24 hours prior to randomisation AND at least one of these three conditions:
6.1 Septic shock (including Staphylococcal toxic shock syndrome)
In adults septic shock is defined as:
Mean Arterial Pressure <70mmHg OR Systolic blood pressure <90mmHg despite at least 3 litres of fluid administration OR
The need for intravenous vasopressors to maintain organ perfusion (i.e. any receipt of adrenaline, noradrenaline, dopamine, dobutamine, vasopressin, or terlipressin)
In children septic shock is defined as sepsis with cardiovascular dysfunction. Sepsis is SIRS in setting of suspected or proven infection. Cardiovascular dysfunction is defined by international paediatric sepsis consensus conference (2005) as: Despite administration of isotonic intravenous fluid bolus ≥40 mL/kg in 1 hour
Decrease in blood pressure (BP) (hypotension) <5th percentile for age or systolic BP <2 SD below normal for age (Table 1) OR
Need for vasoactive drug to maintain BP in normal range (dopamine >5 ug/kg/min or dobutamine, epinephrine, or norepinephrine at any dose) OR
Two of the following:
- Unexplained metabolic acidosis: base deficit >5.0 mEq/L
- Increased arterial lactate >2 times upper limit of normal
- Oliguria: urine output <0.5 mL/kg/hr
- Prolonged capillary refill: >5 secs
- Core to peripheral temperature gap >3°C
6.2 Necrotising lung/pleural space infection
Either:
An exudative pleural fluid aspirate AND has gram positive cocci in clusters on Gram stain (in the presence of MSSA or MRSA from another clinically relevant specimen) OR has grown S. aureus from the pleural fluid OR
Pneumonia which is
Multifocal (within the lung) AND
- aureus has been grown from any of sputum, endotracheal aspirate, bronchial lavage, blood or pleural fluid
The diagnosis of necrotising pneumonia may be aided by computerized tomography (CT) scan, if available.
6.3 Complicated skin/soft tissue/osteoarticular infection which is multifocal and non-contiguous
This includes pyomyositis, septic arthritis, osteomyelitis, skin or soft tissue abscess or carbuncle.
Non-contiguous multifocal means it is at more than one anatomical site, which is likely to be due to systemic spread rather than direct extension. For example, osteomyelitis of the distal tibia with septic arthritis of the ankle joint does not qualify, as it is contiguous. Lumbar vertebral osteomyelitis with direct extension into the psoas muscle does not qualify. Humeral osteomyelitis with psoas abscess does qualify.
Exclusion criteria
Previous severe allergic reaction to both flucloxacillin AND cefazolin (for MSSA), or to both vancomycin AND daptomycin (for MRSA), or to lincosamides
- Previous participation in the trial
- Known pregnancy
- Currently receiving a lincosamide or other potentially anti-toxin antibiotic which cannot be ceased or substituted (listed in the section “antibiotics which act as PSIs” under background)
- Participant’s primary clinician unwilling to enrol patient
- Moribund (expected to die in next 24 hours with or without treatment)
- Treatment limitations which preclude the use of antibiotics
- Significant immunosuppression (Prednisolone >0.5mg/kg/day for ≥ 14 days in the last 30 days, other immunosuppressive medication, known HIV with CD4 count<200, congenital immunodeficiency)
- Necrotising fasciitis
- C. difficile associated diarrhoea OR severe diarrhoea (>6 stools per day (or clinician determined severe diarrhoea in children) from any cause.
Interventions
Control group
The control group will receive “standard therapy”, also called “backbone therapy”. This will consist of IV flucloxacillin 50mg/kg/dose up to 2g q4-6h given intermittently or via 24-hour infusion for MSSA infections. Flucloxacillin can be substituted with IV cefazolin 50mg/kg/dose up to 2g q6-8h if there is a history of minor allergic reaction to penicillin, as defined as rash or unclear allergic reaction, but not anaphylaxis or angioedema, or at the site PI’s discretion. The standard therapy for MRSA infection will consist of IV vancomycin with a loading dose of 25mg/kg in adults (clinician discretion regarding loading dose in children <18 years) followed by maintenance dose of 15-20mg/kg q12h (for adults) or 15mg/kg/dose q6h (for children) with subsequent adjustment to maintain trough levels at 15-20 mg/dL which may require an infusion at clinician discretion OR, IV daptomycin 6-10 mg/kg per day. Paediatric daptomycin dosing guidance [42] for 1 – 6 years old: 12mg/kg/dose Q24h; 7 – 11 years: 9mg/kg/dose Q24H; and 12 – 17 years: 7mg/kg/dose Q24H. The dose of backbone therapy will be adjusted for renal function (additional file, tables 1-5).
Duration of standard therapy is clinician-determined but should be in line with recommendations in the current version of Therapeutic Guidelines (TG) Antibiotic[14] in adults and with expert consensus in children. The choice between vancomycin and daptomycin, and flucloxacillin and cefazolin is clinician determined, and may be based on local practice or minimum inhibitory concentration (MIC) of MRSA isolate against vancomycin.
The usual recommended duration of a standard treatment of S. aureus sepsis in adults is 14-42 days. In children early switch (after 7-14 days of IV therapy) to oral therapy is practiced commonly and is permitted in this trial.
Combination therapy group
All participants assigned to the combination group will receive standard therapy as above. In addition, they will also receive open label clindamycin (10mg/kg/dose up to 600mg QID IV for both adult and children) for 7 days from randomisation (day 1 being the day of randomisation). The intravenous route for clindamycin is recommended but not mandated for the entire duration of therapy (7 days). If switch to oral therapy is thought to be necessary and appropriate by the site PI, transition to oral clindamycin 450mg TDS for adults or 10mg/kg/dose PO TDS (max 450mg) for children is recommended.
Criteria for discontinuing or modifying allocated interventions
- Adjustment for renal impairment
Dosage adjustment for the standard therapy medication is as per the recommendations in TG [14] and antimicrobial dosing in renal impairment guidelines of the Children’s Hospital [43] at Westmead, Sydney, Australia (additional file, tables 1-5; also includes vancomycin therapeutic drug monitoring). Continuous infusion of the backbone antibiotics (flucloxacillin/cefazolin/vancomycin) during inpatient admission is not in routine practice in Australia; however, such a use will not constitute a protocol violation. Clindamycin (IV or PO) does not need dose modification in renal impairment.
- Change of primary standard therapy after randomisation
The change of primary standard therapy between flucloxacillin and cefazolin (for MSSA) or between vancomycin and daptomycin (for MRSA) is permitted at the discretion of treating clinicians, or if issues with supply or stock of these antimicrobials. Any unnecessary changes will be discouraged. Clinicians may change the backbone therapy if the patient develop an adverse drug reaction, such as rash with flucloxacillin or vancomycin, or raised creatinine kinase with daptomycin, or if the vancomycin MIC of MRSA isolate is found to be ≥ 2 micrograms/mL, or in cases of persistent bacteraemia whilst receiving vancomycin.
The change within 7 days of randomisation will still be counted as β-lactam therapy and will not violate per-protocol analysis. However, it will affect the subgroup analysis (flucloxacillin vs. cefazolin; vancomycin vs. daptomycin). Participants who receive the majority of one or the other drugs in the 7 days will be analysed in the respective groups.
- Clindamycin use after day 7 post randomisation
The use of clindamycin after the completion of 7 days of randomisation will be discouraged for up to 90 days post-randomisation. The treating team will be advised to use an alternative to clindamycin if such a treatment is necessary.
Strategies to improve adherence to the protocol, and any procedures for monitoring adherence
- Training of site investigators
Each site will have a PI who will be trained in the study protocol, standard operating procedures and their reporting requirements. The project manager will have regular contact (email or phone) with all enrolling site PIs.
- Documentation in patient’s medical records
On Day 1 of randomisation, the patient’s enrolment in the CASSETTE trial will be documented in the medical record, and the treating team will be made aware of the recruitment. Study information will be placed in the patient’s folder. The PI or their associates (research nurse or registrar) will check drug charts (paper and/or electronic) daily (except weekends and public holidays) during the period of the intervention. Charts will be reviewed before weekends and public holidays to ensure appropriate doses are prescribed for the period, and to check when clindamycin requires ceasing (i.e. will complete 7 days). Follow up will be done on the first working day.
- Monitoring
As this pilot study is determining feasibility as well as refining assumptions and study design in preparation for a definitive RCT we intend to utilise off-site risk-based monitoring to be completed by the central coordinating office. The web-based database will have logic checks included in the design to avoid data entry errors. The central coordinator will also monitor data entry at each site for completeness and data checks will be regularly conducted to ensure protocol compliance.
Relevant concomitant care and interventions that are permitted or prohibited during the trial
Apart from the use of clindamycin, the patient’s management will be at the discretion of the caring team in consultation with the site PI. Procedures undertaken and directly relevant to the study will be recorded, e.g. debridement of infected necrotic tissue, washout of an infected joint, or the use of intravenous immunoglobulin. Actions that clearly violate the study protocol, such as early cessation of clindamycin or use of an additional PSI antibiotic will be discouraged. Site investigators will actively recommend therapeutic drug monitoring or dose adjustment for renal failure per protocol as necessary.
Outcomes
Primary Outcome
The primary outcome is the number of days alive and free of SIRS within the first 14 days post randomisation. “Free of SIRS” is defined as meeting <2 SIRS (i.e. 1 or none) criteria simultaneously. The day of randomisation is counted as Day 1 (not Day 0)
SIRS criteria in adults [44]:
Abnormal body temperature (<36 or 38 0C)
Tachypnoea or mechanical ventilation (RR>20 per minute in an adult, age dependent in children)
Tachycardia (HR >90 per minute in an adult, age dependent in children)
Abnormal leucocyte count, >12x10^9/L or <4x10^9/L (using last observation carried forward from any FBC)
SIRS criteria in children (Table 1):
SIRS is defined as the presence of at least two of the following four criteria, one of which must be abnormal temperature or leucocyte count. The following are modified from the NSW clinical excellence commission sepsis sills guidelines [45] and the international paediatric sepsis consensus conference [46] held in 2002. Heart rate, respiratory rate and temperature will be recorded at least daily for the first 7 days, and after this time will be recorded at least daily as long as the patient remains in hospital or on hospital in the home (HITH).
Abnormal body temperature of <36 or >38 0C
Tachycardia or bradycardia (mean heart rate) that is otherwise unexplained and persists over at least 30 minutes.
Tachypnoea (see Table 1) or mechanical ventilation not related to underlying neuromuscular disease or the receipt of general anaesthesia
Abnormal leucocyte count, or >10% circulating immature neutrophils (“band forms”).
SIRS is considered present if ≥2 criteria were met at the same time on any given calendar day. For example: an adult had a heart rate of 95 (per minute) at 9am but no other criteria at this time. She then had a heart rate <90 for the rest of the day. At 3pm she had a respiratory rate of 22 (per minute) for an hour which also then normalised. Although she had 2 SIRS criteria on the same calendar day, they were not simultaneous and hence she was deemed to be free of SIRS on that day.
If the patient has been discharged from both hospital and HITH before day 14, then SIRS will be assumed to have resolved at the time of discharge if it had not already done so.
White blood counts will be measured on days 1, 3, 5, 7 and 14. There is a +/- 1-day window if the WBC is not collected on the stipulated days with preference given to the preceding day’s results. If more than one WBC is measured on the same day, then the most abnormal results will be recorded.
Secondary outcome measures
- All-cause mortality at 14, 42 and 90 days
- Time to resolution of SIRS (number of days until the patient meets <2 simultaneous SIRS criteria on a calendar day)
- Proportion with microbiological relapse (positive blood culture for MSSA or MRSA at least 72 hours after a preceding negative culture)
- Proportion with microbiological treatment failure (positive sterile site culture for MSSA or MRSA at least 14 days after randomisation).
- Number of surgical procedures performed for the purposes of S. aureus infection source control.
- Duration of intravenous antibiotic treatment
- 7. C. difficile-associated diarrhoea (3 or more loose stools per day along with a positive laboratory test for difficile toxin).
- All cause diarrhoea (3 or more loose stools per day)
- Slope of CRP curve days 1-14 – i.e. rate of change of CRP over time
Participant timeline: Table 2
Eligibility screening
We will identify potential patients as those who meet the two main inclusion criteria of 1) S. aureus (MSSA and MRSA) identified in a clinically relevant specimen; and 2) clinically defined severe disease (septic shock, necrotising lung / pleural space infection, complicated multifocal skin or soft tissue or osteoarticular infection). All such identified patients will be screened and assessed for potential enrolment and randomisation. The identification of such participants will typically be through notification by microbiology staff (e.g., when blood cultures are called through and clinical information obtained from the treating clinician) or other medical staff (e.g., infectious diseases, paediatric, ICU). Identification of S. aureus as MSSA or MRSA can be by any acceptable methods, such as nucleic acid amplification of fem/nuc, mec genes, or phenotypic susceptibility methods.
Informed consent
The PI or their delegate will approach an eligible patient or their next of kin (NOK) for a discussion on participation in the trial. Written information will also be provided. An interpreter will be used if necessary. In the event that a participant who was not competent when initially recruited into the study becomes competent to make their own decisions, the participant will have the study explained to them and an opportunity to consent to remaining in the study or to withdraw. The site investigator or delegate will regularly check to see if the participant becomes competent.
The participant or their NOK, as well as the PI will sign and date the consent form. Where the participant is illiterate, they can sign the consent form with their mark rather than their signature, as long as a witness is able to sign also. If an interpreter is used, their name, date and signature will also be recorded. A copy will be provided to the patient and placed into the medical record. Informed consent from a NOK will only be used in jurisdictions where there is legislative approval to do so, and where the site has research governance approval in place.
Paediatric specific consent issues
All participants under the age of 18 years will have consent sought from a parent/guardian. Children and adolescents will have the study explained to them using appropriate language. Where deemed appropriate the adolescent will be asked to co-sign the parent /guardian consent form. If an adolescent does not want to participate in the study this would be considered a refusal and they will be considered ineligible.
If a participant <18 years of age at the time of enrolment into the study is deemed not competent then informed consent from the parent/guardian will be considered sufficient. Should the participant become competent to make their own decision then the study will be explained to them and consent will be sought for continuation of the study and they will be asked to co-sign and date the consent. Should this be refused, the participant will be withdrawn from the study.
For Aboriginal and Torres Strait Islander children informed consent can be given by a parent or care-giver who is recognised under Aboriginal customary law or Aboriginal tradition as having decision making rights over the child’s health care needs and who assumes day to day parental responsibilities.
If consenting parents are under the age of 18 years, consent will be sought from the child’s grandparent with a parent signing as a witness.
Randomisation and blinding
Patients will be randomized using a module in the web-based study database. The randomisation list will be generated and held by an independent statistician. Randomisation will be stratified by age (child versus adult) in a 1:1 ratio, in permuted blocks of variable size. Randomisation will not be stratified by site, as an average site is only likely to randomise 5-10 patients and hence the strata will be too small. We will not stratify by MSSA / MRSA status for similar reasons – the strata will be too small, and the study is designed as a pilot study with the aim of assessing for feasibility.
Blinding is not relevant as this will be an open label trial.
Days 2-90
PI (or delegate) will visit patient, review medical documentations, or contact treating team in person or by phone daily for the first seven days of randomisation to ensure compliance with the protocol and that the recommended tests are ordered. Case report forms (CRF) with details on illness severity scores, clinical progress and blood results will be completed daily. These details can be retrospectively collected up to 72 hours after the intended day, allowing for weekends and public holidays. Standard operating procedures will contain step-by-step details on how to recruit patients and collect data.
Endpoint assessment
A panel blinded to treatment allocation will determine the primary endpoint. This will consist of three clinicians, each with an expertise in infectious diseases, paediatrics or critical care. The critical care clinician will chair to overcome discrepancies in the decision-making between the three decision makers.
The panel will be given an extract of the database which contains all information needed to determine the number of days alive and free of SIRS over the first 14 days but will not be given any information about the use of clindamycin.
If needed, the panel may request further information (e.g. medical record or observation chart extracts with identifying information redacted) for any particular patient.
Discontinuation/Withdrawal of participants from trial treatment
Participants or NOK can voluntarily withdraw from study at any time if they wish to. Investigators may also discontinue a participant from the study if deemed appropriate at any time. Participants do not necessarily need to provide explanations for their withdrawal. If withdrawn by the site investigator, reasons for discontinuation will be recorded in CRFs. Participants will not be withdrawn from the study due to suspected adverse reactions of study treatment, unless the participant or their treating clinicians’ requests for discontinuation. If the participant or NOK withdraws consent to participate in the study and also withdraws consent for collection of future information, no further evaluations will be performed, and no additional data will be collected. The investigators may retain and continue to use any data collected before such withdrawal of consent. All withdrawal/discontinuation will be discussed with the coordinating investigators.
To avoid missing data, and for use in intention to treat analysis all attempts will be made to collect information at day 90 for participants that discharge early, transfer to another facility, discharge against medical advice, abscond or are lost to follow-up
Sample size considerations
60 patients, at least 20 of whom are aged <16 years. As this is a pilot study, the sample size is based on the number achievable, and the number needed to determine feasibility, and to refine assumptions and study design.
Data management
Data collection
All initial data collection can either be in paper format (with subsequent entry to electronic database) or directly entered to the electronic database. For database entry, each variable will have a validation range to minimise entry error. The coordinating centre will check data for consistency and will seek any missing data with help of the PI.
During randomisation, each participant will be given a unique identifier number. This number and the hospital medical record number will be recorded in each CRF. These two numbers will be crosschecked each time a data entry is performed in CRFs to ensure correct documentation. Date, time and name of the person performing data entry for each entry in the CRF will be mandatory. Any changes made in the CRF will be timed, dated, signed and the reasons for changes documented. CRFs will not contain participant identifying details such as address, initials or date of birth, but will contain age at recruitment.
Clinical details will be obtained from medical records (paper and/or electronic), bedside charts, medication charts, pathology results, correspondence notes and telephone contact with patient or their NOK. Clarification will be made with the treating team or the participants’ general practitioners if necessary.
Data entry and storage
Data collected on paper CRFs will be entered onto a purpose-built secure web-based database. This will be done at each site by the PI or delegate. Paper CRFs will be securely stored at each site. Data will be retained for at least 10 years after study completion.
Statistical methods
Data reporting will follow CONSORT guidelines for reporting of RCTs.
Continuous variables will be analysed using Mann Whitney U test or Student’s t-test as appropriate. Proportions will be analysed by Fisher’s exact test or chi-squared tests as appropriate. 95% confidence interval will be reported for absolute difference in proportions. All-cause mortality will be shown with Kaplan-Meier graphs.
The primary analysis of both primary and secondary endpoints will be according to modified intention to treat principles (all participants with data available for the endpoint will be analysed according to the treatment allocation, regardless of what treatment they received).
Secondary per protocol analysis of all endpoints will be conducted. The per protocol population is defined as 1) for the combination group that received at least 75% of clindamycin dose; 2) standard treatment group received 1 defined daily dose of clindamycin in the week preceding randomisation; 3) has data available for at least 90 days of follow up.
There will be no planned interim efficacy analyses.
Pre-specified subgroup analyses
The number of subgroup analyses will be limited due to the small sample size.
Main treatment was flucloxacillin vs. cefazolin (for the MSSA cohort). Recent data suggest better outcomes of SAB with cefazolin versus nafcillin/oxacillin [47], although it is unclear if this is true, and the effect size is likely to be small.
Those who received >24 hours of lincosamides or other anti-toxin antibiotics (as defined in the eligibility criteria) in the 7 days prior to randomisation, compared with those who did not. Recent receipt of lincosamides is likely to dilute the effect of the randomised intervention.
Children versus adults. The distribution of outcomes is likely to be different in children than in adults, although the effect of the intervention should not differ.
MSSA vs. MRSA infection. MRSA isolates may have higher rates of clindamycin-resistance or may involve patients within certain risk groups (e.g. intravenous drug users, haemodialysis patients, or recent hospitalisation).
Data safety and monitoring board
An independent data safety and monitoring board (DSMB) will be established to review the progress of the study and monitor adherence to the protocol, participant recruitment, outcomes, complications, and other issues related to participant safety. They will also monitor the assumptions underlying sample size calculations for the study and alert the investigators if they see substantial departures from the study protocol as the data accumulate.
The DSMB will be composed of experts in infectious diseases (adult representative and paediatric representative), biostatistics and an intensivist. The DSMB members will all be independent of the investigators (none of them will be chief investigators or site PIs).
Safety aspects of the trial
Adverse Events and Adverse Reaction (solicited and unsolicited)
Clindamycin is registered in Australia for therapeutic use. Clindamycin has a good safety profile but has some recognised adverse effects [48]. Antibiotic associated diarrhoea and C. difficile diarrhoea are the most frequently encountered clinical adverse event with clindamycin. Rash, blood dyscrasias and raised liver enzymes could be difficult to attribute to clindamycin, especially since the trial participants will also be receiving β-lactams and have a severe infection. Nonetheless, these and any other potential adverse events in both standard therapy and combination therapy groups will be monitored and recorded in CRFs. Clindamycin can be ceased if patient develops C. difficile diarrhoea, severe (non-C. difficile diarrhoea), or other serious adverse events.
Vancomycin adverse events include phlebitis, nephrotoxicity, rash and red-man syndrome (if infused rapidly). Daptomycin adverse events include headache, rash, infection site reactions, increased creatinine kinase, increased liver enzymes and hypotension. Less common adverse effects of vancomycin include immune-mediated thrombocytopenia and ototoxicity, and that of daptomycin include eosinophilic pneumonia [48].
Adverse events will be graded as follows (Table 6 in additional file) [49]:
Grade 1: Mild symptoms. Causes nil or minimal interference with usual social and functional activities. No intervention indicated.
Grade 2: Moderate symptoms. Interferes with but does not limit usual social and functional activities. Intervention is indicated.
Grade 3: Severe symptoms. Inability to perform usual social and functional activities. Intervention or hospitalisation is needed.
Grade 4: Potentially life-threatening symptoms. Inability to perform basic self-care functions. Intervention is indicated to prevent permanent impairment, persistent disability, or death.
Grade 5: Death related to adverse event.
Serious Adverse Events
Serious adverse events (SAE’s) are an undesirable experience as a result of the intervention that
Results in death
Is life-threatening
Results in hospitalization (initial or prolongation)
Results in disability or permanent damage
Is a medically important event or reaction
All SAE’s that are considered related (possible, probable or definite) to any of the study drugs (backbone and combination therapy) that met one or more the above definitions require reporting on the SAE form. If the SAE is attributable to disease progression then this does not require expedited reporting in this trial, even when death is the outcome. The site PI is required to report any SAE’s that occur at their site to the approving ethics committee in accordance with local guidelines, in addition the site PI must adhere to any local institutional reporting requirements. Safety reporting will be in line with the National Health and Medical Research Council’s (NHMRC) Guidance: Safety monitoring and reporting in clinical trials involving therapeutic goods (2016).
Suspected Unexpected Serious Adverse Reaction (SUSAR)
If the SAE is considered unexpected (not listed in approved product information and not attributable to disease progression) and related (possible, probable or definite) to the investigational drug (clindamycin) it meets the definition of a SUSAR. All SUSAR’s must be entered on the SAE CRF and reported to the coordinating investigators (CI) or delegate within 24hours from the time of the site study team becoming aware of it. If the SUSAR is fatal or life-threatening the PI will report to the TGA within 7 calendar days of becoming aware and any follow-up reports will be submitted within a further eight calendar days, all other SUSARs will be reported to the Therapeutic Goods Administration (TGA) within 15 calendar days of the PI becoming aware.
The site PI is required to report any SUSAR’s that occurs at their site to the approving ethics committee in accordance with local guidelines, in addition the site PI must adhere to any local institutional reporting requirements. Safety reporting will be in line with the NHMRC’s Guidance: Safety monitoring and reporting in clinical trials involving therapeutic goods (2016).
The relation of adverse event to the treatment will be defined as Not related, Unlikely, Possible, Probable and Definite [50].
Ethical considerations
The trial will be conducted in line with the Declaration of Helsinki. Written informed consent will be obtained from all study participants prior to any study procedure. Approval from a lead HREC and site-specific approval will be finalized at each site before the first patient is enrolled at that site. There will be two lead HRECs: One for the NT site (Menzies and NT Department of Health EC00153), and one for the remaining sites as per the National Mutual Acceptance scheme (Hunter New England EC00403).
Dissemination policy
The chief investigators (JSD, SYCT, AB) will have access to the study dataset. The results of this study will be submitted to peer reviewed journals for publication regardless of the results. They will also be presented at national and/or international scientific meetings. Authorship of the main paper will be all PIs, “on behalf of the CASSETTE study group, the ASID CRN and ANZPID”. The CASSETTE Study Group will consist of all CIs, and all site PIs, as well as up to 2 co-investigators per site if relevant.