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Trial registered on ANZCTR


Registration number
ACTRN12617001416381
Ethics application status
Approved
Date submitted
19/09/2017
Date registered
6/10/2017
Date last updated
16/04/2019
Date data sharing statement initially provided
16/04/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
CASSETTE - Clindamycin Adjunctive therapy for Severe Staphylococcus aurEus Treatment Evaluation – An investigator-initiated, multi-centre, parallel group, open labelled pilot randomised controlled trial
Scientific title
CASSETTE – Clindamycin Adjunctive therapy for Severe Staphylococcus aureus Treatment Evaluation. A multi-centre, pilot RCT to determine if 7 days of clindamycin in combination with standard therapy will lead to a faster resolution of systemic inflammation than standard therapy alone in adults and children with severe S. aureus infection
Secondary ID [1] 293056 0
None
Universal Trial Number (UTN)
Trial acronym
CASSETTE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Severe methicillin-susceptible staphylococcus aureus (MSSA) 304805 0
Methicillin-Resistant Staphylococcus Aureus (MRSA) 312404 0
Condition category
Condition code
Infection 304102 304102 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm1: Interventional Group (Combination therapy group) - will receive standard therapy as per control group in Arm 2. In addition, they will also receive open label clindamycin (10mg/kg/dose up to 600mg 4 times per day intravenously in both adult and children) for 7 days (day 1 being the day of randomisation – hence the actual duration of clindamycin use will range from 6 to 7 days, depending on the time of day that the patient is randomized). The intravenous route for clindamycin is recommended but not mandated for the entire duration of therapy (7days). If switch to oral therapy is thought to be necessary and appropriate by the site PI, transition to oral clindamycin 450mg 3 times per day for adults or 10mg/kg/dose orally 3 times per day (max 450mg) for children is recommended. Each dose of medication will be recorded in the case report form and analysised for adherence to at least 75%of the dosage over the 7 days. This will form part of the study analysis.
Intervention code [1] 299158 0
Treatment: Drugs
Comparator / control treatment
Arm 2: Control Group - will receive “standard therapy”, also called “backbone therapy”.

For patients with methicillin-susceptible staphylococcus Aureus (MSSA) this will consist of intravenous flucloxacillin 50mg/kg/dose up to 2g q4-6h given intermittently or given via 24-hour infusion; If history of penicillin reaction other than severe type 1 hypersensitivity or other severe delayed reactions (e.g. Stevens-Johnson syndrome) or clinician preference Flucloxacillin can be substituted with IV cefazolin 50mg/kg/dose up to 2g q6-8h. The dose of backbone therapy will be adjusted for renal function as per recommendations in TG15 and antimicrobial dosing in renal impairment guidelines of the Children’s Hospital at Westmead.

For patients with methicillin-resistant staphylococcus Aureus (MRSA) intravenous 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 Intravenous daptomycin 6-10 mg/kg per day, adjusted for renal function.

Duration of standard therapy is clinician-determined but should be in line with recommendations in the current version of Therapeutic Guidelines Antibiotic in adults and with expert consensus in children. The choice between vancomycin and daptomycin in MRSA infection, AND flucloxacillin and cefazolin in MSSA infection is clinician determined and may be based on local practice or MIC of S. aureus isolate.

Control group
Active

Outcomes
Primary outcome [1] 303430 0
Number of days alive and free of systemic inflammatory response syndrome (SIRS) within the first 14 days post randomisation.
SIRS criteria:
1. Abnormal temperature (less than 36 or greater than 38 degrees centigrade)
2. Tachypnoea or mechanical ventilation (RR greater than 20 per minute in an adult, age dependent in children)
3. Tachycardia (HR greater than 90 beats per minute in an adult, age dependent in children)
4. Abnormal leucocyte count (using last observation carried forward from any full blood count)
Age-appropriate cut-offs will be used for those aged less than 16 years
Timepoint [1] 303430 0
Within the first 14 days post randomisation
Primary outcome [2] 303490 0
Feasibility
Timepoint [2] 303490 0
Feasibility defined as the ability to recruit the target sample size within 2 years.
Secondary outcome [1] 338902 0
All-cause mortality
Timepoint [1] 338902 0
Post randomisation (Day 1) at 14, 42 and 90 days.
Secondary outcome [2] 338903 0
Time to resolution of SIRS (number of days until the patient meets less than 2 simultaneous SIRS criteria on a calendar day)
SIRS criteria:
1. Abnormal temperature (less than 36 or greater than 38 degrees centigrade)
2. Tachypnoea or mechanical ventilation (RR greater than 20 per minute in an adult, age dependent in children)
3. Tachycardia (HR greater than 90 beats per minute in an adult, age dependent in children)
4. Abnormal leucocyte count (using last observation carried forward from any full blood count)
Age-appropriate cut-offs will be used for those aged less than 16 years
Timepoint [2] 338903 0
Post randomisation (day 1) until 90 days.
Secondary outcome [3] 338904 0
Proportion with microbiological relapse (positive blood culture for MSSA or MRSA at least 72 hours after a preceding negative culture)
Timepoint [3] 338904 0
Post randomisation (day 1) until 90 days.
Secondary outcome [4] 338905 0
Proportion with microbiological treatment failure (positive sterile site culture for MSSA or MRSA at least 14 days after randomisation).
Timepoint [4] 338905 0
At least 14 days post randomisation (day 1) until 90 days.
Secondary outcome [5] 338907 0
Number of surgical procedures needed to achieve source control
Timepoint [5] 338907 0
Post randomisation (day 1) until 90 days
Secondary outcome [6] 338910 0
Duration of intravenous antibiotic treatment
Timepoint [6] 338910 0
Post randomisation (day 1) until 90 days
Secondary outcome [7] 338913 0
Clostridium difficile-associated diarrhoea (3 or more loose stools per day along with a positive laboratory test for Clostridium difficile toxin)
Timepoint [7] 338913 0
Post randomisation (day 1) until 90 days
Secondary outcome [8] 338915 0
All cause diarrhoea (3 or more loose stools per day)
Timepoint [8] 338915 0
Post randomisation (day 1) until 90 days
Secondary outcome [9] 338917 0
Slope of C-reactive protein (CRP) curve days 1-14 – i.e. rate of change of CRP over time
Timepoint [9] 338917 0
Post randomisation (day 1) until 14 days

Eligibility
Key inclusion criteria
1. Age – both children and adults will be eligible. Infants must have a corrected age of greater than or equal to 28 days.
2. S. aureus cultured from at least one clinically relevant specimen (Including an isolation in a polymicrobial culture when the other isolates are determined by the PI to be non-significant)
3. Able to be randomised within 72 hours of index culture
4. Likely to remain as inpatient for at least 7 days following randomisation (or is accessible for follow up by the site Principal Investigator. eg Hospital in the home (HITH)
5. Index culture drawn no later than 48 hours after hospital admission
6. Severe disease – at least one of
6.1 Septic shock (including Staphylococcal toxic shock syndrome)
6.2 Necrotising lung/pleural space infection
6.3 Complicated skin/soft tissue/osteoarticular infection which is multifocal and non-contiguous [e.g. pyomyositis, non-contiguous multifocal pyogenic skin infection (abscess/carbuncle)]
Minimum age
28 Days
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Previous severe allergic reaction to both flucloxacillin and cefazolin (for MSSA), or to both vancomycin and daptomycin (for MRSA), or to lincosamides
2. Previous participation in the trial
3. Known pregnancy
4. Currently receiving a lincosamide or other potentially anti-toxin antibiotic which cannot be ceased or substituted
5. Participant’s primary clinician unwilling to enrol patient
6. Moribund (expected to die in next 24 hours with or without treatment)
7. Treatment limitations which preclude the use of antibiotics
8. Significant immunosuppression (Prednisolone >0.5mg per kg per day for greater than or equal to 14 days in the last 30 days, other immunosuppressive medication, known human immunodeficiency virus (HIV) with CD4 count<200 cells/microlitre, congenital immunodeficiency)
9. Necrotising fasciitis
10. Current clostridium difficile associated diarrhoea or severe diarrhoea from any cause

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be stratified by age (child versus adult) and be 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.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
60 patients, at least 20 of whom are aged less than 16 years. As this is a pilot study, the sample size is based on the number achievable in the time frame, and the number needed to determine feasibility and to refine assumptions and study design.

Analysis of the primary outcome will be by modified intention to treat (all participants with data available for the primary endpoint will be analysed according to the treatment allocation, regardless of what treatment they received). The primary outcome measure will be compared using a Mann-Whitney U or Student’s t-test as appropriate. A per protocol analysis will also be performed. The per-protocol population is defined as 1) for the clindamycin group: received at least 75% of clindamycin doses; 2) for the standard treatment group: received less than equal to 1 defined daily dose of clindamycin post randomisation; 3) has available data to determine primary endpoint. We also plan pre-specified subgroup analyses for the following groups: i) Main treatment was flucloxacillin vs. cefazolin ii) Those who received greater than 24 hours of lincosamides or other anti-toxin antibiotics in the 7 days prior to randomisation compared with those who did not. iii) Children (less than 16 years) versus adults (greater then or equal to 16 years).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,NT,QLD,WA,VIC
Recruitment hospital [1] 9062 0
Royal Perth Hospital - Perth
Recruitment hospital [2] 9064 0
Royal Darwin Hospital - Tiwi
Recruitment hospital [3] 9065 0
The Townsville Hospital - Douglas
Recruitment hospital [4] 9066 0
John Hunter Hospital - New Lambton
Recruitment hospital [5] 9067 0
John Hunter Children's Hospital - New Lambton
Recruitment hospital [6] 9068 0
Westmead Hospital - Westmead
Recruitment hospital [7] 9073 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [8] 9074 0
Blacktown Hospital - Blacktown
Recruitment hospital [9] 9075 0
Sydney Children's Hospital - Randwick
Recruitment hospital [10] 9076 0
Royal Melbourne Hospital - Royal Park campus - Parkville
Recruitment hospital [11] 11426 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 17556 0
6000 - Perth
Recruitment postcode(s) [2] 17558 0
0810 - Tiwi
Recruitment postcode(s) [3] 17559 0
4814 - Douglas
Recruitment postcode(s) [4] 17560 0
2305 - New Lambton
Recruitment postcode(s) [5] 17561 0
2145 - Westmead
Recruitment postcode(s) [6] 17567 0
2148 - Blacktown
Recruitment postcode(s) [7] 17568 0
2031 - Randwick
Recruitment postcode(s) [8] 17569 0
3052 - Parkville
Recruitment postcode(s) [9] 23340 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 297554 0
Other Collaborative groups
Name [1] 297554 0
Menzies School of Health Research - Improving Health Outcomes in the Tropical North (HOT NORTH): Pilot Project Grant
Address [1] 297554 0
Menzies School of Health Research
PO Box 41096
Casuarina
NT 0811
Country [1] 297554 0
Australia
Funding source category [2] 297559 0
Other Collaborative groups
Name [2] 297559 0
Telethon Kids Institute - Wesfarmers WA health research seed grant
Address [2] 297559 0
Telethon Kids Institute
100 Roberts Road
Subiaco
WA 6008
Country [2] 297559 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Menzies School of Health Research
Address
PO Box 41096
Casuarina
NT 0811
Country
Australia
Secondary sponsor category [1] 296567 0
None
Name [1] 296567 0
Address [1] 296567 0
Country [1] 296567 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298650 0
Hunter New England Research Ethics Committee (EC00403)
Ethics committee address [1] 298650 0
Hunter New England Local Health District
Locked Bag 1
New Lambton NSW 2305
Ethics committee country [1] 298650 0
Australia
Date submitted for ethics approval [1] 298650 0
31/08/2017
Approval date [1] 298650 0
11/10/2017
Ethics approval number [1] 298650 0
17/09/20/3.02
Ethics committee name [2] 298654 0
Human Research Ethics Committee of Northern Territory Department of Health and Menzies School of Health Research (EC00153)
Ethics committee address [2] 298654 0
John Mathews Building (Bldg 58)
Royal Darwin Hospital Campus,
Rocklands Drive,
Casuarina
NT 0810
Ethics committee country [2] 298654 0
Australia
Date submitted for ethics approval [2] 298654 0
30/09/2017
Approval date [2] 298654 0
06/10/2017
Ethics approval number [2] 298654 0
2017-2942

Summary
Brief summary
The primary objective of this pilot study is to determine if 7 days of clindamycin in combination with standard therapy will lead to a faster resolution of systemic inflammation than standard therapy alone in adults and children with severe methicillin-susceptible S. aureus (MSSA) infection. We hypothesise that the addition of lincosamides (clindamycin) to standard therapy will lead to more rapid resolution of local and systemic inflammation due to blockade of exotoxin production by Staphylococcus aureus(SA). The results of this pilot study will be used to determine the feasibility and refine study design of a definitive randomised controlled trial assessing the effects of adjunctive lincosamide on patient-centred outcomes in children and adults with severe MSSA infection.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77770 0
A/Prof Joshua Davis
Address 77770 0
Menzies School of Health Research
PO Box 41096,
Casuarina
NT 0811,
Country 77770 0
Australia
Phone 77770 0
+61889468600
Fax 77770 0
Email 77770 0
joshua.davis@menzies.edu.au
Contact person for public queries
Name 77771 0
A/Prof Joshua Davis
Address 77771 0
Menzies School of Health Research
PO Box 41096,
Casuarina
NT 0811,
Country 77771 0
Australia
Phone 77771 0
+61889468600
Fax 77771 0
Email 77771 0
joshua.davis@menzies.edu.au
Contact person for scientific queries
Name 77772 0
A/Prof Joshua Davis
Address 77772 0
Menzies School of Health Research
PO Box 41096,
Casuarina
NT 0811,
Country 77772 0
Australia
Phone 77772 0
+61889468600
Fax 77772 0
Email 77772 0
joshua.davis@menzies.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is a pilot study to determine feasibility of the clinical trial, the recruitment numbers are too small.
What supporting documents are/will be available?
No other documents available
Summary results
No Results