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Trial registered on ANZCTR


Registration number
ACTRN12622000225718
Ethics application status
Approved
Date submitted
29/11/2021
Date registered
8/02/2022
Date last updated
13/04/2022
Date data sharing statement initially provided
8/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot, single-centre, randomised control trial to determine if intensive phase antibiotics alone (intravenous antibiotics for 14 to 42 days) will result in the same clinical outcomes as standard antibiotics (intensive phase antibiotics plus eradication phase antibiotics (90 days of oral antibiotics)) in adults with melioidosis.
Scientific title
Short course antibiotic therapy for melioidosis treatment (SCATMAN) pilot trial
Secondary ID [1] 305915 0
None
Universal Trial Number (UTN)
Trial acronym
SCATMAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Melioidosis 324494 0
Condition category
Condition code
Infection 321977 321977 0 0
Studies of infection and infectious agents
Infection 322516 322516 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All treatment will occur at Cairns Hospital (either within the hospital or through the hospital in the home service) or at a regional hospital in Far North Queensland if a person requires on going non-tertiary level hospital care.

Short course therapy: Intravenous meropenem or ceftazidime, chosen at the discretion of the treating clinician, adjusted for renal function and dosed in accordance with the Australian Therapeutic Guidelines for 14 to 42 days as determined by the treating infectious diseases clinician. The duration of intravenous phase will be determined by the antibiotic duration determining focus and the treating clinician will be encouraged to follow the 2020 Revised Darwin melioidosis guideline. Intravenous meropenem will be dosed at 1-2g three times per day, adjusted for renal function as determined by the treating clinician. Intravenous ceftazidime will be dosed at 2g four times a day, adjusted for renal function as determined by the treating clinician. For the purposes of outpatient parenteral antibiotic therapy, ceftazidime at a dose of 8g daily, adjusted for renal function as determined by the treating clinician, will be administered as a 24-hour intravenous infusion using an elastometric infusion device. To help ensure adherence, the elastometric infusion device will be administered and removed daily by a nurse trained in the use of elastometric devices. No eradication phase therapy will be given.
Intervention code [1] 322313 0
Treatment: Drugs
Comparator / control treatment
All treatment will occur at Cairns Hospital (either within the hospital or through the hospital in the home service) or at a regional hospital in Far North Queensland if a person requires on going non-tertiary level hospital care.

Standard therapy group: Intravenous meropenem or ceftazidime, chosen at the discretion of the treating clinician, adjusted for renal function and dosed in accordance with the Australian Therapeutic Guidelines for 14 to 42 days as determined by the treating infectious diseases clinician. The duration of intravenous phase will be determined by the antibiotic duration determining focus and the treating clinician will be encouraged to follow the 2020 Revised Darwin melioidosis guideline. Intravenous meropenem will be dosed at 1-2g three times per day, adjusted for renal function as determined by the treating clinician. Intravenous ceftazidime will be dosed at 2g four times a day adjusted for renal function as determined by the treating clinician. For the purposes of outpatient parenteral antibiotic therapy, ceftazidime at a dose of 8g daily, adjusted for renal function as determined by the treating clinician, will be administered as a 24-hour intravenous infusion using an elastometric infusion device. To help ensure adherence, the elastometric infusion device will be administered and removed daily by a nurse trained in the use of elastometric devices. Following completion of the intensive phase antibiotics, the eradication phase will begin; oral TMP/SMX will be commenced at a dose of 320+1600 mg twice daily, adjusted for weight and renal function as determined by the treating clinician in accordance with the Australian Therapeutic Guidelines. For the purposes of the study, the duration of the eradication phase will be 90 days (rather than three months) from the end of the intensive phase antibiotics and commence immediately after completion of the intensive phase antibiotics. Concurrent administration of intravenous antibiotics and oral TMP/SMX will be discouraged with the exception of initiation of oral TMP/SMX towards the end of the intensive phase to ensure tolerability of the oral antibiotic as is current common practice at Cairns Hospital. For participants managed entirely at Cairns Hospital, all oral TMP/SMX will be dispensed by Cairns Hospital Pharmacy. For participants transferred from Cairns Hospital to another facility, oral TMP/SMX will be dispensed by the treating hospital with clear written instructions regarding treatment duration on the discharge summary completed when leaving Cairns Hospital. Participants receiving oral medication will be contacted weekly by a study investigator to verbally confirm medication adherence.
Control group
Active

Outcomes
Primary outcome [1] 329732 0
The primary outcome is an episode of recrudescence or relapse of culture-confirmed melioidosis post initial diagnosis of melioidosis. An Investigator will review a participant’s medical chart and contact them via telephone one year and two years following their initial diagnosis of melioidosis to ascertain if a documented culture-confirmed relapse has occurred.
Timepoint [1] 329732 0
Within two years post initial diagnosis of melioidosis.
Secondary outcome [1] 403597 0
All-cause mortality. An Investigator will review a participant’s electronic medical chart to ascertain if this secondary outcome has occurred.
Timepoint [1] 403597 0
At 30 days and 90 days from the date of initial melioidosis diagnosis.
Secondary outcome [2] 403598 0
Clinician suspected relapse of melioidosis (culture-unconfirmed). An Investigator will review a participant’s electronic medical chart and contact them via telephone to ascertain if this secondary outcome has occurred.
Timepoint [2] 403598 0
Within two years post initial diagnosis of melioidosis.
Secondary outcome [3] 403599 0
Proportion of participants with acute kidney injury, rash, or another medication-related adverse event. An Investigator will review each participant face to face regularly (no less than once per week) while the participant remains an inpatient within hospital or as an inpatient admitted to the outpatient parenteral antibiotic service. Blood tests will be collected weekly.

Definitions of medication-related adverse events will be as follows:

Rash: Any development of a new rash; drug rash with eosinophilia and systemic symptoms (DRESS); any development of a new rash with eosinophilia >0.6 x 10 9/L and any systemic symptoms (including fever, lymphadenopathy and any organ involvement).

Gastrointestinal disturbance: Nausea, vomiting, abdominal pain, or any new loose bowel movement.

Bone marrow suppression: Any new: Haemoglobin < 135g/L; neutrophils <2.0 x 10 9/L; platelets <150 x 10 9/L

Acute kidney injury: Increased creatinine 2x from baseline or greater.

Hyperkalaemia: Serum potassium >5.5 mmol/L

Liver function test derangement: Liver function tests >2x the upper limit of normal
Timepoint [3] 403599 0
At end of intensive phase antibiotics.
Secondary outcome [4] 403600 0
Proportion of participants with acute kidney injury, rash, or another medication-related adverse event. An Investigator will review each participant by telephone weekly. Blood tests will be collected monthly.

Definitions of medication-related adverse events will be as follows:

Rash: Any development of a new rash; drug rash with eosinophilia and systemic symptoms (DRESS); any development of a new rash with eosinophilia >0.6 x 10 9/L and any systemic symptoms (including fever, lymphadenopathy and any organ involvement).

Gastrointestinal disturbance: Nausea, vomiting, abdominal pain, or any new loose bowel movement.

Bone marrow suppression: Any new: Haemoglobin < 135g/L; neutrophils <2.0 x 10 9/L; platelets <150 x 10 9/L

Acute kidney injury: Increased creatinine 2x from baseline or greater.

Hyperkalaemia: Serum potassium >5.5 mmol/L

Liver function test derangement: Liver function tests >2x the upper limit of normal
Timepoint [4] 403600 0
At end of eradication phase antibiotics.
Secondary outcome [5] 403601 0
Adherence to the intensive phase therapy as per the 2020 Revised Darwin melioidosis guideline. An Investigator will review a participant’s electronic medical chart to evaluate this secondary outcome.
Timepoint [5] 403601 0
At end of intensive phase antibiotics.

Eligibility
Key inclusion criteria
1. Burkholderia pseudomallei cultured from a clinical specimen.
2. Able to be randomised during the intensive phase of treatment.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected or confirmed central nervous system infection
2. Suspected or confirmed bone or joint infection
3. Suspected or confirmed endovascular infection
4. Moribund (expected to die in < 7 days)
5. Previous participation in the trial
6. Concurrent medical condition requiring trimethoprim/sulphamethoxazole prophylaxis
7. Concurrent medical condition requiring long term treatment with trimethoprim/sulphamethoxazole, doxycycline or amoxicillin/clavulanate
8. Known pregnancy
9. Potential participant not wishing to participate
10. Treating clinician unwilling to enrol potential participant into trial (e.g. concerns about safety of follow-up)

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)
Following written informed consent, the participant will be randomised 1:1 to standard therapy or short course therapy. Randomisation will be in permuted blocks of variable size. Randomisation will be balanced in computer-generated blocks of 20 with allocation codes kept in sealed envelopes until randomisation occurs. The envelopes will remained sealed until the intensive phase duration has been documented by the treating clinician and until <7 days prior to completion of the intensive phase therapy. At this point both the participant and the treating clinician will be informed of the treatment allocation. As the participant will still be receiving intravenous antibiotics at this time, this will be done in person.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be balanced in computer-generated blocks of 20.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Factorial
Other design features
N/A
Phase
Phase 4
Type of endpoint/s
Efficacy
Statistical methods / analysis
The primary outcome will be determined using an intention to treat analysis (all participants with data available for the primary endpoint will be analysed according to the treatment allocation, regardless of what treatment they received). A per protocol analysis will also be performed. Chi-squared tests and Fisher’s exact tests will be used, where appropriate to compare proportions between groups. Difference in proportions will be reported with 95% confidence intervals.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/02/2022
Actual
6/04/2022
Date of last participant enrolment
Anticipated
30/06/2024
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
60
Accrual to date
5
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 21237 0
Cairns Base Hospital - Cairns
Recruitment postcode(s) [1] 36109 0
4870 - Cairns

Funding & Sponsors
Funding source category [1] 310264 0
Hospital
Name [1] 310264 0
Cairns Hospital
Country [1] 310264 0
Australia
Primary sponsor type
Hospital
Name
Cairns Hospital
Address
165 The Esplanade
Cairns
Queensland 4870
Country
Australia
Secondary sponsor category [1] 311370 0
None
Name [1] 311370 0
Address [1] 311370 0
Country [1] 311370 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309936 0
Royal Brisbane & Women's Hospital Human Research Ethics Committee
Ethics committee address [1] 309936 0
Level 2, Building 34
Royal Brisbane & Women's Hospital
Butterfield Street,
Herston
QLD 4029
Ethics committee country [1] 309936 0
Australia
Date submitted for ethics approval [1] 309936 0
27/09/2021
Approval date [1] 309936 0
11/10/2021
Ethics approval number [1] 309936 0
HREC/2021/QRBW/79751

Summary
Brief summary
Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, can affect any organ and be rapidly fatal. The management of melioidosis is complex; antibiotic therapy occurs in two phases – an intensive phase of intravenous antibiotics
followed by an eradication phase of oral antibiotics. Even with effective antibiotics, melioidosis can recur. As adhering to prolonged oral antibiotics is challenging, melioidosis treatment guidelines have evolved to recommend a longer intensive phase. This has
resulted in excellent cure rates and recurrence is now uncommon, even in people who take no oral antibiotics at all. This pilot randomised control trial will investigate if oral antibiotics are still needed in the treatment of melioidosis and aims to provide initial data
to support a larger, randomised control trial. We will recruit 60 participants with melioidosis and allocate them to either standard therapy or short course therapy (intravenous antibiotics only). Participants will be contacted weekly for 90 days and at one and two
years to assess for disease recurrence. We hypothesise that with prolonged intravenous antibiotics, further oral antibiotics are no longer required to cure melioidosis and prevent recurrence.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 115902 0
Dr Simon Smith
Address 115902 0
Department of Medicine
165 The Esplanade
Cairns
QLD 4870
Country 115902 0
Australia
Phone 115902 0
+61 742268545
Fax 115902 0
Email 115902 0
[email protected]
Contact person for public queries
Name 115903 0
Simon Smith
Address 115903 0
Department of Medicine
165 The Esplanade
Cairns
QLD 4870
Country 115903 0
Australia
Phone 115903 0
+61 742260000
Fax 115903 0
Email 115903 0
[email protected]
Contact person for scientific queries
Name 115904 0
Simon Smith
Address 115904 0
Department of Medicine
165 The Esplanade
Cairns
QLD 4870
Country 115904 0
Australia
Phone 115904 0
+61 742268545
Fax 115904 0
Email 115904 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Following de-identification, line-by-line individual participant data will be made available for researchers who meet criteria as per the Queensland Public Health Act 2005.
When will data be available (start and end dates)?
Data will be made available following completion of the study and at the time of publication of the results of the study in a peer-reviewed journal, estimated to be in 2027 for a period of 10 years post study completion.
Available to whom?
Data cannot be shared publicly because of the Queensland Public Health Act 2005. Data will be made available from the Royal Brisbane and Women’s Hospital Human Research Ethics Committee (contact via email [email protected]) for researchers who meet the criteria for access to confidential data.
Available for what types of analyses?
Data will be available for analysis to achieve the aims in the approved proposal.
How or where can data be obtained?
Data can be requested by writing to the Principal Investigator (contact via email [email protected]).


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
14263Study protocol  [email protected]
14264Informed consent form  [email protected]
14265Ethical approval  [email protected]



Results publications and other study-related documents

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