ANZCTR - Registration

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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]

None

Universal Trial Number (UTN)

Trial acronym

SCATMAN

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Melioidosis

Condition category

Condition code

Infection

Studies of infection and infectious agents

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Intervention code [1]

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]

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]

Within two years post initial diagnosis of melioidosis.

Secondary outcome [1]

All-cause mortality. An Investigator will review a participant’s electronic medical chart to ascertain if this secondary outcome has occurred.

Timepoint [1]

At 30 days and 90 days from the date of initial melioidosis diagnosis.

Secondary outcome [2]

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]

Within two years post initial diagnosis of melioidosis.

Secondary outcome [3]

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]

At end of intensive phase antibiotics.

Secondary outcome [4]

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]

At end of eradication phase antibiotics.

Secondary outcome [5]

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]

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?

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

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Cairns Base Hospital - Cairns

Recruitment postcode(s) [1]

4870 - Cairns

Funding & Sponsors

Funding source category [1]

Hospital

Name [1]

Cairns Hospital

Address [1]

165 The Esplanade
Cairns
Queensland 4870

Country [1]

Australia

Primary sponsor type

Hospital

Name

Cairns Hospital

Address

165 The Esplanade
Cairns
Queensland 4870

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Royal Brisbane & Women's Hospital Human Research Ethics Committee

Ethics committee address [1]

Level 2, Building 34
Royal Brisbane & Women's Hospital
Butterfield Street,
Herston
QLD 4029

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

27/09/2021

Approval date [1]

11/10/2021

Ethics approval number [1]

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

Dr Simon Smith

Address

Department of Medicine
165 The Esplanade
Cairns
QLD 4870

Country

Australia

Phone

+61 742268545

Fax

simon.smith2@health.qld.gov.au

Contact person for public queries

Name

Simon Smith

Address

Department of Medicine
165 The Esplanade
Cairns
QLD 4870

Country

Australia

Phone

+61 742260000

Fax

simon.smith2@health.qld.gov.au

Contact person for scientific queries

Name

Simon Smith

Address

Department of Medicine
165 The Esplanade
Cairns
QLD 4870

Country

Australia

Phone

+61 742268545

Fax

simon.smith2@health.qld.gov.au

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 RBWH-Ethics@health.qld.gov.au) 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 simon.smith2@health.qld.gov.au).

What supporting documents are/will be available?

Doc. No.	Type	Email
14263	Study protocol	simon.smith2@health.qld.gov.au
14264	Informed consent form	simon.smith2@health.qld.gov.au
14265	Ethical approval	simon.smith2@health.qld.gov.au

Results publications and other study-related documents

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