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Trial registered on ANZCTR


Registration number
ACTRN12623001155684
Ethics application status
Approved
Date submitted
2/10/2023
Date registered
8/11/2023
Date last updated
28/04/2024
Date data sharing statement initially provided
8/11/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Effect of probenecid or ibuprofen on flucloxacillin exposure in healthy adults
Scientific title
Effect of pharmacokinetic enhancers on flucloxacillin serum and urinary concentrations in healthy adults
Secondary ID [1] 310582 0
None
Universal Trial Number (UTN)
Trial acronym
FLUTE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Methicillin-susceptible Staphylococcus aureus (MSSA) infection 331443 0
Other infections require flucloxacillin for treatment 331779 0
Condition category
Condition code
Infection 328182 328182 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention occurs at the Doherty Clinical Trial unit. Investigational Medicinal Products (IMPs)--flucloxacillin and probenecid—will be administered by registered nurses (Div 1, APRAH) and/or other medical staff listed in the Delegation of Responsibilities Log, unless stated otherwise.

This is a non-randomized study. Participants can choose which group they want to be in, either Group 1 or Group 2, until each group is full.

Group 1. During the 6-day intervention period, participants will be prescribed flucloxacillin and probenecid at various doses, as well as with various durations and modes of administration, as follows.
Day 1. 1 g of flucloxacillin capsule, orally, four times (6 hours apart)--first dose will be administered at Doherty Clinical Trial unit, while the other 3 doses will be administered at home and participants will be provided the required number of capsules and one extra dose in a take-home pack;
Day 2. 1 g of flucloxacillin capsule, orally, one time;
Day 3. 2 g of flucloxacillin, intravenous infusion (IV), one time;
Day 4. Washout (no IMP is prescribed);
Day 5. 1 g of flucloxacillin capsule and 500 mg of probenecid tablet, orally, three times (8 hours apart);
Day 6. 1 g of flucloxacillin capsule and 500 mg of probenecid tablet, orally, one dose (8 hours after the last dose on Day 5).

Blood sampling is to occur before and after doses, except during the washout period. Urine sampling is after the dose, except for Day 1 and 4.
Intervention code [1] 326988 0
Treatment: Drugs
Comparator / control treatment
The intervention occurs at the Doherty Clinical Trial unit. IMPs—flucloxacillin and ibuprofen--will be administered by registered nurses (Div 1, APRAH) and/or other medical staff listed in the Delegation of Responsibilities Log.

Group 2. During the 3-day intervention period, participants will be prescribed flucloxacillin and ibuprofen at various doses, as well as with various durations and modes of administration, as follows.
Day 1. 2 g of flucloxacillin, IV, one time;
Day 2. 2 g of flucloxacillin IV and 400 mg of ibuprofen tablet orally, two times (12 hours apart);
Day 3. 2 g of flucloxacillin IV and 400 mg of ibuprofen tablet orally, one time.

Blood sampling is to occur before and after doses. Urine sampling is after the dose every day.
Control group
Active

Outcomes
Primary outcome [1] 336071 0
Effect of probenecid on the pharmacokinetics of oral flucloxacillin in serum and urine as described by the unbound maximum and minimum concentration, as well as the area under the plasma concentration-time curve over a 24-hour period (AUC24).
Timepoint [1] 336071 0
Blood sampling is to occur at the following times.
Group 1.
Day 1. 0.5h before the first dose.
Day 2. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 6h after the dose.
Day 3. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 5.5h after the dose.
Day 4. Washout (no sampling)
Day 5. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.
Day 6. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.

All urine sampling is post-dose, except on Day 1 and 4 (Washout) for Group 1.
Primary outcome [2] 336346 0
Effect of ibuprofen on the pharmacokinetics of IV flucloxacillin in serum and
urine as described by the unbound maximum and minimum concentration, as well as the area under the plasma concentration-time curve over a 24-hour period (AUC24).
Timepoint [2] 336346 0
Blood sampling is to occur at the following times.
Group 2.
Day 1. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 5.5h after the dose.
Day 2. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.
Day 3. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the dose.

All urine sampling is post-dose.
Secondary outcome [1] 426741 0
Optimum flucloxacillin dosage determined by non-linear mixed effects modelling and dosing simulations using measured concentrations from blood and urine samples.
Timepoint [1] 426741 0
Blood sampling is to occur at the following times.
Group 1.
Day 1. 0.5h before the first dose.
Day 2. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 6h after the dose.
Day 3. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 5.5h after the dose.
Day 4. Washout (no sampling)
Day 5. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.
Day 6. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.

Group 2.
Day 1. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, and 5.5h after the dose.
Day 2. 0.5h before the first dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the first dose.
Day 3. 0.5h before the dose; 0.5h, 1h, 1.5h, 2h, 3h, 4h, 6h and 8h after the dose.

All urine sampling is post-dose, except on Day 1 and 4 (Washout) for Group 1.
Secondary outcome [2] 427407 0
Type and frequency of adverse reactions with each of the probenecid or ibuprofen
containing regimens, summarized based on adverse events documentation on case report form (CRF).
Timepoint [2] 427407 0
Continuous monitoring after intervention commencement until the last urine sampling on day 6 (Group 1) or day 3 (Group 2).

Eligibility
Key inclusion criteria
1. Body mass index (BMI) of 18.0 – 32.0 kg/m2 and body weight >= 50.0 kg.
2. Medically healthy, determined by medical history, physical examination, non-clinically significant laboratory profiles, vital signs, and 12-lead ECG at screening, as deemed by the Investigator.
3. Females must be non-pregnant, non-lactating, or postmenopausal for at least 1 year or surgically sterile for at least 6 months prior to dosing.
4. If relevant, non-pregnant female participants will be required to use an effective form of contraception from 28 days prior to the study until the end of study.
5. Males must not have a pregnant partner and must agree to use condoms as a method of contraception from the time of signing informed consent until the end of study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History of any clinically important cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, and renal, or other major disease, as determined by the Investigator.
2. Significant history of hospitalization for illness within the six months prior to enrolment into the study, or major surgery within the 12 months prior to enrolment into the study, as assessed by the study physician or investigator.
3. A contraindication or significant risk associated with the use of either of IMPs.
4. Likely to have altered drug exposures.
5. Other health risks as determined by the study physician.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 4
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis
Population pharmacokinetic-pharmacodynamic analysis will use non-linear mixed effects modelling (NONMEM). A first-order conditional estimation method will be used to estimate pharmacokinetic parameters (volume, clearance, oral availability) and their variability. Model evaluation will be based on graphical and statistical criteria, including goodness-of-fit plots and visual predictive checks.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
29/01/2024
Actual
29/01/2024
Date of last participant enrolment
Anticipated
12/02/2024
Actual
5/02/2024
Date of last data collection
Anticipated
16/02/2024
Actual
7/02/2024
Sample size
Target
20
Accrual to date
Final
20
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 41342 0
3002 - East Melbourne

Funding & Sponsors
Funding source category [1] 314792 0
Government body
Name [1] 314792 0
National Health and Medical Research Council
Country [1] 314792 0
Australia
Primary sponsor type
University
Name
University of Melbourne
Address
1/21 Bedford Street, North Melbourne, Victoria 3051
Country
Australia
Secondary sponsor category [1] 316791 0
None
Name [1] 316791 0
Address [1] 316791 0
Country [1] 316791 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313804 0
Bellberry Limited
Ethics committee address [1] 313804 0
Ethics committee country [1] 313804 0
Australia
Date submitted for ethics approval [1] 313804 0
28/09/2023
Approval date [1] 313804 0
15/12/2023
Ethics approval number [1] 313804 0
2023-09-1202
Ethics committee name [2] 314523 0
The University of Melbourne
Ethics committee address [2] 314523 0
Ethics committee country [2] 314523 0
Australia
Date submitted for ethics approval [2] 314523 0
05/01/2024
Approval date [2] 314523 0
08/01/2024
Ethics approval number [2] 314523 0
2024-28948-48627-1

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 129398 0
Prof James McCarthy
Address 129398 0
The Peter Doherty Institute for Infection and Immunity, Level 5, 792 Elizabeth Street, Melbourne, 3000, Victoria
Country 129398 0
Australia
Phone 129398 0
+61 3 83440927
Fax 129398 0
Email 129398 0
[email protected]
Contact person for public queries
Name 129399 0
Cindy Natasha
Address 129399 0
The Walter and Eliza Hall Institute of Medical Research, Level 4 West, 1G, Royal Parade, Parkville, Victoria, 3052
Country 129399 0
Australia
Phone 129399 0
+61 491 051 079
Fax 129399 0
Email 129399 0
[email protected]
Contact person for scientific queries
Name 129400 0
Amy Legg
Address 129400 0
The University of Queensland Centre for Clinical Research, Building 71/918 Royal Brisbane and Women’s Hospital Campus, Herston, Brisbane, 4006, Queensland
Country 129400 0
Australia
Phone 129400 0
+61 401882939
Fax 129400 0
Email 129400 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?
Individual participant data underlying published results only.
When will data be available (start and end dates)?
Immediately following publication; no end date determined yet.
Available to whom?
Case-by-case basis at the discretion of Primary Investigator.
Available for what types of analyses?
Any purpose, subject to participants' permission stated on the informed consent form and approvals by Principal Investigator.
How or where can data be obtained?
Access subject to approvals by Principal Investigator ([email protected]).


What supporting documents are/will be available?




Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.