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Trial registered on ANZCTR


Registration number
ACTRN12619000948190
Ethics application status
Approved
Date submitted
3/06/2019
Date registered
5/07/2019
Date last updated
5/07/2019
Date data sharing statement initially provided
5/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Measuring the antibiotic levels in people with cystic fibrosis taking treatment for mycobacterial lung infection.
Scientific title
A Comparative Pharmacokinetic Study of Antibiotics for the Treatment of Non-Tuberculous Mycobacteria in Patients with Cystic Fibrosis
Secondary ID [1] 298396 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
cystic fibrosis 313091 0
non-tuberculous mycobacteria 313092 0
Condition category
Condition code
Infection 311576 311576 0 0
Other infectious diseases
Respiratory 311577 311577 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 311764 311764 0 0
Other inflammatory or immune system disorders
Human Genetics and Inherited Disorders 311958 311958 0 0
Cystic fibrosis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
To describe first dose pharmacokinetics of antimycobacterials in cystic fibrosis (CF) patients including rifampicin, ethambutol, minocycline, clofazimine, azithromycin and clarithromycin. This study will be in subjects who do not have mycobacterial infection.

Unless contraindicated based on allergies, potential drug-drug interactions or other exclusions subjects will receive single concurrent oral doses of (1) rifampicin 600mg tablet, (2) ethambutol 15 mg/kg tablet, (3) clofazimine 100mg tablet, (4) minocycline 200mg tablet, and either (5) clarithromycin 500mg tablet or (6) azithromycin 500mg tablet. If a subject is already on long term azithromycin for biofilm inhibition then they will receive clarithromycin. If they are not on azithromycin they will receive azithromycin as a study drug. This will be determined by chief investigator. Study drugs will be administered by a registered nurse. Subjects will then have intensive plasma sampling to allow for pharmacokinetic analysis.
Intervention code [1] 314640 0
Treatment: Drugs
Comparator / control treatment
No control group. In the discussion sections of any paper a comparison will be made will other findings in non CF populations however due to differing methods a historical control will not be possible.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 320278 0
The primary outcome is the measured plasma concentration of rifampicin at different timepoints after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [1] 320278 0
rifampicin plasma Measurements at 1 hour (primary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.
Primary outcome [2] 320529 0
The primary outcome is the measured plasma concentration of ethambutol at different time points after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [2] 320529 0
ethambutol plasma Measurements at 1 hour (primary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.
Primary outcome [3] 320530 0
The primary outcome is the measured plasma concentration of clarithromycin at different time points after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [3] 320530 0
clarithromycin plasma Measurements at 1 hour (primary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.
Secondary outcome [1] 371060 0
a secondary outcome is the measured plasma concentration of azithromycin at different time points after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [1] 371060 0
azithromycin plasma measurements at 1 hour (secondary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.
Secondary outcome [2] 371930 0
a secondary outcome is the measured plasma concentration of clofazimine at different time points after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [2] 371930 0
clofazimine plasma measurements at 1 hour (secondary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.
Secondary outcome [3] 371931 0
a secondary outcome is the measured plasma concentration of minocycline at different time points after oral administration. PK parameters to be measured include C max, T max, half life, AUC.
Timepoint [3] 371931 0
minocycline plasma measurements at 1 hour (secondary outcome), 2 hours, 3 hours, 4 hours, 6 hours and 8 hours post dose.

Eligibility
Key inclusion criteria
• Age greater or equal to 18 years and able to give consent or under 18 with the consent of a substitute decision maker.
• A negative screen for mycobacteria within the last 6 months for those who are being given a single dose of antibiotics.
• Availability of suitable intravenous access to facilitate sample collection
• Written informed consent has been obtained from the patient or substitute decision maker (according to local regulatory statements for ethical conduct of research at each study site)
• able to tolerate full diet without nasogastric or PEG feeding
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Known adverse reaction to anti-mycobacterial drug being used in study
• On a non-study drug which may have clinically significant interactions with study drug
• Unavailability of intravenous access device for blood collection
• Treating clinicians concerns that the total of volume of blood to be collected may be worsen pre-existing anaemia defined as haemoglobin < 70 g/L.
• Abnormal liver function, at screening, defined as greater than or equal to (>=) 3 time upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), total bilirubin
• Renal impairment with eGFR less than 30 mls/min
• Prolonged QTc of >500ms on ECG or history of cardiac arrhythmia

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
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis

Recruitment
Recruitment status
Not yet 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)
QLD
Recruitment hospital [1] 13892 0
The Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 26665 0
4032 - Chermside

Funding & Sponsors
Funding source category [1] 302938 0
Charities/Societies/Foundations
Name [1] 302938 0
The Prince Charles Hospital Foundation
Address [1] 302938 0
The Prince Charles Hospital
Administration Building
Rode Rd
Chermside 4032
Birsbane
Qld
Country [1] 302938 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
School of Clinical Medicine and Rural Clinical School
Faculty of Medicine
The University of Queensland
Brisbane Qld 4072 Australia
Country
Australia
Secondary sponsor category [1] 302899 0
None
Name [1] 302899 0
Address [1] 302899 0
Country [1] 302899 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 303500 0
The Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 303500 0
The Prince Charles Hospital
Building 14
Rode Road, Chermside QLD 4032
Ethics committee country [1] 303500 0
Australia
Date submitted for ethics approval [1] 303500 0
Approval date [1] 303500 0
16/01/2019
Ethics approval number [1] 303500 0
45323

Summary
Brief summary
It is estimated that in Australia 12% of cystic fibrosis patients are infected with Mycobacterium abscessus, a non-tuberculous mycobacteria (NTM) which is associated with a decline in lung function and increased mortality. Treatment is expensive, toxic and is unsuccessful in most patients. Mycobacterium abscessus is found more commonly in CF patients from Queensland than from more temperate southern states. Another common NTM infection is Mycobacterium avium-intracellulare which has a better cure rate however treatment is for at least twelve months and requires multiple antibiotics some of which cannot be used with newer gene therapies for CF.

Despite this being a research priority in CF there have been no randomised trials carried out to determine optimum therapy. In the absence of these clinical trials, pharmacokinetics – the study of how drugs move through the body - is a key means of discovering the best dose to use in different groups. We believe that the current doses of mycobacterial drugs being used in CF are too low and may be contributing to high rates of treatment failure.

We will test the blood levels of important drugs given to patients with CF with NTM infection and compare to the drug levels in people without cystic fibrosis published in other studies. In this way we can help determine whether the doses we are using are correct or need to be changed. If the doses of antibiotics being used in CF are too low this could lead to new dosing regimens being used in future drug trials.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 93878 0
Dr Andrew Burke
Address 93878 0
Thoracic Dept.
The Prince Charles Hospital
Rode Rd
Chermside 4032
Queensland
Brisbane
Country 93878 0
Australia
Phone 93878 0
+61 07 3139 4000
Fax 93878 0
Email 93878 0
andrew.burke@health.qld.gov.au
Contact person for public queries
Name 93879 0
Dr Andrew Burke
Address 93879 0
Thoracic Dept.
The Prince Charles Hospital
Rode Rd
Chermside 4032
Brisbane
Queensland
Country 93879 0
Australia
Phone 93879 0
+61 07 3139 4000
Fax 93879 0
Email 93879 0
andrew.burke@health.qld.gov.au
Contact person for scientific queries
Name 93880 0
Dr Andrew Burke
Address 93880 0
Thoracic Dept.
The Prince Charles Hospital
Chermside 4032
Queensland
Brisbane
Country 93880 0
Australia
Phone 93880 0
+61 07 3139 4000
Fax 93880 0
Email 93880 0
andrew.burke@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?
De-identified patient data and outcomes including plasma concentrations for antibiotics.
When will data be available (start and end dates)?
from 1/9/2020 to 1/9/2027
Available to whom?
Researchers in pharmacology;
Available for what types of analyses?
pharmacokinetics
How or where can data be obtained?
contact primary investigator, Dr Andrew Burke
best contact: andrew.burke@health.qld.gov.au
What supporting documents are/will be available?
No other documents available
Summary results
No Results