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Trial registered on ANZCTR


Registration number
ACTRN12623001088639
Ethics application status
Approved
Date submitted
9/08/2023
Date registered
17/10/2023
Date last updated
17/10/2023
Date data sharing statement initially provided
17/10/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Study comparing anti-tuberculosis drug levels in saliva, plasma, and urine in patients
Scientific title
Prospective Pharmacokinetic study to evaluate the correlation between isoniazid (incl NAT2 genotyping), rifampicin, pyrazinamide, ethambutol and levofloxacin drug concentration in saliva, plasma and urine in patients with drug susceptible tuberculosis (TB)
Secondary ID [1] 310332 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Tuberculosis 331059 0
Condition category
Condition code
Infection 327850 327850 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients will receive one week of levofloxacin (15 mg/kg, rounded to 750mg-1000mg daily using oral tablets) added to the standard of care regimen which will include isoniazid, rifampicin, ethambutol, and pyrazinamide.
Levofloxacin will be started after a week of starting the standard care regimen.
After a week of levofloxacin which corresponds to Day 14±2 of the start of first-line drugs, patients will have a blood sample for NAT2 genetic testing, paired saliva and plasma samples (0, 1, 2, 4, 6, 8 hours post-dose) and urine samples (0-4, 4-8, 8-12 and 12-24 hours post-dose).
If inpatient, patient's medication administration will be monitored by the ward nurse/clinician. If outpatient, patient's medication adherence will be monitored in the clinic under Directly Observed Therapy.
Saliva samples will be collected using Salivette®. Saliva will be filtered through a syringe with filter (Millex®-GP or Millex®-GV) for removal of Mycobacterium tuberculosis before transport.

Drug concentrations (isoniazid, rifampicin, pyrazinamide, ethambutol, levofloxacin) in saliva and plasma samples will be analysed on liquid chromatography with mass spectrometry (LCMS).
Saliva samples will be additionally analysed on a UV spectrophotometer (NanoPhotometer NP80®).
Urine samples will be collected in collection tubes and stored at -20 °C until analysis. Drug concentrations in urine will also be analysed on LCMS and explored for their feasibility of measurement on the UV spectrophotometer (NanoPhotometer NP80®).
For genetic testing, DNA will be extracted from the EDTA blood samples (3 to 5 mls), using manual or automated Qiagen extraction methods. DNA will then be amplified, the product sequenced and sequence analysis performed. The combination of SNPs identified will be categorised according to published guidelines to identify the NAT2 genotype of the patient and expected isoniazid acetylator status.
Intervention code [1] 326740 0
Treatment: Drugs
Intervention code [2] 327131 0
Treatment: Devices
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 335709 0
Levofloxacin pharmacokinetics in saliva characterised using a population PK model.
Relevant parameters include description of compartment, covariates and estimation of AUC or Cmax.
Timepoint [1] 335709 0
Saliva which is collected simultaneously with plasma samples after a week of levofloxacin, at 0,1,2,4,6 and 8 hours post-dose (on Day 7 of levofloxacin).
Secondary outcome [1] 425252 0
Distribution of levofloxacin from saliva into plasma
Timepoint [1] 425252 0
On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6, and 8 post-dose samples.
Secondary outcome [2] 425254 0
NAT2 genotype determined from plasma samples.
Timepoint [2] 425254 0
On Day 14 (+/-2) of starting the TB treatment
Secondary outcome [3] 425255 0
Feasibility of point-of-care UV spectrophotometer saliva assay for the first-line TB drugs and levofloxacin (determined by successful saliva assay development and validation) using NanoPhotometer NP80® (Implen, Germany).
Timepoint [3] 425255 0
Using samples collected on Day 14 (+/-2) of starting the TB treatment
Secondary outcome [4] 425256 0
Feasibility of urine testing for the first-line TB drugs and levofloxacin determined by successful urine assay development and validation using LCMS and NanoPhotometer NP80® (Implen, Germany).
Timepoint [4] 425256 0
Using samples collected on Day 14 (+/-2) of starting the TB treatment based on 0-4, 4-8, 8-12 and 12-24 hours post-dose samples.
Secondary outcome [5] 426623 0
Distribution of isoniazid from saliva into plasma
Timepoint [5] 426623 0
On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
Secondary outcome [6] 426624 0
Distribution of rifampicin from saliva into plasma
Timepoint [6] 426624 0
On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
Secondary outcome [7] 426625 0
Distribution of ethambutol from saliva into plasma
Timepoint [7] 426625 0
On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
Secondary outcome [8] 426626 0
Distribution of pyrazinamide from saliva into plasma
Timepoint [8] 426626 0
On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.

Eligibility
Key inclusion criteria
-Patients 18 years old or older
-Diagnosis of bacteriologically confirmed active pulmonary and/or extrapulmonary drug-susceptible TB.
-Started treatment with a standard-of-care regimen containing isoniazid, rifampicin, pyrazinamide and ethambutol.
-Provided informed consent for this study.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Patients who avoid levofloxacin or with contra-indications for levofloxacin including:
• hypersensitivity to fluoroquinolones
• patients with known aortic aneurysm or Marfan's syndrome
• agranulocytosis (absolute neutrophil count < 500 cells/mm³)
• thrombocytopenia (count below 50,000 platelets /mm³)
• myasthenia gravis
• renal function loss (creatinine clearance <50ml/min)
• hepatic dysfunction (aspartate aminotransferase and or alanine aminotransferase > 3 times upper level of normal).
-Patients with bleeding mucositis or ulcers which will not allow saliva collection.
-Patients with recently proven C.difficile infection.

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
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/11/2023
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
30
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25352 0
Westmead Hospital - Westmead
Recruitment postcode(s) [1] 41062 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 314537 0
Other Collaborative groups
Name [1] 314537 0
TB CRE (The Centre for Research Excellence in Tuberculosis Control)
Country [1] 314537 0
Australia
Funding source category [2] 314548 0
Government body
Name [2] 314548 0
NSW Health Pathology
Country [2] 314548 0
Australia
Primary sponsor type
Government body
Name
Western Sydney Local Health District
Address
Westmead Hospital, Darcy RoadWestmead NSW 2145
Country
Australia
Secondary sponsor category [1] 316490 0
None
Name [1] 316490 0
Address [1] 316490 0
Country [1] 316490 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 313579 0
Western Sydney Local Health District HREC
Ethics committee address [1] 313579 0
Westmead Hospital, Darcy RoadWestmead NSW 2145
Ethics committee country [1] 313579 0
Australia
Date submitted for ethics approval [1] 313579 0
Approval date [1] 313579 0
20/12/2022
Ethics approval number [1] 313579 0
2022/ETH01949

Summary
Brief summary
Therapeutic drug monitoring (TDM) is recommended for anti-tuberculosis (TB) drugs. Some drugs can penetrate into saliva and urine sufficiently enough to be used as alternative sampling.
Our primary aim is to develop a salivary pharmacokinetic model for levofloxacin. The secondary objectives are to study the salivary penetration ratios for TB drugs, determine the relationship between the genotype of NAT2 and isoniazid level, and determine the feasibility of using saliva or urine for TDM.
A prospective, open-label, observational study will be conducted in 30 adult patients receiving TB drugs. Plasma, saliva, and urine samples will be collected around week 2 for drug analysis. The population PK model will be developed using Nonlinear Mixed Effects Modeling (NONMEM®).
Expected outcomes include a salivary pharmacokinetic model for levofloxacin, the relationship between NAT2 genotype and isoniazid level, and an assessment of the feasibility of using saliva and/or urine for TDM of TB drugs.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 128622 0
Prof Jan-Willem Alffenaar
Address 128622 0
Sydney School of Pharmacy, Faculty of Medicine and HealthS343, Pharmacy Building (A15), The University of Sydney, NSW 2006 & Level 5, K-block, Westmead Hospital, Westmead, NSW 2145
Country 128622 0
Australia
Phone 128622 0
+61286270019
Fax 128622 0
Email 128622 0
johannes.alffenaar@sydney.edu.au
Contact person for public queries
Name 128623 0
Prof Jan-Willem Alffenaar
Address 128623 0
Sydney School of Pharmacy, Faculty of Medicine and HealthS343, Pharmacy Building (A15), The University of Sydney, NSW 2006 & Level 5, K-block, Westmead Hospital, Westmead, NSW 2145
Country 128623 0
Australia
Phone 128623 0
+61286270019
Fax 128623 0
Email 128623 0
johannes.alffenaar@sydney.edu.au
Contact person for scientific queries
Name 128624 0
Prof Jan-Willem Alffenaar
Address 128624 0
Sydney School of Pharmacy, Faculty of Medicine and HealthS343, Pharmacy Building (A15), The University of Sydney, NSW 2006 & Level 5, K-block, Westmead Hospital, Westmead, NSW 2145
Country 128624 0
Australia
Phone 128624 0
+61286270019
Fax 128624 0
Email 128624 0
johannes.alffenaar@sydney.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


What supporting documents are/will be available?

No Supporting Document Provided



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.