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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
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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)
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Secondary ID [1]
310332
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None
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Tuberculosis
331059
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Condition category
Condition code
Infection
327850
327850
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0
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Other infectious diseases
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
326740
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Treatment: Drugs
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Intervention code [2]
327131
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Treatment: Devices
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Comparator / control treatment
No control group
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
335709
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Levofloxacin pharmacokinetics in saliva characterised using a population PK model.
Relevant parameters include description of compartment, covariates and estimation of AUC or Cmax.
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Assessment method [1]
335709
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Timepoint [1]
335709
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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).
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Secondary outcome [1]
425252
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Distribution of levofloxacin from saliva into plasma
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Assessment method [1]
425252
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Timepoint [1]
425252
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On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6, and 8 post-dose samples.
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Secondary outcome [2]
425254
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NAT2 genotype determined from plasma samples.
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Assessment method [2]
425254
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Timepoint [2]
425254
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On Day 14 (+/-2) of starting the TB treatment
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Secondary outcome [3]
425255
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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).
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Assessment method [3]
425255
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Timepoint [3]
425255
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Using samples collected on Day 14 (+/-2) of starting the TB treatment
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Secondary outcome [4]
425256
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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).
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Assessment method [4]
425256
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Timepoint [4]
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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.
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Secondary outcome [5]
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Distribution of isoniazid from saliva into plasma
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Assessment method [5]
426623
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Timepoint [5]
426623
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On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
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Secondary outcome [6]
426624
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Distribution of rifampicin from saliva into plasma
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Assessment method [6]
426624
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Timepoint [6]
426624
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On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
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Secondary outcome [7]
426625
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Distribution of ethambutol from saliva into plasma
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Assessment method [7]
426625
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Timepoint [7]
426625
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On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
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Secondary outcome [8]
426626
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Distribution of pyrazinamide from saliva into plasma
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Assessment method [8]
426626
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Timepoint [8]
426626
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On Day 14 (+/-2) of starting the TB treatment based on 0,1,2,4,6 and 8 hours post-dose samples.
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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.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
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Who is / are masked / blinded?
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Intervention assignment
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
1/11/2023
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Actual
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
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Sample size
Target
30
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
NSW
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Recruitment hospital [1]
25352
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Westmead Hospital - Westmead
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Recruitment postcode(s) [1]
41062
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2145 - Westmead
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Funding & Sponsors
Funding source category [1]
314537
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Other Collaborative groups
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Name [1]
314537
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TB CRE (The Centre for Research Excellence in Tuberculosis Control)
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Address [1]
314537
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Centenary InstituteBuilding 93, RPA Hospital,Missenden Road,Camperdown, Sydney 2050Australia
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Country [1]
314537
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Australia
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Funding source category [2]
314548
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Government body
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Name [2]
314548
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NSW Health Pathology
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Address [2]
314548
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Level 3, NSWHP-ICPMR, Darcy Rd, WestmeadLocked Bag 9001, Westmead, NSW 2145
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Country [2]
314548
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Australia
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Primary sponsor type
Government body
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Name
Western Sydney Local Health District
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Address
Westmead Hospital, Darcy RoadWestmead NSW 2145
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Country
Australia
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Secondary sponsor category [1]
316490
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None
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Name [1]
316490
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Address [1]
316490
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Country [1]
316490
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
313579
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Western Sydney Local Health District HREC
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Ethics committee address [1]
313579
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Westmead Hospital, Darcy RoadWestmead NSW 2145
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Ethics committee country [1]
313579
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Australia
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Date submitted for ethics approval [1]
313579
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Approval date [1]
313579
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20/12/2022
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Ethics approval number [1]
313579
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2022/ETH01949
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Prof Jan-Willem Alffenaar
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Address
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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
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Country
128622
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Australia
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Phone
128622
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+61286270019
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Fax
128622
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Email
128622
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[email protected]
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Contact person for public queries
Name
128623
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Prof Jan-Willem Alffenaar
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Address
128623
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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
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Country
128623
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Australia
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Phone
128623
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+61286270019
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Fax
128623
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Email
128623
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[email protected]
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Contact person for scientific queries
Name
128624
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Prof Jan-Willem Alffenaar
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Address
128624
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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
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Country
128624
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Australia
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Phone
128624
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+61286270019
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Fax
128624
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Email
128624
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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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.
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