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Trial registered on ANZCTR


Registration number
ACTRN12620000447954
Ethics application status
Approved
Date submitted
1/04/2020
Date registered
6/04/2020
Date last updated
6/04/2020
Date data sharing statement initially provided
6/04/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
Use of therapeutic drug monitoring (TDM) to optimise oral/enteral hydroxychloroquine dosing in critically ill patients with COVID-19
Scientific title
Use of therapeutic drug monitoring (TDM) to optimise oral/enteral hydroxychloroquine dosing in critically ill patients with COVID-19
Secondary ID [1] 300904 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 316840 0
Condition category
Condition code
Infection 315048 315048 0 0
Other infectious diseases
Respiratory 315104 315104 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Based on preclinical and non-randomised studies, the Royal Brisbane and Women’s Hospital Intensive Care Unit clinical Consultant Medical Staff, in agreement with the Infectious Diseases Department and the Pharmacy Department, have decided that all patients admitted to the ICU with COVID-19 infection should receive hydroxychloroquine as standard care. Therefore, hydroxychloroquine is NOT considered a trial intervention for the purpose of this study.

The dose of hydroxychloroquine used for COVID-19 infection is extrapolated from that in common use for malaria and other approved indications. However, the organ dysfuction that accompanies critical illness suggests dosing is likely to require adjustment. This study will adjust the dose of hydroxychloroquine using therapeutic drug monitoring (TDM) to a goal concentration known to be safe. The observation period for TDM will be a total of up to 10 days or until the time of ICU discharge, which ever is sooner.

As is routine practice at the RBWH ICU, TDM will be led by the senior ICU pharmacist after initiation of therapy. Trough venous blood samples (3 ml) will be taken via an indwelling arterial cannula. The first TDM should ideally occur before the administration of the FIRST MAINTENANCE DOSE, provided the appropriate loading dose schedule has been completed. Sampling thereafter can occur every 24-48 hours to confirm the appropriateness of ongoing dosing as guided by the Pharmacy and Medical Team. Blood samples will be transported to Queensland Pathology on the Herston Campus for drug analysis. Prescribing of initial and ongoing/revised dosing will remain the responsibility of medical officers, whilst fidelity of the intervention will be maintained through pharmacy dosing adjustment notes which are subjected to auditing. Blood samples will continue to be collected daily until the participant is discharged from ICU.

Samples for assay will be spiked with stable isotope labelled internal standards and drugs extracted by liquid-liquid extraction with tertbutyl methyl ether. Extracts will be analysed by a validated UHPLC-MS/MS chromatographic method to measure total drug concentrations. Test samples will be assayed alongside calibrators and quality controls and be subjected to industry standard batch acceptance criteria.

A pharmacogenetic evaluation of CYP3A4 and CYP2D6 expression will be performed on existing blood samples to ascertain information regarding HCQ metabolism and drug exposure.

In order to further interrogate the collected data and scientifically evaluate the appropriateness of hydroxychloroquine, as a secondary analysis, we will analyse the dosing and concentration data of 100 patients and subject this to population pharmacokinetic modelling using non-parametric pharmacokinetic modelling approach in Pmetrics®. The final pharmacokinetic population parameters estimated from all possible covariates will be chosen based on the value of mean weighted error (describing the precision), mean weighted squared error (describing the bias), and coefficient of determination (r2). Monte Carlo simulations will be performed to identify the most optimal dosing regimens that will target drug concentrations.
Intervention code [1] 317223 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323351 0
Dose adjustment required to attain a steady-state target trough hydroxychloroquine concentration of 0.24mg/L using TDM (proportion of patients / magnitude of adjustments)

Dose adjustment data will be collected and maintained by the senior ICU clinical pharmacist.
Timepoint [1] 323351 0
Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [1] 381628 0
1. Achievement of free HCQ concentrations >0.24 mg/L after dose adjustment using TDM (proportion of patients / magnitude of excess) assessed through serum assays by RBWH central pathology laboratory.
Timepoint [1] 381628 0
1. Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [2] 381633 0
30-day case-fatality following ICU admission
Timepoint [2] 381633 0
30 days after ICU admission
Secondary outcome [3] 381634 0
Hospital case fatality
Timepoint [3] 381634 0
90 days after ICU admission
Secondary outcome [4] 381635 0
ICU case fatality
Timepoint [4] 381635 0
90 days after ICU admission
Secondary outcome [5] 381636 0
Change of worst daily SOFA score
Timepoint [5] 381636 0
Daily up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [6] 381637 0
Time to negative SARS-CoV-2 PCR results
Timepoint [6] 381637 0
Up to 90 days after ICU admission
Secondary outcome [7] 381638 0
Change in routine blood test results (as available). This is an exploratory outcome.
Timepoint [7] 381638 0
Daily up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [8] 381639 0
Routine chest imaging results (as available). This is an exploratory outcome.
Timepoint [8] 381639 0
Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [9] 381640 0
Hydroxychloroquine pharmacological data including drug dose and dosing history, formulation used (tablet, capsule, liquid), administration route (swallowed whole, liquid, crushed), concomitant medication
Timepoint [9] 381640 0
Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [10] 381641 0
Worst daily PaO2 / FiO2
Routine measurements will be recorded via a blood gas record.
Timepoint [10] 381641 0
Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,
Secondary outcome [11] 381642 0
All antibiotics used each day, routinely assessed by ICU clinical pharmacist records.
Timepoint [11] 381642 0
Up to the point of ICU discharge, in the first 10 days after commencement of initial HCQ dose,

Eligibility
Key inclusion criteria
Patients admitted to ICU at the Royal Brisbane & Women's Hospital with suspected or proven severe COVID-19 infection, prescribed hydroxychloroquine as part of their routine management.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Individuals aged <18 years old.

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)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint(s)
Pharmacokinetics
Statistical methods / analysis
The aim of the study is to define the dosing of hydroxychloroquine required to achieve a therapeutic drug level in patients with COVID-19 and critical illness. The number of patients required to achieve this will be determined by the variability of the enrolled population's drug levels. As this is not possible to know in advance, sample size is not possible to define. The study will continue until a robust population pharmacokinetic model taking into account organ dysfunction and other patient characteristics has been defined

Recruitment
Recruitment status
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] 16183 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 29726 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 305353 0
Government body
Name [1] 305353 0
Queensland Health
Address [1] 305353 0
c/o Royal Brisbane & Women's Hospital
Butterfield St, Herston QLD 4029
Country [1] 305353 0
Australia
Primary sponsor type
Hospital
Name
Royal Brisbane & Women's Hospital
Address
Intensive Care Services
3rd Floor, Ned Hanlon Building
Herston QLD 4029 Australia

Country
Australia
Secondary sponsor category [1] 305781 0
None
Name [1] 305781 0
N/A
Address [1] 305781 0
N/A
Country [1] 305781 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305685 0
Royal Brisbane & Women's Hospital Human Research Ethics Committee (RBWH HREC)
Ethics committee address [1] 305685 0
Royal Brisbane & Women's Hospital
Executive Suites, Lower Ground Floor
Dr James Mayne Building
Butterfield Street, Herston QLD 4029
Ethics committee country [1] 305685 0
Australia
Date submitted for ethics approval [1] 305685 0
26/03/2020
Approval date [1] 305685 0
31/03/2020
Ethics approval number [1] 305685 0
HREC/2020/QRBW/63059

Summary
Brief summary
To date, COVID-19 has resulted in nearly 721,000 infections and almost 33,000 deaths globally, with no proven effective therapeutic options to reduce mortality. Hydroxychloroquine (HCQ) is a widely used anti-malarial drug showing great promise in treating COVID-19 in preclinical studies. The intensive care physicians at the Royal Brisbane and Women's Hospital (RBWH) have chosen to treat all COVID-19 patients admitted to the ICU with HCQ. The dose of HCQ used in virtually every other hospital is the same as used for malaria. However, critically ill patients with renal failure and other problems commonly require different doses of many drugs. The aim of this study is to investigate whether the dosing of HCQ for critically ill COVID-19 patients requires adjustment, in order to ensure the safety of practice at RBWH, Inclusion criteria is suspected or proven severe COVID-19 infections admitted to the RBWH ICU. Data will be routinely collected as part of standard ICU practice. The outcome of this study will potentially be of critical importance in the interpretation of results of the large randomised comparative trials of HCT using fixed dosing currently underway.
Trial website
Trial related presentations / publications
Public notes
Study has recruited one test patient following HREC approval but prior to trial registration

Contacts
Principal investigator
Name 101222 0
Prof Kevin B Laupland
Address 101222 0
c/o Intensive Care Services
Royal Brisbane and Women's Hospital
3rd Floor, Ned Hanlon Building
Herston QLD 4029 Australia

Country 101222 0
Australia
Phone 101222 0
+61 7 3646 8897
Fax 101222 0
Email 101222 0
kevin.laupland@qut.edu.au
Contact person for public queries
Name 101223 0
Prof Kevin B Laupland
Address 101223 0
c/o Intensive Care Services
Royal Brisbane and Women's Hospital
3rd Floor, Ned Hanlon Building
Herston QLD 4029 Australia

Country 101223 0
Australia
Phone 101223 0
+61 7 3646 8897
Fax 101223 0
Email 101223 0
kevin.laupland@qut.edu.au
Contact person for scientific queries
Name 101224 0
Prof Kevin B Laupland
Address 101224 0
c/o Intensive Care Services
Royal Brisbane and Women's Hospital
3rd Floor, Ned Hanlon Building
Herston QLD 4029 Australia

Country 101224 0
Australia
Phone 101224 0
+61 7 3646 8897
Fax 101224 0
Email 101224 0
kevin.laupland@qut.edu.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?
Data on baseline characteristics, outcomes and drug levels, after de-identification
When will data be available (start and end dates)?
From 3 months following publication until 2 years after publication
Available to whom?
Only researchers who provide a methodologically sound proposal and who demonstrate capacity to analyse pharmacokinetic data
Available for what types of analyses?
Pharmacokinetic analysis
How or where can data be obtained?
Email to the Principal Investigator listed in this record
What supporting documents are/will be available?
Study protocol
Ethical approval
How or where can supporting documents be obtained?
Type [1] 7479 0
Ethical approval
Citation [1] 7479 0
Link [1] 7479 0
Email [1] 7479 0
kevin.laupland@qut.edu.au
Other [1] 7479 0
Type [2] 7482 0
Study protocol
Citation [2] 7482 0
Link [2] 7482 0
Email [2] 7482 0
kevin.laupland@qut.edu.au
Other [2] 7482 0
Summary results
No Results