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Trial registered on ANZCTR


Registration number
ACTRN12620000665932
Ethics application status
Approved
Date submitted
22/04/2020
Date registered
10/06/2020
Date last updated
10/06/2020
Date data sharing statement initially provided
10/06/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The ROAD Study - Resistant Optimised Antimicrobial Dosing in Critically Ill Patients
Scientific title
The ROAD Study - Resistant Optimised Antimicrobial Dosing in Critically Ill Patients - Pharmacokinetic/pharmacodynamic–optimised beta-lactam dosing to prevent the emergence of bacterial resistance: a proof-of-concept
Secondary ID [1] 301080 0
Nil Known
Universal Trial Number (UTN)
Trial acronym
The ROAD Study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Sepsis / Septic Shock 317148 0
Infection 317149 0
Condition category
Condition code
Infection 315303 315303 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a prospective, open-labeled, single-centre phase IIa clinical study, which aims to evaluate the safety and tolerability, as well as the clinical efficacy of meropenem and piperacillin/tazobactam dosing regimens that are optimised (via PK/PD approach) to prevent the emergence of bacterial resistance in critically ill patients.

The initial meropenem and piperacillin/tazobactam dosing regimens (dose, dosing interval and method of administration) will be determined by treating clinician in accordance to standard prescribing practices, which will be based on patient’s clinical status, body weight and renal function. Once enrolled in the study the subsequent meropenem and piperacillin/tazobactam dosing regimens will be optimised to achieve exposures likely leading to maximal suppression of bacterial resistance.

Based on our hollow-fibre infection model data, which are further corroborated by other studies, these exposures are likely to be: (a) Cmin >/=8 mg/L for meropenem (defined as Cmin exposures that are 4 x EUCAST MIC breakpoint for P. aeruginosa i.e., 2 mg/L); and (b) Cmin >/=64 mg/L for piperacillin (defined as Cmin exposures that are 4 x EUCAST MIC breakpoint for P. aeruginosa i.e., 16 mg/L). However, dosing optimisation will consider previously published toxicity thresholds for meropenem and piperacillin, and will not aim to achieve such concentrations. Therefore, once informed consent is obtained, subsequent dosing regimens will be optimised to achieve these concentrations: Cmin >/=8 mg/L (but not greater than 45 mg/L) for meropenem and Cmin >/=64 mg/L (but not greater than 360 mg/L for piperacillin).

This step to dosing optimisation will be performed by a Consultant Clinical Pharmacist at the RBWH ICU with the aid of Bayesian dose-optimising software, ID-ODS™. ID-ODS™ uses drug concentrations (via TDM) and causative organism’s MIC, combined with patient clinical data (age, height, weight, gender, serum creatinine and previous dosing details), to provide a patient-specific dosing recommendation to reach a concentration target. This approach to dosing optimisation (i.e., combining TDM results with ID-ODS™ to predict dosing requirements) has been routinely used for the last six years by pharmacists at the RBWH ICU. Patients will be continuously monitored whilst in the ICU as per standard ICU care.
Doses will be administered by intensive care nurses or intensive care research nurses.

The possible dosage ranges are as follows:
Mode of administration will be intravenous infusion
(1) Meropenem 1 – 2 g every 8-hourly as determined by treating clinician
(2) Piperacillin/tazobactam 4.5 g every 6 – 8-hourly as determined by treating clinician

The PK/PD-optimised dosing regimens will continue to be administered until either:
(a) the study antibiotic is ceased by treating clinician;
(b) beta-lactam concentrations via TDM are deemed to be toxic at any time-point during the study (concentrations of >/=45 mg/L for meropenem and >/=360 mg/L for piperacillin);
(c) patient manifests signs and symptoms of beta-lactam toxicity;
(d) patient completes 5-days of PK/PD-optimised meropenem and piperacillin/tazobactam dosing; or
(e) the patient is discharged from the ICU, whichever is sooner.


As this is a single site study, protocol adherence will be easily monitored. The study will be conducted in accordance with ethical principles consistent with the Declaration of Helsinki, and all relevant national and local guidelines on the ethical conduct of research. The research team will include experienced research coordinators, intensive care specialists and senior pharmacists all with GCP training and they will have oversight of all study required interventions and protocol adherence.
Although potentially more frequent than standard care all the study procedures are routinely performed within the intensive care environment and will be performed by experienced medical and nursing staff. These procedures are necessary to ensure the safety and effectiveness of the optimised dosing regimens.



Intervention code [1] 317393 0
Treatment: Drugs
Intervention code [2] 317397 0
Prevention
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 323550 0
To evaluate the safety and tolerability following PK/PD-based dosing of meropenem and piperacillin/tazobactam that aims to reduce the emergence of bacterial resistance in critically ill patients.

The safety and tolerability will be assessed by clinical evaluation of adverse events, as well as standard monitoring of vital signs, clinical laboratory tests and electrocardiograms. Given the established safety profiles for both meropenem and piperacillin/tazobactam, a particular attention will be paid to these events:
• Neurotoxicity – patients will be monitored for Beta-lactam-induced encephalopathy, decreased level of consciousness and/or seizures post-initiation of the PK/PD-optimised dosing regimen will be diagnosed clinically by treating clinician.
• Nephrotoxicity - Suspicion of beta-lactam-induced kidney injury is assumed when the definition of acute kidney injury (AKI), based on the Risk, Injury, Failure, Loss, End-stage (RIFLE) criteria is met. AKI status is defined as meeting any one of the RIFLE criteria post-initiation of the PK/PD-optimised dosing regimen.
• Hepatoxicity Suspicion of beta-lactam-induced liver injury is assumed when one of the findings is seen post-initiation of the PK/PD-optimised dosing regimen:
• Hepatocellular liver injury: ALT is >/=5 x the upper limit of the normal reference range OR ALT/ALP ratio is >/= 5
• Cholestatic liver injury: ALP is >/= 2 x the upper limit of the normal reference range OR ALT/ALP ratio </=2
• Mixed pattern of liver injury: ALT/ALP ratio of >2 to <5

Timepoint [1] 323550 0
TDM will be performed daily, throughout the duration of the study dosing regimen and up to 48 hours after cessation.
Laboratory parameters, serum biochemistry, full blood count, renal and hepatic indices and clinical evaluation of adverse events during the study dosing regimen and up to 48 hour post cessation.
Secondary outcome [1] 382221 0
Prevention of emergence of bacterial resistance in critically ill patients. Incidence of bacterial resistance, which is assumed when: >/= 3-fold MIC increase from baseline MIC of the causative organism (measured by broth microdilution and/or Etest) or colonization/infection with newly identified MDR from rectal and nasal swabs.
Timepoint [1] 382221 0
MIC for causative organism and rectal and nasal swabs repeated every other day post-initiation of PK/PD-optimised dosing regimen and 48 hours after cessation of the dosing regimen
Secondary outcome [2] 382222 0
To determine the clinical outcomes associated with PK/PD-based dosing of meropenem and piperacillin/tazobactam – Clinical cure will be assessed by a blinded clinician who has no role in patient management.
Clinical response will be defined as follows:
• Resolution: disappearance of all signs and symptoms related to infection
• Improvement: a marked or moderate reduction in severity and/or number of signs and symptoms related to infection
• Failure: insufficient lessening of the signs and symptoms related to infection to qualify as improvement, including death or indeterminate (no evaluation possible, for any reason)
• Clinical cure: is defined “Yes” for “Resolution” and “No” for all other findings
Timepoint [2] 382222 0
Clinical cure will be assessed on cessation, as well as seven days post-cessation of the PK/PD-optimised dosing regimen

Eligibility
Key inclusion criteria
1. Adult (>18 years old) ICU patient
2. Confirmed or strong suspicion of infection during current ICU admission
3. Patient has been prescribed or is receiving either meropenem or piperacillin/tazobactam for the treatment of current infection
4. Patient is expected to complete at least a 5-day course of meropenem or piperacillin/tazobactam therapy in the ICU
5. Patient has either an arterial line or central venous catheter for blood sampling
6. Informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Patient with a non-complicated urinary tract infection during current ICU admission
2. Suspected or known hypersensitivity towards beta-lactam antibiotics (pre– or post-enrolment)
3. Patient has received study antibiotic for more than 48 hours during current infective episode
4. Patient has any of the following parameters:
• estimated creatinine clearance <15 mL/min OR plasma creatinine concentration >200 µmol/L OR receiving renal replacement therapy (RRT)
• alanine aminotransferase (ALT) OR aspartate aminotransferase (AST) >3 x the upper limit of the normal reference range
• alkaline phosphatase (ALP) >3 x the upper limit of the normal reference range
• total bilirubin >2 x the upper limit of the normal reference range
• haematocrit <21% or haemoglobin <70 g/L
• neutropenia with absolute neutrophil count <500/mm3
• platelet count <50000/mm3 from rectal and nasal swabs.
5. Receiving extracorporeal membrane oxygenation (ECMO)
6. Pregnant patients or lactating mothers

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 not concealed, not randomised.
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
Phase 2 / Phase 3
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
This is a proof-of-concept clinical trial seeking to establish the safety and tolerability, as well as the clinical efficacy of PK/PD-optimised dosing of meropenem and piperacillin/tazobactam in critically ill patients with the aim to proceed with a larger clinical trial. We believe that a sample size of 12 patients per antibiotic, receiving at least 5-days of PK/PD-optimised dosing per antibiotic is appropriate in this pilot study after considering both feasibility and the precision around the estimates to be used to design future trials.

Continuous data will be presented as mean (standard deviation) or median (interquartile range) as appropriate. The rates of adverse events, emergence of bacterial resistance and clinical cure will be presented as number and percentages.

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] 16519 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 30075 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 305517 0
University
Name [1] 305517 0
University of Queensland
Address [1] 305517 0
University of Queensland Strategic Funding Project No: 612030
UQCCR
The University of Queensland, Royal Brisbane and Women’s Hospital, Butterfield St, Herston, Queensland, Australia 4029
Country [1] 305517 0
Australia
Funding source category [2] 305525 0
Government body
Name [2] 305525 0
Reduce Centre of Research Excellence - University of Queensland - National Health and Medical Research Council
Address [2] 305525 0
Australian National Health and Medical Research Council (NHMRC) Reduce – Centre of Research Excellence (CRE) Project No: GNT1099452
16 Marcus Street, Canberra, ACT, Australia 2601
Country [2] 305525 0
Australia
Primary sponsor type
University
Name
Reduce Centre of Research Excellence - University of Queensland
Address
UQCCR
The University of Queensland,
Royal Brisbane and Women’s Hospital,
Butterfield St,
Herston, Queensland, Australia 4029
Country
Australia
Secondary sponsor category [1] 305933 0
None
Name [1] 305933 0
Address [1] 305933 0
Country [1] 305933 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305830 0
The Prince Charles Hospital Ethics Committee
Ethics committee address [1] 305830 0
The Prince Charles Hospital
Human Research Ethics Committee
Building 14
Rode Road CHERMSIDE QLD 4032
Ethics committee country [1] 305830 0
Australia
Date submitted for ethics approval [1] 305830 0
10/10/2019
Approval date [1] 305830 0
02/12/2019
Ethics approval number [1] 305830 0
HREC/QPCH/19/58356

Summary
Brief summary
This is a prospective, open-labelled, single-centre phase IIa clinical study, which aims to evaluate the safety and tolerability, as well as the clinical efficacy of meropenem and piperacillin/tazobactam dosing regimens that are optimised to prevent the emergence of bacterial resistance in critically ill patients.

Sepsis and septic shock are prominent causes of morbidity and mortality in critically ill patients. Antibiotic therapy that is not optimal is associated with substantially increased mortality. However, the process of optimising antibiotic therapy can be highly challenging in the intensive care unit. Increasingly clinical data are suggesting that higher antibiotic exposures are needed for critically ill patients with sepsis and achieving this target exposure may also prevent bacterial resistance.

The general objective of this study is to evaluate the safety and tolerability, as well as the effectiveness of Pharmacokinetic and Pharmacodynamic (PK/PD)-based dosing that aims to prevent the emergence of bacterial resistance in critically ill patients in the ICU, in order to establish feasibility to proceed with a larger clinical trial. We plan to recruit at least 12 participants per antibiotic at the RBWH Intensive Care Unit.

It is hoped that the knowledge gained from this study will enable the development of individualised optimised dosing regimens that ultimately reduce the prevalence of multi-drug resistant organisms in ICU patients.

Whilst this study is classified as a Phase IIa clinical trial we are not testing the safety of a new drug we are only testing the tolerability of higher than standard dosing of two drugs which are currently used in standard practice for treatment of sepsis and septic shock in ICU.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101742 0
Prof Jason Roberts
Address 101742 0
Level 8 University of Queensland Centre for Clinical Research,
The University of Queensland,
Royal Brisbane and Women’s Hospital, Butterfield St,
Herston, Queensland, Australia 4029
Country 101742 0
Australia
Phone 101742 0
+61 409769397
Fax 101742 0
Email 101742 0
j.roberts2@uq.edu.au
Contact person for public queries
Name 101743 0
Prof Jason Roberts
Address 101743 0
Level 8 University of Queensland Centre for Clinical Research,
The University of Queensland,
Royal Brisbane and Women’s Hospital, Butterfield St,
Herston, Queensland, Australia 4029
Country 101743 0
Australia
Phone 101743 0
+61 409769397
Fax 101743 0
Email 101743 0
j.roberts2@uq.edu.au
Contact person for scientific queries
Name 101744 0
Prof Jason Roberts
Address 101744 0
Level 8 University of Queensland Centre for Clinical Research,
The University of Queensland,
Royal Brisbane and Women’s Hospital, Butterfield St,
Herston, Queensland, Australia 4029
Country 101744 0
Australia
Phone 101744 0
+61 409769397
Fax 101744 0
Email 101744 0
j.roberts2@uq.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
No individual patient data will be able to be identified with this study
What supporting documents are/will be available?
No other documents available
Summary results
No Results