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Trial registered on ANZCTR


Registration number
ACTRN12623000032651
Ethics application status
Approved
Date submitted
8/12/2022
Date registered
12/01/2023
Date last updated
12/01/2023
Date data sharing statement initially provided
12/01/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Individualising beta-lactam antibiotic dosing in septic intensive care unit patients based on plasma concentration measurements using therapeutic drug monitoring
Scientific title
The ADAPT-TDM RCT - A beta-lactam antibiotic Dose Adaptation Pilot feasibility randomised controlled Trial utilising Therapeutic Drug Monitoring
Secondary ID [1] 308402 0
Nil known
Universal Trial Number (UTN)
Trial acronym
The ADAPT-TDM RCT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Beta-lactam antibiotic dosing in sepsis

 328200 0
Condition category
Condition code
Infection 325253 325253 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Dose adaptation of beta-lactam antibiotics (meropenem, piperacillin/tazobactam, cefepime) based on plasma concentrations obtained using therapeutic drug monitoring (TDM) in sepsis/septic shock.

Aim: To pilot and implement beta-lactam antibiotic (beta-lactam) TDM to individualise doses in critically ill patients with suspected or proven sepsis

Participants will be randomly allocated to TDM guided dosing or standard dosing (as per site ICU guidelines). The choice of beta-lactam will not be mandated by the study and will be directed by the treating team. The initial dose will be determined by the treating clinician or based on ICU guidelines. Once randomised to the intervention group, the dose will be adapted based on target plasma concentrations.

Participants in the TDM arm will receive the study beta-lactam guided by daily TDM. The initial dose will be per Alfred ICU guidelines. After four doses (steady state) the first plasma sampling will be performed. Subsequent doses will be adjusted based on the concentrations obtained in the TDM arm. Sampling will be performed once daily (Monday to Friday) with result notification and dose adjustment as necessary on the same day. The time commitment for sample collection is estimated to be approximately ten minutes. The subsequent samples will be timed 24-hourly from the first sampling. The dose adjustments will be performed based on algorithm adapted from previously published literature (Reference 1), while taking into account any clinical parameters such as renal function, initiation of renal replacement therapy or recovery from acute renal impairment. The duration of intervention will depend on the duration of therapy. Doses will be adjusted either by increasing or decreasing the strength, increasing or decreasing the frequency of dosing or increasing or decreasing the duration of infusion depending on the plasma target concentration aimed for (see below).
The dose adaptation algorithm used in this study will be compared with doses adjustments predicted based on plasma concentrations by an open access web based Bayesian dose adjustment software platform, TDMx. TDMx will not be used in actual dose modification and will be used to compare the dose adaptation recommendation only. Acceptance of dose adaptation recommendation by treating teams will be audited at the end of the study.

The duration of antibiotic therapy will be determined by the treating physician. All eligible consenting patients with suspected or proven bacterial sepsis receiving study beta-lactams over a period of six months will be included in the control arm of the study.

The pharmacodynamic target for Piperacillin/Cefepime/ Meropenem will be the epidemiological cut-off (ECOFF) value of Pseudomonas aeruginosa for empiric therapy.
The pharmacokinetic/pharmacodynamic (PK/PD) target aimed for in this study is 100% time (fT) > minimum inhibitory concentration (MIC) and concentrations aimed for will be 2-4xMIC.
The ECOFF values (mg/L) for piperacillin, meropenem and cefepime are 16, 2, and 8, respectively.
Below are the minimum and maximum target concentrations (mg/L). The infusion rate will be determined based on initial dosing regimen, target concentrations and patient parameters (renal function, need for organ support) and infection characteristics (focus of infection).

Antibiotic, Min target concentration, Max target concentration (range), Dose range g/24 h:
Piperacillin, 32, 64 - 96, 12 - 24
Meropenem, 4 - 8, 16, 3 - 8
Cefepime, 8 - 16, 20, 3 - 8

Reference:
1 De Waele JJ, Carrette S, Carlier M, et al. Therapeutic drug monitoring-based dose optimisation of piperacillin/tazobactam and meropenem: a randomised controlled trial. Intensive Care Med 2014; 40: 380–387.
Intervention code [1] 324853 0
Treatment: Other
Comparator / control treatment
Standard of care arm
Standard of care participants will receive beta-lactams per usual practice based on local ICU guidelines (Antimicrobial in ICU, Alfred Health, Ver 3.1). TDM (Monday to Friday) will be conducted in this arm. The time commitment for sample collection is estimated to be approximately ten minutes. The treating team will be blinded to the TDM these results. Dose adjustments in the control arm will be based on ICU guidelines which is current standard practice. Duration of antibiotic therapy will be at the discretion of the treating clinician. All eligible consenting patients with suspected or proven bacterial sepsis receiving study beta-lactams over a period of six months will be included in the control arm of the study.
Control group
Active

Outcomes
Primary outcome [1] 333109 0
To test the feasibility of recruitment (number of participants recruited from pool of eligible participants)
The pool of eligible participants will be determined by audit of study recruitment log.
Timepoint [1] 333109 0
At the end of the six month study period.
Primary outcome [2] 333113 0
To test the feasibility of randomisation (number of participants randomised from pool of participants eligible for randomisation - determined by audit of study recruitment log)
Timepoint [2] 333113 0
At the end of the 6-month study period.
Primary outcome [3] 333119 0
To test the fidelity of TDM (the degree to which TDM is delivered as intended - accurate timing of sampling and availability of results within 4 - 6 hours of sampling. This will be assessed as a composite outcome.
Via chart audit.
Timepoint [3] 333119 0
Daily assessment from 24-hours post commencement of antibiotic therapy to cessation of antibiotic therapy.
Secondary outcome [1] 415860 0
To assess the impact of TDM guided dose optimisation on target attainment (appropriate target concentration of 100% fT>2-4xMIC)
Target attainment: Number of days where appropriate antibiotic target concentration of 100% fT>2-4xMIC is attained (for every individual patient), assessed by measuring daily plasma samples. The dose of the antibiotic will be recorded daily.
Timepoint [1] 415860 0
Daily assessment from 24-hours post commencement of antibiotic therapy to cessation of antibiotic therapy.


Secondary outcome [2] 415880 0
Impact on clinical outcomes: organ dysfunction

By calculation of Sequential Organ Failure assessment (SOFA) score and chart audit.
Timepoint [2] 415880 0
Daily assessment for organ dysfunction from 24-hours post commencement of antibiotic therapy to end of antibiotic therapy and for the duration of ICU admission, thereafter.
Secondary outcome [3] 417162 0
Uptake of beta-lactam TDM
- chart audit - whether TDMs were performed as per recommendations
Timepoint [3] 417162 0
Daily assessment from 24-hours post commencement of antibiotic therapy to cessation of antibiotic therapy.
Secondary outcome [4] 417163 0
Uptake of dose adjustment
- chart audit - whether doses were changed based on TDM
Timepoint [4] 417163 0
Daily assessment from 24-hours post commencement of antibiotic therapy to cessation of antibiotic therapy.
Secondary outcome [5] 417164 0
ICU length of stay
Via chart audit
Timepoint [5] 417164 0
At conclusion of data collection or 6-months whichever is later
Secondary outcome [6] 417165 0
Clinical cure (resolution of clinical signs of infection – normalisation of blood pressure, fever resolution, normalisation of white cell counts)
Via chart audit
Timepoint [6] 417165 0
At conclusion of data collection
Secondary outcome [7] 417166 0
Microbiological cure (resolution of bacteraemia)
Via chart audit
Timepoint [7] 417166 0
At conclusion of data collection
Secondary outcome [8] 417167 0
30-day mortality (patients who die within 30 days of being in hospital)
via chart audit
Timepoint [8] 417167 0
30-days post commencement of intervention
Secondary outcome [9] 417168 0
ICU mortality (patients that die in ICU)
Via chart audit
Timepoint [9] 417168 0
Mortality occurring any time in ICU post commencement of intervention
Secondary outcome [10] 417169 0
Duration of antibiotic therapy.
Via chart audit
Timepoint [10] 417169 0
From intervention commencement to the end of antibiotic therapy during ICU admission.
Secondary outcome [11] 417171 0
Comparison of per protocol dosing advice with that of web based software, TDMx for meropenem - this is a descriptive comparison of dose recommendation based on TDM versus that recommended by software


Using correlation co-efficient (comparing total dose over 24 hours per protocol with that advised by TDMx)
Timepoint [11] 417171 0
From commencement of intervention to end of antibiotic therapy.
Secondary outcome [12] 417172 0
Comparison of per protocol dosing advice with that of web based software, TDMx for piperacillin - this is a descriptive comparison of dose recommendation based on TDM versus that recommended by software


Using correlation co-efficient (comparing total dose over 24 hours per protocol with that advised by TDMx)
Timepoint [12] 417172 0
From commencement of intervention to end of antibiotic therapy.

Eligibility
Key inclusion criteria
1. Aged 18 years or over, admitted to the ICU
2. Bacterial infection considered highly likely
3. Informed consent is obtained from the patient or their surrogate decision maker
4. A study beta-lactam has been prescribed and at least four doses have been administered
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy/lactation
2. Imminent death (within 24 hours)
3. Study enrolment deemed inappropriate by treating clinician
4. Hypersensitivity to beta-lactam antibiotics
5. Treatment commenced more than 24 hours prior to randomisation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Permuted block randomisation via computer program
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
No specific sample size calculation is possible given the exploratory nature of this project. Our proposed sample size is 90 (15 per beta-lactam per arm).
Continuous data will be presented as mean (SD) when normally distributed, and median [IQR] where non-normally distributed. Categorical data will be presented as counts (%). Between group comparisons will utilise univariate tests of significance, where analysis assumptions are met. Covariates will subsequently be identified for inclusion in a multivariable modelling. Analysis will primarily be conducted using Stata (StataCorp. 2019. Stata Statistical Software: Release 16. College Station, TX: StataCorp LLC.)

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
31/01/2023
Actual
Date of last participant enrolment
Anticipated
30/06/2023
Actual
Date of last data collection
Anticipated
1/10/2023
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 23564 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 38986 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 312653 0
Hospital
Name [1] 312653 0
The Alfred (Alfred Research Trust Small Project Grant; Alfred Pathology Special Purpose Fund)
Country [1] 312653 0
Australia
Primary sponsor type
Hospital
Name
The Alfred
Address
55 Commercial Road
Melbourne 3004
Victoria
Country
Australia
Secondary sponsor category [1] 314271 0
None
Name [1] 314271 0
Address [1] 314271 0
Country [1] 314271 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311960 0
Alfred Hospital HREC
Ethics committee address [1] 311960 0
Office of ethics and research governance
Level 5, 553 St Kilda Rd,
Melbourne VIC 3004
Ethics committee country [1] 311960 0
Australia
Date submitted for ethics approval [1] 311960 0
26/09/2022
Approval date [1] 311960 0
22/11/2022
Ethics approval number [1] 311960 0

Summary
Brief summary
Sepsis is a serious life threatening condition. Septic patients have significant organ impairment. Prompt administration of right dose of antibiotics is an important cornerstone of resuscitation of sepsis. Currently, doses of beta-lactam antibiotics at administered at a fixed dose or adjusted to renal function.
Septic patients have marked alterations in their physiology that affect the pharmacokinetics of beta-lactams. Fixed doses of beta-lactams in sepsis lead to unpredictable variability in plasma concentrations. Septic patients are likely to have complex comorbidities such as immune compromise, infections with resistant organisms and deep-seated infections such as meningitis or endocarditis. Previous studies have demonstrated variable (sub and supra-therapeutic) concentrations of beta-lactam antibiotics when standard dosing is used. Sub-therapeutic concentrations carry the risk of treatment failure and supra-therapeutic concentrations can lead to toxicity, both scenarios can lead to poor clinical outcomes. Beta-lactam antibiotics are the most commonly prescribed antibiotics in the treatment of sepsis in the ICU.
Therapeutic drug monitoring (TDM) guided dosing involves individualising doses based on plasma concentrations. Over the last decade, TDM of beta-lactams has been increasingly recommended in the literature due to the pharmacokinetic variability seen in critical illness. However, only a few centres have implemented this test. A knowledge gap exists in literature on implementation of beta-lactam TDM.

In this RCT we aim to pilot the implementation of beta-lactam TDM in the ICU in the management of patients with suspected or proven sepsis. We will study the process steps in implementation, the feasibility of randomisation, recruitment and acceptability of variable dosing of beta-lactams. In addition we will compare the dosing advice from software, TDMx with that of researcher recommendation.

This study will provide important information on dose adaptation. The knowledge gained from this study can used to inform implementation of beta-lactam TDM as a clinical service.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 122974 0
Prof Anton Peleg
Address 122974 0
Department of Infectious Diseases
The Alfred
55 Commercial Road
Melbourne VIC 3004
Victoria
Country 122974 0
Australia
Phone 122974 0
+61 3 90766076
Fax 122974 0
Email 122974 0
anton.peleg@monash.edu
Contact person for public queries
Name 122975 0
Dr Rekha Pai Mangalore
Address 122975 0
Department of Infectious Diseases
The Alfred
55 Commercial Road
Melbourne VIC 3004
Victoria
Country 122975 0
Australia
Phone 122975 0
+61 3 90765436
Fax 122975 0
Email 122975 0
rekha.paimangalore@monash.edu
Contact person for scientific queries
Name 122976 0
Dr Rekha Pai Mangalore
Address 122976 0
Department of Infectious Diseases
The Alfred
55 Commercial Road
Melbourne VIC 3004
Country 122976 0
Australia
Phone 122976 0
+61 3 90765436
Fax 122976 0
Email 122976 0
rekha.paimangalore@monash.edu

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All individual de-identified data collected during the study
When will data be available (start and end dates)?
After the publication of the first paper of the collaboration and available for 5 years after publication
Available to whom?
Scientific investigators interested in the field
Available for what types of analyses?
Only to achieve the aims in the approved proposal
How or where can data be obtained?
After contact with the principal investigator via email
anton.peleg@monash.edu


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.