PharmacokineticsNCT03033394
Beta-lactam Pharmacokinetics in Secondary Care
An observational study of Pharmacokinetics and Beta Lactam Adverse Reaction, run by Imperial College London at 1 site in United Kingdom.
Trial summary
Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide antimicrobial agents, given fears over the narrow therapeutic window of these agents and the serious adverse events associated with toxicity. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pharmacokinetics, Beta Lactam Adverse Reaction, Penicillin Allergy
- What is being tested?
- Beta-lactam antibiotic
- How many people
- 65 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 12 Jul 2017to 1 Aug 2019
- Phase
- Observational
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: Participants from a non-critical care setting will be recruited after receiving at least 5 doses of target antimicrobial. Participants receiving oral and intravenous therapy will be eligible.
Who may be able to join
- Adult subjects over 18 years old
- Capacity to consent to participation
- Receiving target antimicrobial (amoxicillin, amoxcillin-clavulanate, cefuroxime, ceftriaxone, flucloxacillin, meropenem, piperacillin-tazobactam) for at least 5 doses prior to sampling
- Appropriate venous access (or for venous access to be gained)
Who cannot join
- Children under 18 years old
- Lacking capacity or prisoner
- Anaemia or bleeding disorder, deemed significant by the patients physician
- Patient's physician deems that they are not suitable for inclusion in the study
- Patients unlikely to be receiving agent for study period
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Defining Adult Beta-lactam Antimicrobial Pharmacokinetics Across the Secondary Care Setting
Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide antimicrobial agents, given fears over the narrow therapeutic window of these agents and the serious adverse events associated with toxicity. However, in critical care the role of TDM for optimisation of therapy has been demonstrated to help optimise dosing of patients who tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). This is of growing importance given that low concentrations of antimicrobial agents, below a micro-organisms minimum inhibitory concentration (MIC) is believed to be a major driver of AMR. The investigators set out to explore whether similar observations in PK-PD target variability are currently being observed across the secondary care setting (outside of critical care) and whether these appear to be impacting on clinical outcomes.
Read the detailed description
STUDY PARTICIPANTS
- Participants receiving oral or intravenous therapy will be included in this study.
- Drug level sampling will be undertaken once the participant is at steady state (after at least 5 doses have been administered to those on treatment).
- All patients will be consented using the participation information leaflet and consent form provided in appendix 1.
DRUG LEVEL SAMPLING
- Patients will be identified for inclusion, and researchers will discuss inclusion in the study with the patient and provide clinical information for them to consider. Individuals will be recruited from all areas of secondary care (including, general medicine, general surgery, augmented care, and out-patient parenteral antimicrobial therapy [OPAT]).
- They will then be consented by researchers after being given at least 24 hours to consider this information and as long as the patient has expressed interest in participating to their treating physician.
- This will include permission for basic, anonymised demographic and clinical data to be collected related to the patients infection, for which they are receiving antimicrobial therapy.
- An extra 3mLs of blood will be collected during the patient's routine daily phlebotomy round following their consent. They will be enrolled for up to 72 hours or two days of routine blood tests (whichever is shorter). Up to 10 samples may be taken during the 2 days the patient is enrolled, depending on the number of routine blood tests the patient receives during that day. No more than 3mLs will be taken per each routine blood sample. For example, if the individuals will only have routine blood tests taken at 8am on day 1 and day 2. Then only two extra samples will be taken (3mLs on D1 and 3mLs on D2).
- The time they received their dose of antimicrobials, the length of infusion time (if available), and time the sample was collected will all be recorded.
- PK/PD indices for evaluation will be calculated post-hoc during pharmacokinetic-pharmacodynamic analysis. TDM sampling can occur at any time during the dosing schedule (in line with routine blood testing).
- A standard operating procedure for this study can be found in appendix 3.
SAMPLE PREPARATION AND ANALYSIS
- All blood samples will be allowed to clot and placed on ice. They will be centrifuged at 2,400rpm for 10 minutes. Sera from each sample will be separated into three vials and stored at -80C.
- Beta-lactam concentrations will be measured using validated high-performance liquid chromatography methods.
- Samples will be stored for up to three years post completion of data collection.
- Consent will be gained for samples to be used for calibration of electrochemical sensors in ex-vivo studies. This will be performed within 90 days of the samples being collected.
PHARMCOKINETIC-PHARMACODYNAMIC MODELLING
- Data will be anonymised and analysed using Pmetrics in R.
- Different pharmacokinetic models will be explored using in built statistical analysis options and visual predictive checks.
- Pharmacodynamic models will then be incorporated into the model using evidence identified in the literature for selection of parameters.
- Monte Carlo simulation will then be used to for simulation of target attainments and analysis of pharmacodynamic outcomes
- Being tested
- Beta-lactam antibiotic
- Keywords
- Penicillins, Drug Monitoring, Pharmacokinetics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Beta-lactam antibioticDrug
Also called Penicillin
Routine clinical dosing
| Study group | Role | What they receive |
|---|---|---|
| Beta-lactam antibiotic | Observational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections. Receives: Drug: Beta-lactam antibiotic |
What is being measured
The primary outcome is the main question the study is designed to answer.
Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT>MIC)
Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.
Measured: Two to 10 samples taken during the first 120 hours of antimicrobial therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Jan 2017 (estimated)
- Study start12 Jul 2017
- Primary completion1 Aug 2019
- Study completion1 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for PharmacokineticsStudies of the same condition, open and under way.
- More trials run by Imperial College LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 65 participants (actual)
Sponsor and investigators
- Lead sponsor
- Imperial College London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Alison H Holmes, MD MPH MBBS, Principal investigator, Health Protection Research Unit in HCAI & AMR
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03033394
- Sponsor's protocol ID
- 207217
- Other IDs
- 16/LO/2179, 33017
- Status last verified
- Aug 2021
- First submitted
- 19 Jan 2017
- Last updated
- 30 Aug 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 30 Aug 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Defining Adult Beta-lactam Antimicrobial Pharmacokinetics Across the Secondary Care Setting
- ClinicalTrials.gov ID
- NCT03033394
- Acronym / sponsor ID
- 207217
- Keywords
- Penicillins, Drug Monitoring, Pharmacokinetics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 65 participants (actual)
- Lead sponsor
- Imperial College LondonUniversity, hospital or other
- Study start
- 12 Jul 2017 (actual)
- Primary completion
- 1 Aug 2019 (actual)
- Study completion
- 1 Aug 2019 (actual)
- First posted
- 26 Jan 2017 (estimated)
- Results
- Posted 30 Aug 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Currently in the UK, TDM is routinely performed for aminoglycosides and glycopeptide antimicrobial agents, given fears over the narrow therapeutic window of these agents and the serious adverse events associated with toxicity. However, in critical care the role of TDM for optimisation of therapy has been demonstrated to help optimise dosing of patients who tend to have variable pharmacokinetic parameters (J. A. Roberts et al,). This is of growing importance given that low concentrations of antimicrobial agents, below a micro-organisms minimum inhibitory concentration (MIC) is believed to be a major driver of AMR. The investigators set out to explore whether similar observations in PK-PD target variability are currently being observed across the secondary care setting (outside of critical care) and whether these appear to be impacting on clinical outcomes.
Detailed description
STUDY PARTICIPANTS
- Participants receiving oral or intravenous therapy will be included in this study.
- Drug level sampling will be undertaken once the participant is at steady state (after at least 5 doses have been administered to those on treatment).
- All patients will be consented using the participation information leaflet and consent form provided in appendix 1.
DRUG LEVEL SAMPLING
- Patients will be identified for inclusion, and researchers will discuss inclusion in the study with the patient and provide clinical information for them to consider. Individuals will be recruited from all areas of secondary care (including, general medicine, general surgery, augmented care, and out-patient parenteral antimicrobial therapy [OPAT]).
- They will then be consented by researchers after being given at least 24 hours to consider this information and as long as the patient has expressed interest in participating to their treating physician.
- This will include permission for basic, anonymised demographic and clinical data to be collected related to the patients infection, for which they are receiving antimicrobial therapy.
- An extra 3mLs of blood will be collected during the patient's routine daily phlebotomy round following their consent. They will be enrolled for up to 72 hours or two days of routine blood tests (whichever is shorter). Up to 10 samples may be taken during the 2 days the patient is enrolled, depending on the number of routine blood tests the patient receives during that day. No more than 3mLs will be taken per each routine blood sample. For example, if the individuals will only have routine blood tests taken at 8am on day 1 and day 2. Then only two extra samples will be taken (3mLs on D1 and 3mLs on D2).
- The time they received their dose of antimicrobials, the length of infusion time (if available), and time the sample was collected will all be recorded.
- PK/PD indices for evaluation will be calculated post-hoc during pharmacokinetic-pharmacodynamic analysis. TDM sampling can occur at any time during the dosing schedule (in line with routine blood testing).
- A standard operating procedure for this study can be found in appendix 3.
SAMPLE PREPARATION AND ANALYSIS
- All blood samples will be allowed to clot and placed on ice. They will be centrifuged at 2,400rpm for 10 minutes. Sera from each sample will be separated into three vials and stored at -80C.
- Beta-lactam concentrations will be measured using validated high-performance liquid chromatography methods.
- Samples will be stored for up to three years post completion of data collection.
- Consent will be gained for samples to be used for calibration of electrochemical sensors in ex-vivo studies. This will be performed within 90 days of the samples being collected.
PHARMCOKINETIC-PHARMACODYNAMIC MODELLING
- Data will be anonymised and analysed using Pmetrics in R.
- Different pharmacokinetic models will be explored using in built statistical analysis options and visual predictive checks.
- Pharmacodynamic models will then be incorporated into the model using evidence identified in the literature for selection of parameters.
- Monte Carlo simulation will then be used to for simulation of target attainments and analysis of pharmacodynamic outcomes
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Beta-lactam antibiotic | – | Drug: Beta-lactam antibioticObservational pharmacokinetic study of non-critical care patients receiving beta-lactam antibiotics for management of infections. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- Participants from a non-critical care setting will be recruited after receiving at least 5 doses of target antimicrobial. Participants receiving oral and intravenous therapy will be eligible.
Key inclusion criteria (4 listed)
- Adult subjects over 18 years old
- Capacity to consent to participation
- Receiving target antimicrobial (amoxicillin, amoxcillin-clavulanate, cefuroxime, ceftriaxone, flucloxacillin, meropenem, piperacillin-tazobactam) for at least 5 doses prior to sampling
- Appropriate venous access (or for venous access to be gained)
Key exclusion criteria (5 listed)
- Children under 18 years old
- Lacking capacity or prisoner
- Anaemia or bleeding disorder, deemed significant by the patients physician
- Patient's physician deems that they are not suitable for inclusion in the study
- Patients unlikely to be receiving agent for study period
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Beta-lactam antibioticAlso: PenicillinRoutine clinical dosing | Drug | Beta-lactam antibiotic |
Primary outcome
Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT>MIC)
Time frame: Two to 10 samples taken during the first 120 hours of antimicrobial therapy
Minimum inhibitory concentration (MIC) is the concentration required to visibly inhibit microbial growth in vitro. The MIC for each drug was defined by non-species related breakpoints provided in EUCAST v11.0. Results are given as a fraction of the dosing interval over which the concentration of the unbound drug is greater than the MIC.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Aug 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Alison H Holmes, MD MPH MBBS principal investigator
Health Protection Research Unit in HCAI & AMR
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pharmacokinetics and Beta Lactam Adverse Reaction, run by Imperial College London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Aug 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Aug 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Fraction of the Dosing Interval Over Which the Concentration of Unbound Drug is Greater Than the Minimum Inhibitory Concentration (fT>MIC) (time frame: Two to 10 samples taken during the first 120 hours of antimicrobial therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Aug 2021.