SepsisTDM-RCTNCT05942157
Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections
A study testing Therapeutic Drug Monitoring (TDM) in people with Sepsis and Hemodynamic Instability, run by Singapore General Hospital at 1 site in Singapore.
Trial summary
A prospective, open-label, randomized controlled trial will be conducted to evaluate a novel TDM-guided therapy in management of DT-GNB infections. We hypothesize that TDM-guided antibiotic therapy will reduce 14-day all-cause mortality by 6% (absolute risk reduction) in septic patients with DT-GNB infections, when… Read more about this study
- Who is it for?
- Ages 16 to 99 years
- Conditions the study is for
- Sepsis, Hemodynamic Instability, Bacterial Infections
- What is being tested?
- Therapeutic Drug Monitoring (TDM)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 810 participants
- Where
- 1 siteSingapore
- Study dates
- 29 Mar 2023to 31 Dec 2025
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 16 to 99 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 16 years or older
- Receive intravenous therapy of the study antibiotics
- Antibiotic treatment should be aimed for at least 3 days at time of inclusion
Who cannot join
- Pregnancy
- Antibiotics cessation before first blood sample collection
- Receiving antibiotics only as prophylaxis
- On palliative care or with less than 48 hours of life expectancy
Trial locations and contacts
1 site in 1 country.
Singapore1 site, 1 recruiting
- Recruiting
Singapore General Hospital
Singapore, 168582
Lim Tze Peng, PhD, lim.tze.peng@sgh.com.sg
About this study
Official title: Evaluation of the Efficacy and Safety of Antibiotic Therapeutic Drug Monitoring (TDM) in Patients With Difficult-to-Treat Gram-Negative Bacterial (DT-GNB) Infections
A prospective, open-label, randomized controlled trial will be conducted to evaluate a novel TDM-guided therapy in management of DT-GNB infections. We hypothesize that TDM-guided antibiotic therapy will reduce 14-day all-cause mortality by 6% (absolute risk reduction) in septic patients with DT-GNB infections, when compared to standard therapy. TDM for 11 antibiotics will be performed for all trial patients although test information will be withheld for the standard therapy arm. The primary aim is to compare the 14-day all-cause mortality rates of novel TDM-guided antibiotic dosing versus standard therapy.
Read the detailed description
Sepsis remains a major cause of morbidity and mortality worldwide in the face of antimicrobial resistance especially in patients with Gram-negative bacteria (GNB) infections. Limited new antibiotics for GNB infections pose a severe threat to clinical management of these patients and thus call for old antibiotics to be repurposed. Dosing regimens of old antibiotics often fail to achieve therapeutic drug concentrations in some septic patients. Septic patients commonly have significant hemodynamic changes and/or undergo extracorporeal interventions that may increase patients' susceptibility to treatment failure and increase the chance of more resistant bacteria emergence, or toxicity from the antibiotic. Hence, the "one size fits all" dosing principle for antimicrobial treatments of suspect sepsis due to infection by antibiotic-resistant- or less susceptible-GNB [collectively known as "difficult-to-treat" (DT)-GNB infections] is no longer viable. This will require therapeutic drug monitoring (TDM) to inform if the dosing is adequate to treat such infections.
This study seeks to provide evidence supporting the application of TDM-guided antibiotic therapy on reducing mortality and morbidity among septic patients with DT-GNB infections and significant hemodynamic changes, which can potentially shift current practice paradigms.
- Conditions
- Sepsis, Hemodynamic Instability, Bacterial Infections, Therapeutic Drug Monitoring, Antimicrobial Resistance
- Being tested
- Therapeutic Drug Monitoring (TDM)
- Keywords
- Sepsis, Hemodynamic Instability, Therapeutic Drug Monitoring, Gram-negative Bacteria, Beta-Lactams, Fosfomycin, Fluoroquinolone, Glycylcycline, Dialysis
- Medical subject headings
- Sepsis, Bacterial Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Therapeutic Drug Monitoring (TDM)Other
Upon randomization and before the bacterial culture results are known, blood sampling will be obtained from the patient during the morning round of initial empiric antibiotic administration. PK/PD target analysis based on the clinical susceptibility breakpoints of Enterobacterales (the most prevalent organism family of DT-GNB infections in our setting) will be performed and a dosage recommendation will be communicated to the primary ID clinician. Antibiotic dosing adjustments (if any) will be made within 8 - 24 hours of the blood sampling by the Primary / Infectious Diseases clinician. In case of inappropriate dosing, where the PK/PD target is not achieved or exceeded with antibiotic side effects observed, the dosage will be increased or decreased, respectively.
| Study group | Role | What they receive |
|---|---|---|
| Control | No intervention | The prescription of antibiotics will follow institution antibiotic prescribing guidelines or at the Infectious Disease (ID) clinician's discretion, based on culture and antibiotic susceptibilities results (whenever available). Empiric antibiotic treatment will be employed prior to the availability of culture or antibiotic susceptibilities results. Antibiotic level measurements, Minimum Inhibitory Concentrations (MIC) testing and Pharmacokinetics/Pharmacodynamics (PK/PD) target analysis will only be performed at Day 14 post enrolment, but the results will not be released to the ID clinician and the primary clinician. |
| Intervention | Experimental | Once a positive GNB culture is known, antibiotic MIC testing will commence, and PK/PD target analysis will be performed using the antibiotic MIC. An every-other-day TDM-guided regimen will be chosen to rapidly adjust the antibiotic doses until the PK/PD target is achieved. In the event the antibiotic dose readjustment is unable to achieve the defined PK/PD target, blood sampling will continue every other day until Day 14 or the PK/PD target is achieved Receives: Other: Therapeutic Drug Monitoring (TDM) |
What is being measured
The primary outcome is the main question the study is designed to answer.
14-day All-Cause Mortality Rate
This is defined as death of any cause. Study aims to compare the difference in 14-day all-cause mortality rates from the day of randomization between both arms.
Measured: 14 Days
Secondary outcomes (4)
Fever Resolution
This is defined as the days to defervescence. Study aims to compare the difference in the days to defervescence after initiation of targeted antibiotic therapy between both arms.
Measured: 14 Days
Microbiological Treatment Cure of Difficult to Treat Gram-Negative Bacteria (DT-GNB)
This is defined as presence of sterile site culture or absence of intended bacterial growth in culture of infection site. Study aims to compare microbiological cure of difficult to treat GNB between both arms.
Measured: 14 Days
Improved or Stabilized Sequential Organ Failure Assessment (SOFA)
This is defined as delta SOFA or change in SOFA score between day 1 (randomization) to day 14. Study aims to compare the changes in SOFA scores between the two arms.
Measured: 14 Days
Incidences of Adverse Drug Reactions
Adverse Drug Reactions (ADRs) are defined as renal failure (defined using RIFLE criteria), Neurologic disorders (defined as altered mental status, peripheral neuropathy, or seizures in the absence of preexisting neurologic conditions, substance-related toxic effects, or infectious syndromes) and hematological disorders (defined as anemia (hemoglobin level <10 g/dL), leukopenia (white blood cell count <4500 cells/μL), or thrombocytopenia (platelet count <150 × 103/μL) with levels below patient's baseline and in the absence of bleeding or myelosuppressive therapies). Study aims to compare the incidences of ADRs between the two arms.
Measured: Start to End of Antibiotic Therapy (Up to 90 days from randomization, discharge or demise, whichever comes earliest)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jul 2023
- Study start29 Mar 2023
- Primary completion31 Dec 2025 (estimated)
- Study completion31 Dec 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for SepsisStudies of the same condition, open and under way.
- More trials run by Singapore General HospitalThe 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
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 810 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Singapore General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Tze Peng Lim, PhD, Principal investigator, Singapore General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05942157
- Sponsor's protocol ID
- TDM RCT
- Acronym
- TDM-RCT
- Status last verified
- Jul 2023
- First submitted
- 20 Jun 2023
- Last updated
- 19 Jul 2023
- Results posted
- No
- Data monitoring committee
- Yes
- 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 19 Jul 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Efficacy and Safety of Antibiotic Therapeutic Drug Monitoring (TDM) in Patients With Difficult-to-Treat Gram-Negative Bacterial (DT-GNB) Infections
- ClinicalTrials.gov ID
- NCT05942157
- Acronym / sponsor ID
- TDM-RCT / TDM RCT
- Conditions
- Sepsis, Hemodynamic Instability, Bacterial Infections, Therapeutic Drug Monitoring, Antimicrobial Resistance
- Keywords
- Sepsis, Hemodynamic Instability, Therapeutic Drug Monitoring, Gram-negative Bacteria, Beta-Lactams, Fosfomycin, Fluoroquinolone, Glycylcycline
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 810 participants (estimated)
- Lead sponsor
- Singapore General HospitalUniversity, hospital or other
- Study start
- 29 Mar 2023 (actual)
- Primary completion
- 31 Dec 2025 (estimated)
- Study completion
- 31 Dec 2025 (estimated)
- First posted
- 12 Jul 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
A prospective, open-label, randomized controlled trial will be conducted to evaluate a novel TDM-guided therapy in management of DT-GNB infections. We hypothesize that TDM-guided antibiotic therapy will reduce 14-day all-cause mortality by 6% (absolute risk reduction) in septic patients with DT-GNB infections, when compared to standard therapy. TDM for 11 antibiotics will be performed for all trial patients although test information will be withheld for the standard therapy arm. The primary aim is to compare the 14-day all-cause mortality rates of novel TDM-guided antibiotic dosing versus standard therapy.
Detailed description
Sepsis remains a major cause of morbidity and mortality worldwide in the face of antimicrobial resistance especially in patients with Gram-negative bacteria (GNB) infections. Limited new antibiotics for GNB infections pose a severe threat to clinical management of these patients and thus call for old antibiotics to be repurposed. Dosing regimens of old antibiotics often fail to achieve therapeutic drug concentrations in some septic patients. Septic patients commonly have significant hemodynamic changes and/or undergo extracorporeal interventions that may increase patients' susceptibility to treatment failure and increase the chance of more resistant bacteria emergence, or toxicity from the antibiotic. Hence, the "one size fits all" dosing principle for antimicrobial treatments of suspect sepsis due to infection by antibiotic-resistant- or less susceptible-GNB [collectively known as "difficult-to-treat" (DT)-GNB infections] is no longer viable. This will require therapeutic drug monitoring (TDM) to inform if the dosing is adequate to treat such infections.
This study seeks to provide evidence supporting the application of TDM-guided antibiotic therapy on reducing mortality and morbidity among septic patients with DT-GNB infections and significant hemodynamic changes, which can potentially shift current practice paradigms.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Control | No intervention | –The prescription of antibiotics will follow institution antibiotic prescribing guidelines or at the Infectious Disease (ID) clinician's discretion, based on culture and antibiotic susceptibilities results (whenever available). Empiric antibiotic treatment will be employed prior to the availability of culture or antibiotic susceptibilities results. Antibiotic level measurements, Minimum Inhibitory Concentrations (MIC) testing and Pharmacokinetics/Pharmacodynamics (PK/PD) target analysis will only be performed at Day 14 post enrolment, but the results will not be released to the ID clinician and the primary clinician. |
| Intervention | Experimental | Other: Therapeutic Drug Monitoring (TDM)Once a positive GNB culture is known, antibiotic MIC testing will commence, and PK/PD target analysis will be performed using the antibiotic MIC. An every-other-day TDM-guided regimen will be chosen to rapidly adjust the antibiotic doses until the PK/PD target is achieved. In the event the antibiotic dose readjustment is unable to achieve the defined PK/PD target, blood sampling will continue every other day until Day 14 or the PK/PD target is achieved |
Who may qualify
- Ages
- 16 to 99 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 16 years or older
- Receive intravenous therapy of the study antibiotics
- Antibiotic treatment should be aimed for at least 3 days at time of inclusion
Key exclusion criteria (4 listed)
- Pregnancy
- Antibiotics cessation before first blood sample collection
- Receiving antibiotics only as prophylaxis
- On palliative care or with less than 48 hours of life expectancy
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 |
|---|---|---|
| Therapeutic Drug Monitoring (TDM)Upon randomization and before the bacterial culture results are known, blood sampling will be obtained from the patient during the morning round of initial empiric antibiotic administration. PK/PD target analysis based on the clinical susceptibility breakpoints of Enterobacterales (the most prevalent organism family of DT-GNB infections in our setting) will be performed and a dosage recommendation will be communicated to the primary ID clinician. Antibiotic dosing adjustments (if any) will be made within 8 - 24 hours of the blood sampling by the Primary / Infectious Diseases clinician. In case of inappropriate dosing, where the PK/PD target is not achieved or exceeded with antibiotic side effects observed, the dosage will be increased or decreased, respectively. | Other | Intervention |
Primary outcome
14-day All-Cause Mortality Rate
Time frame: 14 Days
This is defined as death of any cause. Study aims to compare the difference in 14-day all-cause mortality rates from the day of randomization between both arms.
4 secondary outcomes
Fever Resolution
Time frame: 14 Days
Microbiological Treatment Cure of Difficult to Treat Gram-Negative Bacteria (DT-GNB)
Time frame: 14 Days
Improved or Stabilized Sequential Organ Failure Assessment (SOFA)
Time frame: 14 Days
Incidences of Adverse Drug Reactions
Time frame: Start to End of Antibiotic Therapy (Up to 90 days from randomization, discharge or demise, whichever comes earliest)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 19 Jul 2023.
- 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.
Tze Peng Lim, PhD principal investigator
Singapore General Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Therapeutic Drug Monitoring (TDM) in people with Sepsis and Hemodynamic Instability, run by Singapore General Hospital at 1 site in Singapore.
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 3 inclusion and 4 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: status not confirmed, as of the sponsor's last update on 19 Jul 2023. 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 Singapore. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Tze Peng Lim, PhD (+65 6326 6959, lim.tze.peng@sgh.com.sg), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
14-day All-Cause Mortality Rate (time frame: 14 Days). 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 19 Jul 2023.