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Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections (TDM-RCT)

Primary Purpose

Sepsis, Hemodynamic Instability, Bacterial Infections

Status
Recruiting
Phase
Not Applicable
Locations
Singapore
Study Type
Interventional
Intervention
Therapeutic Drug Monitoring (TDM)
Sponsored by
Singapore General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sepsis focused on measuring Sepsis, Hemodynamic Instability, Therapeutic Drug Monitoring, Gram-negative Bacteria, Beta-Lactams, Fosfomycin, Fluoroquinolone, Glycylcycline, Dialysis

Eligibility Criteria

16 Years - 99 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: 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 Exclusion Criteria: 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

Sites / Locations

  • Singapore General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

No Intervention

Experimental

Arm Label

Control

Intervention

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
June 20, 2023
Last Updated
July 17, 2023
Sponsor
Singapore General Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT05942157
Brief Title
Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections
Acronym
TDM-RCT
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 29, 2023 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Singapore General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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, Dialysis

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
810 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Control
Arm Type
No Intervention
Arm Description
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.
Arm Title
Intervention
Arm Type
Experimental
Arm Description
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
Intervention Type
Other
Intervention Name(s)
Therapeutic Drug Monitoring (TDM)
Intervention Description
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.
Primary Outcome Measure Information:
Title
14-day All-Cause Mortality Rate
Description
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.
Time Frame
14 Days
Secondary Outcome Measure Information:
Title
Fever Resolution
Description
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.
Time Frame
14 Days
Title
Microbiological Treatment Cure of Difficult to Treat Gram-Negative Bacteria (DT-GNB)
Description
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.
Time Frame
14 Days
Title
Improved or Stabilized Sequential Organ Failure Assessment (SOFA)
Description
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.
Time Frame
14 Days
Title
Incidences of Adverse Drug Reactions
Description
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.
Time Frame
Start to End of Antibiotic Therapy (Up to 90 days from randomization, discharge or demise, whichever comes earliest)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tze Peng Lim, PhD
Phone
+65 6326 6959
Email
lim.tze.peng@sgh.com.sg
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tze Peng Lim, PhD
Organizational Affiliation
Singapore General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Singapore General Hospital
City
Singapore
ZIP/Postal Code
168582
Country
Singapore
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Lim Tze Peng, PhD
Email
lim.tze.peng@sgh.com.sg

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Therapeutic Drug Monitoring in Patients With Difficult-to-Treat Gram-Negative Bacterial Infections

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