Clinical trial NCT06444802: Model-informed Precision Dosing for Linezolid
Official title: Model-informed Precision Dosing for Linezolid: a Pilot Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Gram-Positive Bacterial Infections
Keywords: Linezolid
PK-PD Model
TDM
Lead sponsor: University of Hamburg-Eppendorf
Sponsor class: OTHER
First posted: 2024-06-06
Enrollment: 28
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Study Rationale: Previous in vitro and retrospective in vivo studies suggest that optimal linezolid concentrations (between 2 and 7 mg/L) achieve clinical efficacy and microbiological eradication while minimizing side effects like thrombocytopenia and the emergence of resistance. No prospective or randomized clinical trial has confirmed these findings, and there is no consensus on how to adjust linezolid dosing to achieve optimal drug concentrations.

Objectives: The primary objective is to determine if model-informed precision dosing optimizes linezolid dosing to achieve therapeutic trough concentrations compared to a standard dose. Secondary objectives include assessing the PK/PD profile, investigating the prevalence of linezolid resistance among gram-positive bacteria, assessing microbiological resolution of infection, and evaluating the safety and tolerability of linezolid.

Methodology: This study is an open, monocentric pilot randomized controlled trial with two arms: standard dose therapy versus dose adjustment based on model-informed precision dosing using therapeutic drug monitoring and PK/PD targets developed in TMDx software.

Sample Size: 28 patients, 14 in each group. Assumptions are based on only 25% of patients in intensive care achieving the optimal therapeutic range with standard dosing, compared to an expected 80% achieving this with model-informed precision dosing.

Selection Criteria: Adult patients (18+ years) already starting linezolid treatment for gram-positive infections, expected to require treatment beyond the next calendar day. Exclusions include imminent death, expected or confirmed pregnancy, expected linezolid treatment of less than 4 days or more than 4 weeks.

Outcomes: The primary endpoint is defined as the difference in the proportion of patients in the intervention and in the control groups who maintained a trough linezolid concentration of 2 to 7 mg/L on Day 7 and Day 13.


Eligibility criteria: Inclusion Criteria:

1. ≥ 18 years of age
2. Linezolid treatment is indicated or has been started due to pneumonia, skin or soft tissue infection; the patient has received no more than 2 infusions of 600 mg linezolid each
3. with written informed consent of the patient or
4. with written informed consent of his/her legal representative or
5. after using the option of inclusion via spouse according to § 1358 BGB or
6. after application of the independent consultant procedure
7. Patients of childbearing age: negative pregnancy test

Exclusion Criteria:

1. Patients receiving antibiotics active against Gram-positive bacteria at the same time of linezolid
2. Infection other than pneumonia, skin or soft tissue infection, especially tuberculosis, endocarditis and osteomyelitis
3. Death is deemed imminent and inevitable
4. Pregnancy
5. Lactation/breastfeeding

Primary outcomes:
measure: Through concentration in the target
timeFrame: Day 7 of linezolid treatment
Secondary outcomes:
measure: Pharmacokinetic:
timeFrame: Day 7 and day 13 of linezolid treatment
measure: Thrombocytopenia
timeFrame: From the start of linezolid treatment and up to 14 days
measure: lactic acidosis and peripheral neuropathy
timeFrame: From the start of linezolid treatment and up to 14 days
measure: Microbiology
timeFrame: From the start of linezolid treatment and up to 14 days
measure: Microbiology
timeFrame: From the start of linezolid treatment and up to 14 days
measure: Microbiology
timeFrame: At the end of treatment up to the end of 30 day follow-up
Other outcomes:
Locations:
Study officials:
References: