Optimization of Beta-lactam Dosing in Critically Ill Patients With Cystatin C (OPTIMIZE-GNI)

Optimization of Beta-lactam Dosing in Critically Ill Patients With Suspected or Documented Antimicrobial Resistant Gram-Negative Infections With Cystatin-C (OPTIMIZE-GNI)

This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This study will compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the PK profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE), and iohexol in critically ill patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We further hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. Firstly, population PK (PopPK) modeling will be used to develop meropenem and cefepime PopPK models informed by CysC, CysC-based eGFR equations, SCR, and SCREs (renal function biomarkers), and iohexol clearance. Secondly, model diagnostics will then be used to compare the predictive performances of the renal function biomarkers PopPK models for each antibiotic relative to iohexol PopPK model. Lastly, Monte Carlo simulation (MCS) will be used to design PK/ pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker PopPK model with the best predictive performance for use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections.

Study Overview

• Status: Recruiting
• Conditions: Bacterial Infection
• Intervention / Treatment: Drug: Iohexol

Detailed Description

This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This study will compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the PK profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE), and iohexol in critically ill patients with suspected or documented AMR Gram-negative infections. We hypothesize that CysC and CysC-based eGFR equations will characterize the PK profiles of meropenem and cefepime at the population and individual levels with greater accuracy and precision than SCR and SCREs. Iohexol will be administered to patients enrolled in the study and serve as the reference indicator of measured Glomerular Filtration Rate (mGFR), which is the gold standard assessment of kidney function. We further hypothesize that the predictive performances of CysC and CysC-based eGFR equations in estimating the PK profiles of meropenem and cefepime at the population and individual levels will be comparable to iohexol. Firstly, population PK (PopPK) modeling will be used to develop meropenem and cefepime PopPK models informed by CysC, CysC-based eGFR equations, SCR, and SCREs (renal function biomarkers), and iohexol clearance. Secondly, model diagnostics will then be used to compare the predictive performances of the renal function biomarkers PopPK models for each antibiotic relative to iohexol PopPK model. Lastly, Monte Carlo simulation (MCS) will be used to design PK/ pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker PopPK model with the best predictive performance for use in the treatment of critically ill adult patients with suspected or documented AMR Gram-negative infections and varying degrees of renal function. The primary objective of this study is to compare the abilities of renal function biomarkers (CysC, CysC-based eGFR equations, SCR, SCREs) relative to iohexol to characterize the PK profiles of meropenem and cefepime in critically ill adult patients with suspected or documented AMR Gram-negative infections. The secondary objective of this study is to develop PK/PD optimized meropenem and cefepime dosing schemes based on the renal biomarker function PopPK model with the best predictive performance relative to the iohexol PopPK model for critically ill adult patients with suspected or documented AMR Gram-negative infections.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Thomas Lodise; Phone Number: 15186947292; Email: Thomas.lodise@acphs.edu

Study Locations

• United States
  • California
    • Torrance, California, United States, 90505
      • Recruiting
      • Torrance Memorial Medical Center
    • Torrance, California, United States, 90502-2006
      • Recruiting
      • Harbor UCLA Medical Center - Medicine - Infectious Diseases
  • Michigan
    • Detroit, Michigan, United States, 48202-2608
      • Recruiting
      • Henry Ford Health System - Henry Ford Hospital
    • Royal Oak, Michigan, United States, 48073
      • Recruiting
      • Corewell Health - Infectious Disease
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Hospital - Infectious Diseases
    • Greenville, North Carolina, United States, 27834-9997
      • Recruiting
      • East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • Recruiting
      • University of Cincinnati College of Medicine - Division of Infectious Diseases
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Recruiting
      • Oregon Health and Science University - Adult Infectious Diseases Clinic
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213-3403
      • Recruiting
      • University of Pittsburgh - Medicine - Infectious Diseases
  • Virginia
    • Roanoke, Virginia, United States, 24014
      • Recruiting
      • Carilion Roanoke Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age >/=18 years at the time of enrollment.
2. Residing in an ICU.
3. Documented or suspected Antimicrobial Resistant (AMR) Gram-negative infection for which the prospective participant is receiving meropenem or cefepime as part of their clinical management.
4. Expectation that the prospective participant will reside in the ICU and receive meropenem or cefepime for the duration of the study, and that all study procedures will be completed.
5. Expectation that IV access will be sufficient for drug infusion and either IV or arterial access will be sufficient to allow for all protocol-required blood sampling to occur.
6. The prospective participant, or their legally authorized representative (LAR), is able and willing to provide signed informed consent

Exclusion Criteria:

1. Prospective participant has a documented hypersensitivity or allergic reaction to iohexol, any contrast agents, or iodine.
2. Prospective participant has a documented prior history of severe cutaneous reactions to iohexol, any contrast agents, or iodine.
3. Prospective participant received iohexol on the calendar day of enrollment or the expectation that they will receive iohexol for clinical care (i.e., Standard of Care [SOC]) during the study.
4. Prospective participant had a major surgery within one calendar day prior to enrollment.
5. Prospective participant had a recent (within 6 months) burn involving > 25% of total body surface area.
6. Prospective participant had a penetrating injury within one calendar day prior to enrollment.
7. Prospective participant is currently receiving or is expected to receive any type of renal replacement therapy including hemodialysis or extra corporeal membrane oxygenation, during study period.
8. Prospective participant has a documented diagnosis of diabetes with a serum creatinine (SCR) obtained for clinical care purposes (i.e., SOC results) >3 mg/dL during screening.
9. Prospective participant has documented severe thyrotoxicosis as noted in medical records during screening.
10. Prospective participant is homozygous for sickle cell disease as noted in medical history/records.
11. Prospective participant has a documented diagnosis of hepatorenal syndrome as noted in medical records during screening.

12. Prospective participant is anuric* for >/ = 1 calendar day during screening AND has any one of the following documented conditions as noted in medical history/records:

    • Pheochromocytoma
    • Myelomatosis
    • Multiple myeloma
    • Paraproteinemia *Anuria is defined as urine production <100 mL in a calendar day
13. Prospective participant is pregnant or breastfeeding.
14. Prospective participant received or is expected to receive albumin from one calendar day prior to enrollment to end of study period.
15. Prospective participant received or is expected to receive >/= 3 units of any blood product other than platelets from one calendar day prior to enrollment to end of study period.
16. Any condition that, in the judgment of the investigator, precludes participation because it could affect the prospective participant's safety.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Adult patients in the ICU receiving either meropenem or cefepime as part of their clinical management will receive one dose of IV iohexol 1500 mgI (5 mL) via slow push administration on Study Days 1 and 2 prior to the start of first or second daily meropenem or cefepime dose. N=200	Drug: Iohexol; Iohexol,N,N´ -Bis(2,3-dihydroxypropyl)-5-[N-(2,3-dihydroxypropyl)-acetamido]-2,4,6-triiodoisophthalamide, is a non-ionic, water-soluble radiographic contrast medium with a molecular weight of 821.14 (iodine content 46.36%)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clearance (Cl)		Days 1-2
Composite Euclidean distance score	Summarizes predictive precision, accuracy, and bias of the cefepime or meropenem renal function biomarker population pharmacokinetic (PopPK) model relative to the corresponding iohexol clearance PopPK model using the validation dataset.	Days 1-2
Intercompartment rate constant		Days 1-2
Volume of distribution (Vd)		Days 1-2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetic/pharmacodynamics (PK/PD) optimized meropenem and cefepime dosing schemes	For PopPK models	Days 1-2

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Study record dates

Study Major Dates

• Study Start (Actual): February 12, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): October 30, 2026

Study Registration Dates

• First Submitted: October 31, 2024
• First Submitted That Met QC Criteria: November 27, 2024
• First Posted (Actual): November 29, 2024

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 4, 2026
• Last Verified: April 30, 2026

More Information

Terms related to this study

• Keywords: Iohexol; Gram-negative; eGFR; Cefepime; cystatin-C; Meropenem; AMR; Beta-lactam
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Carboxylic Acids; Hydrocarbons, Aromatic; Benzene Derivatives; Acids, Carbocyclic; Benzoates; Triiodobenzoic Acids; Iodobenzoates; Iohexol
• Other Study ID Numbers: 23-0013; 5UM1AI104681-12 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No