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

NCT ID: NCT06709521

Last Updated: 2025-11-10

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 150 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-02-12
• Study Completion Date: 2026-10-30

Brief Summary

The purpose of this study is to evaluate the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the pharmacokinetics (PK) profiles of meropenem and cefepime relative to Serum Creatinine (SCR), Serum Creatinine based Equation (SCRE)and iohexol at the population and individual levels in critically ill adult 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 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. The information obtained in this study will be used to develop PK/pharmacodynamics (PD) optimized meropenem and cefepime dosing schemes based on the renal function biomarker population PK (PopPK) model with the best predictive performance for clinical 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.

Detailed Description

The intent of this study is to compare the abilities of Cystatin C (CysC) and CysC-based estimated Glomerular Filtration Rate (eGFR) equations to characterize the pharmacokinetics (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. 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.

Conditions

Bacterial Infection

Keywords

AMR; Beta-lactam; Cefepime; cystatin-C; eGFR; Gram-negative; Iohexol; Meropenem

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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=150

Group Type: EXPERIMENTAL

Iohexol

Intervention Type: DRUG

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%)

Interventions

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%)

Intervention Type: DRUG

Eligibility Criteria

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 within one calendar day prior to 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 two calendar days prior to enrollment.

*Major surgery will be defined as "the opening of either a body cavity or the mesenchymal barrier, using general anesthesia."

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 two calendar days prior to enrollment.

*Penetrating injury will be defined as an injury caused by a foreign object piercing the skin, which damages the underlying tissues and results in an open wound.

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Harbor UCLA Medical Center - Medicine - Infectious Diseases

Torrance, California, United States

Site Status: RECRUITING

Torrance Memorial Medical Center

Torrance, California, United States

Site Status: RECRUITING

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, United States

Site Status: RECRUITING

Corewell Health - Infectious Disease

Royal Oak, Michigan, United States

Site Status: RECRUITING

Duke University Hospital - Infectious Diseases

Durham, North Carolina, United States

Site Status: RECRUITING

East Carolina University - Infectious Diseases and Tropical/Travel Medicine Clinic

Greenville, North Carolina, United States

Site Status: RECRUITING

University of Cincinnati College of Medicine - Division of Infectious Diseases

Cincinnati, Ohio, United States

Site Status: RECRUITING

Oregon Health and Science University - Adult Infectious Diseases Clinic

Portland, Oregon, United States

Site Status: RECRUITING

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, United States

Site Status: RECRUITING

Carilion Roanoke Memorial Hospital

Roanoke, Virginia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Thomas Lodise

Role: CONTACT

Phone: 15186947292

Email: Thomas.lodise@acphs.edu

Other Identifiers

5UM1AI104681-12

Identifier Type: NIH

Identifier Source: secondary_id

View Link

23-0013

Identifier Type: -

Identifier Source: org_study_id