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

NCT06709521 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: 23-00135UM1AI104681-12
• Study Type: interventional
• Target: 200
• Locations: 1 country
• Sites: 10

Brief Summary

This is a Phase 4, interventional, multi-center pharmacokinetics (PK) study in up to 200 adult patients who are residing in an ICU. This 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.

Conditions

Bacterial Infection

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (1)

• Pharmacokinetic/pharmacodynamics (PK/PD) optimized meropenem and cefepime dosing schemes

  Days 1-2

Study Arms (1)

Arm 1

EXPERIMENTAL

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

Interventions

Iohexol 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%)

Arm 1

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>/=18 years at the time of enrollment.
• Residing in an ICU.
• 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.
• 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.
• 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.
• The prospective participant, or their legally authorized representative (LAR), is able and willing to provide signed informed consent

You may not qualify if:

• Prospective participant has a documented hypersensitivity or allergic reaction to iohexol, any contrast agents, or iodine.
• Prospective participant has a documented prior history of severe cutaneous reactions to iohexol, any contrast agents, or iodine.
• 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.
• Prospective participant had a major surgery within one calendar day prior to enrollment.
• Prospective participant had a recent (within 6 months) burn involving \> 25% of total body surface area.
• Prospective participant had a penetrating injury within one calendar day prior to enrollment.
• 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.
• 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.
• Prospective participant has documented severe thyrotoxicosis as noted in medical records during screening.
• Prospective participant is homozygous for sickle cell disease as noted in medical history/records.
• Prospective participant has a documented diagnosis of hepatorenal syndrome as noted in medical records during screening.
• 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

Sponsors & Collaborators

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

Study Sites (10)

Harbor UCLA Medical Center - Medicine - Infectious Diseases

Torrance, California, 90502-2006, United States

RECRUITING

Torrance Memorial Medical Center

Torrance, California, 90505, United States

RECRUITING

Henry Ford Health System - Henry Ford Hospital

Detroit, Michigan, 48202-2608, United States

RECRUITING

Corewell Health - Infectious Disease

Royal Oak, Michigan, 48073, United States

RECRUITING

Duke University Hospital - Infectious Diseases

Durham, North Carolina, 27710, United States

RECRUITING

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

Greenville, North Carolina, 27834-9997, United States

RECRUITING

University of Cincinnati College of Medicine - Division of Infectious Diseases

Cincinnati, Ohio, 45267, United States

RECRUITING

Oregon Health and Science University - Adult Infectious Diseases Clinic

Portland, Oregon, 97239-3098, United States

RECRUITING

University of Pittsburgh - Medicine - Infectious Diseases

Pittsburgh, Pennsylvania, 15213-3403, United States

RECRUITING

Carilion Roanoke Memorial Hospital

Roanoke, Virginia, 24014, United States

RECRUITING

MeSH Terms

Conditions

Bacterial Infections

Interventions

Iohexol

Condition Hierarchy (Ancestors)

Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Triiodobenzoic Acids; Iodobenzoates; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Central Study Contacts

Thomas Lodise

CONTACT

15186947292; Thomas.lodise@acphs.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 31, 2024
• First Posted: November 29, 2024
• Study Start: February 12, 2025
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): October 30, 2026
• Last Updated: May 5, 2026

Record last verified: 2025-07-18

Locations

US (10)