Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis

December 12, 2024 updated by: Joseph L. Kuti, PharmD, Hartford Hospital

A Multicenter, Open-label Study to Determine the Pharmacokinetics, Safety, and Outcomes of Imipenem/Cilastatin/Relebactam During Treatment of Acute Pulmonary Exacerbations in Adolescent and Adult Patients With Cystic Fibrosis

There is established evidence that patients with Cystic Fibrosis (CF) may have altered antibiotic pharmacokinetics compared with non-CF patients. Imipenem/cilastatin/relebactam is a novel broad spectrum intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic with potent activity against multidrug resistant Gram-negative bacteria, including imipenem non-susceptible Pseudomonas aeruginosa. Relebactam has also been shown to restore imipenem activity in Burkholderia cepacia complex, a group of opportunistic multidrug resistant pathogens that commonly infect patients with CF. This study will determine the pharmacokinetics and tolerability of imipenem/cilastatin/relebactam in 16 adolescent and adult patients with CF acute pulmonary exacerbations at one of seven participating hospitals in the US, with exploratory aim of reporting relative percent increase in FEV1 from pre- to post-treatment and return to baseline FEV1 after treatment with imipenem/cilastatin/relebactam for acute pulmonary exacerbations due to P. aeruginosa in patients with CF. Patients will receive a 10-14 day course of imipenem/cilastatin/relebactam, dosed according to renal function every 6 hours over 30 mins, with or without adjunctive aminoglycoside or fluoroquinolone therapy per local hospital guidelines. Blood will be sampled during one dosing interval at steady-state (i.e. after at least 3 doses) to determine concentrations and pharmacokinetics of imipenem and relebactam. Relative change in pulmonary function will be assessed two weeks after end of therapy. Safety and tolerability will be assessed throughout the duration of the study.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Participants will receive 10-14 days of imipenem/cilastatin/relebactam every 6 hours with dose determined per renal function, with or without adjunctive aminoglycoside or fluoroquinolone therapy as determined by local study site. After receiving at least 3 doses (i.e. steady-state), a total of eight blood samples will be collected over one dosing interval to measure imipenem and relebactam concentrations. Data will be fit to a population pharmacokinetic model. The final model will be utilized in a Monte Carlo simulation to determine the probability of several different dosing regimens retaining both (1) free imipenem concentrations above the minimum inhibitory concentration (MIC) for at least 40% of the dosing interval and (2) free relebactam area under the concentration-time curve at least eight times greater than the MIC. These data will be utilized to determine an optimized dosing regimen for adults and adolescents with CF. Additionally, two weeks after treatment, as part of the exploratory clinical endpoint, patients will complete follow-up pulmonary function tests to determine relative percent increase in FEV1 and return to baseline FEV1 after treatment. These outcomes will be reported descriptively.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
4

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90027
        • Children's Hospital Los Angeles
    • Connecticut
      • Hartford, Connecticut, United States, 06102
        • Hartford Hospital
    • Pennsylvania
      • Pittsburgh, Pennsylvania, United States, 15213
        • University of Pittsburgh Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Documented diagnosis of CF defined based on medical history of two or more clinical features of CF and a documented sweat chloride >60 mEq/L by quantitative pilocarpine iontophoresis test or a genotype showing two well characterized disease causing mutations
  • Hospitalized with an acute pulmonary exacerbation (APE), defined as an exacerbation of respiratory symptoms that requires intravenous antibiotics for any 4 of the following signs or symptoms: change in sputum; new or increased hemoptysis; increased cough; increased dyspnea; malaise, fatigue, or lethargy; temperature above 38C; anorexia or weight loss; change in physical examination of the chest; decrease in pulmonary function by 10 percent or more from a previously recorded value; or radiographic changes indicative of pulmonary infection.
  • APE documented or suspected (based on prior surveillance cultures) to be caused by P. aeruginosa

Exclusion Criteria:

  • If female, currently pregnant or breast feeding;
  • History of any moderate or severe hypersensitivity or allergic reaction to any β-lactam agent (a history of mild rash to a β-lactam followed by uneventful re-exposure is not a contraindication);
  • At the time of enrollment, known or suspected infection caused by methicillin-resistant Staphylococcus aureus, Non-tuberculosis mycobacteria (NTM), Burkholderia cepacia complex, Achromobacter species, Stenotrophomonas maltophilia, or moulds; if these pathogens are identified AFTER enrollment, participants may continue to complete the study for objectives 1 and 2; additional treatment will be at the discretion of the treating clinician and discussion with the principal investigator;
  • Receiving or intent to receive any other intravenous antibiotic therapy except concomitant aminoglycosides or fluoroquinolones (concomitant azithromycin administered as chronic suppression therapy to increase duration between exacerbations is permitted); combination therapy to treat CF APE is considered standard of care with aminoglycosides and fluoroquinolones typically prescribed as second antibiotic; the use of combination therapy will not influence objective 1 and will be considered in assessment of objective 2;
  • Receiving or intent to receive any inhaled antibiotics;
  • Unlikely to remain hospitalized for at least 4 days to ensure pharmacokinetic sampling;
  • Inability to perform pulmonary function tests (PFT) at baseline or 2 weeks after end of therapy;
  • For ADULT Participants (18 years or older): Renal dysfunction defined as a creatinine clearance < 60 mL/min (calculated by the Cockcroft-Gault equation);
  • For ADOLESCENT Participants (12-17 years): Renal dysfunction defined as a creatinine clearance <90 mL/min/1.73m2 (calculated by the Revised Bedside Schwartz Equation) (Note. Imipenem/cilastatin/relebactam has not been studied in adolescent patients with creatinine clearance (CrCL) < 90 ml/min/1.73m2);
  • Has used or plans to use any of the following medications, which are organic anion transporter (OAT) 1 or OAT3 inhibitors, within 1 week prior to screening or at any point between screening and the last PK sample collection: cimetidine, probenecid, indomethacin, mefenamic acid, furosemide or other loop diuretics (eg, bumetanide, torsemide, ethacrynic acid), angiotensin receptor blockers (eg, valsartan), and ketorolac;
  • Has used or plans to use imipenem or valproic acid within 7 days before study drug infusion;
  • Acute liver injury, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 times the upper limit of normal, or AST or ALT > 3 times the upper limit of normal with an associated total bilirubin > 2 times upper limit of normal;
  • Any rapidly-progressing disease or immediately life-threatening illness (defined as imminent death within 48 hours in the opinion of the investigator);
  • Any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of study data

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Imipenem/cilastatin/relebactam
Adult participants will receive intravenous imipenem/cilastatin/relebactam at a dosing regimen consistent with the current prescribing information and according to estimated renal function. Adolescent participants will receive intravenous imipenem/cilastatin/relebactam at a dosing regimen consistent with Phase I data [37.5 (15/15/7.5) mg/kg, up to a maximum dose of 1.25g]. Each dose will be infused over 30 minutes.
Drug: Imipenem/Cilastatin/Relebactam
Patients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days.
Other Names:
  • Recarbrio

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Imipenem Clearance
Time Frame: 6 hours
This outcome determines the clearance in liters/hour of imipenem over the dosing interval
6 hours
Relebactam Clearance
Time Frame: 6 hours
This outcome determines the clearance in liters/hour of relebactam over the dosing interval
6 hours
Imipenem Volume of Distribution
Time Frame: 6 hours
This outcome determines the volume of distribution in liters of imipenem over the dosing interval
6 hours
Relebactam Volume of Distribution
Time Frame: 6 hours
This outcome determines the volume of distribution in liters of relebactam over the dosing interval
6 hours

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Probability of Target Attainment at 2 mg/L
Time Frame: 24 hours
This simulated outcome indicates the likelihood that imipenem will retain free drug concentrations above the MIC for at least 40% of the dosing interval at an MIC of 2 mg/L AND free relebactam area under the concentration-time curve will be at least 8 fold of an MIC of 2 mg/L when administered as 1.25 g (adults) or 37.5 mg/kg up to a max of 1.25 g (adolescents) every 6 hours over 30 minutes. This analysis is conducted via a Monte Carlo simulation using the population pharmacokinetic parameter estimates and dispersion from the 16 participants who contributed pharmacokinetic data to the study.
24 hours

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Pulmonary Function
Time Frame: Day 1 to 2 weeks after end of therapy
This exploratory clinical endpoint will determine the relative percent increase in forced expiratory volume in one second (FEV1) from the Day 1 to Follow up (2 weeks after the end of therapy) spirometry. Relative FEV1 changes will be classified into the following categories for qualitative assessment and interpretation. "Improvement" will be defined as a relative improvement in FEV1 >/=15% of pre-treatment. "Overall Improvement" will be defined as returning to at least 90% of the participant's historical best FEV1, recorded in the 6 months prior to enrollment. These outcomes will be reported descriptively.
Day 1 to 2 weeks after end of therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Hartford Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Merck Sharp & Dohme LLC
University of Texas Southwestern Medical Center
University of Pittsburgh Medical Center
Connecticut Children's Medical Center
Q2 Solutions
Indiana University Health Methodist Hospital
St. Christopher's Hospital for Children
James Whitcomb Riley Hospital for Children

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Joseph L. Kuti, PharmD, Hartford Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 3, 2023

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
October 14, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 11, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
September 27, 2022

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 29, 2022

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
September 30, 2022

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 25, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 12, 2024

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2024

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • HHC-2022-0237

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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