RECRUITING

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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

Official Title

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

Quick Facts

Study Start:2023-01-03

Study Completion:2025-01

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05561764

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.

Ages Eligible for Study:12 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:CHILD, ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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	* 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

Inclusion Criteria

Exclusion 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

* 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

Contacts and Locations

Study Contact

Joseph L. Kuti, PharmD

CONTACT

860-972-3612

joseph.kuti@hhchealth.org

Principal Investigator

Joseph L. Kuti, PharmD

PRINCIPAL_INVESTIGATOR

Hartford Hospital

Study Locations (Sites)

Children's Hospital Los Angeles

Los Angeles, California, 90027

United States

Hartford Hospital

Hartford, Connecticut, 06102

United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213

United States

Collaborators and Investigators

Sponsor: Hartford Hospital

Joseph L. Kuti, PharmD, PRINCIPAL_INVESTIGATOR, 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 Registration Dates

Study Start Date2023-01-03

Study Completion Date2025-01

Study Record Updates

Study Start Date2023-01-03

Study Completion Date2025-01

Terms related to this study

Additional Relevant MeSH Terms

Cystic Fibrosis
Pneumonia, Bacterial