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

NCT05561764 | Terminated Phase 4 FDA Drug

• 1 other identifier: HHC-2022-0237
• Study Type: interventional
• Target: 4
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Cystic Fibrosis; Pneumonia, Bacterial

Outcome Measures

Primary Outcomes (4)

• Imipenem Clearance

  This outcome determines the clearance in liters/hour of imipenem over the dosing interval

  6 hours

• Relebactam Clearance

  This outcome determines the clearance in liters/hour of relebactam over the dosing interval

  6 hours

• Imipenem Volume of Distribution

  This outcome determines the volume of distribution in liters of imipenem over the dosing interval

  6 hours

• Relebactam Volume of Distribution

  This outcome determines the volume of distribution in liters of relebactam over the dosing interval

  6 hours

Secondary Outcomes (1)

• Probability of Target Attainment at 2 mg/L

  24 hours

Other Outcomes (1)

• Pulmonary Function

  Day 1 to 2 weeks after end of therapy

Study Arms (1)

Imipenem/cilastatin/relebactam

EXPERIMENTAL

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

Interventions

Imipenem/Cilastatin/Relebactam DRUG

Patients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days.

Also known as: Recarbrio

Imipenem/cilastatin/relebactam

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hartford Hospital: lead
• Merck Sharp & Dohme LLC: collaborator
• Q2 Solutions: collaborator
• Connecticut Children's Medical Center: collaborator
• St. Christopher's Hospital for Children: collaborator
• University of Texas Southwestern Medical Center: collaborator
• University of Pittsburgh Medical Center: collaborator
• Indiana University Health Methodist Hospital: collaborator
• James Whitcomb Riley Hospital for Children: collaborator

Study Sites (3)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Hartford Hospital

Hartford, Connecticut, 06102, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15213, United States

Location

MeSH Terms

Conditions

Cystic Fibrosis; Pneumonia, Bacterial

Interventions

imipenem, cilastatin and relebactam

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Pneumonia; Respiratory Tract Infections

Study Officials

• Joseph L. Kuti, PharmD

  Hartford Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director, CAIRD

Model Details: Open-label, descriptive, pharmacokinetic and outcome study

Study Record Dates

• First Submitted: September 27, 2022
• First Posted: September 30, 2022
• Study Start: January 3, 2023
• Primary Completion: October 14, 2024
• Study Completion: December 11, 2024
• Last Updated: December 17, 2024

Record last verified: 2024-12

Locations

US (3)