Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis
Primary Purpose
Cystic Fibrosis, Pneumonia, Bacterial
Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Imipenem/Cilastatin/Relebactam
Sponsored by
About this trial
This is an interventional other trial for Cystic Fibrosis
Eligibility Criteria
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
Sites / Locations
- Connecticut Children's Medical Center
- Hartford HospitalRecruiting
- IU Health University Hospital
- Riley Hospital for Children
- St. Christopher's Hospital for Children
- University of Pittsburgh Medical Center
- UT Southwestern Clements University Hospital
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Imipenem/cilastatin/relebactam
Arm Description
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.
Outcomes
Primary Outcome Measures
Imipenem Clearance
This outcome determines the clearance in liters/hour of imipenem over the dosing interval
Relebactam Clearance
This outcome determines the clearance in liters/hour of relebactam over the dosing interval
Imipenem Volume of Distribution
This outcome determines the volume of distribution in liters of imipenem over the dosing interval
Relebactam Volume of Distribution
This outcome determines the volume of distribution in liters of relebactam over the dosing interval
Secondary Outcome Measures
Probability of Target Attainment at 2 mg/L
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.
Full Information
NCT ID
NCT05561764
First Posted
September 27, 2022
Last Updated
January 3, 2023
Sponsor
Hartford Hospital
Collaborators
Merck Sharp & Dohme LLC, Q2 Solutions, Connecticut Children's Medical Center, St. Christopher's Hospital for Children, University of Texas Southwestern Medical Center, University of Pittsburgh Medical Center, Indiana University Health Methodist Hospital, James Whitcomb Riley Hospital for Children
1. Study Identification
Unique Protocol Identification Number
NCT05561764
Brief Title
Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis
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
Study Type
Interventional
2. Study Status
Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
January 3, 2023 (Actual)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hartford Hospital
Collaborators
Merck Sharp & Dohme LLC, Q2 Solutions, Connecticut Children's Medical Center, St. Christopher's Hospital for Children, University of Texas Southwestern Medical Center, University of Pittsburgh Medical Center, Indiana University Health Methodist Hospital, James Whitcomb Riley Hospital for Children
4. Oversight
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
Data Monitoring Committee
No
5. Study Description
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.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis, Pneumonia, Bacterial
7. Study Design
Primary Purpose
Other
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Model Description
Open-label, descriptive, pharmacokinetic and outcome study
Masking
None (Open Label)
Allocation
N/A
Enrollment
16 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Imipenem/cilastatin/relebactam
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Imipenem/Cilastatin/Relebactam
Other Intervention Name(s)
Recarbrio
Intervention Description
Patients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days.
Primary Outcome Measure Information:
Title
Imipenem Clearance
Description
This outcome determines the clearance in liters/hour of imipenem over the dosing interval
Time Frame
6 hours
Title
Relebactam Clearance
Description
This outcome determines the clearance in liters/hour of relebactam over the dosing interval
Time Frame
6 hours
Title
Imipenem Volume of Distribution
Description
This outcome determines the volume of distribution in liters of imipenem over the dosing interval
Time Frame
6 hours
Title
Relebactam Volume of Distribution
Description
This outcome determines the volume of distribution in liters of relebactam over the dosing interval
Time Frame
6 hours
Secondary Outcome Measure Information:
Title
Probability of Target Attainment at 2 mg/L
Description
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.
Time Frame
24 hours
Other Pre-specified Outcome Measures:
Title
Pulmonary Function
Description
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.
Time Frame
Day 1 to 2 weeks after end of therapy
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Joseph L. Kuti, PharmD
Phone
860-972-3612
Email
joseph.kuti@hhchealth.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Joseph L. Kuti, PharmD
Organizational Affiliation
Hartford Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Connecticut Children's Medical Center
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06102
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Craig Lapin, MD
Facility Name
Hartford Hospital
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06102
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Joseph L. Kuti, PharmD
Phone
860-972-3612
Email
joseph.kuti@hhchealth.org
First Name & Middle Initial & Last Name & Degree
Samuel Pope, MD
Facility Name
IU Health University Hospital
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Colleen M Sakon, PharmD
Phone
317-962-9363
Email
csakon@iuhealth.org
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Colleen M. Sakon, PharmD
Facility Name
St. Christopher's Hospital for Children
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19134
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeffrey J Cies, Pharm.D.
Phone
215-427-5176
Email
jeffrey.cies@tenethealth.com
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ryan Shields, PharmD
Facility Name
UT Southwestern Clements University Hospital
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marguerite Monogue, PharmD
Email
Marguerite.Monogue@UTSouthwestern.edu
12. IPD Sharing Statement
Learn more about this trial
Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis
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