Cystic FibrosisPhase 4NCT05561764
Imipenem/Cilastatin/Relebactam Pharmacokinetics, Safety, and Outcomes in Adults and Adolescents With Cystic Fibrosis
A Phase 4 study testing Imipenem/Cilastatin/Relebactam in people with Cystic Fibrosis and Pneumonia, Bacterial, run by Hartford Hospital at 3 sites in United States.
Trial 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… Read more about this study
- Who is it for?
- Ages 12 years and older
- Conditions the study is for
- Cystic Fibrosis, Pneumonia, Bacterial
- What is being tested?
- Imipenem/Cilastatin/Relebactam
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 3 sitesUnited States
- Study dates
- 3 Jan 2023to 11 Dec 2024
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 12 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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;
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- 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
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Hartford Hospital
Hartford, Connecticut, 06102
Children's Hospital Los Angeles
Los Angeles, California, 90027
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, 15213
About this 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
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.
Read the 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.
- Conditions
- Cystic Fibrosis, Pneumonia, Bacterial
- Being tested
- Imipenem/Cilastatin/Relebactam
- Medical subject headings
- Cystic Fibrosis, Pneumonia, Bacterial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Imipenem/Cilastatin/RelebactamDrug
Also called Recarbrio
Patients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Imipenem/Cilastatin/Relebactam |
What is being measured
The primary outcome is the main question the study is designed to answer.
Imipenem Clearance
This outcome determines the clearance in liters/hour of imipenem over the dosing interval
Measured: 6 hours
Relebactam Clearance
This outcome determines the clearance in liters/hour of relebactam over the dosing interval
Measured: 6 hours
Imipenem Volume of Distribution
This outcome determines the volume of distribution in liters of imipenem over the dosing interval
Measured: 6 hours
Relebactam Volume of Distribution
This outcome determines the volume of distribution in liters of relebactam over the dosing interval
Measured: 6 hours
Secondary outcomes (1)
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.
Measured: 24 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Sep 2022
- Study start3 Jan 2023
- Primary completion14 Oct 2024
- Study completion11 Dec 2024
Why it stopped: Difficulty enrolling
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Cystic FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open-label, descriptive, pharmacokinetic and outcome study
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hartford Hospital
- Sponsor type
- University, hospital or other
- 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
- Responsible party
- Principal investigator, Joseph L. Kuti, PharmD, Hartford Hospital
- Investigators
- Joseph L. Kuti, PharmD, Principal investigator, Hartford Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05561764
- Sponsor's protocol ID
- HHC-2022-0237
- Status last verified
- Dec 2024
- First submitted
- 27 Sep 2022
- Last updated
- 17 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05561764
- Acronym / sponsor ID
- HHC-2022-0237
- Conditions
- Cystic Fibrosis, Pneumonia, Bacterial
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Difficulty enrolling
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Hartford HospitalUniversity, hospital or other
- 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
- Study start
- 3 Jan 2023 (actual)
- Primary completion
- 14 Oct 2024 (actual)
- Study completion
- 11 Dec 2024 (actual)
- First posted
- 30 Sep 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open-label, descriptive, pharmacokinetic and outcome study
| Arm | Type | Receives |
|---|---|---|
| Imipenem/cilastatin/relebactam | Experimental | Drug: Imipenem/Cilastatin/RelebactamAdult 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. |
Who may qualify
- Ages
- 12 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (14 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Imipenem/Cilastatin/RelebactamAlso: RecarbrioPatients will receive intravenous imipenem/cilastatin/relebactam every 6 hours for 10-14 days. | Drug | Imipenem/cilastatin/relebactam |
Primary outcome
Imipenem Clearance
Time frame: 6 hours
This outcome determines the clearance in liters/hour of imipenem over the dosing interval
Relebactam Clearance
Time frame: 6 hours
This outcome determines the clearance in liters/hour of relebactam over the dosing interval
Imipenem Volume of Distribution
Time frame: 6 hours
This outcome determines the volume of distribution in liters of imipenem over the dosing interval
Relebactam Volume of Distribution
Time frame: 6 hours
This outcome determines the volume of distribution in liters of relebactam over the dosing interval
1 secondary outcome
Probability of Target Attainment at 2 mg/L
Time frame: 24 hours
Results and safety
The study was stopped early (reason given: Difficulty enrolling). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2024.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joseph L. Kuti, PharmD principal investigator
Hartford Hospital
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Imipenem/Cilastatin/Relebactam in people with Cystic Fibrosis and Pneumonia, Bacterial, run by Hartford Hospital at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Difficulty enrolling). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Imipenem Clearance (time frame: 6 hours). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2024.