PneumoniaNCT02682355
Optimizing Clinical Use of Polymyxin B
An observational study of Pneumonia and Blood Stream Infection, run by Rutgers, The State University of New Jersey at 6 sites in 3 countries.
Trial summary
Polymyxin B is already being used extensively in the USA and other parts of the world; its use is likely to rapidly increase due to the greater burden of infections caused by MDR Gram-negative bacteria and the growing awareness of the limitations inherent in the clinical pharmacology of CMS/colistin. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Pneumonia, Blood Stream Infection, Urinary Tract Infections
- Type of treatment
- Injection or infusion
- How many people
- 155 participants
- Where
- 6 sitesin 3 countries
- Study dates
- Feb 2016to 3 Aug 2022
- Phase
- Observational
- 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: The human subjects involved in this study will be receiving intravenous polymyxin B as part of their routine clinical care because of infection due to bacteria resistant to all other first-line antibiotics.
Who may be able to join
- Patient of 18 years of age or older
- Expectation of hospitalization and receipt of polymyxin B of ≥ 48 hours
- Receipt of intravenous polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis
- Provision of written informed consent by the patient or by the patient's health care proxy if the patient cannot give consent
- Adequate venous access to enable collection of blood for determination of concentrations of polymyxin B and co-administered antibiotics
Who cannot join
- Age <18 years
- Currently incarcerated
- Concomitant use of polymyxin B delivered directly into the respiratory tract
- Cystic fibrosis
- Known allergy to CMS/colistin or polymyxin B
- Anticipated death within 48 h of commencing polymyxin B therapy
Trial locations and contacts
6 sites in 3 countries.
6 sites in 3 countries
United States3 sites
Northwestern University
Chicago, Illinois, 60611
Columbia University Medical Center
New York, New York, 10032
New York Presbyterian-Weill Cornell Medical Center
New York, New York, 10065
Brazil2 sites
Hospital Sao Lucas da - PUC / RS
Porto Alegre, 10032
Hospital Moinhos de Vento
Porto Alegre, 90035-001
About this study
Official title: Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs
Polymyxin B is already being used extensively in the USA and other parts of the world; its use is likely to rapidly increase due to the greater burden of infections caused by MDR Gram-negative bacteria and the growing awareness of the limitations inherent in the clinical pharmacology of CMS/colistin. Cross resistance exists between the two polymyxins and thus both must be dosed optimally; but the recently generated scientifically-based dosage regimens for CMS/colistin cannot be extrapolated to polymyxin B. It is essential that an adequately powered study is conducted to define the clinical PK/PD/TD relationships of polymyxin B and identify, using next-generation proteomics, biomarkers for early detection of kidney injury. This will allow the development of scientifically-based dosage regimens for various categories of patients and an adaptive feedback control clinical tool for optimized dosing of polymyxin B in future individual patients.
Read the detailed description
Multidrug-resistant (MDR) Gram-negative 'superbugs' are rapidly spreading around the world, and polymyxin B and colistin (polymyxin E) are often the only effective antibiotics. Since polymyxin B was released in the 1950s, its pharmacokinetics, pharmacodynamics, toxicodynamics (PK/PD/TD) have never been defined. Recent pharmacological research on polymyxins has predominantly focused on colistin methanesulfonate (CMS, an inactive prodrug of colistin) and demonstrates that CMS has significant limitations. Thus, polymyxin B is increasingly being viewed as the preferred polymyxin. Unfortunately, recently developed scientifically-based dosing recommendations for CMS cannot and should not be applied to polymyxin B, as the latter is administered as its active entity. Therefore, it is essential to determine the PK/PD/TD of polymyxin B in critically-ill patients, refine optimal dosage regimens, and develop the user-friendly adaptive feedback control (AFC) clinical tool.
The Specific Aims are:
- To develop a population PK model for polymyxin B;
- To investigate relationships between the PK of polymyxin B, duration of therapy and patient characteristics, with the development and timing of nephrotoxicity; and to use next-generation proteomics to identify the most predictive biomarker(s) of polymyxin B associated nephrotoxicity; and to develop the population PK/TD model;
- To establish the relationships between polymyxin B PK, bacterial susceptibility and patient characteristics, with the probability of attaining and time to achieving clinical and bacteriological outcomes; and
- To employ the models from Aims 1-3 and Monte Carlo simulation to develop scientifically-based dosage regimens of polymyxin B and to develop an AFC algorithm for future individual patients.
Research Design: Patients being treated with intravenous polymyxin B will be identified at three clinical sites in the USA and one in Singapore. Patients (n = 250) will have blood collected at various times surrounding a dose of polymyxin B between days 1 and 5 of therapy. Development of nephrotoxicity, clinical response, and bacteriological response will be examined. Total and free plasma concentrations of polymyxin B will be determined. Bacterial isolates will be examined for the emergence of polymyxin resistance. The relationships between polymyxin B PK, PD and TD end-points (e.g. clinical and bacteriological responses, development of toxicity and resistance) will be assessed using pharmacometric analyses. Finally, the obtained information will be used to apply Monte Carlo simulation to examine the impact of various patient characteristics and other factors on polymyxin B PK, PD and TD, in order to establish optimal dosage regimens and AFC algorithms for individual critically-ill patients.
Significance: No new antibiotics will be available for Gram-negative 'superbugs' for many years. This landmark multicenter study will provide essential information for optimizing polymyxin B use in critically-ill patients, while minimizing resistance and toxicity. This proposal aligns perfectly with the NIAID priority "To teach old drugs new tricks" and the recent Executive Order of the White House to combat antibiotic resistance.
- Conditions
- Pneumonia, Blood Stream Infection, Urinary Tract Infections, Respiratory Tract Infection (Including Tracheobronchitis), Sepsis
- Medical subject headings
- Pneumonia, Urinary Tract Infections, Respiratory Tract Infections, Sepsis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Study cohort | Patients receiving IV polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis |
What is being measured
The primary outcome is the main question the study is designed to answer.
Polymyxin B plasma concentrations
Measured: 28 days after enrollment
Secondary outcomes (3)
Changes in serum creatinine
Measured: 28 days after enrollment
Clinical response based on resolution of signs and symptoms of infection
Measured: 28 days after enrollment
Microbiologic response based on eradication of pathogens from blood and respiratory cultures
Measured: 28 days after enrollment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2016 (estimated)
- Study startFeb 2016
- Primary completion31 May 2022
- Study completion3 Aug 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PneumoniaStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 155 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rutgers, The State University of New Jersey
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Keith S. Kaye, MD, MPH, Rutgers, The State University of New Jersey
- Investigators
- Keith S Kaye, MD, MPH, Principal investigator, Rutgers University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02682355
- Sponsor's protocol ID
- R01AI119446-01
- Status last verified
- Nov 2024
- First submitted
- 11 Jan 2016
- Last updated
- 2 Dec 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 2 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs
- ClinicalTrials.gov ID
- NCT02682355
- Acronym / sponsor ID
- R01AI119446-01
- Conditions
- Pneumonia, Blood Stream Infection, Urinary Tract Infections, Respiratory Tract Infection (Including Tracheobronchitis), Sepsis
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 155 participants (actual)
- Lead sponsor
- Rutgers, The State University of New JerseyUniversity, hospital or other
- Study start
- Feb 2016
- Primary completion
- 31 May 2022 (actual)
- Study completion
- 3 Aug 2022 (actual)
- First posted
- 15 Feb 2016 (estimated)
- 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.
Polymyxin B is already being used extensively in the USA and other parts of the world; its use is likely to rapidly increase due to the greater burden of infections caused by MDR Gram-negative bacteria and the growing awareness of the limitations inherent in the clinical pharmacology of CMS/colistin. Cross resistance exists between the two polymyxins and thus both must be dosed optimally; but the recently generated scientifically-based dosage regimens for CMS/colistin cannot be extrapolated to polymyxin B. It is essential that an adequately powered study is conducted to define the clinical PK/PD/TD relationships of polymyxin B and identify, using next-generation proteomics, biomarkers for early detection of kidney injury. This will allow the development of scientifically-based dosage regimens for various categories of patients and an adaptive feedback control clinical tool for optimized dosing of polymyxin B in future individual patients.
Detailed description
Multidrug-resistant (MDR) Gram-negative 'superbugs' are rapidly spreading around the world, and polymyxin B and colistin (polymyxin E) are often the only effective antibiotics. Since polymyxin B was released in the 1950s, its pharmacokinetics, pharmacodynamics, toxicodynamics (PK/PD/TD) have never been defined. Recent pharmacological research on polymyxins has predominantly focused on colistin methanesulfonate (CMS, an inactive prodrug of colistin) and demonstrates that CMS has significant limitations. Thus, polymyxin B is increasingly being viewed as the preferred polymyxin. Unfortunately, recently developed scientifically-based dosing recommendations for CMS cannot and should not be applied to polymyxin B, as the latter is administered as its active entity. Therefore, it is essential to determine the PK/PD/TD of polymyxin B in critically-ill patients, refine optimal dosage regimens, and develop the user-friendly adaptive feedback control (AFC) clinical tool.
The Specific Aims are:
- To develop a population PK model for polymyxin B;
- To investigate relationships between the PK of polymyxin B, duration of therapy and patient characteristics, with the development and timing of nephrotoxicity; and to use next-generation proteomics to identify the most predictive biomarker(s) of polymyxin B associated nephrotoxicity; and to develop the population PK/TD model;
- To establish the relationships between polymyxin B PK, bacterial susceptibility and patient characteristics, with the probability of attaining and time to achieving clinical and bacteriological outcomes; and
- To employ the models from Aims 1-3 and Monte Carlo simulation to develop scientifically-based dosage regimens of polymyxin B and to develop an AFC algorithm for future individual patients.
Research Design: Patients being treated with intravenous polymyxin B will be identified at three clinical sites in the USA and one in Singapore. Patients (n = 250) will have blood collected at various times surrounding a dose of polymyxin B between days 1 and 5 of therapy. Development of nephrotoxicity, clinical response, and bacteriological response will be examined. Total and free plasma concentrations of polymyxin B will be determined. Bacterial isolates will be examined for the emergence of polymyxin resistance. The relationships between polymyxin B PK, PD and TD end-points (e.g. clinical and bacteriological responses, development of toxicity and resistance) will be assessed using pharmacometric analyses. Finally, the obtained information will be used to apply Monte Carlo simulation to examine the impact of various patient characteristics and other factors on polymyxin B PK, PD and TD, in order to establish optimal dosage regimens and AFC algorithms for individual critically-ill patients.
Significance: No new antibiotics will be available for Gram-negative 'superbugs' for many years. This landmark multicenter study will provide essential information for optimizing polymyxin B use in critically-ill patients, while minimizing resistance and toxicity. This proposal aligns perfectly with the NIAID priority "To teach old drugs new tricks" and the recent Executive Order of the White House to combat antibiotic resistance.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Study cohort | – | –Patients receiving IV polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- The human subjects involved in this study will be receiving intravenous polymyxin B as part of their routine clinical care because of infection due to bacteria resistant to all other first-line antibiotics.
Key inclusion criteria (5 listed)
- Patient of 18 years of age or older
- Expectation of hospitalization and receipt of polymyxin B of ≥ 48 hours
- Receipt of intravenous polymyxin B for treatment of bacteremia and/or urinary tract infection and/or respiratory tract infection (including tracheobronchitis) or sepsis
- Provision of written informed consent by the patient or by the patient's health care proxy if the patient cannot give consent
- Adequate venous access to enable collection of blood for determination of concentrations of polymyxin B and co-administered antibiotics
Key exclusion criteria (6 listed)
- Age <18 years
- Currently incarcerated
- Concomitant use of polymyxin B delivered directly into the respiratory tract
- Cystic fibrosis
- Known allergy to CMS/colistin or polymyxin B
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Polymyxin B plasma concentrations
Time frame: 28 days after enrollment
3 secondary outcomes
Changes in serum creatinine
Time frame: 28 days after enrollment
Clinical response based on resolution of signs and symptoms of infection
Time frame: 28 days after enrollment
Microbiologic response based on eradication of pathogens from blood and respiratory cultures
Time frame: 28 days after enrollment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Dec 2024.
- Individual participant dataSharing planned: Yes
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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.
Keith S Kaye, MD, MPH principal investigator
Rutgers University
6 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Pneumonia and Blood Stream Infection, run by Rutgers, The State University of New Jersey at 6 sites in 3 countries.
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 5 inclusion and 6 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: finished, as of the sponsor's last update on 2 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 6 sites in United States, Brazil, Singapore. 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.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Polymyxin B plasma concentrations (time frame: 28 days after enrollment). 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 2 Dec 2024.