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Optimizing Clinical Use of Polymyxin B

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT02682355
Recruitment Status : Recruiting
First Posted : February 15, 2016
Last Update Posted : May 28, 2020
Information provided by (Responsible Party):
Keith Kaye, University of Michigan

Brief 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. 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.

Condition or disease
Pneumonia Blood Stream Infection

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:

  1. To develop a population PK model for polymyxin B;
  2. 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;
  3. 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
  4. 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.

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Study Type : Observational
Estimated Enrollment : 250 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Optimizing Clinical Use of Polymyxin B: Teaching an Old Drug to Treat Superbugs
Study Start Date : February 2016
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2021

Resource links provided by the National Library of Medicine

Study cohort
Patients receiving IV polymyxin B for treatment of pneumonia and/or bloodstream infection

Primary Outcome Measures :
  1. Polymyxin B plasma concentrations [ Time Frame: 28 days after enrollment ]

Secondary Outcome Measures :
  1. Changes in serum creatinine [ Time Frame: 28 days after enrollment ]
  2. Clinical response based on resolution of signs and symptoms of infection [ Time Frame: 28 days after enrollment ]
  3. Microbiologic response based on eradication of pathogens from blood and respiratory cultures [ Time Frame: 28 days after enrollment ]

Biospecimen Retention:   Samples With DNA
  • Blood and Respiratory cultures from infection site.
  • Urine Samples for Proteomic testing.
  • Blood Specimen for Pharmacokinetic/Pharmacodynamic testing.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
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.

Inclusion Criteria:

  1. Patient of 18 years of age or older
  2. Expectation of hospitalization and receipt of polymyxin B of ≥ 48 hours
  3. Receipt of intravenous polymyxin B for treatment of a bloodstream infection (according to CDC criteria 55) and/or pneumonia
  4. Provision of written informed consent by the patient or by the patient's health care proxy if the patient cannot give consent
  5. Adequate venous access to enable collection of blood for determination of concentrations of polymyxin B and co-administered antibiotics

Exclusion Criteria:

  1. Age <18 years
  2. Currently incarcerated
  3. Concomitant use of polymyxin B delivered directly into the respiratory tract
  4. Cystic fibrosis
  5. Known allergy to CMS/colistin or polymyxin B
  6. Anticipated death within 48 h of commencing polymyxin B therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02682355

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Contact: Jolene Daniel 734-615-1901

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United States, Illinois
Northwestern University Terminated
Chicago, Illinois, United States, 60611
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10032
Contact: Michael T Yin, MD    646-644-0381   
New York Presbyterian-Weill Cornell Medical Center Terminated
New York, New York, United States, 10065
United States, Ohio
The Ohio State University Wexner Medical Center Withdrawn
Columbus, Ohio, United States, 43210
Hospital Sao Lucas da - PUC / RS Recruiting
Porto Alegre, Brazil, 10032
Contact: Ana Sandri, MD    + 55 51 3320 5047   
Contact: Larissa Sanches    + 55 51 3320 3000 ext 2031   
Hospital Moinhos de Vento Recruiting
Porto Alegre, Brazil, 90035-001
Contact: Alexandre P Zavascki, MD    (51) 3537-8240   
Singapore General Hospital Recruiting
Singapore, Singapore, 16908
Contact: Andrea Kwa, MD    65-6321-3401   
Sponsors and Collaborators
University of Michigan
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Principal Investigator: Keith S Kaye, MD, MPH University of Michigan
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Responsible Party: Keith Kaye, Project Director, Principle Investigator, University of Michigan Identifier: NCT02682355    
Other Study ID Numbers: R01AI119446-01 ( U.S. NIH Grant/Contract )
First Posted: February 15, 2016    Key Record Dates
Last Update Posted: May 28, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Additional relevant MeSH terms:
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Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Systemic Inflammatory Response Syndrome
Pathologic Processes