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Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli

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ClinicalTrials.gov Identifier: NCT01597973
Recruitment Status : Recruiting
First Posted : May 15, 2012
Last Update Posted : September 26, 2019
Sponsor:
Information provided by (Responsible Party):
Keith Kaye, University of Michigan

Tracking Information
First Submitted Date  ICMJE May 8, 2012
First Posted Date  ICMJE May 15, 2012
Last Update Posted Date September 26, 2019
Study Start Date  ICMJE October 2012
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 5, 2014)
mortality [ Time Frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks ]
Determine whether the treatment regimen of colistin combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for all-cause mortality during the 30 day post-enrollment period compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).
Original Primary Outcome Measures  ICMJE
 (submitted: May 10, 2012)
mortality [ Time Frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks ]
Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with Imipenem-cilistatin (imipenem) is associated with a decreased risk for mortality compared to colistin alone for patients with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB.
Change History Complete list of historical versions of study NCT01597973 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 6, 2014)
resistance [ Time Frame: patients resistance data will be collected at 28 days ]
Determine what treatment regimen (colistin monotherapy or colistin combined a carbapenem (imipenem or meropenem)is more likely to reduce the frequency of emergence of colistin resistance among XDR-GNB isolates during therapy.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2012)
resistance [ Time Frame: patients resistance data will be collected at 28 days ]
Determine what treatment regimen (colistin monotherapy or colistin combined with imipenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
Official Title  ICMJE Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli
Brief Summary

Approximately 444 subjects who are greater than or equal to 18 to 95 years of age, are non-pregnant, and are in the inpatient setting of one of the study sites will be evaluated to treatment efficacy. Analysis will include subjects with bloodstream infection (BSI) or pneumonia due to at least one of the following gram-negative bacilli organisms: Acinetobacter baumannii, Klebsiella spp, Escherichia coli, Enterbactor spp. and/or Pseudomonas aeruginosa that demonstrates in vitro non-susceptibility defined as extensively drug-resistant Gram-negative bacilli (XDR-GNB) which includes XDR-AB, XDR-PA and CRE. If a subject has both BSI and pneumonia at the time of study enrollment, they will be included as a subject with pneumonia.

Objectives:

Primary:

•Determine whether the treatment regimen of Colistimethate sodium (colistin) combined with a carbapenem (imipenem or meropenem) is associated with a decreased risk for mortality compared to colistin alone for subjects with bloodstream infection (BSI) and/or pneumonia due to XDR-GNB.

Secondary:

•Determine what treatment regimen (colistin monotherapy or colistin combined with a carbapenem (imipenem or meropenem) is more likely to reduce the emergence of colistin resistance among XDR-GNB isolates during therapy.

Detailed Description

The Gram-negative bacilli organisms Acinetobacter baumannii, Klebsiella spp., Escherichia coli, Enterbactor spp. and Pseudomonas aeruginosa have become a frequent cause of bloodstream infection and pneumonia in the hospital and other healthcare settings. Among these pathogens, antimicrobial resistance has emerged to many classes of antimicrobial agents. Most concerning, has been the emergence of resistance to group 2 carbapenems (such as imipenem). In several regions of the world, including Southeastern Michigan, strains of extensively-drug resistant Gram-negative bacilli (XDR-GNB) that exhibit resistance to most, and in some cases all types of available antimicrobial agents, including group 2 carbapenems, have emerged and disseminated. Treatment options for XDR-GNB typically include Colistimethate sodium (referred to as colistin in this study), used alone (monotherapy) or in combination with other agents. Unfortunately, resistance to colistin has begun to emerge in some strains of XDR-GNB, which is a truly concerning development, since colistin is one of the last remaining treatment options for XDR-GNB. No prospective, randomized controlled trials have been conducted to evaluate the clinical efficacy of colistin monotherapy versus colistin-containing combination therapy or the impact of these therapeutic modalities on the emergence of colistin resistance among XDR-GNB. We plan to conduct a double-blind randomized controlled trial including patients with pneumonia and bloodstream infection due to XDR-GNB. After enrollment, subjects will be randomized to receive 14 days of either colistin monotherapy or colistin plus meropenem.

In the Detroit metro area, infections due to XDR-GNB have developed into a regional challenge and common problem. We have assembled a multi-disciplinary team that includes Infectious Diseases researchers, clinicians, infectious diseases pharmacists, microbiologists, epidemiologists and statistical experts to address critically important questions and challenges regarding the management of bloodstream infection and pneumonia due to XDR-GNB. Specifically, we hypothesize that the combination of colistin and imipenem will provide superior efficacy in the treatment of XDR-GNB pneumonia and bloodstream infection and will prevent the emergence of decreased susceptibility to colistin among XDR-GNB strains. We also aim to analyze tools that could be used in "real time" to aid clinicians treating patients with infection due to XDR-GNB. For example, we aim to analyze the association between the presence of in vitro synergy of the colistin and carbapenem (imipenem or meropenem) combination (as determined by E-test) and clinical outcomes; and the association between colistin plasma levels and clinical outcomes and the development of nephrotoxicity.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Condition  ICMJE
  • Pneumonia
  • Blood Stream Infection
Intervention  ICMJE
  • Drug: colistin and meropenem
    colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function
    Other Names:
    • Colistimethate
    • Meropenem
  • Drug: colistin and placebo
    colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)
    Other Name: Colstimethate
Study Arms  ICMJE
  • Active Comparator: colistin and meropenem
    Intervention: Drug: colistin and meropenem
  • Active Comparator: colistin and placebo
    Intervention: Drug: colistin and placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2012)
444
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2021
Estimated Primary Completion Date August 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites.
  • Diagnosis of BSI and/or pneumonia due to a preliminary result of gram-negative non-lactose fermenter that is oxidase negative; or a final results of XDR-A. baumannii; carbapenem-resistant Enterobacteriaciae; or XDR- P. aeruginosa and/or patients with suspected BSI and/or HAP and who have had a prior history (within last 6 months) of XDR-GNB that was susceptible to colistin.

    o If final results do not indicate that the pathogen is an XDR-GNB, and identifies alternative treatment options, the patient would be eligible for the study if the subject is allergic to all the alternative treatment options.

  • Patients with polymicrobial respiratory or blood infections, including XDR-GNB and one or more pathogens, will be included in the study, as long as the XDR-GNB is determined to be a true pathogen (AB, CRE or PA). Other pathogens will be treated with antimicrobial agents as determined by the treating physician.
  • If more than one XDR-GNB study pathogens is identified as a study pathogen causing BSI and/or pneumonia, then the first study pathogen recovered will be considered as the primary study pathogen. If more than one study pathogen is recovered from the same culture, then the infection will be categorized as being caused by multiple study pathogens.
  • Patients with a life expectancy of > 24 hours
  • Signed written informed consent and HIPAA Authorization form (US sites)

Exclusion Criteria:

  • Female patients who are pregnant
  • Female patients who are nursing
  • Patients who are prisoners
  • Patients who are less than 18 years of age or greater than or equal to 96 years of age
  • Patients with neutropenia (WBC < 500 cells/mm3)
  • The presence of any of the following known clinical syndromes involving XDR-GNB as a pathogen which necessitate durations of antimicrobial therapies greater than 14 days: endocarditis, osteomyelitis, prosthetic joint infections, meningitis and/or other central nervous system infections.
  • Patients receiving valproic acid (with or without a known seizure disorder).
  • Patients who received 72 hours or more of polymyxin treatment (intravenous or inhaled [pneumonia]) within 96 hours of enrollment.
  • Patients who have end-stage renal disease requiring hemodialysis, will be excluded from evaluation pertaining to nephrotoxicity in the per protocol population.
  • Patients with known Type 1 or other severe drug allergy to either of the study drugs or to β-lactams.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 95 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jolene Daniel, CCRP 734-615-1901 jolened@med.umich.edu
Listed Location Countries  ICMJE Bulgaria,   Greece,   Israel,   Italy,   Taiwan,   Thailand,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01597973
Other Study ID Numbers  ICMJE NIH 10-0065
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Keith Kaye, University of Michigan
Study Sponsor  ICMJE University of Michigan
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Keith S Kaye, MD, MPH University of Michigan
PRS Account University of Michigan
Verification Date September 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP