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

This study is currently recruiting participants.
Verified April 2014 by Kaye, Keith, M.D., M.P.H.
Sponsor:
Information provided by (Responsible Party):
Keith Kaye, M.D., M.P.H., Kaye, Keith, M.D., M.P.H.
ClinicalTrials.gov Identifier:
NCT01597973
First received: May 8, 2012
Last updated: April 15, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Pneumonia
Blood Stream Infection
Drug: colistin and meropenem
Drug: colistin and placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli

Resource links provided by NLM:


Further study details as provided by Kaye, Keith, M.D., M.P.H.:

Primary Outcome Measures:
  • mortality [ Time Frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks ] [ Designated as safety issue: Yes ]
    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).


Secondary Outcome Measures:
  • resistance [ Time Frame: patients resistance data will be collected at 28 days ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 444
Study Start Date: October 2012
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: August 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: colistin and meropenem 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
Active Comparator: colistin and placebo Drug: colistin and placebo
colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)
Other Name: Colstimethate

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 imipenem.

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 imipenem combination (as determined by E-test) and clinical outcomes; and the association between colistin plasma levels and clinical outcomes and the development of nephrotoxicity.

  Eligibility

Ages Eligible for Study:   18 Years to 95 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 48 hours or more of polymyxin treatment (intravenous or inhaled [pneumonia]) within 72 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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01597973

Contacts
Contact: Debbie DeCamillo, RN, BSN 3139660045 ddecamil@med.wayne.edu

Locations
United States, Florida
Jackson Memorial Hospital-Jackson Health System Recruiting
Miami, Florida, United States, 33136
Contact: L. Silvia Munoz-Price, MD    305-585-6820    SMunozPrice@med.miami.edu   
Principal Investigator: L.Silvia Munoz-Price, MD         
United States, Michigan
Wayne State University Recruiting
Detroit, Michigan, United States, 48201
Contact: Debbie DeCamillo, BSN, RN    313-966-0045    ddecamil@med.wayne.ed   
Principal Investigator: Keith Kaye, MD, MPH         
Henry Ford Health System Terminated
Detroit, Michigan, United States, 48202
Beaumont Health System Not yet recruiting
Royal Oak, Michigan, United States, 48073
Contact: Matt Sims, MD, PhD    248-551-0027    matthew.sims@beaumont.edu   
Principal Investigator: Matthew Sims, MD, PhD         
United States, New York
New York Presbyterian-Weill Cornell Medical Center Active, not recruiting
New York, New York, United States, 10065
Mount Sinai Hospital Not yet recruiting
New York, New York, United States, 10029
Contact: Gopi Patel, MD, MS    212-659-9566    gopi.patel@mssm.edu   
Principal Investigator: Gopi Patel, MD, MS         
United States, Ohio
The Ohio State University Wexner Medical Center Recruiting
Columbus, Ohio, United States, 43210
Contact: Kurt Stevenson, MD, MPH    614-293-5666    kurt.stevenson@osumc.edu   
Principal Investigator: Kurt Stevenson, MD, MPH         
Thailand
Sirraj Hospital Recruiting
Bangkoknoi, Bangkok, Thailand, 10700
Contact: Visanu Thamlikitkul, MD       sivth@mahidol.ac.th   
Principal Investigator: Visanu Thamlikitkul, MD         
Sponsors and Collaborators
Kaye, Keith, M.D., M.P.H.
Investigators
Principal Investigator: Keith S Kaye, MD, MPH Wayne State University and the Detroit Medical Center
  More Information

No publications provided

Responsible Party: Keith Kaye, M.D., M.P.H., Keith Kaye, M.D.,M.P.H Study PI, Kaye, Keith, M.D., M.P.H.
ClinicalTrials.gov Identifier: NCT01597973     History of Changes
Other Study ID Numbers: NIH 10-0065
Study First Received: May 8, 2012
Last Updated: April 15, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Pneumonia
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Colistin
Meropenem
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014