NCT01597973

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

Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant Gram-negative Bacilli (OVERCOME)

• Status: Completed
• Phase: Phase 3
• Study type: Interventional
• Enrollment: 467 (actual)
• Sponsor: University of Michigan · Academic / Other
• Sex: All
• Age: 18 Years – 95 Years
• Healthy volunteers: Not accepted

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, Enterobacter 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, Enterobacter 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. Due to the growing threat of XDR-GNB around the world, several international sites were subsequently added including sites in Asia, Israel, and Europe.

Conditions

• Pneumonia
• Blood Stream Infection

Interventions

Type	Name	Description
DRUG	colistin and meropenem	colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function
DRUG	colistin and placebo	colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)

Timeline

• Start date: 2012-10-06
• Primary completion: 2020-08-09
• Completion: 2020-08-09
• First posted: 2012-05-15
• Last updated: 2022-11-14
• Results posted: 2021-11-30

Locations

19 sites across 7 countries: United States, Bulgaria, Greece, Israel, Italy, Taiwan, Thailand