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

NCT ID: NCT01597973

Last Updated: 2022-11-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 467 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-10-06
• Study Completion Date: 2020-08-09

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, 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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

colistin and meropenem

Group Type: ACTIVE_COMPARATOR

colistin and meropenem

Intervention Type: DRUG

colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function

colistin and placebo

Group Type: ACTIVE_COMPARATOR

colistin and placebo

Intervention Type: DRUG

colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)

Interventions

colistin and meropenem

colistin standard loading dose, maintenance dose based on patients renal function meropenem- dose based on patients renal function

Intervention Type: DRUG

colistin and placebo

colistin- loading dose standard, maintenance dosed based on patients renal function placebo- mimic meropenem (blinded)

Intervention Type: DRUG

Other Intervention Names

Colistimethate; Meropenem; Colistimethate

Eligibility 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 Enterobacteriaceae; or XDR- P. aeruginosa and/or patients with suspected BSI and/or HAP (hospital acquired pneumonia) 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 95 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Michigan

OTHER

Sponsor Role: lead

Responsible Party

keith kaye

Keith Kaye, M.D.,M.P.H Study PI

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Keith S Kaye, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Michigan

Locations

Jackson Memorial Hospital-Jackson Health System

Miami, Florida, United States

Wayne State University

Detroit, Michigan, United States

Henry Ford Health System

Detroit, Michigan, United States

Beaumont Health System

Royal Oak, Michigan, United States

Mount Sinai Hospital

New York, New York, United States

The Ohio State University Wexner Medical Center

Columbus, Ohio, United States

University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov"

Sofia, , Bulgaria

University Hospital of Heraklion

Crete, Crete, Greece

Evangelismos General Hospital of Athens

Athens, , Greece

General Hospital of Athens "Laiko" 1st Department of Medicine

Athens, , Greece

Attikon University General Hospital of Athens

Athens, , Greece

Hippokration General Hospital of Thessaloniki

Thessaloniki, , Greece

Assaf Harofeh Medical Center

Ẕerifin, Beer Yaakov, Israel

Rabin Medical Centre, Beilinson Campus

Petah Tikva, Central District, Israel

Rambam Health Care Campus

Haifa, , Israel

Tel-Aviv Sourasky Medical Center

Tel Aviv, , Israel

Universita della Campania 'Luigi Vanvitelli'

Naples, , Italy

Chang Gung Memorial Hospital

Taoyuan District, Kwei-San, Taiwan

Siriraj Hospital

Bangkoknoi, Bangkok, Thailand

Countries

United States; Bulgaria; Greece; Israel; Italy; Taiwan; Thailand

References

Kaye KS, Marchaim D, Thamlikitkul V, Carmeli Y, Chiu CH, Daikos G, Dhar S, Durante-Mangoni E, Gikas A, Kotanidou A, Paul M, Roilides E, Rybak M, Samarkos M, Sims M, Tancheva D, Tsiodras S, Kett D, Patel G, Calfee D, Leibovici L, Power L, Munoz-Price S, Stevenson K, Susick L, Latack K, Daniel J, Chiou C, Divine GW, Ghazyaran V, Pogue JM. Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms. NEJM Evid. 2023 Jan;2(1):10.1056/evidoa2200131. doi: 10.1056/evidoa2200131. Epub 2022 Dec 6.

Reference Type: DERIVED

PMID: 37538951 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NIH 10-0065

Identifier Type: -

Identifier Source: org_study_id