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

NCT01597973 | Completed Phase 3 Results DMC

• 1 other identifier: NIH 10-0065
• Study Type: interventional
• Target: 467
• Locations: 7 countries
• Sites: 19

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.

Conditions

Pneumonia; Blood Stream Infection

Outcome Measures

Primary Outcomes (1)

• Mortality

  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 combined with a placebo for subjects with bloodstream infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB).

  participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks

Secondary Outcomes (4)

• Number of Participants Who Develop Colistin Resistance

  patients' resistance data will be collected up to 30 days

• Clinical Failure at the End of Therapy

  48 hours after end of treatment, that is up to 16 days

• Microbiologic Cure at the End of Therapy

  From 5 days after enrollment up to 14 days following enrollment (i.e. end of treatment)

• Number of Participants With Toxicities Related to Treatment Medications

  Up to 16 days

Study Arms (2)

colistin and meropenem

ACTIVE COMPARATOR

Drug: colistin and meropenem

colistin and placebo

ACTIVE COMPARATOR

Drug: colistin and placebo

Interventions

colistin and meropenem DRUG

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

Also known as: Colistimethate, Meropenem

colistin and meropenem

colistin and placebo DRUG

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

Also known as: Colistimethate

colistin and placebo

Eligibility Criteria

• Age: 18 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Michigan: lead

Study Sites (19)

Jackson Memorial Hospital-Jackson Health System

Miami, Florida, 33136, United States

Location

Wayne State University

Detroit, Michigan, 48201, United States

Location

Henry Ford Health System

Detroit, Michigan, 48202, United States

Location

Beaumont Health System

Royal Oak, Michigan, 48073, United States

Location

Mount Sinai Hospital

New York, New York, 10029, United States

Location

The Ohio State University Wexner Medical Center

Columbus, Ohio, 43210, United States

Location

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

Sofia, 1606, Bulgaria

Location

University Hospital of Heraklion

Crete, Crete, 71110, Greece

Location

Evangelismos General Hospital of Athens

Athens, 10676, Greece

Location

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

Athens, 11527, Greece

Location

Attikon University General Hospital of Athens

Athens, 12461, Greece

Location

Hippokration General Hospital of Thessaloniki

Thessaloniki, 54642, Greece

Location

Assaf Harofeh Medical Center

Ẕerifin, Beer Yaakov, 70300, Israel

Location

Rabin Medical Centre, Beilinson Campus

Petah Tikva, Central District, 49100, Israel

Location

Rambam Health Care Campus

Haifa, 31096, Israel

Location

Tel-Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Universita della Campania 'Luigi Vanvitelli'

Naples, 80131, Italy

Location

Chang Gung Memorial Hospital

Taoyuan District, Kwei-San, 33305, Taiwan

Location

Siriraj Hospital

Bangkoknoi, Bangkok, 10700, Thailand

Location

Related Publications (1)

• 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.

  PMID: 37538951 DERIVED

MeSH Terms

Conditions

Pneumonia

Interventions

Colistin; Meropenem; colistinmethanesulfonic acid

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Polymyxins; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Lipopeptides; Lipids; Antimicrobial Cationic Peptides; Peptides; Amino Acids, Peptides, and Proteins; Antimicrobial Peptides; Pore Forming Cytotoxic Proteins; Membrane Proteins; Proteins; Thienamycins; Carbapenems; beta-Lactams; Lactams; Amides; Organic Chemicals; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Jolene Daniel
• Organization: University of Michigan

jd1557@rwjms.rutgers.edu

732 235-7713

Study Officials

• Keith S Kaye, MD, MPH

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Keith Kaye, M.D.,M.P.H Study PI

Study Record Dates

• First Submitted: May 8, 2012
• First Posted: May 15, 2012
• Study Start: October 6, 2012
• Primary Completion: August 9, 2020
• Study Completion: August 9, 2020
• Last Updated: November 14, 2022
• Results First Posted: November 30, 2021

Record last verified: 2022-11

Locations

TH (1); GR (5); IL (4); IT (1); US (6); BU (1); TW (1)