AzTrials
AzTrials

PneumoniaPhase 3NCT01597973

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

A Phase 3 study testing colistin and meropenem in people with Pneumonia and Blood Stream Infection, run by University of Michigan at 19 sites in 7 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 95 years
Conditions the study is for
Pneumonia, Blood Stream Infection
What is being tested?
colistin and meropenem
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
467 participants
Where
19 sitesin 7 countries
Study dates
6 Oct 2012to 9 Aug 2020
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 95 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)

Who cannot join

  • 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.
Show all 10Show fewer
  • 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.

Trial locations and contacts

19 sites in 7 countries.

19 sites in 7 countries

United States6 sites
  • The Ohio State University Wexner Medical Center

    Columbus, Ohio, 43210

  • Wayne State University

    Detroit, Michigan, 48201

  • Henry Ford Health System

    Detroit, Michigan, 48202

  • Jackson Memorial Hospital-Jackson Health System

    Miami, Florida, 33136

  • Mount Sinai Hospital

    New York, New York, 10029

  • Beaumont Health System

    Royal Oak, Michigan, 48073

Other trials in United States

Greece5 sites
  • Evangelismos General Hospital of Athens

    Athens, 10676

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

    Athens, 11527

  • Attikon University General Hospital of Athens

    Athens, 12461

  • University Hospital of Heraklion

    Crete, Crete, 71110

  • Hippokration General Hospital of Thessaloniki

    Thessaloniki, 54642

Other trials in Greece

Israel4 sites
  • Rambam Health Care Campus

    Haifa, 31096

  • Rabin Medical Centre, Beilinson Campus

    Petah Tikva, Central District, 49100

  • Tel-Aviv Sourasky Medical Center

    Tel Aviv, 64239

  • Assaf Harofeh Medical Center

    Tsrifin, Beer Yaakov, 70300

Other trials in Israel

Bulgaria1 site
  • University Multiprofile Hospital for Active Treatment and Emergency Medicine "N.I. Pirogov"

    Sofia, 1606

Other trials in Bulgaria

Italy1 site
  • Universita della Campania 'Luigi Vanvitelli'

    Naples, 80131

Other trials in Italy

Taiwan1 site
  • Chang Gung Memorial Hospital

    Taoyuan, Kwei-San, 33305

Other trials in Taiwan

Thailand1 site
  • Siriraj Hospital

    Bangkoknoi, Bangkok, 10700

Other trials in Thailand

About this study

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

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:

Read more

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.

Read the 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.

Being tested
colistin and meropenem, colistin and placebo
Medical subject headings
Pneumonia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • colistin and meropenemDrug

    Also called Colistimethate, Meropenem

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

  • colistin and placeboDrug

    Also called Colistimethate

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

Study groups in NCT01597973
Study groupRoleWhat they receive
colistin and meropenemActive comparatorNot described
Receives: Drug: colistin and meropenem
colistin and placeboActive comparatorNot described
Receives: Drug: colistin and placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

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

Secondary outcomes (4)
  1. Number of Participants Who Develop Colistin Resistance

    Determine what treatment regimen (colistin monotherapy (combined with placebo)) 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. Measurements of Minimum Inhibitory Concentration of colistin to XDR-GNB. This is shown below as numbers of those subjects who develop colistin resistance and their percentages of the total completed population.

    Measured: patients' resistance data will be collected up to 30 days

  2. Clinical Failure at the End of Therapy

    Clinical failure as defined by either Blood Stream Infection (BSI) or Pneumonia; based on death between 48 hours and end of treatment, medication change from protocol, a positive blood culture after 5 days of blood stream infection treatment, or no improvements in PaO2/FiO2 at end of treatment.

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

  3. Microbiologic Cure at the End of Therapy

    Microbiologic cure at the end of therapy as defined by the number of participants who no longer have the causative XDR-GNB pathogens for their BSI or pneumonia identified based on microbiologic testing

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

  4. Number of Participants With Toxicities Related to Treatment Medications

    Frequency is shown for each of the following: Nephrotoxicity, Hepatotoxicity, Seizures, Neurotoxicity, Hypersensitivity reaction

    Measured: Up to 16 days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 May 2012 (estimated)
  2. Study start6 Oct 2012
  3. Primary completion9 Aug 2020
  4. Study completion9 Aug 2020

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Care provider, Investigator
Enrolment
467 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01597973
Sponsor's protocol ID
NIH 10-0065
Status last verified
Nov 2022
First submitted
8 May 2012
Last updated
14 Nov 2022
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 37538951

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing colistin and meropenem in people with Pneumonia and Blood Stream Infection, run by University of Michigan at 19 sites in 7 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 19 sites in United States, Greece, Israel, Bulgaria, Italy and 2 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Nov 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Mortality (time frame: participants will be followed daily for the duration of hospital stay, an expected average of 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01597973, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Nov 2022.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in