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The European Union Clinical Trials Register   allows you to search for protocol and results information on:
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    Summary
    EudraCT Number:2017-002110-32
    Sponsor's Protocol Code Number:10-0065
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-06-26
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGreece - EOF
    A.2EudraCT number2017-002110-32
    A.3Full title of the trial
    DMID Protocol Number: 10-0065
    OVERCOME Trial: Randomized Controlled Trial for the Treatment of Extensively Drug-Resistant
    Gram-negative Bacilli
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized treatment with either Colistin/Meropenem or Colistin/Placebo for extremely drug resistant Gram-negative Bacilli
    A.3.2Name or abbreviated title of the trial where available
    OVERCOME
    A.4.1Sponsor's protocol code number10-0065
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01597973
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRegents of the University of Michigan
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institute of Allergy and Infectious Diseases (NIAID)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRegents of the University of Michigan
    B.5.2Functional name of contact pointKeith Kaye
    B.5.3 Address:
    B.5.3.1Street Address1150 West Medical Center Drive
    B.5.3.2Town/ cityAnn Arbor
    B.5.3.3Post code48109
    B.5.3.4CountryUnited States
    B.5.4Telephone number1 734615-1901
    B.5.5Fax number1734764-6022
    B.5.6E-mailkeithka@med.umich.edu
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMeropenem
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMeropenem
    D.3.9.3Other descriptive nameMEROPENEM TRIHYDRATE
    D.3.9.4EV Substance CodeSUB21617
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameColistimethate sodium (Colistin)
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCOLISTIMETHATE SODIUM
    D.3.9.1CAS number 8068-28-8
    D.3.9.4EV Substance CodeSUB06801MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Blood stream Infection (BSI) and/or pneumonia due to extensively drug-resistant Gram-negative bacilli (XDR-GNB) including XDR-AB, CRE and XDR-PA
    E.1.1.1Medical condition in easily understood language
    Blood stream infection and/or pneumonia
    E.1.1.2Therapeutic area Diseases [C] - Bacterial Infections and Mycoses [C01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10004031
    E.1.2Term Bacterial infection due to other gram-negative organisms
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10035701
    E.1.2Term Pneumonia gram-negative bacterial NOS
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10064977
    E.1.2Term Acinetobacter bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10051190
    E.1.2Term Pneumonia Pseudomonas aeruginosa
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10035679
    E.1.2Term Pneumonia due to Escherichia coli (E. Coli)
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054280
    E.1.2Term Escherichia coli bacteraemia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10021860
    E.1.2Term Infection Pseudomonas aeruginosa
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10023456
    E.1.2Term Klebsiella pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10058883
    E.1.2Term Klebsiella bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10054218
    E.1.2Term Enterobacter pneumonia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10058884
    E.1.2Term Enterobacter bacteremia
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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).

    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Hospitalized Adults (> 18 years to 95 years of age), at one of the study sites.
    • Diagnosis of BSI and/or pneumonia (refer to Section 5.2.3 for definitions), due to a preliminary result of gram-negative non-lactose fermenter that is oxidase negative; ; or E. coli, Klebsiella spp. or Enterobacter spp. that are suspected to be CRE based on a screening test result (meropenem, imipenem, doripenem or ertapenem MIC>1 ug/ml); or result of a rapid molecular test performed indicating presence of A. baumannii, E. coli, Klebsiella spp., Enterobacter spp. or P. aeruginosa; or a final result of XDR-A. baumannii; carbapenem-resistant Enterobacteriaceae; or XDR- P. aeruginosa (refer to List of Abbreviations and Definition Section for pathogen definitions) and/or patients with suspected BSI and/or 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, according to study definitions, and alternative treatment options are identified, the patient would be eligible for the study if the patient is allergic to non-carbapenem beta-lactam treatment options.Patients are also eligible for inclusion if they have pneumonia or BSI due to Pseudomonas aeruginosa that, while “susceptible” to a beta-lactam option by current in vitro breakpoint definitions, the isolate is not considered to be treatable by the prescribing physician due to inability to achieve adequate clinical efficacy and/or pharmacokinetic/pharmacodynamic targets using standard approved dosages of these beta-lactam antimicrobials. For the purposes of this study, patients would be eligible if they have an infection due to a strain of Pseudomonas aeruginosa with a cefepime MIC of 8 mcg/ml; or imipenem/meropenem/doripenem MIC of 2 mcg/mL or aztreonam MIC of 8mcg/mL; where the treating physician does not feel that treatment with these agents would be adequate or optimal to treat this type of Pseudomonas aeruginosa strain. Recent literature suggests that current CLSI breakpoints may not be appropriate126,127.
    o In addition, if the pathogen is A. baumannii that is susceptible to ampicillin/sulbactam and the treating physician feels that ampicillin/sulbactam is not appropriate therapy, then the patient would be eligible for the trial, as the role and optimal dose of ampicillin/sulbactam remains uncertain for the treatment of invasive A. baumannii infections. Patients are also eligible at sites where the clinical microbiology laboratory does not differentiate between A. baumannii and non-baumannii Acinetobacter, because it is assumed that all XDR Acinetobacter are XDR A. baumannii.
    o Patients can also be included if they have isolates that are susceptible to ceftolazane-tazobactam and/or ceftazidime-avibactam and/or antimicrobials approved by the FDA after 1/1/2017.
    • 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 (if applicable) form
     For Assaf Harofeh Medical Center ICF exception refer to SOP #7 in the MOP.
    E.4Principal 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 study 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 (excluding inhaled and topical formulations) within 96 hours of enrollment.
    • Patients who have end-stage renal disease requiring hemodialysis are not excluded from the study but 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.
    o If patients with β-lactam allergy have previously received carbapenems safely then they would not be excluded.

    No exclusions were made based upon gender or demographic preferences. Children <18 years of age were excluded from the study as they have not frequently developed infections due to XDR-GNB at study hospitals and the PK/PD of study drugs would have been different in this population
    E.5 End points
    E.5.1Primary end point(s)
    All-cause mortality 28-30 days after study enrollment
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 28
    E.5.2Secondary end point(s)
    Clinical failure at the end of therapy as defined by the following:
    • Clinical failure
    • BSI:
     One or more positive blood cultures (of the study pathogen) obtained after day 5 of enrollment
     Death after 48 hours of enrollment but prior to End of Treatment (EOT)
     Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen
    • Pneumonia:
     Death after 48 hours of enrollment but prior to End of Treatment (EOT)
     Lack of improvement in PaO2/FiO2 at End of Treatment (EOT)
     Clinical instability or clinical worsening during the trial requiring rescue antimicrobial drug therapy for treatment of the study pathogen
    E.5.2.1Timepoint(s) of evaluation of this end point
    End of therapy
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Bulgaria
    Greece
    Israel
    Italy
    Taiwan
    Thailand
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Once the enrollment goal of 444 subjects has been met.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months10
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 149
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 295
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Subjects may be enrolled in the research if permitted by an advance directive (e.g., living will, durable power of attorney for proxy consent) or if consent is obtained from the Legally Authorized Representative (LAR).
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state126
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 140
    F.4.2.2In the whole clinical trial 444
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-06-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-15
    P. End of Trial
    P.End of Trial StatusOngoing
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