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    Summary
    EudraCT Number:2013-003048-21
    Sponsor's Protocol Code Number:Uni-Köln-1667
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-09-20
    Trial results View 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 ConcernedGermany - BfArM
    A.2EudraCT number2013-003048-21
    A.3Full title of the trial
    CONTROLING INTESTINAL COLONIZATION OF HIGH-RISK PATIENTS WITH EXTENDED- SPECTRUM BETALACTAMASE PRODUCING ENTEROBACTERIACEAE (ESBL-E) – A RANDOMIZED TRIAL (CLEAR)
    Kontrolle der intestinalen Kolonisierung von Hämatologischen Hochrisikopatienten mit Extended-Spectrum Beta-Lactamase Produzierenden Enterobakterien (ESBL-E) – Eine Randomisierte Studie (CLEAR)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate treatment for colonization with certain multidrug-resistant bacteria in the gut in patients with a compromised immune system.
    Studie zur Überprüfung einer Therapie von Besiedlung mit multiresistenten Bakterien im Darm bei Patienten mit geschwächtem Immunsystem.
    A.3.2Name or abbreviated title of the trial where available
    CLEAR
    A.4.1Sponsor's protocol code numberUni-Köln-1667
    A.5.4Other Identifiers
    Name:ClinicalTrials.gov Number:NCT01931592
    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 SponsorUniversity of Cologne
    B.1.3.4CountryGermany
    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 supportDZIF 3632 5511 21
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Cologne
    B.5.2Functional name of contact pointMaria J.G.T. Vehreschild
    B.5.3 Address:
    B.5.3.1Street AddressKerpener Strasse 62
    B.5.3.2Town/ cityCologne
    B.5.3.3Post code50937
    B.5.3.4CountryGermany
    B.5.4Telephone number0049221478 6494
    B.5.5Fax number0049221478 3611
    B.5.6E-mailMaria.Vehreschild@ctuc.de
    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.2.1.1.1Trade name Monuril
    D.2.1.1.2Name of the Marketing Authorisation holderPierre Fabre Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Granules for oral solution in sachet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFOSFOMYCIN
    D.3.9.1CAS number 23155-02-4
    D.3.9.4EV Substance CodeSUB07797MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3
    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.2.1.1.1Trade name Diarönt mono
    D.2.1.1.2Name of the Marketing Authorisation holderCNP Pharma GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Powder for oral solution
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNColistin sulphate
    D.3.9.3Other descriptive nameCOLISTIN SULPHATE
    D.3.9.4EV Substance CodeSUB11844MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5.95
    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: 3
    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.2.1.1.1Trade name Refobacin
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGentamicin
    D.3.9.3Other descriptive nameGENTAMICIN
    D.3.9.4EV Substance CodeSUB02326MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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 placeboGranules for oral solution in sachet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboPowder for oral solution
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 3
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection/infusion
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Immunocompromised patients at high risk of bloodstream infections with colonizing bacteria.
    E.1.1.1Medical condition in easily understood language
    Patients with an compromised immune system and an increased risk of contracting infections in their bloodstream due to bacteria colonizing their gut.
    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 16.1
    E.1.2Level LLT
    E.1.2Classification code 10066481
    E.1.2Term Hematological malignancy
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10067862
    E.1.2Term Allogeneic stem cell transplantation
    E.1.2System Organ Class 100000004865
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10054990
    E.1.2Term Immunodeficiency secondary to organ transplantation
    E.1.2System Organ Class 100000004870
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10021458
    E.1.2Term Immunodeficiency secondary to transplantation chemotherapy
    E.1.2System Organ Class 100000004870
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level LLT
    E.1.2Classification code 10021452
    E.1.2Term Immunodeficiency secondary to chemotherapy (excl corticosteroids)
    E.1.2System Organ Class 100000004870
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Assessment of efficacy and safety of an antimicrobial regimen in the short-term and long-term eradication of ESBL-E from the intestinal flora of immunocompromised high-risk patients.
    E.2.2Secondary objectives of the trial
    See secondary endpoints (section E 5.2)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Fecal colonization with ESBL-E, as confirmed by a positive sample (rectal swab or stool sample) obtained within 14 days prior to study enrolment
    • Ongoing or scheduled immunosuppression:
    o allogeneic or autologous hematopoietic stem cell transplantation within 14 days after enrolment or
    o chemotherapy with an expected duration of chemotherapy-associated neutropenia of at least 7 days within 14 days after enrolment or
    o solid organ transplantation within 14 days after enrolment or
    o administration of high-dose corticosteroids or other immunosuppressants for acute rejection of a solid organ transplant or for graft versus host disease after stem cell transplantation
    • Age of at least 18 years
    • Subject is not legally incapacitated
    • Written informed consent from the trial subject has been obtained
    E.4Principal exclusion criteria
    • Current or scheduled administraton of ESBL-E active antibiotic treatment or prophylaxis after receipt of the most recent sample showing intestinal ESBL-E colonization and within 10 days after randomization
    • Planned selective digestive tract decolonization (SDD) within 42 days following randomization
    • Known hypersensitivity or allergy to any of the components of the study treatment
    • Moderate or severe liver dysfunction at baseline, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN), AND a total bilirubin level greater than two times the ULN
    • Serum creatinine > 2 x the ULN
    • Current pregnancy or nursing period
    • Failure to use highly-effective contraceptive methods
    • Concurrent participation in another clinical trial with an investigational drug is not permitted, unless the drug under study is related to the treatment of the underlying condition, transplantation or immunosuppression
    E.5 End points
    E.5.1Primary end point(s)
    • Short-term intestinal eradication, defined as a fecal sample, negative for ESBL-E on day 6+/-1 and day 11+/-2
    E.5.1.1Timepoint(s) of evaluation of this end point
    on day 6+/-1 and day 11+/-2
    E.5.2Secondary end point(s)
    • Long-term intestinal eradication d28, defined as a fecal sample, negative for ESBL-E on day 28+/-4
    • Long-term intestinal eradication d42, defined as a fecal sample, negative for ESBL-E on day 42+/-4
    • Short-term non-intestinal eradication, defined as a combination of ESBL-E negative samples from skin, urine and the throat on day 6+/-1 and day 11+/-2
    • Long-term non-intestinal eradication d28, defined as a combination of ESBL-E negative samples from skin, urine and the throat on day 28+/-4
    • Long-term non-intestinal eradication d42, defined as a combination of ESBL-E negative samples from skin, urine and the throat on day 42+/-4
    • Short-term overall eradication, defined as a combination of ESBL-E negative samples from feces, skin, urine and the throat on day 6+/-1 and day 11+/-2
    • Long-term overall eradication d28, defined as a combination of ESBL-E negative samples from feces, skin, urine and the throat on day 28+/-4
    • Long-term overall eradication d42, defined as a combination of ESBL-E negative samples from feces, skin, urine and the throat on day 42+/-4
    • Emerging presence of non-ESBL multi-drug resistant bacteria in the intestine, defined as identification of vancomycin resistant Enterococci (VRE), 4 multi-drug-resistant gram negative rods (MRGN) according to the KRINKO definition or colistin-resistant bacteria in a fecal sample on day 6+/-1, day 11+/-2, day 28+/-4 or day 42+/-4
    • Association between the intestinal microbiome pattern and the outcome of eradication on baseline, day 6+/-1, day 11+/-2, day 28+/-4 or day 42+/-4
    • Quantitative assessment of intestinal ESBL-E burden on baseline, day 6+/-1, day 11+/-2, day 28+/-4 or day 42+/-4
    • Incidence and severity of AEs
    • Rate of AE-related study drug discontinuations
    E.5.2.1Timepoint(s) of evaluation of this end point
    day 6+/-1, day 11+/-2, day 28+/-4 or day 42+/-4
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 Yes
    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) No
    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 concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    Premature termination of the trial will be considered if:
    • The risk-benefit balance for the trial subject changes markedly
    • It is no longer ethical to continue treatment with the IMP
    • The sponsor considers that the trial must be discontinued for safety reasons
    • An interim analysis or results of other research show that one of the trial treatments is superior or inferior to another
    • It is no longer practicable to complete the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days0
    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: 37
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state47
    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)
    according to standard care
    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 Decision2014-03-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2017-05-31
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