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    Summary
    EudraCT Number:2013-000634-35
    Sponsor's Protocol Code Number:CB-17-01/08
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-03-20
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2013-000634-35
    A.3Full title of the trial
    Effect of oral administration of Methylene Blue MMX® tablets
    on double-stranded DNA damage
    assessed by γH2AX analysis of colon biopsy samples
    Effetto della somministrazione orale di Methylene Blue MMX® compresse sul danno al DNA a doppia-elica valutato su biopsie di colon mediante analisi del γH2AX
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of oral administration of Methylene Blue MMX® tablets
    on DNA damage assessed by analysis of colon biopsy samples
    Effetto della somministrazione orale di Methylene Blue MMX® compresse sul danno al DNA valutato su biopsie di colon
    A.3.2Name or abbreviated title of the trial where available
    Methylene blue MMX double stranded DNA effect
    Effetto del Methylene Blue MMX sul DNA a doppia-elica
    A.4.1Sponsor's protocol code numberCB-17-01/08
    A.5.4Other Identifiers
    Name:Study protocol Number:CRO-13-113
    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 SponsorCosmo Technologies Ltd.
    B.1.3.4CountryIreland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCosmo Technologies Ltd.
    B.4.2CountryIreland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCROSS S.A.
    B.5.2Functional name of contact pointStudy Management Unit
    B.5.3 Address:
    B.5.3.1Street AddressVia F.A. Giorgioli 14
    B.5.3.2Town/ cityArzo
    B.5.3.3Post code6864
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41 916300510
    B.5.5Fax number+41916300511
    B.5.6E-mailcorporate@croalliance.com
    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 No
    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 nameMethylene blue MMX® 25 mg modified release tablets
    D.3.2Product code CB-17-01
    D.3.4Pharmaceutical form Modified-release tablet
    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 INNMethylthioninium chloride
    D.3.9.2Current sponsor codeCB-17-01
    D.3.9.3Other descriptive nameMETHYLENE BLUE
    D.3.9.4EV Substance CodeSUB21957
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Out-patients of both sexes scheduled for a screening or surveillance colonoscopy and identified as having the clinical requirement for a second colonoscopy within 2 weeks of the initial colonoscopy.
    Pazienti ambulatoriali di entrambi i sessi con indicazione ad effettuare una coloscopia e che alla coloscopia presentino caratteristiche endoscopiche e cliniche tali da richiedere di procedere, entro 2 settimane, ad una seconda coloscopia.
    E.1.1.1Medical condition in easily understood language
    Out-patients scheduled for a colonoscopy and identified as having the clinical requirement for a second colonoscopy within 2 weeks of the initial colonoscopy.
    Pazienti ambulatoriali con indicazione ad effettuare una coloscopia e che alla coloscopia presentino caratteristiche tali da procedere,entro 2 settimane,ad una seconda coloscopia.
    E.1.1.2Therapeutic area Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level PT
    E.1.2Classification code 10010007
    E.1.2Term Colonoscopy
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluation of the effect of a total oral dose of 200 mg of Methylene Blue MMX® tablets on colonic epithelial double-stranded DNA during a full chromoendoscopy in comparison with a standard white light colonoscopy without use of Methylene Blue MMX®.
    Lo studio ha lo scopo di valutare se la somministrazione orale di compresse contenenti blu di metilene può avere qualche effetto dannoso sulla struttura a doppia-elica del DNA delle cellule della mucosa del colon.
    E.2.2Secondary objectives of the trial
    1. To evaluate the safety and tolerability of oral Methylene Blue MMX® tablets.
    2. To evaluate the staining quality obtained with oral Methylene Blue MMX® tablets.
    3. To evaluate the colonoscopy duration with and without intake of Methylene Blue MMX® tablets.

    1. Valutare sicurezza e tollerabilità delle compresse di Methylene Blue MMX®;
    2. Valutare il grado di colorazione della mucosa intestinale in seguito all’assunzione di compresse di Methylene Blue MMX®;
    3. Valutare, per ciascuna procedura endoscopica, il tempo per raggiungere il cieco ed il tempo di ritorno.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age: 18-75 years old inclusive
    2. Indication: outpatients scheduled for screening or surveillance colonoscopy identified as having the clinical requirement for a second colonoscopy within 2 weeks of the initial colonoscopy
    3. Contraception: women of childbearing potential must use at least one reliable method of contraception or be abstinent. Women of non-child-bearing potential or in post-menopausal status must have been in that status for at least 1 year. For all women, pregnancy test result must be negative at screening
    4. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study
    5. Informed consent: signed written informed consent before inclusion in the study
    1. Età compresa tra 18 e 75 anni;
    2. Pazienti ambulatoriali con indicazione ad effettuare una coloscopia e che presentino alla prima coloscopia caratteristiche endoscopiche e cliniche tali da richiedere di procedere, entro 2 settimane, ad una seconda coloscopia;
    3. Le donne in età fertile dovranno usare almeno un efficace metodo contraccettivo, oppure astenersi totalmente da rapporti sessuali; le donne sterili o in post-menopausa dovranno essere tali da almeno 1 anno. Sarà comunque richiesto, in tutti i casi, di avere un test di gravidanza negativo prima di ricevere le compresse di Methylene Blue MMX®;
    4. Essere in grado di comprendere completamente la natura e lo scopo dello studio, inclusi i possibili rischi ed eventi avversi ed essere in grado di collaborare con il medico sperimentatore e di seguire le procedure previste durante tutta la durata dello studio;
    5. Aver firmato il modulo di consenso informato prima dell’inclusione nello studio.
    E.4Principal exclusion criteria
    1. Pregnancy: pregnant or lactating women or women undergoing fertility treatment
    2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
    3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness; in particular, ALT, AST, γ-GT, bilirubin, creatinine or urea greater than 2.5 x the upper limit for normal, based on local laboratory testing
    4. Allergy: ascertained or presumptive hypersensitivity to methylene blue and/or ingredients of both Methylene Blue MMX tablets and PEG-based bowel cleansing preparation; history of anaphylaxis to drugs or allergic reactions in general, which the investigator considers may affect the outcome of the study
    5. Diseases: known or suspected gastrointestinal obstruction or perforation, toxic megacolon, major colonic resection, severe diverticulosis with diverticulitis, heart failure (Class III or IV), serious cardiovascular disease, severe liver failure, end-stage renal insufficiency, clinical alarm symptoms or history of anaemia (previously recorded haemoglobin of less than 10mg/dL), frank blood in the stool within the last 30 days prior to enrolment, known deficiency of glucose-6-phosphate dehydrogenase, known deficiency of NADPH reductase, methaemoglobinemia and any other medical condition that in the investigator’s opinion would make the administration of the study drug or procedures hazardous to the subject
    6. Medications: previous or concomitant treatment with any monoamine oxidase inhibitor in accordance with a drug safety alert published by FDA (40). In particular, previous or concomitant treatment with the selective serotonin reuptake inhibitors (paroxetine, fluvoxamine, sertraline, citalopram, etc.), the serotonin-norepinephrine reuptake inhibitors (venlafaxine, devenlafaxine, duloxetine), tricyclic antidepressants (amitriptyline, desipramine, clomipramine, imipramine, nortriptyline, protriptyline, doxepin, trimipramine) and other psychiatric drugs (amoxapine, maprotiline, nefazodone, trazodone, bupropion, buspirone, vilazodone, mirtazapine) within 2 weeks before the study, previous or concomitant treatment with fluoxetine within 5 weeks before the study and/or previous or concomitant treatment with anticoagulants or antiaggregants inducing an INR>1.5
    1. Donne in stato di gravidanza o in allattamento, o donne sottoposte a trattamento per la fertilità;
    2. Alterazioni delle condizioni fisiche clinicamente significative che possano interferire con gli obiettivi dello studio;
    3. Valori di laboratorio con alterazioni clinicamente significative indicative di una condizione patologica concomitante, in particolare valori di ALT, AST, GGT, bilirubina, creatinina, o urea superiori a 2,5 volte il limite superiore al normale;
    4. Ipersensibilità accertata/presunta al blu di metilene e/o ai suoi eccipienti. Ipersensibilità accertata/presunta alla preparazione intestinale per la pulizia del colon e/o ai suoi ingredienti; storia medica di anafilassi ai farmaci o in generale reazioni allergiche, che il medico sperimentatore giudichi non compatibili con lo studio;
    5. Accertate o presunte ostruzioni o perforazioni gastrointestinali, megacolon tossico, resezioni maggiori del colon, severa diverticolosi con diverticolite, insufficienza cardiaca (classe III o IV), gravi malattie cardiovascolari o del fegato, insufficienza renale allo stadio finale, presenza di sintomi clinici allarmanti o storia di anemia (valori di emoglobina precedentemente valutati inferiori a 10mg/dL) o sangue franco nelle feci negli ultimi 30 giorni prima della partecipazione allo studio, carenza nota di glucosio-6-fosfato deidrogenasi, carenza nota di NADPH reduttasi, metaemoglobinemia o qualsiasi altra patologia che, a giudizio del medico sperimentatore, renderebbe la somministrazione del farmaco in studio, o la conduzione delle procedure previste dal protocollo, pericolose per il soggetto;
    6. Trattamento precedente o concomitante con inibitori della monoamino-ossidasi. In particolare trattamento concomitante, o trattamento nelle 2 settimane precedenti lo studio, con inibitori della ricaptazione della serotonina, inibitori del riassorbimento della serotonina-noradrenalina, antidepressivi triciclici e altri psicofarmaci. Trattamento concomitante, o precedente entro 5 settimane, con Fluoxetina (Prozac). Trattamento precedente o concomitante con anticoagulanti, o antiaggreganti, inducenti un INR> 1,5.
    E.5 End points
    E.5.1Primary end point(s)
    Evaluation, by histone γH2AX analysis, of the effect of a total oral dose of 200 mg of Methylene Blue MMX® tablets on colonic epithelial double-stranded DNA in colonic biopsy samples collected during chromoendoscopy as compared to control biopsies collected during standard white light colonoscopy without Methylene Blue MMX®.
    Valutare l’effetto della somministrazione orale di Methylene Blue MMX® compresse (8 compresse da 25 mg ciascuna) sul danno al DNA a doppia-elica valutato su biopsie di colon mediante analisi del γH2AX. Le biopsie prese durante la prima endoscopia saranno confrontate con quelle prese alla seconda endoscopia, eseguita dopo l’assunzione di Methylene Blue MMX® compresse.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Samples for γH2AX analysis will be collected from colonic regions of apparently normal appearance during the first and the second endoscopy
    Campioni bioptici per l'analisi del γH2AX saranno prelevati da diversi punti del colon non affetti da malattia nel corso della prima e della seconda colonoscopia
    E.5.2Secondary end point(s)
    1. safety and tolerability of oral Methylene Blue MMX® tablets;
    2. staining quality obtained with oral Methylene Blue MMX® tablets;
    3. colonoscopy duration with and without intake of Methylene Blue MMX® tablets.
    1. sicurezza e tollerabilità delle compresse di Methylene Blue MMX®;
    2. grado di colorazione della mucosa intestinale in seguito all’assunzione di compresse di Methylene Blue MMX®;
    3. tempo per raggiungere il cieco ed il tempo di ritorno di ciascuna procedura endoscopica.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety and tolerability of oral Methylene Blue MMX® tablets will be evaluated prior, during and after the second colonoscopy.
    Mucosal staining quality will be scored during the second colonoscopy, according to a subjective six-point scale scoring system.
    Colonoscopy duration will be evaluated during each endoscopy.
    Sicurezza e tollerabilità delle compresse di Methylene Blue MMX® saranno valutate prima, durante e dopo la colonoscopia.
    Il grado di colorazione della mucosa sarà valutato durante la seconda colonoscopia, assegnando un punteggio secondo una scala a 6 punti.
    Il tempo per raggiungere il cieco ed il tempo di ritorno sarà valutato per ciascuna procedura endoscopica.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    Ultima visita dell'ultimo soggetto
    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 months6
    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: 7
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state10
    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
    Nessuno
    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 Decision2013-05-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-03-25
    P. End of Trial
    P.End of Trial StatusCompleted
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