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    Summary
    EudraCT Number:2014-004554-34
    Sponsor's Protocol Code Number:2014-004554-34
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-16
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2014-004554-34
    A.3Full title of the trial
    An open label, explorative pharmacokinetic trial, to investigate the Cytochrome (CYP) CYP3A4, - 2E1 and – 1A2 clearance in Obese – versus Non Obese Children by use of well-tested probes (midazolam, chlorzoxazone, caffeine)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Drug metabolism related to obesity
    A.4.1Sponsor's protocol code number2014-004554-34
    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 SponsorBispebjerg Hospital
    B.1.3.4CountryDenmark
    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 supportKlinisk Farmakologisk Afdeling Bispebjerg Hospital
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKlinisk Farmakologisk Afdeling, Bispebjerg Hospital
    B.5.2Functional name of contact pointHelle Holst
    B.5.3 Address:
    B.5.3.1Street AddressBispebjerg Bakke 23, opgang 51
    B.5.3.2Town/ cityCopenhagen NV
    B.5.3.3Post code2400
    B.5.3.4CountryDenmark
    B.5.6E-mailhelle.holst.01@regionh.dk
    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 Klorzoxazon "DAK"
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda
    D.2.1.2Country which granted the Marketing AuthorisationDenmark
    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 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 INNCHLORZOXAZONE
    D.3.9.1CAS number 95-25-0
    D.3.9.4EV Substance CodeSUB06215MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number250 to 500
    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 Midazolam
    D.2.1.1.2Name of the Marketing Authorisation holderHameln
    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 Suspension for injection
    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 INNMIDAZOLAM
    D.3.9.1CAS number 59467-70-8
    D.3.9.4EV Substance CodeSUB08950MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,001
    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
    E.1.1.1Medical condition in easily understood language
    We want to investigate, whether the activity of some of the most important drug metabolizing enzymes, is altered in obese children versus non-obese children.
    E.1.1.2Therapeutic area Body processes [G] - Metabolic Phenomena [G03]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10029885
    E.1.2Term Obesity, unspecified
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Research hypotheses:
    • CYP2E1- clearance is higher in obese children versus non-obese children
    • CYP3A4- clearance is lower in obese children versus non-obese children
    • CYP1A2- clearance is altered in obese children versus non-obese children
    Primary objectives:
    We want to investigate, whether the activity of some of the most important drug metabolizing enzymes, is altered in obese children versus non-obese children.
    Primary endpoints:
    These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein).
    CYP2E1-, CYP1A2- and CYP3A4 clearance will be determined by following methods:
    • Chlorzoxazone multi-sample method (CYP2E1 activity)
    • Caffeine urinary metabolic ratio method (CYP1A2 activity)
    • Midazolam microdosing method (CYP3A4 activity)

    Cmax, Tmax , AUC, T1/2, and Vd will be defined blood samples collected at specific times and from urine collected for 24 hours.
    E.2.2Secondary objectives of the trial
    Secondary objective
    From and exploratory objective, we want to investigate whether an altered enzyme activity of CYP3A4, CYP2E1 and CYP1A2, is accociated with metabolic syndrome.
    Secondary endpoints:
    - Lipid profile
    - Inflammatory markers
    - Steatosis

    Markers of metabolic syndrome and steatosis:
    -Lipid profile: LDL, HDL, total cholesterol, triglyceride
    -Markers of insulin-resistance: Hba1C, Blood Glucose, Insuline
    -Inflammatory markers: TNFalfa, interleukin 6, leptin, adiponectin and CRP
    -Liver test: ASAT, ALAT, alkaline phosphatase, bilirubin, albumine and liver MR scanning (to verify steatosis)
    -24-hour blood pressure
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Obese children (BMI ≥ 99 % percentile)
    • Healthy non-obese children (BMI≤ 90 % percentile)
    • Age 11-18 years
    • Both genders (block stratified)
    • Postmenarche (females)
    • Written informed consent from both parents (age<18)
    Females included will be post menarche (Tanner stage 4) in order to avoid bias, as maturation of CYP1A2 activity mirrors pubertal growth, which peaks early in females.
    E.4Principal exclusion criteria
    • Acute or chronic Liver diseases
    • Other chronic diseases, except from allergic rhinitis, rash etc.
    • Intake of drugs known to induce of inhibit CYP2E1-, CYP3A4 and/or CYP1A2, including paracetamol, ciprofloxacin, azithromycin, ketoconazol, estradiol etc.
    • Citrus fruit
    • Alcohol intake within minimum 72 hours
    • Caffeine (Coca Cola©, coffee and tea) intake 48 h prior to administration of the caffeine-probe
    • Smoking 96 hours prior to administration of the caffeine-probe, screening test will be performed (nicotine metabolite: cotinine)
    • Kidney disease and dialysis
    • Pregnancy (test will be performed)
    • Known hypersensitivity to chlorzoxazone, midazolam or caffeine
    • vigorous exercise 24 hours before administration
    E.5 End points
    E.5.1Primary end point(s)
    These are the combined primary endpoints: Clearance of CYP2E1-, CYP1A2- and CYP3A4 substrates, defined by using well-tested probes (midazolam, chlorzoxazone and caffein).
    CYP2E1-, CYP1A2- and CYP3A4 will be determined by following methods:
    •Chlorzoxazone clearance (CYP2E1 activity)
    •Caffeine urinary metabolic ratio method (CYP1A2 activity)
    •Midazolam microdosing methodErythromycin breath test (CYP3A4 activity)
    E.5.1.1Timepoint(s) of evaluation of this end point
    All of the three probes will be given as single doses (t=0) to all included trial subjects (Chlorzoxazone and Caffeine orally and midazolam intravenousmethyl-erythromycin i.v.). Blood samples will be taken at specific times: After administration of chlorzoxazone: (t=10, 20, 30, 40, 50, 60, 90, 120 min and hourly for the next 4 hours) After administration of midazolam: Group 1 (25 obese and 25 non.obese trial participants): t=0, 2, 10, 20, 45, 90, 150, 210, 270, 360, 420, 480, 540 min. Group 2(25 obese and 25 non-obese trial participants): t=0, 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 min.
    Urine will be collected completely for 24 hours post-dose.
    E.5.2Secondary end point(s)
    For Chlorzoxazone and midazolam: Cmax (maximum plasma concentration), Tmax (time to maximum plasma concentration), AUC (areal under the drug concentration /time curve), T1/2 (elimination half time) and Vd (volume of distribution) will be defined from blood samples taken at specific times.

    Lipid profile (LDL, HDL, total cholesterol, triglyceride), markers of insulin- resistance (Hba1C, Blood Glucose, insuline) ,inflammatory markers (TNF╬▒, interleukin 6, leptin, adiponectin and CRP), liver tests (ASAT, ALAT, alkaline phosphatase, bilirubin, albumin), and creatinine .
    E.5.2.1Timepoint(s) of evaluation of this end point
    Baseline blood samples, and after administration of chlorzoxazone: (t=10, 20, 30, 40, 50, 60, 90, 120 min and hourly for the next 4 hours) After administration of midazolam: Group 1 (25 obese and 25 non.obese trial participants): t=0, 2, 10, 20, 45, 90, 150, 210, 270, 360, 420, 480, 540 min. Group 2(25 obese and 25 non-obese trial participants): t=0, 5, 15, 30, 60, 120, 180, 240, 300, 360, 420, 480, 540 min.
    Urine will be collected completely for 24 hours post-dose.
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    An open exploratory pharmacokinetic trial
    E.7.2Therapeutic exploratory (Phase II) No
    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 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 Yes
    E.8.2.3.1Comparator description
    obese versus non-obese children
    E.8.2.4Number of treatment arms in the trial1
    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
    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 months1
    E.8.9.1In the Member State concerned days15
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 68
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 68
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    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 No
    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 state68
    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
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-02-24
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-05-31
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