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    Summary
    EudraCT Number:2016-001445-61
    Sponsor's Protocol Code Number:FLO-02
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2016-10-03
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2016-001445-61
    A.3Full title of the trial
    Open label, multi-centre, parallel group study to compare the pharmacokinetics (PK), pharmacodynamics (PD) and safety of febuxostat between pediatric patients (≥6<18 years of age) and adults.
    A febuxostat farmakokinetikájának (PK), farmakodinámiájának (PD) és biztonságosságának nyílt, multicentrikus, párhuzamos csoportos, összehasonlító vizsgálata (≥6 - <18 éves) gyermek és felnőtt betegek között.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to compare the pharmacokinetic (Pharmacokinetic is the effect the body has on the drugs) , pharmacodynamic (pharmacodynamic is the effect that drugs have on the body) and safety of Febuxostat between paediatric patients (≥6<18 years of age) and adults.
    A.3.2Name or abbreviated title of the trial where available
    FLORET
    A.4.1Sponsor's protocol code numberFLO-02
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/285/2015
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMenarini Ricerche S.p.A.
    B.1.3.4CountryItaly
    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 supportMenarini Ricerche S.p.A.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMenarini Ricerche S.p.A.
    B.5.2Functional name of contact pointCorporate Clin Research Directorate
    B.5.3 Address:
    B.5.3.1Street AddressVia Sette Santi 1
    B.5.3.2Town/ cityFlorence
    B.5.3.3Post code50131
    B.5.3.4CountryItaly
    B.5.4Telephone number+39055 56809900
    B.5.5Fax number+390555680597
    B.5.6E-mailACapriati@menarini-ricerche.it
    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 Adenuric® 120 mg
    D.2.1.1.2Name of the Marketing Authorisation holderMenarini International Operations Luxembourg S.A.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameFebuxostat
    D.3.4Pharmaceutical form Film-coated 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 INNFEBUXOSTAT
    D.3.9.1CAS number 144060-53-7
    D.3.9.4EV Substance CodeSUB25382
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    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 Adenuric® 80 mg
    D.2.1.1.2Name of the Marketing Authorisation holderMenarini International Operations Luxembourg S.A.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameFebuxostat
    D.3.4Pharmaceutical form Film-coated 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 INNFEBUXOSTAT
    D.3.9.1CAS number 144060-53-7
    D.3.9.4EV Substance CodeSUB25382
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number80
    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 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 nameFeboxostat 20 mg
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    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 INNFEBUXOSTAT
    D.3.9.1CAS number 144060-53-7
    D.3.9.4EV Substance CodeSUB25382
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    Hematological malignancies at intermediate to high risk of Tumor Lysis Syndrome ( TLS) prevention.
    E.1.1.1Medical condition in easily understood language
    Tumore Lysis Syndrome ( TLS) results from the rapid killing of a large quantity of tumor cells which occurs most often after the start of Chemotherapy in patients with haematologic cancer
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10045170
    E.1.2Term Tumour lysis syndrome
    E.1.2System Organ Class 10027433 - Metabolism and nutrition disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    -To assess the pharmacokinetics (PK) of febuxostat in paediatric patients (≥6<18 years of age) and in adults suffering from hematological malignancies at intermediate to high risk of TLS.
    -To compare the febuxostat exposure in pediatric patients (≥6<18 years of age) with the one achieved in adults administered with a dose of 120 mg/QD.
    E.2.2Secondary objectives of the trial
    -To compare the pharmacodynamics (PD) of febuxostat between pediatric patients (≥6<18 years of age) and adults.
    -To evaluate and compare the PK/PD relationship of febuxostat in pediatric patients (≥6<18 years of age) and adults.
    -To evaluate the safety of febuxostat between pediatric patients (≥6<18 years of age) and adults.
    -To evaluate the occurrence of Laboratory TLS (LTLS) and Clinical TLS (CTLS) according to Cairo and Bishop Criteria
    -To assess the age-appropriate formulation acceptability in children.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients meeting ALL the following criteria will be eligible to enter the study:

    1.male and female children of 6 to less than 12 years of age, adolescents of 12 to less than 18 years of age, and adults:
    a.scheduled for first cytotoxic chemotherapy cycle, regardless of the line of treatment, because of hematologic malignancies, and
    b.at intermediate or high risk for TLS, and
    c.with serum uric acid (sUA) levels < 10 mg/dL at Visit 1 (Day 1), and
    d.with no access to rasburicase;

    2.Karnofsky performance status (KPS) of 100 to 30 for patients aged 16 years and older; Lansky Play performance status (LPS) of 100 to 30 for patients aged less than 16 years;

    3.A female of childbearing potential may be enrolled providing she:
    - has a negative pregnancy test during screening period and
    - is routinely using a highly effective method of birth control resulting in a failure rate of less than 1% per year when used consistently and correctly (e.g. combined [estrogen and progestogen containing] hormonal contraception associated with inhibition of ovulation [oral, intravaginal, transdermal], progestogen-only containing hormonal contraception associated with inhibition of ovulation [oral, injectable, implantable], intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or total sexual abstinence) until 6 months from the last study drug administration. ;

    4.informed consent before any study-related procedures obtained by patient for adults or by patient’s parents (one or both according to local regulation) or legal guardian for children and adolescents;

    5.life expectancy >1 month.
    E.4Principal exclusion criteria
    Patients will not be eligible to participate in the study if they meet ANY of the following exclusion criteria:

    1.patients known to be hypersensitive to febuxostat or to any components of the formulation;
    2.patients with hereditary problems of galactose intolerance, the lapp lactase deficiency, or glucose-galactase malabsorption;
    3.pregnant or breastfeeding women;
    4.patients receiving febuxostat or any other urate-lowering therapy (e.g. allopurinol, rasburicase, probenecid) within 30 days prior to Visit 1 (Day 1);
    5.patients receiving mercaptopurine and azathioprine within 14 days prior to Visit 1 (Day 1);
    6.patients with severe renal insufficiency;
    7.patients with severe hepatic insufficiency;
    8.patients with diagnosis of Laboratory TLS (LTLS) or Clinical TLS (CTLS) at Visit 1 (Day 1).
    9.Patients receiving any other investigational agent within 30 days prior to study Visit 1 (Day 1).
    E.5 End points
    E.5.1Primary end point(s)
    Pharmacokinetic endpoints derived from the study will include:
     Primary PK parameters: CL/F, Vd/F and Ka.
     Derived PK parameters: AUC and Cmax.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Blood samples will be collected on Visits 2, 3, 4, 5, 6, 7 and 8 (i.e., after the first treatment administration and on each following visit until the Evaluation Visit).
    Four additional blood samples are required for each patient on Visit 7 (Day 7) at the selected sampling intervals: 0.5-2 hours, 2-4 hours, 4-6 hours and 6-8 hours post study drug intake.
    E.5.2Secondary end point(s)
    Pharmacodynamic endpoint:
    1. Area under the curve of sUA from baseline (Visit 1, Day 1) to the Evaluation Visit (Visit 8, Day 8) (AUC sUA 1-8) based on central laboratory results.

    PK/PD endpoint:
    2.The PK/PD relationship will be evaluated based on sUA levels and febuxostat exposure.

    Clinical endpoints:
    3. Incidence of Laboratory TLS (LTLS) from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8), based on local laboratory results.
    -Incidence and grading of Clinical TLS (CTLS) from Start of Chemotherapy (Visit 3, Day 3) to the Evaluation Visit (Visit 8, Day 8) based on local laboratory results.

    Safety endpoints:
    4.Incidence, severity (both through Mild/Moderate/Severe scale and NCI-CTCAE grade), seriousness and treatment causality of Treatment-Emergent Signs and Symptoms (TESS).
    -Frequency of clinically significant abnormalities in physical examination, safety laboratory tests, vital signs and 12 Lead ECG.
    -Change in PS according to Karnofsky/Lansky scales.

    5. Acceptability assessment of the age-appropriate formulation only for children.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Blood samples for sUA analysis will be performed from Visits 1 to 8 (i.e., before 1st drug intake, on each following visit until the Evaluation Visit).
    2. PK/PD timepoints are the same of both primary endpoint and the pharmacodynamic timepoints.
    3. From start of treatment (day 1) to the end of study visit 10 (day 14±2)
    4. From start of chemotherapy (day 3) to evaluation visit (day 8)
    5. From start of treatment (day 1) to visit 7 (day 7 ) or 9 (day 9) based on investigator's judgment.

    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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
    To assess the PK and PD of febuxostat in pediatric patients (≥6<18 years of age).
    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.8.2.4Number of treatment arms in the trial5
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Hungary
    Italy
    Spain
    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 years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    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: 96
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 48
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 48
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 4
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Paediatric population from 6 to less than 18 years of age.
    F.3.3.7Others Information not present in EudraCT
    F.4 Planned number of subjects to be included
    F.4.1In the member state76
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 120
    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)
    After the completetion of the trial participation, a standard TLS prevention treatment could be applied during the following
    chemotherapy cycles, as per standard local clinical practice.
    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 Decision2017-02-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-12-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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