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    Summary
    EudraCT Number:2012-000845-11
    Sponsor's Protocol Code Number:TIRCON2012V1
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-09-19
    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 ConcernedUK - MHRA
    A.2EudraCT number2012-000845-11
    A.3Full title of the trial
    A randomized, double-blind, placebo-controlled trial of deferiprone in patients with pantothenate kinase-associated neurodegeneration (PKAN)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An international trial of deferiprone in patients with iron storage brain disorders
    A.3.2Name or abbreviated title of the trial where available
    TIRCON
    A.4.1Sponsor's protocol code numberTIRCON2012V1
    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 SponsorApoPharma Inc
    B.1.3.4CountryCanada
    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 supportEuropean Commission (main monetary support)
    B.4.2CountryBelgium
    B.4.1Name of organisation providing supportApoPharma Inc (sponsor and providing drug free of charge)
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationApoPharma Inc
    B.5.2Functional name of contact pointFernando Tricta
    B.5.3 Address:
    B.5.3.1Street Address200 Barmac Drive
    B.5.3.2Town/ cityWeston (Toronto), Ontario
    B.5.3.3Post codeM9L 2Z7
    B.5.3.4CountryCanada
    B.5.4Telephone number001 416 401 7543
    B.5.5Fax number001 416 401 3867
    B.5.6E-mailftricta@apopharma.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 Yes
    D.2.1.1.1Trade name Ferriprox
    D.2.1.1.2Name of the Marketing Authorisation holderApotex Europe B.V.
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    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 nameDeferiprone 80 mg/mL oral solution (Ferriprox)
    D.3.4Pharmaceutical form Oral solution
    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 INNDeferiprone
    D.3.9.1CAS number 30652-11-0
    D.3.9.2Current sponsor codeV03AC02
    D.3.9.3Other descriptive nameDeferiprone
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboOral solution
    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
    Pantothenate Kinase-Associated Neurodegeneration (PKAN)
    E.1.1.1Medical condition in easily understood language
    Neurodegeneration with brain iron accumulation
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10053643
    E.1.2Term Neurodegenerative disorder
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The Co Primary objectives
    1- To evaluate the change in severity of dystonia (BAD scale) in patients with PKAN treated with deferiprone for 18 months compared to placebo.
    2- To evaluate the patient's global impression of condition's improvement in patients treated with deferiprone for 18 months compared to placebo (PGI-I)

    The study will be considered positive if both co-primary endpoints reach statistical significance.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    1- To evaluate the effect of deferiprone compared to placebo in the change in globus pallidus iron levels (MRI) (subset of patients);
    2- To evaluate the effect of deferiprone compared to placebo on the change in motor symptoms (UPDRS);
    3- To evaluate the effect of deferiprone compared to placebo on a measure of functional independence (WeeFIM or FIM);
    4- To evaluate the effect of deferiprone compared to placebo on quality of life (PedsQL);
    5- To evaluate the effect of deferiprone compared to placebo on the patient's quality of sleep (PSQI);
    6- To evaluate the pharmacokinetics of deferiprone and its 3-Ο- glucuronide metabolite (subset of patients);
    7- To evaluate the safety and tolerability of deferiprone in patients with PKAN.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Patients will have the option to participate in PK sub study in addition to main study. Patients and patients legal representative if applicable will be asked to read and sign an additional consent before taking part. The PK study is to examine the steady state pharmacokinetic profile of deferiprone and deferiprone 3-O-glucuronide following administration of twice daily deferiprone oral dose.
    E.3Principal inclusion criteria
    1.Males and females 4 years of age and older at screening visit;

    2.Patients must have PKAN, confirmed by genetic testing;

    3.Patients having a BAD total score > = 3 at the screening visit;

    4.Patients who have Deep Brain Stimulation (DBS) systems or baclofen pumps in place will be eligible for the study, but they must have had a stable setting for at least 2 months prior to the screening visit and stimulation parameters / pump settings must remain stable for the duration of the trial. Enrollment of non-DBS patients will be given priority in order to ensure the majority can undergo imaging;

    5. Potentially sexually active female patients of childbearing potential must have a negative pregnancy test result at Screening Visit (if applicable; in cases where the Investigator determines there is no reasonable risk of pregnancy because of significant incapacity, pregnancy testing will not be performed);

    6.Fertile potentially sexually active males must use an effective method of contraception or must confirm partner’s use of effective contraception;

    7.Informed consent/assent obtained before any study-related activities are undertaken;

    8.Ability and willingness to adhere to the protocol including appointments and evaluation schedule.
    E.4Principal exclusion criteria
    1.Evidence of iron deficiency defined by Fe:TIBC ratio <15%, or serum ferritin < 12 ng/mL;

    2.Treatment with deferiprone in the past 12 months;

    3.Previous failure of treatment with deferiprone, or previous discontinuation of treatment with deferiprone due to adverse events;

    4.Evidence of abnormal liver or renal function (serum liver enzyme level(s) > 3 times upper limit of normal at screening) or abnormal creatinine levels at screening visit;

    5.Disorders associated with neutropenia (absolute neutrophil count (ANC) < 1.5 x 109/L) or thrombocytopenia (platelet count < 50 x 109/L) in the 12 months preceding the initiation of the study medication. Exception: for patients whose neutropenia was attributed by the treating physician to episodes of infection or to drugs associated with a decline in the neutrophil count and in whom ANC has fully recovered at the screening visit;

    6.Pregnant, breastfeeding, or planning to become pregnant during the study;

    7.Initiation or discontinuation of treatment with baclofen, trihexyphenidyl, clonazepam, tizanidine within 30 days prior to baseline; and initiation or discontinuation of treatment with tetrabenazine within 90 days prior to baseline;

    8. Treatment with an investigational drug within 30 days or 5 half-lives (whichever is longer) preceding the baseline;

    9. Currently taking iron chelators;

    10.Patients who, in the opinion of the physician, represent a high medical or psychological risk;

    11. History of or active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements;

    12.Patients and patient's legal representative (if applicable) with a mental incapacity, unwillingness or language barriers precluding adequate understanding or co-operation.

    13.Baclofen pump placement less than two months prior to the beginning of the study.
    E.5 End points
    E.5.1Primary end point(s)
    1) Change in the Barry-Albright Dystonia Scale (BAD) total score from baseline to Month 18 in patients treated with deferiprone compared to placebo, as assessed by central blinded evaluation of video-tapes;

    2) Patient's Global Impression of Improvement (PGI-I) from baseline to Month 18 in patients treated with deferiprone compared to placebo.

    E.5.1.1Timepoint(s) of evaluation of this end point
    Timepoints:

    Baseline, 6m, 12m, 18m
    E.5.2Secondary end point(s)
    1) Proportion of patients with improved or unchanged BAD scale total score between baseline and Month 18 (responder analysis);

    2) Change from baseline to Month 18 in BAD scale score per body region (eyes, mouth, neck, trunk, each upper and lower extremity), as assessed by central blinded evaluation of video-tapes;

    3) Proportion of patients showing an improvement on PGI-I at the Month 18 visit (responder analysis);

    4) Change from baseline to Month 18 in globus pallidus iron levels as measured by MRI R2* (subset of patients without deep brain stimulators who can tolerate MRI scan);

    5) Change from baseline to Month 18 in UPDRS Parts I, II, III and VI scores, respectively;

    6) Change from baseline to Month 18 in global WeeFIM score (Or FIM for patients > 18 years);

    7) Change from baseline to Month 18 in WeeFIM (or FIM for patients >18 years) score per item;

    8) Change from baseline to Month 18 in quality of life (PedsQL);

    9) Change from baseline to Month 18 in quality of sleep (PSQI).

    Other secondary endpoints:

    Safety Endpoints: (1) Frequency of Adverse Events (AEs); (2) Frequency of Serious Adverse Events (SAEs); (3) Discontinuation due to AEs; (4) Hematology assessments; (5) Blood clinical biochemistry assessments; (6) ECG.

    Pharmacokinetic Endpoints: Steady state pharmacokinetics of deferiprone and its 3-O-glucuronide metabolite will be assessed in a subset of up to 24 patients over 12 hours. The following standard pharmacokinetic parameters will be derived from plasma concentrations of deferiprone: Cmax, Tmax, Cmin, AUCSS, CL/F, T1/2, Vd/F.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Timepoints:
    Secondary endpoints: Baseline, 6m, 12m, 18m; except Brain MRI: Baseline and 18m.

    Safety endpoints:
    Physical exam: at Screening, Baseline, 1.5m, 3m, 6m, 12m, 18m.
    Hematology: at Screening,weekly after dosing starts.
    Biochemistry: at Screening, 1.5m, 3m, 6m, 12m, 18m.
    ECG: at Screening and 18m.
    Adverse events and SAEs: Baseline and at each telephone contant and study visits.
    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 No
    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) 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 Yes
    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 concerned20
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA4
    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
    Germany
    Italy
    Poland
    United Kingdom
    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
    LVLS. Based on the total individual study duration of 18 months, the last patient will have their final study visit at month 34, followed by analysis and interpretation of the results.
    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 months0
    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 months8
    E.8.9.2In all countries concerned by the trial days1
    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: 72
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 36
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 36
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 18
    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 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
    Children > 4 years
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 90
    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)
    If the preliminary evidence indicates that the medicine is safe and effective for the specified indication, after the end of the study deferiprone will be offered to patients (irrespective of whether they were in the deferiprone or in the placebo arm) until approval of the product for that indication or withdrawal of the drug for that indication occurs.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation TIRCON
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-10-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-10-21
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