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    Summary
    EudraCT Number:2015-004344-19
    Sponsor's Protocol Code Number:LA48-0215
    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:2016-02-16
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-004344-19
    A.3Full title of the trial
    A Dose-Ranging Study of the Efficacy, Safety, and Pharmacokinetics of Deferiprone Delayed Release Tablets in Patients with Parkinson’s Disease
    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 Parkinson’s disease
    A.3.2Name or abbreviated title of the trial where available
    LA48-0215
    A.4.1Sponsor's protocol code numberLA48-0215
    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
    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 supportApoPharma
    B.4.2CountryCanada
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationApoPharma
    B.5.2Functional name of contact pointJohn Connelly
    B.5.3 Address:
    B.5.3.1Street Address200 Barmac Drive
    B.5.3.2Town/ cityToronto, Ontario
    B.5.3.3Post codeM9L 2Z7
    B.5.3.4CountryCanada
    B.5.4Telephone number14164017296
    B.5.5Fax number14164013869
    B.5.6E-mailjconnell@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 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 nameDeferiprone 600 mg delayed release tablet
    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 INNDEFERIPRONE
    D.3.9.1CAS number 30652-11-0
    D.3.9.4EV Substance CodeSUB06941MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number600
    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 placeboModified-release tablet
    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
    Parkinson’s disease
    E.1.1.1Medical condition in easily understood language
    Parkinson’s disease
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10061536
    E.1.2Term Parkinson's disease
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Primary objective is to evaluate the efficacy of four different dosages of deferiprone delayed release (deferiprone-DR) tablets in patients with Parkinson’s disease.
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    • To evaluate the safety and tolerability of deferiprone-DR tablets in patients with Parkinson’s disease
    • To evaluate the pharmacokinetics of deferiprone-DR tablets in a subset of study participants
    • To evaluate the relationship between the pharmacokinetics and pharmacodynamics of deferiprone-DR tablets

    Exploratory objectives are:
    • To determine whether the efficacy responses to deferiprone differ depending on the genotype of certain enzymes that are implicated in Parkinson’s disease
    • To determine whether the efficacy responses to deferiprone are correlated with ceruloplasmin levels or ceruloplasmin ferroxidase activities
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female aged ≥18 to < 80 years

    2. Body weight ≥60 kg but ≤100 kg

    3. Parkinson’s disease diagnosed according to UK Parkinson’s Disease Society Brain Bank Clinical Diagnostic Criteria and based on the presence of at least two of the three cardinal features of the disease (rest tremor, bradykinesia, and rigidity). If rest tremor is not present, patient must have unilateral onset of symptoms.

    4. Absolute neutrophil count (ANC) ≥1.5 x 109/L (≥1.0 x 109/L for Black population) at screening

    5. On a stable dose for at least 3 months prior to the screening visit of any of the following treatments at an L-dopa equivalent daily dose of up to 600 mg:
    o Dopaminergic agonist alone
    o L-dopa alone
    o Combination therapy with dopaminergic agonist and L-dopa
    o Rasagiline
    o At an early stage of the disease, without motor fluctuations and/or L-dopa–induced dyskinesia
    E.4Principal exclusion criteria
    1. Diagnosis of Parkinson’s disease more than 3 years prior to screening visit

    2. Hoehn and Yahr stage ≥ 3

    3. Atypical or secondary Parkinsonism without dopa-sensitivity (e.g., vascular parkinsonism, supranuclear palsy, multisystem atrophy)

    4. Progressing Axis I psychiatric disorders (psychosis, hallucinations, compulsive disorders, substance addiction, bipolar disorder, severe depression, anxiety) as assessed in a semi-structured interview in accordance with the Diagnostic and Statistical Manual of Mental Disorders

    5. Not stabilized in terms of the current antiparkinsonian therapeutic regimen: already requires dose adaptation and/or is likely to require any change in dopamine therapy over the duration of the trial

    6. Current treatment with bromocriptine

    7. Current treatment with any antiparkinsonian drug other than those listed in the inclusion criteria

    8. Current treatment with coenzyme Q10 or idebenone. (Patients who are on these medications but stop taking them at least 2 weeks prior to baseline may be enrolled.)

    9. Current use of a Deep Brain Stimulation (DBS) system. (Patients who previously had a DBS system but have had it removed may be enrolled.)
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy criterion:
    Change from baseline to Month 9 in the motor examination subscale (Part III) of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy assessments:
    • The MDS-UPDRS and MoCA will be completed at baseline and Months 3, 6, and 9

    Note: The MDS-UPDRS and MoCA are to be administered early in the morning, at approximately the same time (± 1 hour) at each visit, and by the same qualified investigator.
    E.5.2Secondary end point(s)
    Secondary efficacy criteria:
    • Change from baseline to Month 9 in the following measures:
    - Total score on the MDS-UPDRS
    - Scores on the individual subscales Part I (non-motor experiences of daily living), Part II (motor experiences of daily living), and Part IV (motor complications) of the MDS-UPDRS
    - Combined scores from Parts II and III of the MDS-UPDRS
    - Overall cognitive function, as assessed by the Montreal Cognitive Assessment (MoCA) test
    - Pharmacodynamics measures of the following oxidative stress biomarkers: total antioxidant status, lipid peroxidation (malondialdehyde), protein carbonyls, 8-OHdG, glutathione, superoxide dismutase
    - Pharmacodynamics measures of the following inflammatory factor biomarkers: TNF alpha and IL-6
    • Time elapsed until the need for rescue medication

    Exploratory efficacy criteria:
    Mechanism of action (MOA) biomarkers to evaluate the following:
    • Whether specific genotypes of the following enzymes which play a role in Parkinson’s disease affect the potential disease-modifying action of deferiprone:
    - D544E polymorphisms of the glycoprotein ceruloplasmin
    - V158M polymorphisms of the enzyme catechol O-methyltransferase (the only analysis will be determination at baseline of the COMT genotype)
    • Whether the degree of change from baseline in ceruloplasmin levels and ceruloplasmin ferroxidase activity is correlated with the efficacy of deferiprone

    Safety Criteria:
    • Adverse events (AEs): frequency, intensity, time to onset, duration, and relatedness to study drug
    • Serious adverse events (SAEs): frequency, intensity, time to onset, duration, and relatedness to study drug
    • Number of discontinuations due to AEs
    • Laboratory measures (hematology, blood chemistry, and urinalysis)
    • ECG
    • Vital signs
    • Physical examination
    • Assessment of suicidality (based on the Columbia Suicide Severity Rating Scale)

    Pharmacokinetics Criteria:
    The following PK parameters will be determined for deferiprone and its 3-O-glucuronide metabolite in the subset of patients who undergo extensive PK sampling: Cmax, Tmax, AUC0-t, AUC0-∞, λZ and T½.
    T½ and AUC0-∞ will be determined only in patients in whom the log-linear terminal phase can be clearly defined.

    Pharmacokinetics/Pharmacodynamics Criteria:
    Possible relationships between pharmacokinetic findings and efficacy biomarkers and endpoints will be evaluated.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy assessments:
    • Blood samples at baseline, Months 3, 6, and 9
    • Urine samples at baseline, Months 3, 6, and 9

    Safety assessments:
    • Hematology: Screening and weekly up to Month 9
    • Blood chemistry: Screening, Months 1, 2, 3, 4, 5, 6, and 9
    • Urinalysis: Screening, Months 3, 6, and 9
    • ECG: Screening and Month 9
    • Vital signs: Each visit up to Month 9
    • Physical examination: Screening, baseline, Months 2, 4, 6, and 9
    • Assessment of suicidality: Baseline and each visit up to Month 9
    • Adverse events: Throughout, baseline (post–Dose 1) to Month 10

    Pharmacokinetics assessments:
    Assay of deferiprone and its 3-O-glucuronide metabolite at:
    •CSF samples: Month 3
    •Sparse collection of blood samples: Baseline and Month 3
    •Extensive collection of blood samples: Month 1
    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 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) 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA21
    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
    Canada
    France
    Germany
    United Kingdom
    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
    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 months9
    E.8.9.1In the Member State concerned days24
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial days14
    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: 82
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 58
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 137
    F.4.2.2In the whole clinical trial 140
    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)
    There are no safety concerns with patient stopping deferiprone once the study ends. Patients will go back to their standard of care at study completion.
    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 Decision2016-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-03-31
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-09-04
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