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    Summary
    EudraCT Number:2011-005529-34
    Sponsor's Protocol Code Number:TRx-237-007
    National Competent Authority:Croatia - MIZ
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2014-09-03
    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 ConcernedCroatia - MIZ
    A.2EudraCT number2011-005529-34
    A.3Full title of the trial
    A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of Leuco-methylthioninium bis(hydromethanesulfonate) in Subjects with Behavioral Variant Frontotemporal Dementia (bvFTD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison study of LMTM and placebo in patients with behavioral variant frontotemporal dementia
    A.3.2Name or abbreviated title of the trial where available
    TRx-237-007
    A.4.1Sponsor's protocol code numberTRx-237-007
    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 SponsorTauRx Therapeutics Ltd
    B.1.3.4CountrySingapore
    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 supportTauRx Therapeutics Ltd
    B.4.2CountrySingapore
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTauRx Therapeutics Ltd
    B.5.2Functional name of contact pointInformation Desk
    B.5.3 Address:
    B.5.3.1Street AddressLiberty Building, University of Aberdeen, Foresterhill Road
    B.5.3.2Town/ cityAberdeen, Scotland
    B.5.3.3Post codeAB25 2ZP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number +441224 555191
    B.5.5Fax number+44 1224 555173
    B.5.6E-mailinfo@taurx.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/805
    D.3 Description of the IMP
    D.3.1Product nameLeuco-methylthioninium bis(hydromethanesulfonate)
    D.3.2Product code LMTM/TRx0237
    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 INNN/A
    D.3.9.1CAS number 1236208-20-0
    D.3.9.2Current sponsor codeTRx0237
    D.3.9.3Other descriptive nameN,N,N’,N’-tetramethyl-10H-phenothiazine-3,7-diaminium bis(methanesulfonate)
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 placeboTablet
    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
    behavioral variant Frontotemporal Dementia (bvFTD)
    E.1.1.1Medical condition in easily understood language
    Frontotemporal Dementia
    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 18.1
    E.1.2Level PT
    E.1.2Classification code 10068968
    E.1.2Term Frontotemporal dementia
    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
    To demonstrate the efficacy of LMTM as assessed by the change from Baseline on:
    • Addenbrooke's Cognitive Examination-Revised (ACE-R)
    • Symptomatic effect as reflected by the Functional Activities
    Questionnaire (FAQ)
    • Disease-modifying effect based on reduction in decline in whole brain volume (WBV), using change from Baseline as measured by the Brain Boundary Shift Integral (BBSI) by MRI imaging
    E.2.2Secondary objectives of the trial
    To evaluate the effect of LMTM as measured by the following additional global, disease severity, and motor impairment scales:
    • Modified Alzheimer's Disease Cooperative Study – Clinical Global Impression of Change (Modified ADCS-CGIC) – independently rated
    • Frontotemporal Dementia Rating Scale (FRS)
    • Unified Parkinson's Disease Rating Scale (UPDRS Parts II and III)
    - To evaluate the safety and tolerability of LMTM
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    MT plasma concentrations: Provided the site has a refrigerated centrifuge and adequate capability to reliably freeze samples, blood will be collected at Baseline (Visit 2; pre-dose and approximately 3.5 hours post-dose) and, to the extent possible, at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations; samples may also be analyzed for other analytes, such as metabolites, depending on method availability. The time of the prior dose and the time of the blood sample will be recorded. All samples will be tested in accordance with the terms of the subjects’ consent.
    E.3Principal inclusion criteria
    1. Diagnosis of probable bvFTD according to the International Consensus Criteria for bvFTD
    2. Centrally rated frontotemporal atrophy score of 2 or greater, taken as the maximum of right or left frontal or anterior temporal lobes on brain MRI of sufficient quality obtained at Screening or within a maximum of 42 days before Baseline, irrespective of pre-existing structural or functional imaging evidence supporting a diagnosis of bvFTD
    3. MMSE ≥20 at the Screening visit
    4. Age <80 years at the Screening visit
    5. Modified Hachinski ischemic score of ≤4 at the Screening visit
    6. Females must meet one of the following:
    • Surgically sterile (hysterectomy, bilateral salpingectomy / oophorectomy) for at least 6 months minimum
    • Have undergone bilateral tubal occlusion / ligation at least 6 months prior
    • Post-menopausal for at least 1 year
    • Using adequate contraception (a barrier method [such as condom, diaphragm, or cervical/vault cap] with spermicidal foam, gel, film, cream, or suppository; intrauterine device [IUD] or system, or oral or long-acting injected or implanted hormonal contraceptives for at least 3 months prior to Baseline; or vasectomized partner [with the appropriate post-vasectomy documentation of the absence of spermatozoa in the ejaculate]), or true abstinence (when this is in line with the preferred and usual lifestyle of the subject); subjects must be competent to use adequate contraception and to agree to continue to maintain adequate contraception throughout participation in the study
    OR In Italy, have avoided a pregnancy for at least 3 months prior to Baseline and accept to avoid a pregnancy throughout participation in the study
    7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) consistent with national law is/are able to read, understand, and provide written informed consent in the designated language of the study site
    8. Has one or more identified adult caregivers who meets the following criteria:
    • Either lives with the subject or sees the subject on average for ≥ 2 hours/day ≥ 3 days/week, or in the investigator’s opinion, the extent of contact is sufficient to provide meaningful assessment of changes in subject behavior and function over time and provide information on safety and tolerability
    • Is willing to provide written informed consent for his/her own participation
    • Is able to read, understand, and speak the designated language at the study site
    • Agrees to accompany the subject to each study visit
    • Is able to verify daily compliance with study drug
    9. If currently taking an AChEI (i.e., donepezil, galantamine, or rivastigmine) and/or memantine, at the time of Screening:
    • The subject must have been taking such medication(s) for ≥ 3 months
    • The current dosage regimen and dosage form must be within the locally approved dose range and must have remained stable for ≥ 6 weeks
    • It must be planned that the dosage regimen will remain stable throughout participation in the study
    Subjects not being treated with an AChEI or memantine (for ≥ 6 weeks before Screening) may also be enrolled if initiation of an AChEI or memantine is not planned for the time period during which the subject will be participating in this study
    10. Able to comply with the study procedures in the view of the investigator
    E.4Principal exclusion criteria
    1.Significant CNS disorder other than bvFTD
    2.Other significant intracranial pathology seen on brain MRI scan that would lead to a diagnosis other than probable bvFTD or that puts the subject at risk of Amyloid Related Imaging Abnormalities including:large confluent white matter hyperintense lesions, other focal brain lesion(s),a single area of superficial siderosis, >4 cerebral microhemorrhages,evidence of a prior macrohemorrhage.
    3.Biomarker evidence of underlying AD pathology as etiology of dementia
    4.Expressive language deficits such that the subject is too severely impaired to allow testing at Baseline
    5.Meets research criteria for Amyotrophic Lateral Sclerosis or motor; evidence of mild motor neuron disease on examination is allowed if not expected to interfere with subject’s completion of study but prominent bulbar symptoms would be exclusionary
    6.Meets diagnostic criteria for probable bvFTD but has a proven mutation producing non-tau, non-TDP-43 pathology
    7.Clinical evidence or history of:
    ∙Cerebrovascular accident (2 years)
    ∙Transient ischemic attack (6 months)
    ∙Significant head injury with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
    ∙Other unexplained or recurrent loss of consciousness ≥15 minutes (2 years)
    8.Epilepsy(a single prior seizure is considered acceptable)
    9.Rapid eye movement sleep behavior disorder
    10.DSM IV-TR criteria met for the following (within specified period):
    ∙Major depressive disorder(current)
    ∙Schizophrenia (lifetime)
    ∙Other psychotic disorders, bipolar disorder (within the past 5 years), or substance related disorders (within the past 2 years)
    11.Metal implants in the head (except dental),pacemaker, any other non-removable items that are contraindications to MR imaging;any device proven to be MR compatible will be allowed
    12.Resides in hospital or moderate to high dependency continuous care facility
    13.History of swallowing difficulties
    14.Pregnant or breastfeeding
    15.G6PD deficiency
    16.History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
    ∙Hereditary or acquired methemoglobinemia or Baseline measurement of MetHb >2.0%
    ∙Hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
    ∙Screening hemoglobin value below lower limit of the normal range
    17.Abnormal serum chemistry laboratory value at Screening clinically relevant. In addition, subjects with the following abnormalities must be excluded:
    ∙Creatinine clearance <50 mL/min at Screening
    ∙Thyroid stimulating hormone above laboratory normal range
    18.Clinically significant cardiovascular disease or abnormal assessments such as:
    ∙Hospitalization for acute coronary syndrome or symptoms consistent with angina pectoris, within the 12 months preceding Baseline
    ∙Signs or symptoms of clinical heart failure within the 12 months preceding Baseline
    ∙Evidence of uncontrolled atrial fibrillation on Screening ECG or history of atrial fibrillation that is not currently controlled or where the QT interval cannot be assessed by triplicate ECGs
    ∙QTcF at Screening >460 msec in males or >470 msec in females,or low or flat T waves making measurement of QT interval unreliable
    ∙Recent history of poorly controlled hypertension
    ∙Hypotension
    ∙Heart rate <48 bpm or >96 bpm by measurement of vital signs or by ECG at Screening
    19.Preexisting or current signs or symptoms of respiratory failure. Subjects with previously diagnosed moderate to severe sleep apnea not adequately controlled should be excluded
    20.Concurrent acute or chronic clinically significant immunologic, hepatic,or endocrine disease and/or other unstable or major disease other than bvFTD.
    ∙Subjects with hepatitis or primary biliary cirrhosis should be excluded
    ∙HTLV-III, LAV (incl.any mutants/derivatives),any condition associated with Acquired Immunodeficiency Syndrome
    21.Diagnosis of cancer within the past 2 years prior to Baseline (other than basal cell or squamous cell skin cancer or Stage 1 prostate cancer) unless treatment has resulted in complete freedom from disease for at least 2 years
    22.Prior intolerance or hypersensitivity to MT-containing drug, similar organic dyes, or any of the excipients
    23.Treatment currently or within 3 months before Baseline with the following medications:
    ∙Tacrine
    ∙Amphetamine or dexamphetamine
    ∙Antipsychotics:clozapine, olanzapine (other antipsychotics are allowable if they have not been initiated within 3 months before Baseline and are used in a stable dose and regimen)
    ∙Carbamazepine, primidone
    ∙Other mood stabilizers
    ∙Drugs associated with methemoglobinemia
    24.Current or prior participation in a clinical trial:
    ∙Clinical trial of a product for cognition with last dose received within 90 days prior to Screening (unless randomized to placebo)
    ∙Clinical trial of a drug, biologic,device, or medical food with last dose received within 28 days prior to Baseline
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy endpoints:
    • Change from Baseline to Week 52 in the ACE-R
    • Either of two co-primary endpoints:
    o Change from Baseline to Week 52 in FAQ
    o Reduction in decline in whole brain volume at Week 52 using change
    from Baseline as measured by the Brain Boundary Shift Integral (BBSI)
    by MRI imaging
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy will be evaluated at baseline and after 4 months (16 weeks), 8 months (32 weeks), and 12 months (52 weeks)
    E.5.2Secondary end point(s)
    Secondary clinical endpoints include the following:
    • Modified CGIC
    • FRS
    • UPDRS Parts II and III

    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety assessment will performed during screening, then at Baseline (pre-dose and post-dose during the 4-hour observation), and 4,8,16,24,32,42 and 52 weeks after Baseline, and approximately 4 weeks after the last dose of study drug (if applicable)

    Blood will be collected at Baseline and as possible at each subsequent on-treatment visit through Week 52 for purposes of population pharmacokinetic (PK) analysis of MT concentrations.

    A single blood sample for genotyping may be collected any time after eligibility for randomization and participation in the study has been confirmed at Baseline (Visit 2).
    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 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 Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    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 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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    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
    Australia
    Canada
    Croatia
    Germany
    Italy
    Netherlands
    Poland
    Romania
    Singapore
    Spain
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    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: 90
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 90
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Either Subject or Subject’s legally acceptable representative is able to read, understand, and provide written informed consent in the designated language of the study site.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 180
    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)
    Subjects who complete the treatment period may be offered an opportunity to subsequently receive treatment with LMTM in a separate open-label extension study. Otherwise, a follow-up visit will occur approximately 28 days after the last dose of study drug for those subjects discontinuing early or not entering the open-label extension.
    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 DeNDRoN
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 2
    G.4.1Name of Organisation SDCRN
    G.4.3.4Network Country United Kingdom
    G.4 Investigator Network to be involved in the Trial: 3
    G.4.1Name of Organisation Konsortium zur Erforschung der frontotemporalen Lobärdegeneration
    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 Decision2014-04-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-02-10
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