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    Summary
    EudraCT Number:2017-003558-17
    Sponsor's Protocol Code Number:TRx-237-039
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-03-28
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2017-003558-17
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 12-Month, Safety and Efficacy Study of Hydromethylthionine Mesylate (LMTM) Monotherapy in Subjects with Alzheimer’s Disease Followed by a 12-Month Open-Label Treatment
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A comparison study of TRx0237 (LMTM) and placebo in patients with Alzheimer's Disease.
    A.4.1Sponsor's protocol code numberTRx-237-039
    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 Address395 King Street
    B.5.3.2Town/ cityAberdeen
    B.5.3.3Post codeAB24 5RP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441224440905
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLeuco-methylthioninium bis(hydromethanesulfonate)
    D.3.2Product code TRx0237
    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 INNNot yet established
    D.3.9.1CAS number 1236208-20-0
    D.3.9.2Current sponsor codeTRx0237
    D.3.9.3Other descriptive nameLEUCO-METHYLTHIONINIUM BIS (HYDROMETHANESULFONATE)
    D.3.9.4EV Substance CodeSUB91958
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated 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
    Alzheimer’s Disease
    E.1.1.1Medical condition in easily understood language
    Alzheimer’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 LLT
    E.1.2Classification code 10001896
    E.1.2Term Alzheimer's disease
    E.1.2System Organ Class 100000004852
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the LMTM dose of 16 mg/day with the placebo group on the following co-primary endpoints:
    a. ADAS-cog11
    b. ADCS-ADL23
    2. To assess the safety and tolerability of LMTM 16 mg/day given for up to 52 weeks
    E.2.2Secondary objectives of the trial
    3. To compare the LMTM dose of 16 mg/day with the placebo group in annualized rate of whole brain atrophy over 52 weeks as measured by brain MRI and quantified using the BSI
    4. To compare the LMTM dose of 16 mg/day with the placebo group in temporal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening
    5. To compare the LMTM dose of 8 mg/day with the placebo group in temporal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 52 weeks, restricted to subjects with CDR 0.5 at Screening
    6. To compare the LMTM dose of 8 mg/day with the placebo group on the co-primary endpoints (ADAS-cog11 and ADCS-ADL23)
    7. To compare the LMTM doses of 8 and 16 mg/day with the placebo group in annualized rate of temporal and parietal lobe atrophy over 52 weeks as measured by MRI and quantified using the BSI
    For additional secondary objectives please refer to protocol
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    A single blood sample will be obtained only from subjects who provide legally acceptable informed consent for genotyping evaluation of ApoE. The blood sample may be collected any time after eligibility for randomization and continued participation in the study has been confirmed but prior to Visit 7 (end of double-blind treatment period). A volume of approximately 2 mL is to be collected and shipped ambient to the central laboratory (Covance) on the day of collection. Genotyping results will not be provided to the study sites or to subjects.
    E.3Principal inclusion criteria
    1. AD, encompassing probable AD and mild cognitive impairment due to AD (MCI-AD) based on 2011 National Institute on Aging (NIA)/ Alzheimer's Association (AA) criteria
    • All cause dementia and probably AD (probably AD) In brief, subjects with probable AD dementia must have insidious onset, worsening impairment in at least two cognitive areas (learning and recall, language, executive function, visuospatial skills), sufficient to significantly interfere with work or usual activities, that is not explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder. The accuracy of the diagnosis will be confirmed independently by the diagnosing phisician at site
    OR
    • MCI-AD In subjects with MCI-AD, there should be evidence of concern about a change in cognition, in comparison with the person's previous level verified by a knowledgeable informant or clinician. Other mild
    cognitive deficits may also be present, but there must be preservation of independence in functional abilities. Subjects should not meet the criteria for dementia. The cognitive changes must be mild and there must be no evidence of a significant impairment in social or occupational functioning. Impairments must not be explained by delirium, drugs, major psychiatric disorder, medical illness, cerebrovascular disease, other forms of dementia, or neurological disorder.
    2.Documented PET scan that is positive for amyloid; if most recent PET scan was performed >3 years prior to Screening and was negative, it
    may be repeated (subjects are not eligible if their most recent PET scan was performed within the 3 years prior to Screening and was negative)
    3. MMSE score of 16-27 (inclusive) at Screening
    4. Global CDR score of 0.5 to 2 at Screening (if 0.5, including a score of > 0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care)
    5. Age < 90 years at Screening
    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 90
    days 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 (including up to 4
    weeks after the last dose of study drug).
    7. Subject and/or, in the case of reduced decision-making capacity, legally acceptable representative(s) (LAR(s)), consistent with local and national law, is able to read, understand and provide written informed
    consent in the designated language of the study site
    8. Has one or more identified adult study partner (i.e. a caregiver or informant) who meets the following criteria:
    • Either lives with the subject , 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 (e.g., sees the subject on average
    for ≥1 hour/day ≥3 days/week)
    • 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 compliance with study drug
    9. The subject must not have been taking either an AChEI, i.e., donepezil, galantamine, or rivastigmine, and/or memantine, for at least 60 days at the time of the Baseline assessments
    •Screening may be extended for subjects who are using (or have recently discontinued) an AChEI and/or memantine at the initial Screening visit.
    •Subjects never previously treated with an AChEI and/or memantine may be enrolled if initiation of treatment with these medications 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 central nervous system (CNS) disorder other than probable Alzheimer’s disease or MCI-AD, e.g., Lewy body dementia, Parkinson’s disease, multiple sclerosis, progressive supranuclear palsy, hydrocephalus, Huntington’s disease, any condition directly or indirectly caused by Transmissible Spongiform Encephalopathy (TSE), CreutzfeldtJakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), or new variant Creutzfeldt-Jakob Disease (nvCJD)
    2. Significant intracranial focal or vascular pathology seen on brain MRI scan within a maximum of 42 days before Baseline that would, based on the independent reviewer imaging evaluation, lead to a diagnosis other than probable Alzheimer’s disease or MCI-AD, including but not limited to:
    •Large confluent white matter hyperintense lesions (i.e., Fazekas score of 3)
    •Other focal brain lesions judged clinically relevant by the investigator
    •Evidence of a prior or current macrohemorrhage
    3. Clinical evidence or history of any of the following (within specified
    period prior to Baseline):
    • Cerebrovascular accident (2 years)
    • Transient ischemic attack (6 months)
    • Significant head injury, for example, with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
    • Other unexplained or recurrent loss of consciousness (2 years)
    4. Diagnosed with epilepsy (a single prior seizure >6 months prior to Screening, is considered acceptable)
    5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria met (for any of the following within specified period:
    • Major depressive disorder (current)
    • Schizophrenia (lifetime)
    • Other psychotic disorders, bipolar disorder (within the past 5 years)
    • Substance (including alcohol) related disorders (within the past 2 years)
    6. Metal implants in the head (except dental), pacemaker, cochlear implants, or any other non-removable items that are contraindications to MRI. MRI compatible prosthetics, clips, stents, or any other device proven to be compatible are allowed
    7. Resides in hospital or moderate to high dependency continuous care facility (residence in low grade assisted living facility where there is sufficient autonomy to permit valid evaluation of activities of daily living is allowed so long as it is not mandated by an order issued either by the judicial or the administrative authorities)
    8.Any physical disability that would prevent completion of study procedures or assessments (e.g., blindness or significant uncorrected visual impairment, deafness or significant hearing loss not corrected by hearing aids, non AD-related speech impairment)
    9. History of swallowing difficulties (note: study drug should be swallowed whole and MUST NOT be broken, crushed, chewed, or dissolved in fluids prior to ingestion)
    10. Pregnant or breastfeeding
    11. Glucose-6-phosphate dehydrogenase (G6PD) deficiency based on World Health Organization classification (<60% of normal, i.e., <6.1 U/g
    hemoglobin [Hgb])
    12. History of significant hematological abnormality or current acute or chronic clinically significant abnormality, including:
    • History of hemoglobinopathy, myelodysplastic syndrome, hemolytic anemia, or splenectomy
    • Screening HgB value (confirmed upon repeat) below age/sex appropriate lower limit of the central laboratory normal range. Subjects in whom folate is < 4.0 ng/mL may be entered into the study provided folate supplementation (approximately 1 mg/day) is initiated and maintained for the duration of the study. Subjects in whom Vitamin B12 is < 150 pg/mL can be allowed if the investigator confirms that it does not affect the cognitive state of the subject and that the subject is supplemented as appropriate prior to the initiation of study drug
    13. Abnormal serum chemistry laboratory value at Screening deemed to be clinically significant by the investigator. In addition, subjects with either of the following abnormalities must be excluded:
    • Creatinine clearance <30 mL/min, estimated by the central laboratory according to the Cockcroft and Gault equation
    • Thyroid stimulating hormone (TSH) above laboratory normal range (subject may be treated [if clinically indicated based on further laboratory testing] and re-screened after 90 days)

    For exclusion criteria 14 to 20 please refer to the protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoints for Double-Blind Treatment Period
    • ADAS-cog11 (LMTM 16 mg/day versus placebo)
    • ADCS-ADL23 (LMTM 16 mg/day versus placebo)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through the trial
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoints for Double-Blind Treatment Period
    • Annualized rate of whole brain atrophy on brain MRI using BSI (LMTM 16 mg/day versus placebo)
    • Difference in temporal lobe 18F-FDG-PET change in SUVR normalized to pons in subjects with CDR 0.5 at Screening (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)
    • ADAS-cog11 and ADCS-ADL23 (LMTM 8 mg/day versus placebo)
    • Annualized rate of temporal and parietal lobe atrophy on brain MRI using BSI (LMTM 16 mg/day versus placebo, and LMTM 8 mg/day versus placebo)

    17.1.3 Secondary Endpoint for Open-Label, Delayed-Start Phase

    • Difference in disease progression on the co-primary clinical endpoints and the MRI imaging endpoint for subjects who started treatment in the double-blind treatment phase and those who started treatment in the
    open-label, delayed-start phase (referred to as "early" and "late" LMTM starters, respectively)
    o Only ADAS-cog11 will serve as a secondary endpoint; ADCS-ADL23 and other imaging endpoints are exploratory with the aim to be directionally supportive

    For exploratory endpoints, please refer to protocol.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    open label study following double blind period
    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 trial3
    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 concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA51
    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
    Belgium
    Canada
    France
    Italy
    Poland
    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
    Last Subject Last Visit
    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 months4
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months4
    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 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: 113
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 337
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 165
    F.4.2.2In the whole clinical trial 450
    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 study and receive treatment with LMTM up to and including the last open-label visit may be subsequently offered an opportunity to receive treatment with LMTM in a separate Expanded Access Program (EAP).

    Otherwise subject will return to the standard of care as determined by their physician.
    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 Decision2018-06-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-10
    P. End of Trial
    P.End of Trial StatusOngoing
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