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    Summary
    EudraCT Number:2017-003558-17
    Sponsor's Protocol Code Number:TRx-237-039
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-01-18
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-003558-17
    A.3Full title of the trial
    Randomized, Double-Blind, Placebo-Controlled, Three-Arm, 9-Month, Brain Imaging and Safety and Efficacy Study of Leuco-methylthioninium bis(hydromethanesulfonate) (LMTM) in Subjects with Early Alzheimer’s Disease.
    TRx-237-039: Estudio aleatorizado, doble ciego, controlado con placebo, de tres grupos, con técnicas de imagen cerebrales y de 9 meses de duración para determinar la seguridad y la eficacia de leucometiltioninio bis(hidrometanosulfonato) (LMTM) en sujetos con enfermedad de Alzheimer incipiente.
    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 early Alzheimer's Disease.
    Un estudio comparativo de TRx0237 (LMTM) y placebo en pacientes con enfermedad de Alzheimer incipiente.
    A.4.1Sponsor's protocol code numberTRx-237-039
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03446001
    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.5.6E-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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Alzheimer’s Disease
    Enfermedad de Alzheimer
    E.1.1.1Medical condition in easily understood language
    Alzheimer’s Disease
    Enfermedad de Alzheimer
    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
    1. To demonstrate that the LMTM dose of 8 mg/day (given as 4 mg bid) is effective compared to placebo based on the following primary imaging endpoint:
    • Difference in temporal lobe 18F-FDG-PET change in Standardized Uptake Value Ration (SUVR (normalized to pons) over 39 weeks

    2. To compare the LMTM dose of 8 mg/day with the placebo group on a composite cognitive/functional scale based on a subset of items selected from the ADAS-cog11 and the ADCS ADL23 (“Composite Scale”)

    3. To assess the safety and tolerability of LMTM 8 mg/day given for up to 39 week
    1. Demostrar que la dosis de LMTM de 8 mg/día (administrada en 4 mg dos veces al día) es efectiva comparada con el placebo en base al siguiente criterio de valoración principal de imagenología:
    • Diferencia en el cambio de la 18tomografía por emisión de positrones con F-fluorodeoxiglucosa (18F-FDG-TEP) del lóbulo temporal en la proporción del valor de captación normalizado (SUVR) (normalizado para protuberancia) durante 39 semanas
    2. Comparar la dosis de LMTM de 8 mg/día con el grupo de placebo en una escala cognitiva/funcional combinada basada en un subconjunto de elementos seleccionados de la Escala de Evaluación de la Enfermedad de Alzheimer, versión de 11 elementos (ADAS-cog11) y el Estudio Cooperativo de la Enfermedad de Alzheimer - Actividades de la Vida Diaria, versión de 23 elementos (ADAS ADL23) (“Escala combinada”)
    3. Evaluar la seguridad y tolerabilidad de LMTM 8 mg/día administrados hasta un máximo de 39 semanas
    E.2.2Secondary objectives of the trial
    To compare the LMTM dose of 8 mg/day with the placebo group in the difference in frontal and parietal lobe 18F-FDG-PET change in SUVR (normalized to pons) over 39 weeks
    To examine the associations between the measures of temporal, frontal, and parietal lobe SUVR using region-of-interest (ROI) approaches with the following clinical measure: Composite Scale
    To evaluate the outcomes described in the Primary and Secondary Objectives above for LMTM 16 mg/day (given as 8 mg bid) and placebo
    To compare the LMTM dose of 8 mg/day with the placebo group in annualized rate of temporal and parietal lobe atrophy between months 0 to 9 as measured by the Boundary Shift Integral (BSI) as measured by brain MRI
    To examine the associations between temporal and parietal lobe atrophy (and other MRI brain regions) with the following clinical measure: Composite Scale
    For additional secondary and exploratory objective please refer to the protocol
    Comparar la dosis de LMTM de 8 mg/día con el grupo de placebo en la diferencia del cambio de 18F-FDG-TEP del lóbulo frontal y parietal en SUVR (normalizado a protuberancia) durante 39 semanas
    Examinar las asociaciones entre las medidas del SUVR de los lóbulos temporal, frontal y parietal mediante enfoques de región de interés (ROI) con la siguiente medida clínica: Escala combinada
    Evaluar los resultados descritos en objetivos principales y secundarios anteriores para LMTM 16 mg/día (8 mg 2 veces al día) y placebo
    Comparar la dosis de LMTM de 8 mg/día con el grupo de placebo en la tasa anualizada de atrofia de los lóbulos temporal y parietal entre los meses 0 y 9, medida por el Boundary Shift Integral (BSI), medido por RM cerebral
    Examinar las asociaciones entre la atrofia del lóbulo temporal y parietal (y otras regiones cerebrales por RM) con la siguiente medida clínica: Escala combinada
    Para información adicional sobre objetivos secundarios y exploratorios, consulte el protocolo
    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 from subjects who agree to participate in genotyping evaluation of Apolipoprotein E (ApoE), if a separate informed consent is signed by the subject or by a legally acceptable representative. The blood sample may be collected any time after eligibility for randomization and continued participation in the study has been confirmed. A volume of approximately 10 mL is to be collected and immediately stored under frozen conditions (placed on dry ice) prior to shipment. Samples should then be shipped frozen (on dry ice) to the central laboratory (Covance) on the day of collection where they will be stored at -70°C. Samples will be destroyed at the end of the study.
    Se obtendrá una única muestra de sangre de los sujetos que acepten participar en la evaluación del genotipado de la apolipoproteína E (ApoE), si el sujeto o un representante legalmente aceptable firman un consentimiento informado por separado. La muestra de sangre se puede tomar en cualquier momento después de la elegibilidad para la aleatorización y se ha confirmado la continuación de la participación en el estudio. Se debe recoger un volumen de aproximadamente 10 ml y almacenar inmediatamente en condiciones de congelación (colocar en hielo seco) antes del envío. Las muestras deben enviarse congeladas (en hielo seco) al laboratorio central (Covance) el día de la recolección, donde se almacenarán a -70 ° C. Las muestras serán destruidas al final del estudio
    E.3Principal inclusion criteria
    1. Early 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.
    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. There should also be evidence of lower performance in episodic memory than would be expected for the subject’s age and educational background (typically 1 to 1.5 standard deviations below the mean). 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 20-27 (inclusive) at Screening

    4. Global Clinical Dementia Rating (CDR) score of 0.5 at Screening (including a score of > 0 in one of the functional domains: Community Affairs, Home and Hobbies, or Personal Care) (for both probable AD and MCI-AD)
    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 consistent with 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 daily 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 18F-FDG-PET.
    •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
    1.EA temprana, que abarca EA probable y deterioro cognitivo leve debido a EA (DCL-EA) según criterios de 2011 del National Institute on Aging (NIA)/Alzheimer’s Association (AA):
    •Demencia por todas las causas y probable EA
    En resumen, los sujetos con demencia por EA probable deben tener un inicio insidioso, un empeoramiento del deterioro en al menos 2 áreas cognitivas (aprendizaje y memoria, lenguaje, función ejecutiva, habilidades visuoespaciales), suficiente para interferir significativamente con el trabajo o las actividades habituales, que no se explica por delirio, fármacos, trastornos psiquiátricos mayores, enfermedades médicas, enfermedades cerebrovasculares, otras formas de demencia o trastornos neurológicos. La precisión del diagnóstico se confirmará independientemente.
    O
    •MCI-EA
    En sujetos con MCI-EA, debe haber indicios de preocupación por cambio en la cognición, en comparación con el nivel previo de la persona verificado por un informador o clínico experto. También debe haber indicios de menor rendimiento en la memoria episódica de lo que cabría esperar para la edad y nivel educativo del sujeto (típicamente de 1 a 1,5 desviaciones estándar bajo la media). También puede haber otros déficits cognitivos leves, pero debe haber preservación de la independencia en capacidades funcionales. Los sujetos no deben cumplir criterios para demencia. Los cambios cognitivos deben ser leves y no debe haber indicios de deterioro significativo en funcionamiento social u ocupacional. Los impedimentos no deben justificarse por delirio, fármacos, trastorno psiquiátrico grave, enfermedad médica, enfermedad cerebrovascular, otras formas de demencia o trastorno neurológico.
    2.Una TEP documentada positiva para amiloide; si la TEP más reciente se realizó >3 años antes de la selección y fue negativa, puede repetirse (los sujetos no son aptos si su TEP más reciente se realizó en los 3 años antes de la selección y fue negativa).
    3.Puntuación del MEC de 20-27 (incluido) en la selección
    4.Calificación clínica global de demencia (CDR) de 0,5 en la selección (incluyendo una puntuación de >0 en uno de los dominios funcionales: Asuntos Comunitarios, Hogar y Aficiones, o Cuidado Personal) (tanto para EA como para MCI-EA probables)
    5.Edad <90 años en la selección
    6.Las mujeres deben cumplir con uno de los siguientes:
    •Ser estéril quirúrgicamente (histerectomía, salpingectomía bilateral/ooforectomía) durante al menos 6 meses
    •Haberse sometido a una oclusión/ligadura de trompas bilateral al menos 6 meses antes
    •Postmenopáusica durante al menos 1 año
    •Usar anticonceptivos adecuados (método de barrera [como preservativo, diafragma o capuchón cervical/bóveda] con espuma, gel, película, crema o supositorio espermicida; dispositivo intrauterino [DIU] o sistema, o anticonceptivos hormonales orales o de acción prolongada inyectados o implantados durante al menos 90 días antes del inicio; o pareja vasectomizada [con documentación posvasectomía apropiada de ausencia de espermatozoides en eyaculado]) o verdadera abstinencia (cuando esto se adecúa al estilo de vida preferido y usual del sujeto); los sujetos deben ser competentes para usar anticonceptivos adecuados y estar de acuerdo en continuar manteniendo anticonceptivos adecuados durante toda la participación en el estudio (incluyendo 4 semanas después de la última dosis del medicamento de estudio)
    7.El sujeto, de acuerdo con la legislación nacional, es capaz de leer, comprender y dar consentimiento informado por escrito en el idioma del centro de estudio
    8.Tiene 1 (o varios) acompañantes de estudio adultos identificados (es decir, un cuidador o un informador) que cumple los siguientes criterios:
    •Ya sea porque viva con el sujeto, o en opinión del investigador, el grado de contacto es suficiente para proporcionar una evaluación significativa de cambios en el comportamiento y la función del sujeto a lo largo del tiempo, y proporcionar información sobre seguridad y tolerabilidad. (p.ej. ve al sujeto una media de ≥1 hora/día ≥3 días/semana)
    •Está dispuesto a dar consentimiento informado por escrito para su participación
    •Es capaz de leer, entender y hablar el idioma del centro del estudio
    •Acepta acompañar al sujeto en cada visita de estudio
    •Es capaz de verificar el cumplimiento diario con el medicamento en estudio
    9.El sujeto no debe haber estado tomando un AChEI, es decir, donepezil, galantamina o rivastigmina, y/o memantina, durante al menos 60 días en el momento de la 18F-FDG-TEP inicial.
    •La selección puede extenderse a sujetos que están usando (o que recientemente han dejado de usar) un AChEI y/o memantina en la visita inicial de selección.
    •Sujetos que nunca han sido tratados con un AChEI y/o memantina pueden inscribirse si el inicio del tratamiento con estos medicamentos no está planeado para el periodo de tiempo durante el cual el sujeto estará participando en este estudio.
    10.Capaz de cumplir con los procedimientos del estudio en opinión del investigador
    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 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 with associated loss of consciousness, skull fracture or persisting cognitive impairment (2 years)
    • Other unexplained or recurrent loss of consciousness ≥15 minutes (2 years)
    4.Previously diagnosed with epilepsy (a single prior seizure is considered acceptable)
    5. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) 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 imaging. 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 relevant by the investigator, e.g., those considered to have the potential to increase the risk associated with study participation or administration of investigational product and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. In addition, subjects with either of the following abnormalities must be excluded:
    • Creatinine clearance < 30 mL/min at Screening, 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.
    1.Trastorno significativo del sistema nervioso central (SNC) que no sea EA o MCI-EA probable, es decir, demencia de los cuerpos de Lewy, enfermedad de Parkinson, esclerosis múltiple, parálisis supranuclear progresiva, hidrocefalia, enfermedad de Huntington, cualquier afección causada directa o indirectamente por encefalopatía espongiforme transmisible (EET), enfermedad de Creutzfeldt-Jakob (ECJ), la variante de la enfermedad de Creutzfeldt-Jakob (v-ECJ) o la nueva variante de la enfermedad de Creutzfeldt-Jakob (nv-ECJ)
    2.Patología vascular o focal intracraneal significativa observada en resonancia magnética cerebral que, según la evaluación por imágenes de un revisor independiente, se traduciría en diagnóstico distinto a EA o MCI-EA probable, por ejemplo:
    •Grandes lesiones hiperintensas confluentes de materia (es decir, puntuación de Fazekas de 3)
    •Otras lesiones cerebrales focales consideradas clínicamente relevantes por el investigador
    •Indicios de una macrohemorragia previa o actual
    3.Indicios clínicos o antecedentes de cualquiera de lo siguiente (dentro del periodo especificado antes del inicio):
    •Accidente cerebrovascular (2 años)
    •Accidente isquémico transitorio (6 meses)
    •Lesión significativa en cabeza con pérdida de conciencia asociada, fractura de cráneo o deterioro cognitivo persistente (2 años)
    •Otra pérdida de conciencia inexplicable o recurrente ≥15 minutos (2 años)
    4.Haber sido diagnosticado previamente con epilepsia (una sola convulsión previa se considera aceptable)
    5.Cumplir con criterios del Manual Diagnóstico y Estadístico de Trastornos Mentales, Quinta Edición (para cualquiera de los siguientes dentro del periodo especificado):
    •Trastorno depresivo mayor (actual)
    •Esquizofrenia (de por vida)
    •Otros trastornos psicóticos, trastorno bipolar (últimos 5 años)
    •Trastornos relacionados con las sustancias (incluyendo el alcohol) (últimos 2 años)
    6.Implantes metálicos en la cabeza (excepto dentales), marcapasos, implantes cocleares o cualquier otro artículo no extraíble que sea una contraindicación para la RM. Se permiten prótesis, clips, stents o cualquier otro dispositivo compatible con la RM
    7.Reside en un hospital o en un centro de atención continua de dependencia moderada a alta (se permite la residencia en centros tutelados de bajo grado donde hay suficiente autonomía para permitir una evaluación válida de actividades de la vida diaria, siempre y cuando no sea por mandato de una orden emitida por las autoridades judiciales o administrativas)
    8.Cualquier discapacidad física que impida que se completen los procedimientos o las evaluaciones del estudio (p. ej., ceguera o impedimento visual significativo no corregido, sordera o pérdida auditiva significativa no corregida con audífonos, impedimento del habla no relacionado con EA)
    9.Antecedentes de dificultades para deglutir (Nota: El medicamento en estudio debe ser ingerido en su totalidad y NO DEBE romperse, aplastarse, masticarse o disolverse en líquidos antes de ser ingerido)
    10.Estar embarazada o en periodo de lactancia
    11.Deficiencia de glucosa-6-fosfato deshidrogenasa (G6PD) basada en la clasificación de la Organización Mundial de la Salud (<60 % de lo normal, es decir, <6,1 U/g hemoglobina [Hgb])
    12.Antecedentes de anomalía hematológica significativa o anomalía actual aguda o crónica clínicamente significativa, por ejemplo:
    •Antecedentes de hemoglobinopatía, síndrome mielodisplásico, anemia hemolítica o esplenectomía
    •Detección del valor de Hgb (confirmado en la repetición) por debajo del límite inferior apropiado para la edad/sexo del rango normal del laboratorio central
    Los sujetos en quienes el folato es <4,0 ng/ml pueden incorporarse al estudio siempre y cuando se inicie y mantenga aporte complementario de folato (aproximadamente 1 mg/día) durante la duración del estudio
    Los sujetos en los que la vitamina B12 es <150 pg/ml se pueden aceptar si el investigador confirma que no afecta al estado cognitivo del sujeto y que este se complementa según proceda antes del inicio del medicamento de estudio
    13.Valor anormal analítico de bioquímica sérica en la selección considerado clínicamente relevante por el investigador, p. ej., los que se considera que tienen potencial de aumentar el riesgo asociado con la participación en el estudio o la administración del producto en investigación y que, a juicio del investigador, harían que el sujeto sea inapropiado para entrar en este estudio. Asimismo, deben excluirse sujetos con cualquiera de las siguientes anomalías:
    •Aclaramiento de creatinina <30 ml/min en la selección, estimado por el laboratorio central de acuerdo con la ecuación de Cockcroft y Gault
    •Hormona estimulante de la tiroides (TSH, por sus siglas en inglés) por encima del rango normal de laboratorio (el sujeto puede ser tratado [si está clínicamente indicado de conformidad con las pruebas de laboratorio adicionales] y reevaluado después de 90 días)
    Para criterios de exclusión 14 a 20, consulte el protocolo
    E.5 End points
    E.5.1Primary end point(s)
    Primary Imaging Endpoint
    Decline in glucose uptake in the temporal lobe on 18F-FDG-PET (change in SUVR normalized to pons) over 39 weeks

    Primary Efficacy Endpoint
    Decline in the Composite Scale (as defined in the SAP) prior to database lock over 39 weeks
    Criterio de valoración principal de imagenología
    Disminución de la captación de glucosa en el lóbulo temporal en 18F-FDG-PET (cambio en SUVR normalizado para protuberancia) durante 39 semanas

    Criterio de valoración principal de eficacia
    Disminución en la escala combinada (como se define en el SAP) antes del bloqueo de la base de datos durante 39 semanas
    E.5.1.1Timepoint(s) of evaluation of this end point
    Through the trial
    A lo largo del ensayo
    E.5.2Secondary end point(s)
    Secondary Efficacy Endpoint: Brain MRI imaging

    Decline in glucose uptake of other regions using ROI approaches and all available SUVR data on 18F-FDG-PET (change in SUVR normalized to pons), including frontal and parietal lobes
    • Annualized rate of temporal and parietal lobe atrophy on brain MRI using BSI
    • Annualized rate of atrophy on other brain MRI regions (including hippocampus, and whole brain and lateral ventricular volumes)


    Other secondary endpoints

    ADAS-cog13
    ADCS-ADL23
    ApoE genotype
    Criterio de valoración secundario de eficacia: imágenes de resonancia magnética cerebral

    Disminución en la captación de glucosa de otras regiones utilizando enfoques de ROI y todos los datos SUVR disponibles en 18F-FDG-TEP (cambio en SUVR normalizado para protuberancia), incluidos los lóbulos frontal y parietal
    • Tasa anualizada de atrofia del lóbulo parietal y temporal en la RM cerebral utilizando BSI
    • Tasa anual de atrofia en otras regiones de RM cerebral (incluido el hipocampo y el cerebro completo y los volúmenes ventriculares laterales)

    Otros criterios de valoración secundarios

    ADAS-cog13
    ADCS-ADL23
    Genotipo ApoE
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the trial:
    A lo largo del ensayo
    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) Yes
    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 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 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 concerned4
    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
    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
    Última visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months11
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days7
    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: 93
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 282
    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 state13
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 138
    F.4.2.2In the whole clinical trial 375
    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, whether on or off study drug, may be offered an opportunity to subsequently receive treatment with LMTM in a separate expanded access program.

    Otherwise subject will return to the standard of care as determined by their physician.
    A los sujetos que completen el estudio, ya sea dentro o fuera del fármaco del estudio, se les puede ofrecer la oportunidad de recibir posteriormente el tratamiento con LMTM en un programa separado de acceso ampliado.

    De lo contrario, el sujeto volverá al tratmiento clínico habitual según lo determine su médico
    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 Decision2019-03-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-02-28
    P. End of Trial
    P.End of Trial StatusOngoing
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