E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Frontotemporal Dementia |
Demencia Frontotemporal |
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E.1.1.1 | Medical condition in easily understood language |
A type of dementia that causes problems with behaviour and language |
Un tipo de demencia que causa problemas en el comportamiento y el lenguaje |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10068968 |
E.1.2 | Term | Frontotemporal dementia |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of AL001 compared with placebo in carriers of progranulin gene (GRN) mutations causative of frontotemporal dementia (FTD) as measured by the Clinical Dementia Rating Dementia Staging Instrument PLUS National Alzheimer’s Disease Coordinating Center frontotemporal lobar degeneration Behavior & Language Domains Sum of Boxes (CDR® plus NACC FTLD-SB). |
Evaluar la eficacia de AL001 en comparación con placebo en portadores de mutaciones en el gen de la progranulina (GRN) causantes de demencia frontotemporal (DFT), determinada mediante el instrumento de estadificación de la demencia de valoración de la demencia clínica MÁS suma de recuadros de los dominios de comportamiento y lenguaje en la degeneración lobular frontotemporal del National Alzheimer’s Disease Coordinating Center (CDR® más FTLD-SB del NACC) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate the clinical effects, safety, and tolerability of AL001 compared with placebo in carriers of GRN mutations causative of FTD as measured by:
Secondary Objective: Clinical outcome assessments (COAs)
Secondary Pharmacodynamic (PD) Objective: Disease pathology biomarkers
Secondary Safety Objective: Safety assessments and antidrug antibodies (ADAs) |
Los objetivos secundarios de este estudio son evaluar los efectos clínicos, la seguridad y la tolerabilidad de AL001 en comparación con placebo en portadores de mutaciones en GRN causantes de DFT determinados mediante:
Objectivo secundario: Evaluaciones de resultados clínicos (ERC)
Objetivo farmacodinámico (FD) secundario: Biomarcadores anatomopatológicos de la enfermedad
Objetivo secundario de seguridad: Evaluaciones de la seguridad y anticuerpos contra el fármaco (ACF) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Each participant must meet all of the following criteria to be enrolled in this study.
Key Inclusion Criteria: • Known progranulin genetic mutation causing FTD. • CDR plus NACC-FTLD score 0-2. • If symptomatic, one of the criteria for the diagnosis of probable behavioral variant FTD or FTD-semantic subtype or FTD-Progressive Nonfluent Aphasia. • Study partner who consents to study participation and who cares for/visits the patient daily for at least 5 hours per week. • Written informed consent must be obtained and documented (from the patient or, where jurisdictions allow it, from their legal decision maker). |
Los pacientes deberán cumplir todos los criterios siguientes para poder participar en este estudio.
Criterios de inclusión fundamentales: Mutación genética conocida que cusante de DFT. Una puntuación CDR más FTLD del NACC entre 0 y 2 En participantes sintomáticos, uno de los criterios para el diagnóstico de posible demencia frontotemporal de variante conductual o de subtipo semántico o de afasia progresiva primaria El paciente dispone de una persona (“acompañante del estudio”) con la que tiene un contacto frecuente y suficiente (al menos 5 horas a la semana de contacto en persona), que otorgue el consentimiento informado necesario.
El paciente está dispuesto a otorgar su consentimiento informado. Si el paciente no es competente, un representante legal deberá otorgar su consentimiento informado en su nombre |
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E.4 | Principal exclusion criteria |
Dementia due to a condition other than FTD including, but not limited to, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, Huntington disease, or vascular dementia. Known history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric, human, or humanized antibodies or fusion proteins. Current uncontrolled hypertension, diabetes mellitus or thyroid disease. Clinically significant heart disease, liver disease or kidney disease. History or evidence of clinically significant brain disease other than FTD. Females who are pregnant or breastfeeding, or planning to conceive within the study period. Any experimental vaccine or gene therapy. History of cancer except: If considered to be cured If not being actively treated with anti-cancer therapy or radiotherapy and, in the opinion of the investigator, not likely to require treatment in the ensuing 3 years Is considered to have low probability of recurrence For prostate cancer, no significant progression over the previous 2 years Current use of anticoagulant medications (e.g., coumadin, heparinoids, apixaban). Residence in a skilled nursing facility, convalescent home, or long term care facility at screening; or requires continuous nursing care. |
1.Demencia debida a una enfermedad distinta de la DFT, entre otras, enfermedad de Alzheimer, enfermedad de Parkinson, demencia con cuerpos de Lewy, enfermedad de Huntington o demencia vascular. 2.El paciente tiene antecedentes conocidos de reacciones alérgicas, anafilácticas u otras reacciones de hipersensibilidad graves a anticuerpos quiméricos, humanos o humanizados o a proteínas de fusión. 3.El paciente tiene hipertensión, diabetes mellitus o enfermedad de tiroides no controladas 4.Enfermedad clínicamente significativa cardiaca, hepática o renal 5.Evidencia de enfermedad cerebral clínicamente significativa distinta a la DFT 6.Mujeres embarazadas o dando de mamar o que planean tener hijos durante el periodo del estudio 7.Haber recibido terapia génica o vacunas experimentales 8.El paciente tiene antecedentes de cáncer, excepto si: a.Se considera probable que se cure. b.No está recibiendo tratamiento antineoplásico o radioterapia de forma activa y, en opinión del investigador, no es probable que precise tratamiento en los 3 años siguientes. c.Se considera que tiene pocas probabilidades de recidiva d.En caso de cáncer de próstata, no ha presentado progresión significativa en los 2 últimos años. 9.Uso de Anticoagulantes (por ejemplo, warfarina, heparinoides o apixabán) 10.El paciente reside en un centro de cuidados especializados, una clínica de reposo o un centro de cuidados a largo plazo en la selección o requiere cuidados de enfermería continuos. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint: •The CDR® plus NACC FTLD-SB |
Criterio de valoración primario: CDR más FTLD del NACC |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline and weeks 16, 32 and 48 for symptomatic patients and baseline and weeks 16,32, 48, 64, 80 and 96 for pre symptomatic patients. |
Basal y semanas 16, 32 y 48 para pacientes sintomáticos y basal y semanas 16,32, 48, 64, 80 y 96 para pacientes pre sintomáticos. |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints: •Clinical Global Impression-Severity (CGI S) •Clinical Global Impression-Improvement (CGI I) •The changes from baseline in the scores of the following COAs: o Frontotemporal Dementia Rating Scale (FRS) o Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Secondary PD Endpoints: •The changes from baseline in the following: o Structural volumetric magnetic resonance imaging (MRI) whole and regional brain volume o Progranulin protein (PGRN) concentrations in plasma and optional cerebrospinal fluid (CSF) o Neurofilament-light chain (NfL) concentrations in serum and optional CSF
Secondary Safety Endpoints: •Incidence, nature, and severity of adverse events and serious adverse events •Physical examination abnormalities •Neurological examination abnormalities •Changes in vital signs from baseline over time •Changes in electrocardiograms from baseline over time •MRI abnormalities •Changes in clinical laboratory tests from baseline over time •Sheehan-Suicidality Tracking Scale (Sheehan STS) •Incidence of ADAs to AL001 |
Criterios de Valoración Secundarios: •Impresión clínica global-Intensidad (CGI-S) •Impresión clínica global-Mejoría (CGI-I) •Cambios desde el momento basal en la puntuación de los siguientes ERCs: - Escala de valoración de la de la demencia frontotemporal (FRS) - Batería repetible para la evaluación del estado neuropsicológico (RBANS)
Criterios de valoración FD secundarios: •Variaciones con respecto al momento basal de lo siguiente: - Volumen cerebral total y regional mediante resonancia magnética (RM) volumétrica estructural - Concentraciones de proteína progranulina (PGRN) en plasma y líquido cefalorraquídeo (LCR) opcional - Concentraciones de cadenas ligeras de neurofilamentos (NfL) en suero y LCR opcional
Criterios de valoración secundarios de la seguridad: •Incidencia, naturaleza e intensidad de los acontecimientos adversos y acontecimientos adversos graves. •Anomalías en la exploración física •Anomalías en la exploración neurológica •Variaciones de las constantes vitales con respecto al momento basal a lo largo del tiempo •Variaciones de los electrocardiogramas con respecto al momento basal a lo largo del tiempo. •Anomalías en la RM •Variaciones de los análisis clínicos con respecto al momento basal a lo largo del tiempo. •Escala de seguimiento de la tendencia suicida de Sheehan (Sheehan STS) •Incidencia de ACF contra AL001 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints: every 16 weeks.
PD endpoints: MRI every 24 weeks PGRN and NfL measurements every 8 weeks and safety assessments every 4 weeks. |
Criterios de valoración secundarios: cada 16 semanas
Criterios de valoración FD secundarios: RM cerebral cada 24 semanas, medidas de PGRN y NfL cada 8 semanas y evaluaciones de seguridad cada 4 semanas. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 31 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Belgium |
Canada |
France |
Germany |
Italy |
Netherlands |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
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E.8.7 | Trial 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
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LVLS |
Ultima Visita del Ultimo Paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |