Resumen

El propósito de este estudio de investigación es evaluar el fármaco en estudio, denominado remternetug, para determinar su eficacia en el tratamiento de la enfermedad de Alzheimer asintomática (en riesgo) en personas con mutaciones causantes de EA. Este estudio también investigará los efectos de remternetug sobre biomarcadores (medidas de la enfermedad que incluyen estudios de imagen cerebral, análisis de sangre y líquido cefalorraquídeo), examinará los datos de seguridad para identificar posibles beneficios o riesgos, y evaluará la tolerabilidad de remternetug por parte de los participantes. La Etapa 1 determinará si el tratamiento con el fármaco en estudio previene o revierte la acumulación de amiloide beta (Aβ) en comparación con placebo en participantes con Enfermedad de Alzheimer de herencia dominante (DIAD). La Etapa 2 evaluará el efecto del tratamiento antiamiloide temprano sobre los biomarcadores secundarios de EA en participantes tratados en comparación con grupos control externos.

Descripción detallada

La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad, caracterizado por un declive progresivo en la función cognitiva y la capacidad de realizar actividades de la vida diaria. La hipótesis amiloide de la EA postula que la acumulación de amiloide beta (Aβ) es un evento temprano y necesario en la patogénesis de la EA. Esta hipótesis sugiere que las intervenciones que enlentecen la acumulación de placa de Aβ en el cerebro o aumentan la eliminación de Aβ podrían ser capaces de enlentecer la progresión del síndrome clínico de la EA. La EA se presenta en un continuo que va desde la fase asintomática (preclínica) hasta el deterioro cognitivo leve (DCL) y luego hacia la demencia en estadios leve, moderado y grave. La evidencia de cohortes con riesgo genético y con riesgo por edad, como en la EA de herencia dominante (DIAD), sugiere que el proceso fisiopatológico de la EA comienza bien más de una década antes del estadio clínico que actualmente se reconoce como demencia por EA, y que la neurodegeneración ya es evidente en la RM en el estadio de deterioro cognitivo leve. Datos recientes de ensayos clínicos sugieren que el tratamiento de la EA en estadios más tempranos podría tener el mayor beneficio potencial sobre la enfermedad al enlentecer su progresión. La capacidad de identificar con un alto grado de certeza a los individuos destinados a desarrollar la enfermedad de Alzheimer (EA) ofrece una oportunidad única para evaluar la eficacia de las terapias en estadios asintomáticos y muy tempranos de la demencia. Las familias con mutaciones causantes de enfermedad conocidas son extremadamente raras y están geográficamente dispersas por todo el mundo. Los participantes en este estudio aún no habrán desarrollado ningún síntoma clínico de EA; serán portadores "asintomáticos" de mutaciones que causan DIAD y se esperaría que tuvieran un desempeño normal en las pruebas cognitivas y funcionales estándar. Además, la mayoría de los portadores de mutaciones tendrán niveles de amiloide beta (Aβ) asociado a la EA y biomarcadores no Aβ similares a los de los no portadores. El amiloide beta es una proteína que se acumula en el cerebro de las personas con EA. Aunque no entendemos exactamente qué causa la EA, se cree que la acumulación anormal de la proteína amiloide beta en el cerebro desempeña un papel importante en los síntomas de la EA. Estudios de investigación recientes indican que el amiloide beta puede comenzar a acumularse en el cerebro 15 años o más antes del inicio de la pérdida de memoria. Se utilizarán biomarcadores de imagen y fluidos para demostrar que los compuestos en tratamiento han interactuado con sus dianas terapéuticas. Se recopilarán un conjunto de medidas cognitivas diseñadas para evaluar los cambios cognitivos más tempranos y sutiles. Los objetivos generales de este estudio son evaluar el efecto sobre biomarcadores, la seguridad y la tolerabilidad de los fármacos en investigación en participantes con una mutación causante de EA conocida. El objetivo primario de la Etapa 1 es determinar si el tratamiento con el fármaco en estudio previene o enlentece la tasa de acumulación patológica de Aβ demostrada mediante imagen de tomografía por emisión de positrones (PET) con PiB de Aβ. El objetivo primario de la Etapa 2 es evaluar el efecto del tratamiento antiamiloide temprano sobre la progresión de la enfermedad, evaluando biomarcadores secundarios no Aβ de EA (p. ej., tau total en LCR, NfL, volumen en RM) en comparación con un grupo control del estudio de historia natural DIAN Obs y los participantes tratados con placebo de DIAN-TU-001. Remternetug es un anticuerpo monoclonal. Su mecanismo de acción consiste en dirigirse y eliminar la placa de amiloide agregada, un sello fisiopatológico clave de la EA, mediante eliminación mediada por microglía. Remternetug ha demostrado capacidad para reducir la placa de amiloide cerebral. El brazo de remternetug forma parte del Protocolo Marco DIAN-TU-002 (NCT05552157).

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

Provide written informed consent, signed, and dated by the participant and study partner, or by the participant's legally authorized representative if applicable, according to local regulations for the ICF and, if applicable, country specific ICFs.
Participant is at least 18 years old.
People of childbearing potential
Must have a negative serum pregnancy test at screening (V1)
Must agree not to try to become pregnant during the study until 5 half-lives after the last dose of any study drug.
Must agree not to breastfeed from the time of signed ICF until 5 half-lives after the last dose of any study drug.
If partner is not sterilized, must agree to use highly effective contraceptive measures from screening (V1) until 5 half lives after last dose of any study drug
Mutation Status:
Participant is a carrier of a mutation in an APP, PSEN1, or PSEN2 gene that is associated with DIAD or does not know their mutation status and there is a mutation in their family pedigree that puts them at a direct risk of inheriting the known mutation;
Participant is -25 to -11 years from predicted age of cognitive symptom onset based on their mutation type or family pedigree Note: If the at-risk parent is deemed a non-carrier through confirmed genetic testing at any time during the study, the participant will be withdrawn.
Cognitive status of participant is normal (CDR-SB 0).
Fluency in DIAN-TU trial approved language and evidence of adequate premorbid intellectual functioning. Participants must be fluent in languages for which cognitive and clinical measures have been translated and validated for use in the DIAN-TU. Fluency is generally defined as daily or frequent functional use of a language generally from birth or a young age. In cultures where multiple languages are spoken or for participants who are multilingual, determination as to whether a participant's level of fluency in languages for which clinical and cognitive measures are available meets qualification for the study should be made by the site PI.
Participant has adequate visual and auditory abilities to perform all aspects of the cognitive and clinical assessments.
Participant is receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to baseline visit (V2) except for medications taken for episodic conditions (e.g., migraine abortive therapy, antibiotics, and other medications for upper respiratory and gastrointestinal ailments).
Participant has a study partner who in the PI's judgment can provide accurate information as to the participant's cognitive and functional abilities, who agrees to provide information at the study visits that require study partner input for scale completion, and who signs the necessary ICF, if applicable.
The participant agrees not to donate blood or blood products for transfusion from the time of Screening (V1) for a study drug arm, for the duration of the study, and for 5 half lives after the final dose of study drug.
In the opinion of the PI, the participant will be compliant and have a high probability of completing the study.
The participant is able and willing to complete all study-related testing, evaluations, and procedures.

Criterios de exclusión

Significant neurologic disease (other than AD) or psychiatric disease that may currently or during the study affect cognition or the participant's ability to complete the study. This would include disorders such as: recent or severe head trauma causing cognitive change, seizure disorder, neurodegenerative disease other than DIAD, hydrocephalus, cerebral/spinal hematoma, inflammatory disease, CNS infection (e.g., encephalitis or meningitis), neoplasm, toxic exposure, metabolic disorder (including hypoxic or hypoglycemic episodes) or endocrine disorder; psychiatric disorders such as schizophrenia, schizoaffective disorder, bipolar disorder or major depression, or any other psychiatric condition/disorder which could significantly interfere with the participant's cooperative participation (e.g., prominent anxiety, agitation or behavioral problems). Disorders that are controlled medically or remote history of these disorders (e.g., history of febrile seizures in childhood) that are not likely to interfere with cognitive function and compliance with study procedures are not exclusionary.
At high risk for suicide, e.g., significant suicidal ideation or attempt within last 12 months, current major depression (as defined in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition \[DSM-V\]), or increased suicide risk based on screening Columbia Suicide Severity Rating Scale (C-SSRS). Current stable mild depression or current use of antidepressant medications are not exclusionary.
History of clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis, plaque, or other prominent risk factor for stroke or cerebral hemorrhage (including atrial fibrillation and anticoagulation, documented transient ischemic attack \[TIA\] in the last 12 months) that may be interfering with cognition or is likely to impact with the participant's ability to complete the study. Low dose aspirin (≤ 325 mg daily) is not exclusionary.
Alcohol or substance use sufficient to meet DSM-V criteria currently or within the past year.
History of or Baseline (V2) visit brain MRI scan indicative of any other significant abnormality, definite microhemorrhages, evidence of a cerebral contusion, encephalomalacia, or aneurysms. Minor or clinically insignificant imaging findings are not exclusionary.
Presence of certain implanted medical devices, such as some pacemakers, aneurysm clips, artificial heart valves, ear implants, or foreign metal objects in the eyes, skin, or body which would preclude MRI scan.
Cardiovascular complications such as uncontrolled hypertension, history of myocardial infarcts, heart failure, atrial fibrillation, long QT interval on ECG likely to interfere with participation in or analysis of the trial in the opinion of the investigator
Hepatic or renal abnormalities that in the opinion of the investigator would interfere with participation in or analysis of the trial.
History of Human Immunodeficiency Virus (HIV) infection, history of Hepatitis B infection within the past year, history of Hepatitis C infection which has not been adequately treated, history of spirochete infection (e.g., syphilis, Lyme) of the CNS or history of other infection with high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
History of clinically significant multiple or severe drug allergies, significant atopy, or severe post-treatment hypersensitivity reactions (including but not limited to erythema multiforme major, linear IgA dermatosis, toxic epidermal necrolysis, and/or exfoliative dermatitis) or sensitivity to study-drug specific PET imaging agents with a high risk for interfering with participation or interpretation of the study in the opinion of the investigator.
Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within 90 days prior to Baseline (V2) visit (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
Current clinically significant abnormalities of thyroid function, or clinically significant deficiency in vitamin B12. Vitamin B12 less than the lower limits of normal with normal methylmalonic acid (MMA)/homocysteine is not deemed clinically significant, therefore not exclusionary.
Unstable or poorly controlled diabetes which the investigator believes may interfere with participation in or analysis of the study protocol. Participants may be rescreened after 3 months to allow optimization of diabetic control
Morbid obesity with significant comorbidities or that would preclude MRI imaging.
Current use of anticoagulants (e.g., warfarin, dabigatran, rivaroxaban, or apixaban). Daily use of low dose (\< 325 mg) aspirin is not exclusionary.
Have been exposed to a monoclonal antibody targeting Aβ peptide within the past 6 months or 5 half-lives from screening, whichever is longer.
Received any other investigational pharmacological treatment within 3 months of Screening or 5 half-lives, whichever is longer.
Note: Use of approved treatments for AD and other medications may be permitted in this study.
Lack of sufficient venous access.
Clinically relevant abnormalities in hematology, coagulation, or clinical chemistry.
History of cancer that the investigator believes has high risk of recurrence and impacting study participation or analysis.
Any other medical condition that could be expected to progress, recur, or change to such an extent that it could bias the assessment of the clinical or mental status of the participant to a significant degree or put the participant at special risk.
Currently, or within the last month prior to screening, participated in a clinical study, including a nonpharmacological study, without prior approval.
Participants with the "Dutch" APP E693Q mutation.
Unable to complete baseline visit (V2) procedures with appropriate cognitive and clinical scores for eligibility
A centrally read MRI demonstrating presence of ARIA-E, \> 4 cerebral microhemorrhages, any superficial siderosis, any macrohemorrhage, or severe white matter disease at screening.
Exposure to lecanemab, donanemab, or other investigational amyloid lowering agents within the past 6 months or five half-lives from screening, whichever is longer.
Note: Use of approved treatments for AD and other medications may be permitted.
Investigator site personnel directly affiliated with this trial and/or their immediate families, defined as a spouse, parent, child, or sibling, whether biological or legally adopted
Lilly employees or employees of a third-party organization (TPO) involved in this study that requires exclusion of their employees or have study partners who are Lilly employees or are employees of TPOs involved in this study that require exclusion of their employees

Ensayo de plataforma de fase II/III multicéntrico, aleatorizado, doble ciego, controlado con placebo, de diseño adaptativo en dos etapas, de tratamientos en investigación para la prevención primaria de la progresión de la enfermedad en la Enfermedad de Alzheimer de herencia dominante

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

Remternetug

Matching Placebo (Remternetug)

Ubicaciones

Instituto de Investigaciones Neurologicas Raul Carrea, FLENI

Patrocinadores

Contactos

Jamie Bartzel

Ellen Ziegemeier