| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alzheimer's disease |
| Enfermedad de Alzheimer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Alzheimer's disease |
| Enfermedad de Alzheimer |
|
| 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 | 19.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10001896 |
| E.1.2 | Term | Alzheimer's disease |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Safety Objective:
- To evaluate the safety and tolerability of repeated doses of ABvac40 in a population of patients with a-MCI or vm-AD.
Primary Efficacy (Immunogenicity) Objective:
- To assess (quantify) the immune response produced during the study by repeated doses of ABvac40 in a population of a-MCI or vm-AD. |
Objetivo principal de seguridad
- Evaluar la seguridad y la tolerabilidad de dosis repetidas de ABvac40 en una población de pacientes con deterioro cognitivo leve de tipo amnésico (DCL-a) o enfermedad de Alzheimer muy leve (EA-ml).
Objetivo principal de eficacia (inmunogenicidad)
- Evaluar (cuantificar) la respuesta inmune producida durante el estudio debido a la administración de dosis repetidas de ABvac40 en una población con DCL-a o EA-ml |
|
| E.2.2 | Secondary objectives of the trial |
Secondary (Exploratory) Efficacy Objectives:
- To characterize the immune response elicited by repeated doses of ABvac40 in a population of a-MCI or vm-AD.
- To assess the changes in the disease biomarkers elicited by ABvac40 in the study population stratified by amyloid-PET positivity.
- To assess the changes in cognition and quality of life elicited by ABvac40 in the study population stratified by amyloid-PET positivity. |
Objetivos secundarios (exploratorios) de eficacia
- Caracterizar la respuesta inmune provocada por dosis repetidas de ABvac40 en una población de individuos con DCL-a o EA-ml.
- Evaluar los cambios en los biomarcadores de la enfermedad inducidos por ABvac40 en la población del estudio estratificada según positividad en PET-amiloide.
- Evaluar los cambios en la cognición y la calidad de vida inducidos por ABvac40 en la población del estudio estratificada según positividad en PET-amiloide. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female between 55 and 80 years of age, both inclusive, at the time of signing informed consent.
2. The patient (or legal representative, if applicable) and a close relative/caregiver must read the subject information sheet, agree to participate in the clinical trial and sign the informed consent form (the patient and a close relative/caregiver).
3. Presence of a stable caregiver to attend the patient study visits.
4. Mini-Mental Status Examination (MMSE) score between 24 and 30 points (inclusive), according to age and education level.
5. Clinical Dementia Rating (CDR) scale scoring 0.5.
6. Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Score on the Delayed Memory Index (DMI) of 85 or lower.
7. The results of the patient’s MRI brain scan must be concordant with the diagnosis of clinical a-MCI or vm-AD according to the following criteria: Scheltens scale, and measurement of white matter and past haemorrhages.
8. If the patient is receiving treatment for AD, must have been stable during the two months before the selection visit.
9. Treatment for concomitant diseases must be stable during the previous month before the treatment of the study.
10. Positive assessment of the candidate by the investigator for complying with the requirements and procedures of the study. |
1. Hombres o mujeres de entre 55 y 80 años de edad, ambas inclusive, en el momento de la firma del consentimiento informado.
2. El paciente (o el representante legal, si procede) y un familiar cercano/cuidador deben leer la hoja de información al paciente, aceptar participar en el ensayo clínico y firmar el formulario de consentimiento informado (el paciente y un familiar cercano/cuidador).
3. Presencia de un cuidador estable que acuda a las visitas del estudio del paciente.
4. Puntuación MMSE (Mini-Mental Status Examination) de entre 24 y 30 puntos (inclusive), en función de la edad y el nivel educativo.
5. Puntuación de 0,5 en la escala CDR (Clinical Dementia Rating).
6. Puntuación de RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) en el DMI (Delayed Memory Index) de 85 o inferior.
7. Los resultados de la RM cerebral del paciente deben ser concordantes con el diagnóstico clínico de DCL-a o EA-ml de acuerdo con los siguientes criterios: escala Scheltens, y medición de la sustancia blanca y hemorragias previas.
8. Si el paciente está recibiendo tratamiento para la enfermedad de Alzheimer, dicho tratamiento debe haber permanecido estable durante los dos meses anteriores a la visita de selección.
9. El tratamiento para las enfermedades concomitantes debe ser estable durante el mes anterior al tratamiento del estudio.
10. Valoración positiva del candidato por el investigador en cuanto al cumplimiento de los requisitos y procedimientos del estudio. |
|
| E.4 | Principal exclusion criteria |
1. Known allergy to components of the vaccine or prior history of anaphylaxis, a severe allergic reaction or a history of hypersensitivity to any component of the formulation. Allergy to fish or shellfish.
2. Active infectious disease (i.e. hepatitis B, C). Positive syphilis serology.
3. History or presence of autoimmune disease, except mild eczema, rhinitis or psoriasis.
4. Presence or history of immunodeficiency (i.e. HIV).
5. Significant kidney and/or liver disease, as defined by plasma creatinine ≥2.5 mg/dL (221 µmol/l) and/or total bilirubin >3 mg/dL (51.3 µmol/l) measured at the local site laboratory.
6. History of asthma or reactive airway disease with bronchospasm in the last 6 months, or currently on regular treatment.
7. Major uncontrolled systemic condition (e.g. diabetes, congestive heart failure, hypertension).
8. History of cancer (≤5 years since the last specific treatment). Exceptions: basocellular carcinoma.
9. Significant alterations in hematological, biochemical or urine analytical parameters, particularly those relating to levels of vitamin B12, folic acid or thyroid tests.
10. History of any other central nervous system disorder, degenerative or non-degenerative neurological or psychiatric condition that, in the investigator's opinion could be the cause of the dementia, or could explain the cognitive impairment, or that might interfere with cognitive function directly or by its treatment.
11. Geriatric Depression Scale (GDS; abbreviated version), score >5
12. Has a “yes” answer to C-SSRS suicidal ideation items 4 or 5, or any suicidal behavior within 6 months before Screening, or has been hospitalized or treated for suicidal behavior in the past 5 years before Screening.
13. History or signs of cerebrovascular disease (ischemic or haemorrhagic stroke, transient ischemic attack), or diagnosis of possible, probable or clear vascular dementia according to NINDS-AIREN criteria.
14. Presence on MRI of a relevant pattern of microvascular disease (Leukoaraiosis, Fazekas score ≥2 in the deep white matter scale or ≥4 in the global score) or more than one lacunar or territorial infarcts. Any other MRI finding that, in the opinion of the investigator, might be a relevant contributing cause of subject´s cognitive impairment.
15. History of bleeding disorder or predisposing conditions, blood clotting or clinically significant abnormal results on coagulation profile at Screening, as determined by the Investigator. Presence of up to 3 microhemorrhages will be acceptable.
16. Patients being treated with anticoagulants or antiaggregant therapy (aspirin at a prophylactic dose ≤325 mg daily or clopidogrel at a dose ≤75 mg daily are allowed) should not be recruited in the study.
17. Modified Hachinski Ischemic Scale, score higher than 4.
18. Surgery (with general anaesthetic) within the previous three months to be included in the trial, or programed during the study period.
19. Treatment within 30 days prior to visit 0 with systemic corticosteroids or other immunosuppressant’s.
20. The vaccination against influenza, must be avoided within 3 months before inclusion.
21. Patients, who have previously been randomized in this trial.
22. Participation in another clinical trial within the previous 1 month to screening visit, or within the previous 12 months after the last dose to the screening visit in the case of subjects who participated in trials with a study drug whose intention was to modify the progression AD unless documentation of receipt of placebo is available. The patient cannot be included in the study if the experimental drug was an immunotherapeutic drug, including IVIG or a vaccine against Alzheimer's disease unless documentation of receipt of placebo is available.
23. Patients with alcohol or drug abuse or dependence.
24. Absolute (having a pacemaker or implantable defibrillator) or relative (bare metal stent or stent implanted in the last six months) contraindications to MRI examination. Feeling of claustrophobic do not let perform MRI or PET scan.
25. Patients unlikely to comply with the protocol (e.g., unable to return for follow-up visits).
26. Women of childbearing age, pregnant or nursing. |
1. Alergia conocida a los componentes de la vacuna o antecedentes de anafilaxia, una reacción alérgica grave o antecedentes de hipersensibilidad a cualquiera de los componentes de la formulación. Alergia al pescado o al marisco.
2. Enfermedad infecciosa activa (es decir, hepatitis B, C). Serología positiva para sífilis.
3. Antecedentes o presencia de enfermedad auto inmune, excepto eccema, rinitis o psoriasis leve.
4. Presencia o antecedentes de inmunodeficiencia (es decir, VIH).
5. Enfermedad hepática o renal significativa, definida por una creatinina plasmática 2,5 mg/dl (221 mol/l) y/o bilirrubina total > 3 mg/dl (51,3 mol/l), evaluada por el laboratorio local del centro.
6. Antecedentes de asma o enfermedad reactiva de las vías respiratorias, con broncoespasmo en los últimos 6 meses, o que está recibiendo tratamiento habitual.
7. Afección sistémica importante no controlada (p. ej., diabetes, insuficiencia cardíaca congestiva, hipertensión).
8. Antecedentes de cáncer (≤ 5 años desde el último tratamiento específico). Excepciones: carcinoma basocelular.
9. Alteraciones significativas en los parámetros analíticos de hematología, bioquímica u orina, especialmente los relativos a concentraciones de vitamina B12, ácido fólico o en las pruebas tiroideas.
10. Antecedentes de cualquier otra enfermedad del sistema nervioso central, afección psiquiátrica o neurológica degenerativa o no degenerativa que, en opinión del investigador, pudiera ser causa de demencia, o pudiera explicar el deterioro cognitivo, o que pudiera interferir con la función cognitiva directamente o debido a su tratamiento.
11. Puntuación > 5 en la escala GDS (Geriatric Depression Scale; versión abreviada)
12. Ha respondido «sí» a los ítems 4 o 5 de ideación suicida del C-SSRS, o tiene cualquier conducta suicida en los 6 meses anteriores a la selección, o ha sido hospitalizado o tratado por conducta suicida en los 5 años previos a la selección.
13. Antecedentes o signos de enfermedad cerebrovascular (ictus isquémico o hemorrágico, accidente isquémico transitorio), o diagnóstico de demencia vascular posible, probable o evidente de acuerdo con los criterios NINDS-AIREN.
14. Presencia en la RM de un patrón de enfermedad microvascular (leucoaraiosis, puntuación Fazekas ≥ 2 en la escala de sustancia blanca profunda o ≥ 4 en la puntuación global) o más de un infarto lacunar o territorial. Cualquier otro resultado de la RM que, en opinión del investigador, podría ser una importante causa contributiva al deterioro cognitivo del paciente.
15. Antecedentes de trastorno hemorrágico o afecciones predisponentes, coagulación sanguínea o resultado anómalo clínicamente significativo en el perfil de coagulación en la selección, según la determinación del investigador. Se aceptará la presencia de hasta 3 microhemorragias.
16. Pacientes que reciban tratamiento con anticoagulantes o tratamiento antiagregante (ácido acetilsalicílico a una dosis profiláctica ≤ 325 mg al día o clopidogrel a una dosis ≤ 75 mg al día están permitidos) no podrán ser admitidos en el estudio.
17. Puntuación superior a 4 en la escala isquémica de Hachinski modificada.
18. Cirugía (con anestesia general) en los tres meses previos a la inclusión en el ensayo, o programada durante el periodo del estudio.
19. Tratamiento con corticoesteroides sistémicos u otros inmunosupresores en los 30 días anteriores a la visita 0.
20. La vacunación frente al virus de la gripe deberá evitarse en los 3 meses previos a la inclusión.
21. Pacientes que hayan sido aleatorizados anteriormente en este estudio.
22. Participación en otro ensayo clínico en 1 mes previo a la visita de selección, o después de la última dosis en los 12 meses anteriores a la visita de selección en caso de pacientes que participaron en ensayos con un fármaco del estudio cuya intención era modificar la progresión de la EA, a menos que esté disponible documentación de la recepción de placebo. No puede incluirse al paciente en el estudio si el fármaco experimental era un fármaco inmunoterapéutico, incluyendo IVIG o una vacuna contra la enfermedad de Alzheimer, a menos que esté disponible documentación de la recepción de placebo.
23. Antecedentes conocidos de alcoholismo o drogadicción.
24. Contraindicaciones absolutas (tener un marcapasos o desfibrilador implantable) o relativas (endoprótesis metálica convencional o endoprótesis implantada en los últimos seis meses) a la exploración con RM. Sensación de claustrofobia que no permite realizar la exploración mediante RM o PET.
25. Pacientes que sea poco probable que cumplan con el protocolo (p. ej., que no pueden acudir a visitas de seguimiento).
26. Mujeres en edad fértil, embarazadas o en periodo de lactancia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint for safety is the incidence of AEs (overall or grouped as neurological, psychiatric or cardiovascular).
The hypothesis for the primary endpoint for safety is that ABvac40 will be safe for human administration, according to the observed pattern of AEs. The trial will be considered satisfactory if the pattern of AEs (overall or grouped as neurological, psychiatric or cardiovascular) is consistent with a good safety and tolerability profile of ABvac40 for human administration at the final visit.
The primary efficacy endpoint is the average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA).
The hypothesis for the primary efficacy endpoint for is that ABvac40 will elicit immune responses to Aβ40 (statistical superiority compared to placebo). The trial will be considered successfully confirmatory regarding efficacy (immunogenicity) of ABvac40 if the average maximal increment (MΔ) of anti-Aβ40 antibody signal (OD in ELISA) in the verum group is ≥ 1.778 OD than the average MΔ in the placebo group (the difference reached between both groups in the phase I clinical trial of ABvac40) at the final of the study. |
Variable principal de seguridad:
Tasa (%) de acontecimientos adversos (AA)
Variable principal de eficacia:
Nivel plasmático de anticuerpos anti-aβ40 (expresado como señal de densidad óptica (DO) en titulación ELISA y/o títulos de anticuerpos). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint for safety: 24 months
The primary efficacy endpoint: Day 0, week 50 and 104 |
Variable principal de seguridad: 24 meses
Variable principal de eficacia: día 0, semana 50 y semana 104 |
|
| E.5.2 | Secondary end point(s) |
Secondary safety endpoints:
- number of withdrawn patients due to adverse events (AEs)
- number of withdrawn patients due to other causes
- number of serious adverse events (SAEs)
- number of clinically significant changes in physical and neurological examination
- number of clinically significant changes in vital signs (blood pressure, heart rate, respiratory rate, body temperature), body mass (weight, height).
- number of clinically significant changes in brain MRI
- number of clinically significant changes in electrocardiogram (EKG)
- number of clinically significant changes in analytical haematology, biochemistry, coagulation, serology and urinalysis
Secondary efficacy endpoints:
- Characterization of the immune response:
· Levels of Aβ peptides in plasma.
· Level of anti-Aβ40 antibodies in CSF
· Levels of cytokines in plasma including IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, TNF-α and IFN-γ.
· Relative number of peripheral blood mononuclear cells (cluster of differentiations; CD) including CD3, CD4, CD8, CD19, CD25, CD27 and CD69.
· Levels of antibody secreting cells and cytokine-secreting cells (including IFN-γ, TNF-α and IL-13)
- Assessment of disease biomarkers:
· Levels of Aβ peptides in plasma
· Cortical fibrillary amyloid deposition assessed by PET scans.
· Levels of CSF biomarkers (Aβ42, Tau, P-tau and neurogranin) and other Aβ peptide species
· Brain volumetric and atrophy of the hippocampus using magnetic resonance imaging
- Assessment of cognition and quality of life:
· Mini Mental State Examination (MMSE)
· Clinical Dementia Rating scale (CDR)
· Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
· Alzheimer’s Disease Cooperative Study – Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI)
· COLUMBIA Suicide Severity Rating Scale (C-SSRS)
· Trail Making Test (TMT)
· Euroqol 5 Dimensions (EQ-5D) |
Variables secundarias de seguridad:
Se evaluarán otros criterios de valoración secundarios de la seguridad, incluidos:
- Criterios de retirada (decisión sobre la continuación)
- Número de pacientes retirados debido a acontecimientos adversos (AA); causa de su retirada
- Acontecimientos adversos graves (AAG)
- Exploración física y neurológica
- Medicación concomitante
- Constantes vitales (presión arterial, frecuencia cardiaca, frecuencia respiratoria y temperatura corporal), masa corporal (peso, estatura).
- RM cerebral
- Electrocardiograma
- Hematología analítica, toxicología (proteína c-reactiva), bioquímica, coagulación, serología y análisis de orina
Variables secundarias de eficacia:
- Caracterización de la respuesta inmune :
o Niveles de péptidos aβ en plasma.
o Nivel de anticuerpos anti-aβ40 en el LCR.
o Niveles de citocinas en plasma incluidas IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, IL-15, TNF-α e IFN-γ.
o Número relativo de células mononucleares en sangre periférica (grupos de diferenciación; CD), incluidas CD3, CD4, CD8, CD19, CD25, CD27 y CD69.
o Niveles de células secretoras de anticuerpos y células secretoras de citocinas (incluidas IFN-γ, TNF-α e IL-13)
- Evaluación de biomarcadores de la enfermedad:
o Niveles de péptidos aβ en plasma
o Depósito de amiloide en fibras corticales evaluado mediante PET.
o Niveles de biomarcadores en el LCR (aβ42, Tau, P-tau y neurogranina) y otros péptidos de tipo aβ.
o Volumetría cerebral y atrofia del hipocampo, mediante resonancia magnética
- Evaluación de la cognición y la calidad de vida:
o Mini Examen del Estado Mental (MMSE)
o Escala de valoración de la demencia clínica (CDR)
o Batería repetible para la evaluación del estado neuropsicológico (RBANS)
o Alzheimer’s Disease Cooperative Study – Activities of Daily Living, Mild Cognitive Impairment (ADCS-ADL MCI)
o Escala de severidad suicida COLUMBIA (C-SSRS)
o Test del trazo (TMT)
o Euroqol 5 dimensiones (EQ-5D-5L) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary safety endpoints: throughout the study
Secondary efficacy endpoints:
Levels of Aβ peptides, cytokines, antibody secreting cells and cytokine-secreting cells in plasma; relative number of peripheral blood mononuclear cells: -1 month, Day 0, week 2, 6, 10, 14, 18, 24, 40, 44, 50, 77 and 104
Levels of anti-Aβ40 antibodies, CSF biomarkers and other Aβ peptide species in CSF: day 0, week 50 and 104
Cortical fibrillary amyloid deposition (PET): – 1 month, week 50 and 104
Brain volumetric and atrophy of the hippocampus (MRI): – 1 month, week 10, 24, 40, 50 and 104
Assessment of cognition and quality of life: throughout the study |
Variables secundarias de seguridad: durante el estudio.
Variables secundarias de eficacia: -1 mes, día 0, semana 2, 6, 10, 14, 18, 24, 40, 44, 50, 77 y 104. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 21 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
| LVLS |
| La última visita del último paciente |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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