E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Autosomal Dominant Alzheimer's disease |
Enfermedad de Alzheimer autosomica dominante |
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E.1.1.1 | Medical condition in easily understood language |
Alzheimer's disease |
Enfermedad de Alzheimer |
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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 | 16.1 |
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 |
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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 |
E1. Assess safety and tolerability of gantenerumab and solanezumab in individuals who have mutations causing dominantly inherited Alzheimer?s disease.
2. Assess biological efficacy/target engagement of gantenerumab and solanezumab in individuals who have mutations causing dominantly inherited Alzheimer?s disease as measured by the primary biomarker measure for each drug. Primary endpoints are specified for each drug based on mechanism of action. Depending on proposed mechanism of action, the primary biomarker endpoint will be either 1) change in amyloid deposition as measured by [11C]PiB-PET composite standardized uptake value ratio (C-SUVR, average of precuneus, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) or, 2) changes in free and total amyloid beta (A?) isoforms in CSF. |
1. Evaluar la seguridad y toleravilidad de gantenerumab and solanezumab en indiciduos que contienen las mutaciones que causan la enfermedad de Alzheimer autosomica dominante.
2. Evaluar la eficacia biologica de gantenerumab y solanezumab en individuos que tienen la muatcion que causa la enfermedad de Alzheimer dominante hereditaria |
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E.2.2 | Secondary objectives of the trial |
Secondary study endpoints will include:
1) Change in amyloid deposition as measured by [11C]PiB-PET C-SUVR (used as a secondary outcome measure when not the primary outcome measure).
2) Change in CSF amyloid-beta peptide concentrations (used as a secondary outcome measure when not the primary outcome measure).
3) Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group.
4) Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI).
5) Change in FDG-PET metabolism in specific regions of interest in treated group as compared to pooled placebo group.
6) Exploratory cognitive and behavioral outcome measures
7) Exploratory imaging measures
8) Assess longitudinal change in biomarker and cognitive measures in individuals who do not have mutations causing dominantly inherited Alzheimer?s disease |
Los criterios de valoración secundarios son, entre otros:
1. Cambio en los depósitos de amiloide medidos a través de la media combinada del SUVR en [11C]-PiB-PET
2.Cambio en las concentraciones de péptido amiloide β en el LCR 3.Cambio en los biomarcadores τ y p-τ181 del LCR comparados entre los sujetos tratados con fármaco activo (gantenerumab o solanezumab) y los portadores de mutación en el grupo combinado tratado con placebo.
4.Índice de atrofia cerebral en los grupos con tratamiento activo en comparación con el grupo combinado tratado con placebo medido por el espesor cortical de las regiones de interés,RM volumétrica
5.Cambio en el metabolismo de la FDG-PET en regiones específicas de interés en el grupo de tratamiento activo con respecto al grupo combinado tratado con placebo
6.Criterios de valoración exploratorios cognitivos y conductuales
7.Imágenes exploratorias
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet ALL inclusion criteria:
1.Know they have an AD-causing mutation or be unaware of their genetic status and have a 50% chance of having an AD-causing mutation (e.g. parent or sibling with known AD-causing mutation)
2.Are within -15 to + 10 years of the parental age of symptom onset
3. CDR 0-1 inclusive
4. Are able to undergo MRI, LP, PET, and complete all study related testing and evaluations. |
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E.4 | Principal exclusion criteria |
Subjects will be excluded if they have a major or unstable illness or are unable to complete all study related testing. Exclusions include implanted metal that cannot be removed for MR scanning, required anticoagulation and pregnancy. Baseline MRI scan indicative of any other significant abnormality, including more than 4 definite micro hemorrhages. Clinically relevant abnormalities in chemistry, hematology or coagulation studies. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is specific for each drug based on mechanism of action. Each primary endpoint for study drugs is listed in the drug-specific appendix. Endpoints include:
1) Cerebral amyloid imaging using [11C]PiB-PET. Change in the amount of fibrillar amyloid deposition as measured by [11C]PiB-PET scans is the primary outcome for gantenerumab. Most mutation carriers who are in the range of -15 to + 10 years of dementia onset have increased [11C]PiB-PET signal in some brain regions (see Figure 1 above and Bateman et al., 2012). The composite PiB standardized uptake value ratio (C-SUVR, the composite SUVR of precuneous, caudate, gyrus rectus, occipital cortex, parietal cortex, prefrontal cortex and temporal cortex) is used as the primary outcome.
2) Free and Total Abeta isoforms in CSF. The concentrations of CSF A? species will be the primary outcome for solanezumab, specifically different treatment effects on free (unbound) CSF A?42 (increase or no change) and free CSF A?40 (decrease) with comparable treatment-associated increases in CSF total (bound + unbound) A?42 and total A?40 after 104 weeks. An increase, or ?normalization? of free CSF A?42 levels, is postulated to represent increased egress of A?42 from brain to CSF (Siemers et al., 2010). |
Entre los criterios de valoración se encuentran:
1) Imágenes de amiloide cerebral mediante [11C]PiB-PET. La cantidad de depósito de amiloide fibrilar determinada mediante exploraciones de [11C]PiB-PET constituye el criterio principal de valoración de gantenerumab. La mayoría de los portadores de mutaciones que se encuentran en el intervalo entre -15 y + 10 de inicio de la demencia presentan un aumento de la señal de [11C]PiB-PET en ciertas regiones cerebrales (véanse la figura 1 y Bateman et al., 2012b). Como criterio principal de valoración se utilizará la media del cociente del valor de captación estandarizado en [11C]PiB-PET (AVG-SUVR, SUVR medio de la precuña, el caudado, la circunvolución recta, la corteza occipital, la corteza parietal y la corteza prefrontal).
2) Aβ42 libre en el LCR. Las concentraciones de la especie Aβ en el LCR serán el criterio principal de valoración para solanezumab, y específicamente los distintos efectos del tratamiento sobre el Aβ42 libre (no ligado) en el LCR (incremento o sin variaciones) y el Aβ40 libre en el LCR (disminución) con incrementos similares asociados al tratamiento en el Aβ42 libre total (ligado + no ligado) y en el Aβ40 total en el LCR al cabo de 108 semanas. Se considera que un incremento o “normalización” de las concentraciones de Aβ42 libres en el LCR representa una mayor salida de Aβ42 desde el cerebro hacia el LCR (Siemers et al., 2010).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint of evaluation at week 0, 52 & 104 |
Evaluaciones en las semanas: 0, 52 y 104. |
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E.5.2 | Secondary end point(s) |
Secondary study endpoints will include:
1) Change in amyloid deposition as measured by [11C]PiB-PET C-SUVR (used as a secondary outcome measure when not the primary outcome measure).
2) Change in CSF amyloid-beta peptide concentrations (used as a secondary outcome measure when not the primary outcome measure).
3) Change of CSF biomarkers tau and ptau181 values compared between subjects on active drug (gantenerumab or solanezumab) and mutation carriers in the pooled placebo group.
4) Rate of brain atrophy in treatment groups vs. pooled placebo group as measured by cortical thickness of regions of interest (volumetric MRI).
5) Change in FDG-PET metabolism in specific regions of interest (e.g., precuneus) in treated group as compared to pooled placebo group measured. |
Los criterios secundarios de valoración del estudio son, entre otros, los siguientes:
1) Cambio en los depósitos de amiloide determinados mediante la media combinada del SUVR en [11C]-PiB-PET (utilizado como criterio secundario de valoración cuando no se use como criterio principal de valoración).
2) Cambio en las concentraciones de péptido amiloide β en el LCR (utilizado como criterio secundario de valoración cuando no se use como criterio principal de valoración).
3) Cambio en los biomarcadores τ y p-τ181 del LCR comparados entre los sujetos tratados con fármaco activo (gantenerumab o solanezumab) y los portadores de mutación en el grupo combinado tratado con placebo.
4) Índice de atrofia cerebral en los grupos con tratamiento activo en comparación con el grupo combinado tratado con placebo determinado por el espesor cortical de las regiones de interés (RM volumétrica).
5) Cambio en el metabolismo de la FDG-PET en regiones específicas de interés (p. ej., en la precuña) en el grupo de tratamiento activo con respecto al grupo combinado tratado con placebo.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Same criteria as above for the primary endpoint. |
Mismo criterio que en la variable principal |
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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 | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | 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 | 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 | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Canada |
France |
Italy |
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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The end of the study is week 112 (protocol p76/114); for gantenerumab = week 112 (page 95/114);
ref xxxii: for Solanezumab =week 104 + End of Stufy visit needed if there are safety concerns that require follow-up (= week 112) |
El final del ensayo es en la semana 112(Portocolo: p76/114); para gantenerumab= semana 112 (pagina 95/114); ref xxxii. para solanezumab = semana 104 + visita final del ensayo si hay problemas de seguridad que requieren seguimiento (= semana 112) |
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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 | 2 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |