E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
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 |
To evaluate safety and tolerability of long-term AADvac1 treatment of patients with mild Alzheimer’s disease. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate efficacy of AADvac1 treatment in slowing or cessation of cognitive and functional decline in patients with mild Alzheimer’s disease, as measured by Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). • To evaluate efficacy of AADvac1 treatment in slowing or cessation of cognitive decline in patients with mild Alzheimer’s disease, as measured by a composite score of a battery of cognitive tests assessing multiple domains of cognition. • To evaluate the effect of AADvac1 treatment on patient functioning as measured by the ADCS-MCI-ADL questionnaire • To evaluate immunogenicity of AADvac1 by measuring antibody titres and antibody isotype profiles. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patient has a diagnosis of probable Alzheimer’s disease according to the revised NIA-AA criteria (McKhann 2011). 2. Patient has a MMSE total score ≥ 20 and ≤ 26 at Screening. 3. Patient has a brain MRI finding consistent with the diagnosis of Alzheimer’s disease at Screening. 4. Patient has evidence of the AD pathophysiological process at Screening, defined as one or both of the following: a. medial temporal lobe atrophy as assessed on brain MRI and according to a Scheltens score of ≥ 2 (rated on a scale of 0-4 on the more atrophied side) b. positive AD biomarker signature in the CSF (total tau protein > 400 pg/mL AND pT181 tau protein > 60 pg/mL AND Aβ42 < 600 pg/mL AND Aβ42:Aβ40 ratio < 0,089) 5. Patient had completed 6 years of formal elementary education. 6. Patients aged 50-85 years inclusive at Screening. 7. Patient is fluent in the local language and possesses sufficient auditory and visual capacities to allow neuropsychological testing. 8. Patient is able to read and understand the informed consent. 9. Patient is on a stable therapy with an acetylcholinesterase inhibitor for at least 3 months prior to screening visit. 10. If the patient is on memantine treatment, the dose regimen must be stable for at least 3 months prior to Screening (V01). 11. Patient has a Hachinski Ischemia Scale score ≤ 4 at Screening. 12. Availability of a caregiver who sufficiently knows the patient and will be able to accompany the patient on the study visits and to participate in study assessments of the patient where required. 13. Female patients are only eligible for the study if they are either surgically sterile or at least 2 years postmenopausal. 14. Male patients must either be surgically sterile, or he and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (1 of which must be a barrier method) starting at screening and continuing throughout the study period. 15. Patient provides written informed consent.
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E.4 | Principal exclusion criteria |
1. Female patient who is pregnant or breastfeeding. 2. Patient has been participating in another clinical study within 3 months prior to Screening. 3. Patient is not expected to complete the clinical study. 4. Patient has known allergy to components of the vaccine currently or in the past, if considered relevant by the investigator. 5. Patient has known contraindication for MRI imaging such as MRI-incompatible metallic endoprosthesis or MRI-incompatible stent implantation or other as judged by the Investigator. 6. Any of the following detected by brain MRI: a) Infarction in the territory of large vessels b) More than one lacunar infarct defined as a focal lesion of CSF signal intensity with a diameter of less than 1.5 cm in any dimension. c) Any lacunar infarct in a strategically important location such as the thalamus, hippocampus of either hemisphere, head of the left caudate nucleus. d) Confluent hemispheric deep white matter lesions (Fazekas grade 3). e) Other focal lesions which may be responsible for the cognitive status of the patient such as infectious disease, space-occupying lesions, normal pressure hydrocephalus or any other abnormalities associated with significant central nervous disease other than Alzheimer’s disease. 7. Patient underwent surgery (under general anaesthesia) within 3 months prior to screening and/or has scheduled surgery (under general anaesthesia) during the whole study period. 8. Patient has a history and/or currently suffers from a clinically significant autoimmune disease, or is expected to receive immunosuppressive or immunomodulatory treatment at the present or in the future. 9. Patient has a recent history of cancer (last specific treatment ≤ 5 years prior to Screening) (Exceptions: basal cell carcinoma, intraepithelial cervical neoplasia). 10. Patient had myocardial infarction within the last 2 years prior to Screening. 11. Patient has Hepatitis B, C, HIV or Syphilis confirmed by serology. 12. Patient suffers from an active infectious disease. 13. Presence and/or history of immunodeficiency. 14. Patient currently suffering from a clinically important systemic illness that is likely to result in deterioration of the patient’s condition or affect the patient’s safety during the study: *poorly controlled congestive heart failure (NYHA ≥ 3) *BMI > 40 *poorly controlled diabetes (HbA1c > 7.5%) *severe renal insufficiency (eGFR < 30 mL/min) *chronic liver disease – ALT (alanine aminotransferase) > 66 U/L in females or > 80 U/L in males, AST (aspartate aminotransferase) > 82 U/L *other clinically significant systemic illness, if considered relevant by the investigator 15. Patient suffers from hypothyroidism, defined as TSH (thyroid-stimulating hormone) elevation > 5.0 mIU/mL, and/or FT4 levels < 0.7 ng/dL. Patients with corrected hypothyroidism are eligible for the study provided that treatment has been stable for 3 months before study entry. 16. Patient has valid diagnosis of a significant psychiatric illness such as schizophrenia, any type of psychotic disorder or bipolar affective disorder. 17. Patient has a current depressive episode (Geriatric Depression Scale GDS ≥ 6 at Visit 01) or had a major depressive episode within the last 1 year. 18. Patient has a metabolic or toxic encephalopathy or dementia due to a general medical condition. 19. Patient has a history of alcohol or drug abuse or dependence within the past 2 years. 20. Patient has Wernicke’s encephalopathy. 21. Patient has a history or evidence of any CNS disorder other than AD that could be the cause of dementia (e.g., infectious or inflammatory/demyelinating CNS conditions, Creutzfeldt-Jakob disease, Parkinson’s disease, Huntington’s disease, brain tumour, subdural haematoma) 22. Patient has a history with evidence of cerebrovascular disease (ischemic or haemorrhagic stroke), or diagnosis of possible, probable or definite vascular dementia. 23. Patient has a history or presence of diagnosis of epilepsy. 24. Patient is currently treated and/or was treated with experimental immunotherapeutics including IVIG within 3 months prior to screening. 25. Patient is currently being treated and/or was treated with experimental therapies for AD aiming at disease-modification within 3 months prior to screening. 26. Patient is currently being treated or was treated in the past with any active vaccines for AD. 27. Patient is currently being treated with immunosuppressive drugs. 28. Change in dose of previous and current medications which the patient is taking because of concomitant illnesses according to the medical history within the last 30 days prior to Screening (V01), if considered clinically relevant by the investigator. 29. Patient has vitamin B12 deficiency (serum vitamin B12 < 191 pg/mL). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The safety assessment is based on the number, type and severity of adverse events. - The incidence of adverse events for each group will be summarized by system organ class, severity and duration. - Descriptive statistics for laboratory values, imaging and clinical observations, and their change from baseline will be prepared for each group. - Safety will be statistically analysed. Statistical analysis will only be used to draw attention to areas of concern.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- for active patients at every visit V01-V17 |
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E.5.2 | Secondary end point(s) |
• Mean change in CDR-SB score from Baseline to Visit V16 (week 104) • Mean change in standard (composite z-score) score of Custom Cognitive Battery from Baseline to Visit V16 (week 104). The composite Z score is calculated from the results of the following tests: o Cogstate International Shopping List Task (immediate and delayed recall, recognition): verbal episodic memory o Cogstate One Card Learning and One Card Back tasks: visual episodic memory o Letter Fluency Test & Category Fluency Test: executive function o Digit-Symbol Coding test: processing speed, working memory, executive function • Mean change in ADCS-MCI-ADL score from Baseline to Visit V16 (week 104). • Percentage of AADvac1-treated patients who develop an IgG antibody response against the “Axon peptide 108” component of AADvac1. • Geometric mean titre of AADvac1-induced antibodies (IgM and IgG against Axon peptide 108, anti-KLH)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
* Cognition (CDR-SB, Custom Cognitive Battery, and ADCS-MCI-ADL): V02, V05, V08, V09, V11, V12, V14, V15 and V16 * Percentage of AADvac1-treated patients who develop an IgG antibody response against the “Axon peptide 108” component of AADvac1 (at any point in the study) * Geometric mean titre of AADvac1-induced antibodies (IgM and IgG against Axon peptide 108, anti-KLH): V02-V16
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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 | Yes |
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 | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 44 |
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
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |