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 | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
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 |
To assess the safety and tolerability of the ACI-24 formulations in patients with mild Alzheimer’s disease. To assess the effects of ACI-24 formulations on induction of anti-Aβ antibody responses in serum. To assess the effects of ACI-24 formulations on brain amyloid load in patients with mild Alzheimer’s disease, assessed by florbetaben-PET imaging at 52 weeks (12 months) and 76 weeks (18months).
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E.2.2 | Secondary objectives of the trial |
To explore the effects of ACI-24 formulations on putative biomarkers of the progression of Alzheimer’s disease including concentrations of total tau and phosphorylated tau protein (phosphotau) and Aβ (Aβ1-42 and Aβ1-40) in blood and/or CSF. To explore the effects of ACI-24 formulations on T cell activation in blood. To explore the effects of ACI-24 formulations on whole brain and hippocampal volume by volumetric MRI. To explore the effects of ACI-24 formulations on clinical and cognitive endpoints in patients with mild Alzheimer’s disease. To explore the influence of ACI-24 formulations on blood inflammatory cytokines. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Probable AD dementia according to NIA-AA core clinical criteria 2. Florbetaben-PET scan at screening consistent with the presence of amyloid pathology 3. Mini-Mental Status Examination (MMSE) 20-28 points 4. Age greater than or equal to 50 and less than or equal to 85 years 5. Patients receiving acetylcholinesterase inhibitor at a stable dose for at least 3 months prior to screening or patients not receiving acetylcholinesterase inhibitor treatment for at least 3 months prior to screening 6. Patients cared for by a reliable spouse or caregiver to assure compliance, assist with clinical assessments and report safety issues, and spouse or caregiver consents to serve in this role. 7. Women must be post-menopausal for at least one year, surgically sterilized or using reliable contraceptive measures. Male patients with partners of child bearing potential must be willing to use appropriate contraceptive measures (i.e. condoms) during the study 8. Patients who in the opinion of the investigator are able to understand and provide written informed consent 9. Patients and caregivers must be fluent in the official language(s) of the country they are living in and able to comply with all study procedures 10. Patients are lucid, clear and oriented x4(awareness of person, knowledge of place, time/date and event)
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E.4 | Principal exclusion criteria |
1. Patients whose MRI scan (1.5 or 3T) at screening shows alternative pathology including severe vascular encephalopathy and/or more than 5 micro-hemorrhages. 2. Patients who meet NINDS/AIREN criteria for vascular dementia 3. Patients with other medical conditions which may influence cognitive performance e.g. Parkinson’s disease 4. Patients with any unstable medical condition (e.g. uncontrolled epilepsy, uncontrolled hypertension) and/or history of chronic or recurrent infectious or inflammatory conditions which could hamper interpretation of safety 5. Patients receiving memantine within 3 months prior to screening 6. Patients with a history of hemorrhagic stroke 7. Patients with a history of non-hemorrhagic stroke or myocardial infarction within the last year 8. Patients with a history of major psychiatric disorder within the past 2 years including abuse of drug or alcohol 9. Significant risk of suicide defined, using the Columbia-Suicide Severity Rating Scale, as the subject answering: “yes” to suicidal ideation questions 4 or 5 or answering: “yes” to suicidal behavior within the past 12 months 10. Patients with a history of inflammatory neurological disorders including meningoencephalitis 11. Patients with deviations from normal values for hematologic parameters, liver function tests, and other biochemical measures, that are judged to be clinically significant by the site investigator 12. Patients with a history of autoimmune disease 13. Patients with a history of cancer within the past 5 years other than treated squamous cell carcinoma, basal cell carcinoma and melanoma in situ, or in-situ prostate cancer or in-situ breast cancer which have been fully removed and are considered cured 14. Patients who have received any vaccine within the past 2 weeks before screening 15. Patients who have previously received AD immune therapeutic agents, except passive immunotherapy with the last dose received at least 6 months before screening or five half-lives whichever is longer 16. Patients unable to undergo MRI and/or PET-scan examination for any reason, including metal implants contraindicated for MRI studies and claustrophobia; patients having contra-indication for CSF sampling 17. Patients with a positive HIV and/or Hepatitis B or C test at screening 18. Patients with positive syphilis serology 19. Women who are pregnant or planning to become pregnant, or who are lactating 20. Patients receiving any anticoagulant drug or anti-platelet therapy, except aspirin at doses of 100 mg daily or lower 21. Patients with a history of sustained significant behavioral disturbances secondary to Alzheimer’s disease such as hallucinations, delusions, or agitation
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety and tolerability: Adverse events; global assessment of tolerability; physical and neurological examination results; vital signs; suicidal ideation/behavior; MRI results; electrocardiogram; routine hematology and biochemistry evaluation in blood and urine; inflammatory markers in blood and CSF Biological Effect: Immune response titer (serum anti-Aβ antibody response) Target Engagement: Change from baseline of brain Aβ load as assessed with PET amyloid imaging
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Adverse events: all visits through 104 weeks of study duration Safety: selected visits through 104 weeks Tolerability: selected visits during 76 weeks of treatment period Biological Effect: all site visits through 104 weeks of study duration Efficacy/Target Engagement: at baseline, 52 and 76 weeks |
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E.5.2 | Secondary end point(s) |
Biological Effects: Whole brain and hippocampal volume assessed by volumetric MRI, T-cell activation assessed by ELISPOT analysis, Inflammatory cytokines titer in blood, biomarkers in blood and/or CSF (e.g. total tau and phosphotau and Aβ levels), immune response in blood/CSF (e.g. anti- Aβ IgM titer in blood and anti-Aβ IgG titer in blood and optionally in CSF) Clinical Efficacy: Change from baseline of cognitive tests (COWAT, Trail Making Test parts A and B, Category Fluency Test, ADAS-cog 13 and MMSE), Global function [change from baseline in CDR-SB (Clinical Dementia Rating Scale-Sum of Boxes)], Activities of Daily Living (ADL) [change from baseline in (ADCS-ADL-MCI)]; behavior (change from baseline in NPI) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Biological Effects: selected visits during 104 weeks of study duration Clinical Efficacy: selected visits during 104 weeks of study duration
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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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 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 | 2 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |