| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Patients with Alzheimer disease living at home or community dwelling expected to attend all study visits with a study partner able to visit him/her approximately 5 times per week |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10012271 |
| E.1.2 | Term | Dementia Alzheimer's type |
| E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
| 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 multiple doses of ACC 001 in subjects with mild to moderate AD. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the immunogenicity of each dose level of ACC 001 with or without QS-21 in subjects with mild to moderate AD.
Exploratory objectives: To evaluate the efficacy of ACC 001 in subjects with mild to moderate AD. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent in accordance with local regulations. The subject’s caregiver must also consent to participate in the study.
2. Diagnosis of probable Alzheimer’s disease (AD) according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s disease and Related Disorders (NINCDS-ADRDA) criteria.
3. Age 50 to 85 years at enrollment.
4. Mini-Mental Status Examination (MMSE) score of 21-26 in Germany only.
5. Rosen Modified Hachinski Ischemic score <=4
6. Lives at home with an appropriate caregiver capable of accompanying the subject on all clinic visits, or community dwelling with caregiver capable of accompanying the subject on all clinic visits and visiting with the subject approximately 5 times per week for the duration of the study.
7. Screening visit brain MRI scan is consistent with the diagnosis of AD.
8. Fluency in native language and evidence of adequate premorbid intellectual functioning. Subject must have adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
9. Receiving stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to baseline. Concurrent treatment with acetylcholinesterase inhibitors and/or memantine is allowed if the following conditions are met: (a) subject is maintained on a stable dose regimen for at least 120 days prior to baseline; (b) subject is free of any clinically significant side effects attributable to the drug; and (c) subject and caregiver agree that, barring unforeseen circumstances, they will continue the same regimen for the duration of the trial.
10. Likely to be able to participate in all scheduled evaluations and complete all required tests.
11. In the opinion of the investigator, the subject and caregiver will be compliant and have a high probability of completing the study. |
|
| E.4 | Principal exclusion criteria |
1. Significant neurological disease, other than AD, that may affect cognition.
2. Screening visit brain MRI scan indicative of any other significant abnormality including but not limited to multiple microhemorrhages (2 or more) or evidence of a single prior hemorrhage > 1 cm3, multiple lacunar infarcts (2 or more) or evidence of a single prior infarct > 1 cm3, evidence of a cerebral contusion, encephalomalacia, aneurysms, vascular malformations, subdural hematoma, or space-occupying lesions (eg, arachnoid cysts or brain tumors, such as meningioma).
3. Current presence of a clinically significant major psychiatric disorder (e.g., Major Depressive Disorder) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR), or symptom (e.g., hallucinations), that could affect the subject’s ability to complete the study.
4. Current clinically significant systemic illness that is likely to result in deterioration of the subject’s condition or affect the subject’s safety during the study.
5. History of encephalitis.
6. History of clinically evident stroke or history of clinically significant carotid or vertebrobasilar stenosis or plaque.
7. History of seizures, excluding febrile seizures in childhood.
8. History or evidence of any clinically significant autoimmune disease or disorder of the immune system.
9. History or evidence of clinically significant renal disorder.
10. Clinically significant infection within the last 30 days (e.g., chronic persistent or acute infection eg. bronchitis).
11. Treatment with immunosuppressive medications (e.g., systemic corticosteroids) within the last 90 days (topical and nasal corticosteroids and inhaled corticosteroids for asthma are permitted) or chemotherapeutic agents for malignancy within the last 3 years.
12. Myocardial infarction within the last 2 years.
13. History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma and squamous cell carcinoma of the skin.
14. Evidence of clinically significant uncontrolled hypertension.
15. Other clinically significant abnormality on physical, neurological, laboratory, or ECG examination (e.g., atrial fibrillation) that could compromise the study or be detrimental to the subject.
16. Hemoglobin less than 11g/dL.
17. Excessive smoking defined as > 20 cigarettes a day.
18. Multiple drug allergies.
19. History of alcohol or drug dependence or abuse within the last 2 years.
20. Hamilton Psychiatric Rating Scale for Depression (HAM-D17) (17 item) score >12.
21. Current use of anticonvulsants for seizure, anti-Parkinson’s, anticoagulant (except the use of aspirin 325 mg/day or less), clopidogrel [Plavix], CNS stimulants (e.g., methylphenidate [Ritalin]), or narcotic medications.
22. Current use of prescription or nonprescription (eg, Gnikgo Bioloba, huperzine) medication for cognitive enhancement other than cholinesterase inhibitors and memantine as previously described.
23. Subjects who have discontinued cholinesterase inhibitors, memantine, cognitive enhancing agents, or drugs that potentially affect cognition in the 60 days prior to baseline.
24. Unless maintained on a stable dose regimen for at least 30 days prior to baseline, any other medications with the potential to affect cognition other than cholinesterase inhibitors or memantine (including, but not limited to, anxiolytics, sedatives, hypnotics, antipsychotics, herbal, antidepressants, over-the-counter (OTC) sleeping aids, sedating anti-allergy medications, vitamin E, thyroid supplements, and vitamin B12 supplements by injection).
25. Use of experimental medications for AD or any other investigational medications or devices for treatment of indications other than AD within 30 days prior to baseline or within 5 half-lives of use of such a medication prior to baseline, whichever is longer.
26. Any prior experimental treatment with AN1792, AAB-001, or other experimental immunotherapeutic or vaccine for AD.
27. Any prior treatment with a biological product other than for the treatment of AD within the last 3 years with the exception of non-experimental or non-therapeutic vaccinations (eg, yearly flu vaccination). Allowable vaccinations must not be given within two weeks of test article administration.
28. Women of childbearing potential (a woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives).
29. Subjects who have donated blood (routine blood donation) in the 90 days prior to baseline.
30. Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, Cerebral Spinal Fluid (CSF) shunts, metal fragments or foreign objects in the eyes, skin or body that would contraindicate a brain MRI scan. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The incidence and severity of treatment-emergent adverse events (TEAEs); Clinically important changes in safety assessment results (including AEs , vital signs, weight, clinical laboratory tests, electrocardiograms [ECGs], magnetic resonance imaging [MRI] scans, and physical and neurological exams). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At screening, Day 1 and each study visit thereafter |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
- Change from baseline levels of anti-A-beta IgG total at Weeks 2, 4, 6, 8, 10, 14, 16, 24, 28, 30, 40, 50, 54, 56, 66, 78, 91, and 104;
- Change from baseline levels of anti-A-beta IgM at Weeks 2, 4, 6, 8, 10, 14, 16, 24, 28, 30, 40, 50, 54, 56, 66, 78, 91, and 104;
- If applicable, change from baseline levels of IgG subtypes at visits where an IgGtotal response is measurable. Exploratory End points:
- change from baseline scores for the Neuropsychological Test Battery (NTB), the Alzheimer’s Disease Assessment Scale - Cognitive subscale (ADAS COG), Disability Assessment Scale for Dementia (DAD), Clinical Dementia Rating Sum of Boxes (CDR-SOB), Neuropsychiatric Inventory (NPI), and Mini-Mental State Exam (MMSE) at months 3, 6, 12, 18, and 24;
- Change from baseline volumes for whole brain volume, brain boundary shift integral (BBSI), ventricular volume, hippocampal boundary shift integral (HBSI) and ventricular boundary shift integral (VBSI), at month 18 (Week 78).
- To evaluate the change from baseline in cerebrospinal fluid (CSF) of A beta, anti-A-beta, tau and p-tau at week 50 and 78 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At screening, and at Weeks 2, 4, 6, 8, 10, 14, 16, 24, 28, 30, 40, 50, 54, 56, 66, 78, 91, 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 | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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