| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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 |
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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 |
Primary efficacy objective:
To investigate efficacy of multiple doses of intravenously (IV) administered bapineuzumab compared with placebo in subjects with mild to moderate AD as measured by change in scores from baseline to week 78 in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) and the Disability Assessment for Dementia (DAD) (co-primary measures).
Safety objective:
To assess the safety of intravenously (IV) administered bapineuzumab compared with placebo in subjects with mild to moderate AD. The safety objective includes the incidence and severity of treatment-emergent adverse events (TEAEs) and the clinically important changes in safety assessments results.
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| E.2.2 | Secondary objectives of the trial |
To investigate the efficacy of multiple doses of intravenously (IV) administered bapineuzumab compared with placebo in subjects with mild to moderate AD as measured by change in scores from baseline to week 78 in the Neuropsychological Test Battery (NTB) and the Clinical Dementia Rating Sum of Boxes (CDRSOB) (key secondary measures).
Biomarker objectives: please refer to section E.2.3 / E.2.3.1.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudies are incorporated into the main protocol, and so do not have a separate title/date/version. Four substudies are included: a cerebrospinal fluid (CSF) substudy, a volumetric MRI substudy, an amyloid PET substudy, and an FDG-PET substudy.
Objectives:
To evaluate the effect of multiple doses of IV administered bapineuzumab compared with placebo on biomarkers that may be indicative of disease modification in subsets of subjects with mild to moderate AD.
• The change from baseline total tau or phospho-tau levels in the CSF to week 71 in a subset of subjects.
• The change from baseline brain boundary shift integral (BBSI) assessed by MRI to week 71 in a subset of subjects.
the change from screening WBV, VV and VBSI to week 71 as assessed by MRI
• The change from baseline brain amyloid burden to week 71 assessed by amyloid PET imaging in a subset of subjects.
• The change from baseline brain glucose metabolism to week 71 assessed by FDG PET imaging in a subset of subjects. |
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| E.3 | Principal inclusion criteria |
1) Signed and dated written informed consent obtained from the subject or the subject’s legally acceptable representative (if applicable) in accordance with the local regulations. The subject’s caregiver must also consent to participate in the study.
2) Man or surgically sterile or postmenopausal woman, aged ≥50 to <89 years.
3) Diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria.
4) MMSE score of 16 to 26, inclusive.
5) Rosen Modified Hachinski Ischemic Score ≤4.
6) Lives at home with 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 consistent with the diagnosis of AD.
8) Fluency in local language and evidence of adequate premorbid intellectual functioning.
9) Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
10) Receiving stable doses of medication(s) for the treatment of nonexcluded medical condition(s) for at least 30 days prior to screening, and, if treated with cholinesterase inhibitors and/or memantine, all of the following conditions are also met: (a) The subject is maintained on a stable dose regimen for at least 120 days prior to screening. (b) The subject is free of any clinically important side effects attributable to the drug. (c) The subject and caregiver agree that, barring unforeseen circumstances, they will continue the same regimen for the duration of the trial.
11) The subject and caregiver are likely to be able to participate in all scheduled evaluations and complete all required tests.
12) Willing to undergo apolipoprotein E (ApoE) testing and agree to disclosure of ApoE4 status.
13) Noncarrier of ApoE4 according to genotyping at screening (ie, has zero copies of ApoE4).
14) In the opinion of the investigator, the subject and caregiver will be compliant and have a high probability of completing the study. |
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| E.4 | Principal exclusion criteria |
1) Significant neurologic disease, other than AD, that may affect cognition.
2) History of or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to multiple microhemorrhages (two or more), history 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).
NOTE: the screening MRI scan shall be interpreted by the local and central radiologists prior to enrolling the subject. Both local and central interpretations shall be reviewed by the investigator for determination of subject eligibility relative to Inclusion Criteria #7 and Exclusion Criteria #2.
3) Current presence of a clinically important major psychiatric disorder (eg, major depressive disorder) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) or symptom (eg, hallucinations) that could affect the subject’s ability to complete the study.
4) Current clinically important 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 clinically evident stroke or history of clinically important carotid or vertebrobasilar stenosis or plaque.
6) History of seizures, excluding febrile seizures in childhood.
7) Weight greater than 120 kg (264 lb).
8) History or evidence of any clinically important autoimmune disease or disorder of the immune system (eg, Crohn disease, rheumatoid arthritis).
9) Clinically important infection within the last 30 days (eg, chronic persistent or acute infection, such as bronchitis or urinary tract infection [UTI]).
10) Treatment with immunosuppressive medications (eg, 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.
11) Myocardial infarction within the last 2 years.
12) History of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma, and squamous cell carcinoma of the skin.
13) Uncontrolled hypertension within 6 months prior to screening.
14) Other clinically important abnormality on vital signs, physical examination, neurologic examination, laboratory results, or electrocardiogram (ECG) examination (eg, atrial fibrillation) that could compromise the study or be detrimental to the subject.
15) Hemoglobin level less than 11 g/dL.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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) | No |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
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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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| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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