E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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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 | 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 Objective and Endpoints
To demonstrate the efficacy of multiple doses of IV-administered bapineuzumab
(bapineuzumab IV; 0.5- and 1.0-mg/kg) compared to placebo in subjects with
mild to moderate AD.
Co-Primary Endpoints:
The change from baseline to Week 78 in the Alzheimer’s Disease Assessment
Scale – Cognitive subscale (ADAS-Cog/11) total score
The change from baseline to Week 78 in the Disability Assessment Scale for
Dementia (DAD) total score
Safety Objective and Endpoints
To assess the safety of multiple doses of bapineuzumab IV compared to placebo
in subjects with mild to moderate AD.
The incidence and severity of treatment-emergent adverse events (TEAEs)
Clinically important changes in safety assessment results (including, as
appropriate, brain magnetic resonance imaging [MRIs], vital signs, weight,
clinical laboratory tests, electrocardiograms [ECGs], and physical and
neurological examinations). |
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E.2.2 | Secondary objectives of the trial |
To demonstrate the effect of multiple doses of bapineuzumab IV compared to placebo on time to first clinically meaningful deterioration in subjects with mild to moderate AD.
To demonstrate the effect of multiple doses of bapineuzumab IV compared to placebo on subject dependence (amount of assistance needed) in subjects with mild to moderate AD.
To demonstrate the effect of multiple doses of bapineuzumab IV compared to placebo on biomarkers that are indicative of disease pathophysiology in substudies of subjects with mild to moderate AD.
To demonstrate divergence of effect (increasing separation with time compared
with placebo) observed with multiple doses of bapineuzumab IV, in subjects with mild to moderate AD.
To demonstrate the effect of multiple doses of bapineuzumab IV compared to placebo on a global clinical assessment (Clinical Dementia Rating Sum of Boxes [CDR-SB]) in subjects with mild to moderate
AD. |
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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 |
Amend 5. Cerebrospinal fluid substudy:
CSF will be collected from subjects who consent to this optional component of the study to assess levels of bapineuzumab, anti-bapineuzumab antibodies, pharmacodynamic endpoints, Aβ and tau; and, for safety information glucose, protein levels, and cell counts during screening and at the Week 71 (or ET).
Amend 6. Pharmacogenomic substudy:
To obtain data for potential interpretation of pharmacodynamic efficacy, safety and tolerability measurements, as necessary, and to allow for the characterisation of genetic factors associated with AD. |
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E.3 | Principal inclusion criteria |
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.
AGE from 50 to < 89 years.
DIAGNOSIS of probable Alzheimer’s Disease according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association (NINCDS/ADRDA) criteria.
MINI-Mental State Examination (MMSE) score of 16-26, inclusive.
ROSEN Modified Hachinski Ischemic score ≤4.
LIVES at home with appropriate caregiver capable of accompanying the subject on all clinic visits or; lives independently in community dwelling and has 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.
SCREENING visit brain MRI scan consistent with the diagnosis of AD.
FLUENCY in local 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.
RECEIVING stable doses of medication(s) for the treatment of non-excluded medical condition(s) for at least 30 days prior to screening. Concurrent treatment with cholinesterase 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 screening; (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.
WILLING to undergo ApoE testing and agree to disclosure of ApoE4 status.
NON-carrier of ApoE4 allele according to genotyping at screening.
IN the opinion of the investigator, the subject and caregiver will be compliant and have a high probability of completing the study, including all scheduled evaluations and required tests.
THE caregiver must be a reliable informant in the opinion of the investigator |
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E.4 | Principal exclusion criteria |
HAS significant neurological disease, other than AD, that may affect cognition.
HISTORY of or screening visit brain MRI scan indicative of any other significant abnormality, including but not limited to multiple microhemorrhages (2 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 MRI scan shall be interpreted by a local radiologist and a central radiologist prior to enrolling the subject. Both local and central interpretations shall be reviewed by the investigator for determination of subject eligibility.
CURRENT presence of a clinically significant major psychiatric disorder (eg, Major Depressive Disorder) according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) or symptom (eg, hallucinations) that could affect the subject’s ability to complete the study.
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.
HISTORY of clinically evident stroke or history of clinically significant carotid or vertebrobasilar stenosis or plaque.
HISTORY of seizures, excluding febrile seizures in childhood.
WEIGHT greater than 120kg (264lbs).
HISTORY or evidence of any clinically significant autoimmune disease or disorder of the immune system (eg, Crohn’s Disease, Rheumatoid Arthritis).
CLINICALLY significant infection within the last 30 days eg, chronic persistent or acute infection (eg, upper respiratory infection, urinary tract infection).
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.
MYOCARDIAL infarction within the last 2 years.
HISTORY of cancer within the last 5 years, with the exception of nonmetastatic basal cell carcinoma, and squamous cell carcinoma of the skin.
UNCONTROLLED hypertension within the last 6 months.
OTHER clinically significant abnormality on physical, neurological, laboratory, vital signs or ECG examination that could compromise the study or be detrimental to the subject.
HEMOGLOBIN less than 11g/dL.
SUBJECTS who have donated blood (routine blood donation) in the 30 days prior to screening.
EXCESSIVE smoking defined as >20 cigarettes per day.
HISTORY of alcohol or drug dependence or abuse as defined by DSM-IV criteria within the last 2 years.
CURRENT use of anticonvulsant drugs for seizures, antiparkinson drugs, anticoagulant medications (except the use of aspirin 325 mg/day or less, plavix, and persantine but not for stroke), or opioid pain relievers and related synthetic derivatives.
CURRENT use of prescription or nonprescription medication for cognitive enhancement, other than cholinesterase inhibitors and memantine as previously described.
HAS discontinued cholinesterase inhibitors, memantine, or cognitive enhancing agents within 60 days prior to screening, or drugs that potentially affect cognition in the 30 days prior to screening (including but not limited to anxiolytics, sedatives, hypnotics, antipsychotics, herbal preparations, antidepressants, over-the-counter sleeping aids, sedating anti-allergy medications, vitamin E, thyroid supplements, vitamin B12 supplements by injection).
UNLESS maintained on a stable dose regimen for at least 30 days prior to screening, any other medications with the potential to affect cognition other than cholinesterase inhibitors or memantine.
USE of experimental medications for AD or any other investigational medications or devices for treatment of indications other than AD within 60 days prior to screening or within 5 half-lives of use of such a medication prior to screening, whichever is longer.
ANY prior experimental treatment with AN1792, bapineuzumab, ACC 001 or other experimental immunotherapeutic or vaccine for AD.
ANY prior treatment with a biological product other than for the treatment of AD within the last 3 years with the exception of yearly routine vaccine(s) that is (are) commercially available.
ANY known hypersensitivity to any of the excipients contained in the study drug formulation.
WOMEN of childbearing potential.
PRESENCE of pacemakers, aneurysm clips, artificial heart valves, ear implants, CSF shunts, claustrophobia, metal fragments or foreign objects in the eyes, skin, or body that would contraindicate a brain MRI scan.
DO not have adequate venous access that would allow intravenous drug delivery or multiple blood draws.
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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 | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 8 |
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 |
Austria |
Canada |
Germany |
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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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |