Primary objectives: To evaluate the long-term safety and tolerability of IV administered bapineuzumab in subjects with AD.Secundary objectives: Efficacy. To explore the long-term efficacy of IV administered bapineuzumab in subjects with AD, using…
ID
Source
Brief title
Condition
- Dementia and amnestic conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Health Outcomes Endpoints:
To explore effect on health outcomes of long-term treatment of IV administered
bapineuzumab in subjects with AD, using the following scales:
* Dependence Scale (DS)
* Resource Utilization in Dementia, version 2.4 (RUD Lite v2.4)
* Health Utilities Index (HUI)
Immunogenicity:
To explore the effect on immunogenicity of long-term treatment with IV
administered bapineuzumab in subjects with AD, using the following scales:
* Serum anti-bapineuzumab antibody levels.
* In a subset of subjects, CSF anti-bapineuzumab antibody levels.
Biochemical characterization:
To determine clearance characteristics of bapineuzumab product isoforms
bapineuzumab in sera of a subset of subjects with AD, using immunoaffinity
chromatography.
Secondary outcome
* Alzheimer*s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
* Disability Assessment Scale for Dementia (DAD)
* Mini Mental State Examination (MMSE)
* Neuropsychiatric Inventory (NPI )
Background summary
Preclinical experiments in platelet-derived growth factor promoter (PDAPP)
transgenic mice suggest that passive immunization with anti-amyloid-beta
protein (A*) antibodies would be efficacious in reducing or halting the
progression of Alzheimer disease (AD) pathology in humans. Bapineuzumab
(formerly referred to as AAB-001 or ELN115727) is a humanized monoclonal
antibody proposed for the treatment of AD by passive immunization. The
first-in-humans single ascending dose study, 3133K1-100-US, tested 3 doses of
bapineuzumab (0.5, 1.5, and 5.0 mg/kg). While this was a single dose study
designed to assess safety, tolerability, and pharmacokinetics (PK) of
bapineuzumab, there was a trend in the exploratory efficacy measure of
Mini-Mental State Examination (MMSE) scores. Further information on
bapineuzumab from unblinded sponsor review of the interim data from the phase 2
studies, AAB-001-201 and AAB-001-202, was a key factor in the rationale for the
doses selected in the phase 3 program commenced in December 2007 and which is
still ongoing. The phase 3 program includes four studies: 2 studies in ApoE4
noncarriers (Wyeth study 3133K1-3000 and Elan study ELN115727-301); and 2
studies in ApoE4 carriers (Wyeth 3133K1-3001 and Elan ELN115727-302). The
3133K1-3000 noncarrier study is comprised of 2 protocols: 3133K1-3000-US and
3133K1-3000-WW. Similarly, the 3133K1-3001 study is comprised of 2 protocols:
3133K1-3001-US and 3133K1-3001-WW. The present extension protocol
3133K1-3002-WW and the extension protocol 3133K1-3002-US propose to further
investigate the long-term safety and tolerability of intravenous (IV)
administered bapineuzumab in subjects with AD who participated in the
3133K1-3000-WW protocol and the 3133K1-3000-US protocol. The *US and *WW
protocols are separated for administrative reasons and are not intended to be
analyzed as independent studies.
Across completed and ongoing trials to date, over 1500 subjects have been
treated with bapineuzumab. A review of data from ongoing and completed studies
is available in the investigator brochure (IB). While generally well tolerated,
bapineuzumab has been associated with vasogenic edema in the brain in some
subjects. The doses of bapineuzumab in the above phase 3 studies and to be
assessed in this phase 3 extension protocol have been selected based on a
careful analysis of the risk of vasogenic edema in carriers and noncarriers of
the apolipoprotein E *4 allele (ApoE4). Ongoing experience with bapineuzumab
suggests that vasogenic edema is more likely to occur at doses of bapineuzumab
that are greater than 0.5 mg/kg. Further, experience to date suggeststhat
subjects who carry the ApoE4 genotype (subjects with 1 or 2 copies of the ApoE
*4 allele) have a higher risk of vasogenic edema than noncarriers at doses *
1.0 mg/kg.
Study objective
Primary objectives:
To evaluate the long-term safety and tolerability of IV administered
bapineuzumab in subjects with AD.
Secundary objectives:
Efficacy. To explore the long-term efficacy of IV administered bapineuzumab in
subjects with AD, using the following scales:
* Alzheimer*s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog)
* Disability Assessment Scale for Dementia (DAD)
* Mini Mental State Examination (MMSE)
* Neuropsychiatric Inventory (NPI )
Study design
Design:
This is a multicenter, randomized, double-blind, long-term extension study to
protocol 3133K1-3000-WW.
Subjects originally randomized to bapineuzumab in study 3133K1-3000-WW will
continue to receive treatment with
bapineuzumab via IV infusion once every 13 weeks at the dose level assigned in
study 3133K1-3000-WW (i.e.,
subjects assigned to receive bapineuzumab at the 0.5 mg/kg or 1.0 mg/kg dose
levels in study 3133K1-3000-WW
will continue to receive the same dose in study 3133K1-3002-WW).
NOTE: Subjects in study 3133K1-3000-WW who were originally randomized to 2.0
mg/kg were reassigned to the
1.0 mg/kg after discontinuation of 2.0 mg/kg dosage and will continue the 1.0
mg/kg dose in study
3133K1-3002-WW.
Intervention
Admission of investigational product intravenously with an interval of 13
weeks.
Study burden and risks
See protocol flow chart on pages 26 through 29.
Rivium Westlaan 142
Capelle aan de Ijssel 2909 LD
NL
Rivium Westlaan 142
Capelle aan de Ijssel 2909 LD
NL
Listed location countries
Age
Inclusion criteria
- Subject has completed all 6 infusions planned in protocol 3133K1-3000; or, if the subject was requred to temporarily suspend investigational product (e.g. because of VE), he/she continued with required visits, has completed all study visits through the Week 78 visit and his/her current status indicates that he/she resumed or is eligible to resume investigational product. NOTE: Subjects who developed VE during study 3133K1-3000 may be considered for study 3133K1-3002 participation if the abnormality is resolved and the subject met criteria to resume investigational product. Medical monitor is required prior to enrollment.
- Brain MRI scan from Week 71 of study 3133K1-3000 is available for local radiology and central radiology evalutation and remains consistent with the diagnosis of AD.
- MMSE score * 10 at screening (Week 78 of 3133K1-3000).
- Continues to live at home or community dwelling with appropriate caregiver capable of accompanying the subject on all clinic visits and visiting with the subject at least 5 days per week, on average for the duration of the study.
- In the opinion of the principal investigator, the subject and the caregiver will be compliant, and likely to participate in all scheduled evaluations.
Exclusion criteria
- Any medical or psychiatric contraindication or clinically significant abnormality on physical, neurological, laboratory, vital signs, or electrocardiogram (ECG) examiniation (e.g. atrial fibrillation) that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in and completion of the study, or could preclude the evaluation of the subject's response.
- Brain MRI scan from study 3133K1-3000 Week 71 visit indicative of any significant abnormality, including but not limited to multiple microhemorrhages (2 or more), history or evidence of a single prior hemorrhage > 1 cm3, mulitple lacunar infarct (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 (e.g., arachnoid cysts or brain tumors such as meningioma).
- Use of any investiogational drugs or devices, other than bapineuzumab within the last 60 days prior to screening.
- Current use of herbal preparations containing ginkgo biloba or use of anticoagulants. NOTE: Platelet anti-aggregants (e.g. aspirin 325 mg/day or less, clopidogrel bisulfate, dipyridamole for indications other than stroke) are allowed.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2009-015079-29-NL |
| ClinicalTrials.gov | NCT00996918 |
| CCMO | NL33737.029.10 |