Primary objectives: To evaluate the long-term safety and tolerability of IV administered bapineuzumab in subjects with AD.Secundary objectives:To explore the long-term efficacy of IV administered bapineuzumab in subjects with AD, using the following…
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.
Pharmacokinetics: To determine clearance characteristics of bapineuzumab
product isoforms bapineuzumab in sera of a subset of subjects with AD, using
biochemical characterization with 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 3133K1-3003-WW and the extension protocol
3133K1-3003-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 3001 WW protocol and in the 3133K1-3001-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 suggests that 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.
Current data suggest that a dose of 0.5 mg/kg for carriers may be safely
administered without excessive risk of vasogenic edema.
Study objective
Primary objectives:
To evaluate the long-term safety and tolerability of IV administered
bapineuzumab in subjects with AD.
Secundary objectives:
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
This is a multicenter, long-term extension to protocol 3133K1-3001-WW. The
subjects will all receive
0.5 mg/kg bapineuzumab via IV infusion once every 13 weeks, whether they had
been randomized to receive bapineuzumab or placebo in protocol 3133K1-3001-WW.
Intervention
Bapineuzumab 0.5 mg/kg will be administered by IV infusion approximately every
13 weeks. Investigational product will be supplied in sterile vials to be made
up in 100 mL bags of 0.9% saline (site supplied) by a drug dispenser/pharmacist
at the study site. The admixture shall be administered to the subjects by
qualified study staff.
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
1. Subject has completed all 6 infusions planned in protocol 3133K1-3001; or, if the subject
was required 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 3133K1-3001 may be considered for
study 3133K1-3003 participation if the abnormality is resolved and the subject met
criteria to resume investigational product. Medical monitor approval is required prior to enrrollment.
2. Brain MRI scan from Week 71 of study 3133K1-3001 is available for local radiology and
central radiology evaluation and remains consistent with the diagnosis of AD.
3. MMSE score *10 at screening (Week 78 of 3133K1-3001).
4. 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.
5. 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
1. Any medical or psychiatric contraindication or clinically significant abnormality on
physical, neurological, laboratory, vital signs, or electrocardiogram (ECG) examination
(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.
2. Brain MRI scan from study 3133K1-3001 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, multiple 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).
3. Use of any investigational drugs or devices, other than bapineuzumab, within the last
60 days prior to screening.
4. 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, or
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 | EUCTR2009-015080-13-NL |
| ClinicalTrials.gov | NCT00998764 |
| CCMO | NL33927.029.10 |