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Abstract
Background: Bapineuzumab, a humanized anti-amyloid-beta (Aβ) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD.
Methods: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer's Disease Assessment Scale–Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline.
Results: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences (p < 0.05, unadjusted for multiple comparisons) on cognitive and functional endpoints in study “completers” and APOE ε4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE ε4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms.
Conclusions: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE ε4 carrier status.
Classification of evidence: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.
Glossary
- AD=
- Alzheimer disease;
- ADAS-Cog=
- Alzheimer's Disease Assessment Scale–Cognitive subscale;
- AE=
- adverse event;
- APP=
- amyloid precursor protein;
- CDR-SB=
- Clinical Dementia Rating–Sum of Boxes;
- CI=
- confidence interval;
- DAD=
- Disability Assessment for Dementia;
- mITT=
- modified intent-to-treat;
- MMSE=
- Mini-Mental State Examination;
- NTB=
- Neuropsychological Test Battery;
- RM=
- repeated measures;
- SMC=
- Safety Monitoring Committee;
- VE=
- vasogenic edema.
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