Neurology 2003;61:46C54. patients were asymptomatic; 6 experienced transient symptoms. Conclusions: Main 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 4 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 ScaleCCognitive subscale; AE = adverse event; APP = amyloid precursor protein; CDR-SB = Clinical Dementia RatingCSum of Boxes; CI = confidence interval; DAD = Disability Assessment for Dementia; mITT = altered intent-to-treat; MMSE = Mini-Mental State Examination; NTB = Neuropsychological Test Battery; RM = repeated steps; SMC = Security Monitoring Committee; VE = vasogenic edema. Alzheimer disease (AD) is usually a progressive dementing disease characterized by cerebral neuronal loss, deposits of extracellular -amyloid (A) plaques, and intraneuronal neurofibrillary tangles.1 Studies in transgenic mice producing extra A have shown that antibodies directed against the N-terminal of A reduce amyloid deposits in both brain tissue and cerebral vasculature.2,3 These antibodies also GAP-134 (Danegaptide) block the synaptotoxic effects of A oligomers and improve cognitive performance in amyloid precursor protein (APP) transgenic mice.4,5 Previous A immunotherapy studies in humans utilizing active immunization with the full length A42 peptide suggested clinical benefits.6,7 However, meningoencephalitis developed in 6% of patients,8 likely due to a proinflammatory T-cell response against the A peptide.9 One potential means of eliminating the proinflammatory T-cell response is by passively infusing anti-A antibodies. Bapineuzumab, an antibody targeted against the N-terminus of A, is a passive A immunotherapy being tested for AD. Bapineuzumab is usually hypothesized to bind to A in the brain and facilitate its removal, yielding beneficial clinical effects. A phase 1 study with bapineuzumab decided a half-life of 24 days (unpublished data), leading to phase 2 dosing every 13 weeks. The current multiple ascending dose study was initially GAP-134 (Danegaptide) designed and powered to evaluate the security of bapineuzumab within individual dose cohorts. Although the study design remained unchanged, the protocol was amended to evaluate efficacy as the primary objective based partly on preliminary results from the phase 1 study. It was acknowledged that the small cohorts in this study would provide sufficient power to detect only very large treatment differences; however, if successful, the urgency of delivering an effective treatment to patients with AD argued for making efficacy the primary outcome. METHODS This phase 2, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose study was conducted at 30 sites in the United States between April 2005 and March 2008. Patients. Eligible patients were aged 50 to 85 years inclusive, met criteria for probable AD,10 and experienced an MRI consistent with AD. Additional inclusion criteria were a Mini-Mental State Examination (MMSE) score of 16C2611 and a Rosen Modified Hachinski Ischemic score 4.12 Patients were excluded for clinically significant neurologic disease other than AD; a major psychiatric disorder, history GAP-134 (Danegaptide) of stroke or seizures, a Hamilton Rating Scale score for Depressive disorder 1213; current anticonvulsant, antiparkinsonian, anticoagulant, or narcotic medications; recent immunosuppressive or malignancy chemotherapy medications; or cognitive enhancers other than acetylcholinesterase inhibitors or memantine at a stable dose for at least 120 days before screening. Standard protocol approvals, registrations, and patient consents. The study (ClinicalTrials.gov number “type”:”clinical-trial”,”attrs”:”text”:”NCT00112073″,”term_id”:”NCT00112073″NCT00112073) was approved by each site’s local institutional review table, and written informed consent was obtained from each patient (or legally authorized representative). Study design and treatment. A total of 234 patients were randomly assigned to receive either IV bapineuzumab or IL-20R1 placebo, in an 8:7 ratio, in 1 of 4 sequential dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Adaptive stratified randomization was used to achieve a balance of baseline acetylcholinesterase inhibitor or memantine use and screening MMSE score (low = 16C21 vs high = 22C26). Patients received study drug as a 1-hour IV infusion every 13 weeks for 6 infusions during the 18-month study. An independent.
