146 Current Alzheimer Research, 2009, Vol. 6, No. 2 formed these tests without knowledge of the patient’s group assignment or antibody status. Patients and caregivers were given access to treatment assignment upon request at the end of the AN1792-201 phase 2a study, however, they were not provided information regarding whether they were antibody responders or nonresponders. Site-specific, local, independent ethics committees ap- proved the protocol, amendments, and related informed con- sent forms prior to implementation of each study. The stud- ies were conducted in accordance with the International Con- ference on Harmonization Tripartite Guidelines on Good Clinical Practice and in compliance with the Declaration of Helsinki 1964 as modified in October 2000. Study 251 Outcome Measures and Statistical Analyses An enzyme-linked immunosorbent assay (ELISA) was used to determine total anti-AN1792 immunoglobulin (Ig)G levels in follow-up study baseline serum samples. The ELISA had a lower limit of detection of 1:50 for serum IgG. Patients who achieved a serum anti-AN1792 titer 1:2,200 any time after the first injection in the phase 2a study were considered antibody responders. A titer 1:2,200 was prese- lected as the minimum threshold anti-AN1792 titer likely to be of significant clinical benefit, based on preclinical data (Elan Pharmaceuticals, Inc., data on file). Functional, Dependence, and Global Endpoints The DAD scale was administered to caregivers to meas- ure the patients’ performance of instrumental and basic ac- tivities of daily living over a 2-week period before the scheduled follow-up visit [14]. For each activity, questions were asked to evaluate the patients’ performance on initia- tion, planning and organization, and effectiveness. Change from phase 2a study baseline for the DAD score was ana- lyzed using an analysis of covariance (ANCOVA) model with change from phase 2a study baseline DAD score as the response, study group (Study 201 antibody responder classi- fication vs. placebo) as a factor, and phase 2a study baseline DAD score as a covariate. The Dependence Scale [15], also completed by the care- giver, asks 13 questions assessing the required amount of assistance or care from others needed by the patient. The scale is scored as a sum of items, with patients having the least degree of dependence scored a 0 and patients with the highest level of need receiving a 15. Comparisons of the total Dependence Scale scores in the follow-up study were performed using analysis of variance (ANOVA). The CDR-SOB scale measures patient impairment due to cognitive loss by evaluating 6 categories or box scores: memory, orientation, judgment and problem solving, com- munity affairs, homes and hobbies, and personal care [16]. The rating is based on interviews conducted with both the patient and the caregiver. Change from baseline for the CDR-SOB score was analyzed using an ANCOVA model with change from phase 2a study baseline CDR-SOB score as the response, study group as a factor, and phase 2a study baseline CDR-SOB score as a covariate. Vellas et al. Cognitive Endpoints The NTB was used to assess cognitive and executive function, and consisted of 6 memory tests (Wechsler Mem- ory Visual Paired Associates–Immediate and Delayed Re- call; Wechsler Memory Verbal Paired Associates–Immediate and Delayed Recall; Rey Auditory Verbal Learning Test– Immediate and Delayed Recall) and 3 executive function tests (Wechsler Memory–Digit Span; Controlled Word As- sociation Test [FAS]; Category Fluency Test [animals]) [17]. Raw scores on each of the 9 NTB tests were converted to z- scores using the baseline means and standard deviations (SDs) of phase 2a study participants for each test. The resul- tant z-scores were averaged to obtain a composite z-score, incorporating all 9 NTB tests. The NTB was further analyzed in subgroups of the overall composite NTB z-score, includ- ing the all memory z-score (utilizing all 6 memory tests) and executive function z-score (utilizing the 3 executive function tests). Change from baseline was calculated as the post- baseline composite z-score minus the phase 2a study base- line score, such that a positive change indicates an improve- ment from baseline. NTB scores were analyzed using an ANCOVA model with change from phase 2a study baseline NTB score as the response, study group as a factor, and phase 2a study baseline NTB score as a covariate. In addition to the NTB, other cognitive endpoints in- cluded the MMSE and the ADAS–Cog [18, 19]. Analysis of the MMSE and ADAS-Cog were handled similarly to the NTB, using an ANCOVA model with change from the phase 2a study baseline score as the response, study group as a factor, and phase 2a study baseline score as a covariate. Additional Endpoints Caregivers were queried as to where the patients lived at the start and finish of the phase 2a study and at the time of the follow-up study. The frequency and percentage of pa- tients who remained in their own home or who entered a long-term care facility or nursing home from the beginning of the phase 2a study were determined. Changes in brain, ventricular, and hippocampal volume were determined by MRI methods previously described [10]. Brain boundary shift integral was only calculated on scan pairs that did not have a significant acquisition change be- tween time points. All decisions on patient suitability for scan acquisition or inclusion for analysis were made blind to treatment status. Similarly, all MRI measurements were per- formed blind to treatment status. Change on MRI was evalu- ated from baseline as well as from the final MRI visit in the phase 2a study (Month 12). In each case, as appropriate, the baseline volume or final MRI volume was included in the model as a covariate. Safety Information about SAEs that occurred since the end of the phase 2a study was collected and summarized. Patients’ vital status (ie, alive or dead) was also recorded and compared between treatment groups.