Long-Term Follow-Up of Patients Immunized with AN1792 Current Alzheimer Research, 2009, Vol. 6, No. 2 145 the safety and tolerability of AN1792. Efficacy measures continued to be assessed. At the end of the 1-year follow-up assessments in the phase 2a study, AN1792-treated patients who were antibody responders (anti-A titers 1:2,200) showed improvements in cognitive measures as assessed by a 9-component neuro- psychological test battery (NTB) z-score, a composite of tests assessing memory and executive function. Furthermore, antibody responders showed a reduction in cerebrospinal fluid (CSF) tau levels compared with placebo-treated pa- tients, which suggested a reduced level of neurodegeneration compared with baseline [9]. Volumetric brain MRI results revealed a decrease in whole brain volume (WBV) and an increase in ventricular volume in antibody responders com- pared with placebo-treated patients. Interestingly, despite the greater loss of brain volume, antibody responders maintained a cognitive advantage compared with placebo-treated pa- tients, implying that the extra brain volume reduction seen in the responders was not due to neuronal loss [10]. Autopsy of 4 patients who were treated with AN1792 (2 with encephali- tis and 2 without encephalitis) showed evidence of amyloid plaque clearance [11-13]. This follow-up study (Study 251) was designed to evalu- ate whether those patients who were antibody responders in the phase 2a study had altered clinical outcomes or rates of brain atrophy after long-term follow up in the absence of treatment compared with placebo-treated patients. Evidence of clinical benefit would provide further support for A im- munotherapy as a potential treatment approach in AD. METHODS Patients Patients were required to have participated in the phase 2a study and to have provided appropriate written informed consent to participate in the follow-up analysis [9]. Patients eligible for entry to the phase 2a study were 50 to 85 years of age, met the criteria for a diagnosis of probable AD as de- fined by the National Institute of Neurologic and Communi- cative Disorders and Stroke–AD and Related Disorders As- sociation, and had an MRI brain scan supporting the clinical diagnosis of AD. Additional inclusion criteria were a score of 15 to 26 on the Mini-Mental State Examination (MMSE), a Rosen-Modified Hachinski Ischemic score of 4, and writ- ten informed consent from the patient and the patient’s care- giver for the original protocol and subsequent amendments. Patients were excluded if they had clinically significant neu- rologic disease (other than AD) that might affect cognition, a major psychiatric disorder, systemic illness or symptoms that could affect the patient’s ability to complete the study, a Hamilton Psychiatric Rating Scale for Depression (17 item) score of >12, used anticonvulsant, antiparkinsonian, antico- agulant, narcotic, or immunosuppressive medication within 3 months prior to baseline, used medication with the potential to affect cognition (unless maintained on a stable low-to- moderate–dose regimen for at least 3 months prior to base- line), or used medication for cognitive enhancement other than a stable dosing regimen of an acetylcholinesterase in- hibitor ( 6 months). Study 201 Design and Treatment This randomized, placebo-controlled, double-blind, phase 2a clinical trial, reported by Gilman and colleagues in 2005, was conducted at 28 centers in the United States and Europe between September 2001 and December 2002 [9]. A total of 372 patients with mild-to-moderate AD were randomly as- signed in a double-blind manner to receive treatment with a suspension of AN1792 225 g (Elan Pharmaceuticals, Inc., South San Francisco, CA) and QS-21 50 g (Antigenics, Framingham, MA) containing 0.4% polysorbate-80, or nor- mal saline (placebo) in a 4:1 ratio. A 6-member independent Data Safety Monitoring Committee assessed the safety of the study drug throughout Study 201. In each group, treatment was administered as a single 0.5 mL intramuscular (IM) injection and dosing was to occur on Day 0 and at Months 1, 3, 6, 9, and 12 according to the original protocol. Due to the early discontinuation of the immunization, patients received only 1 to 3 injections [9]. All patients enrolled in the study (including those who dis- continued early) were invited to participate in the safety fol- low-up period, which continued blinded and lasted until Month 12 (ie, at least 9 months after their last dose of study treatment). Follow-Up Study 251 Design This was a multi-center out-patient follow-up study in patients with AD who had participated in the phase 2a study described above [9]. The follow-up study was conducted at 23 centers in the United States and Europe between January and October 2006. No study medication was dispensed in this follow-up study. An initial telephone contact was made to assess interest in participation. Subsequently, a clinic visit was conducted after obtaining informed consent. At this visit, a blood sam- ple to assess serum anti-AN1792 antibody titers and plasma A concentration was collected. The following functional and cognitive assessments were performed: Disability As- sessment for Dementia (DAD), Dependence Scale, Clinical Dementia Rating–Sum of Boxes (CDR-SOB), MMSE, NTB, and Alzheimer’s Disease Assessment Scale Cognitive Sub- scale (ADAS-Cog). A volumetric brain MRI scan was also performed. Changes in the patients’ living situation since the beginning of the phase 2a study were queried. Any serious adverse events (SAEs) that occurred after the last visit in the initial phase 2a study were assessed, and the relationship to study drug was determined by the investigator. A home visit or telephone contact, in lieu of the clinic visit, was conducted if the patient could not attend the clinic. In these patients, the DAD, Dependence Scale, CDR-SOB, and questions regarding changes in living situation were ad- ministered over the telephone. The telephone contact was also used to collect patient information regarding any SAEs that may have occurred since the previous phase 2a study. Antibody titers were not assayed and follow-up MRIs were not conducted in this group that could not attend clinic. The clinical raters performing the cognitive and func- tional instruments in the AN1792-251 follow up study per-