Methodological Aspects of the Phase Ii Study Aff006 Evaluating Amyloid-Beta -Targeting Vaccine Affitope® Ad02 in Early Alzheimer’s Disease – Prospective Use of Novel Composite Scales

Abstract

BACKGROUND: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer’s disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aβ)-targeting vaccine to elicit anti-Aβ antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. OBJECTIVES: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. DESIGN: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. RESULTS: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. CONCLUSION: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.

Adjuvant effects of multifunctional transcription factor and BCG target YB-1: exogenous YB-1 enhances specific antibody productionin vivoand protects mice against lethalE. colichallenge

“…Previous exposure to a range of vaccines (diphtheria, tetanus, poliomyelitis, influenza) was reported in 2001 to be associated with a 40% reduced risk of AD development [52]. More recently, in a Phase II trial of an AD vaccine, Affiris AG reported that administration of the adjuvant, alum, to control patients retarded AD-related cognitive decline across multiple measures [53,54]. Importantly, in a study of patients with bladder cancer, where BCG administration is the standard of care [55], the risk of developing AD was reported to be 4.8-fold lower in those receiving BCG than in untreated patients [56].…”

“Time Saved” Calculations to Improve Decision-Making in Progressive Disease Studies

“…Historically, composite scores have often been derived to measure the most progressive aspects of disease, resulting in a decline that is as linear as possible in a specific disease stage ( 12 – 14 ). Commonly, these composite scores are weighted linear combinations of individual items from one or more clinical scales, where the weightings are determined by the magnitude of progression on each item, with faster progressing items receiving greater weight ( 13 ). If these composite scores are nearly linear, they approximate a perfect time metric.…”

“Time Saved” Calculations to Improve Decision-Making in Proof-of-Concept Studies as Illustrated with a Post-hoc Analysis of IMM-AD04 Phase 2 Data in Patients with Early Alzheimer's Disease

“…The time savings assessed from individual scales can be combined across multiple outcomes into a single inference using a method similar to a global statistical test that accounts for correlations between outcomes and is referred to as a global TCT (gTCT) (1). Historically, composite scores were derived to measure the most progressive aspects of disease, resulting in a decline that is as linear as possible in a speci c disease stage (7)(8)(9). These composite scores are weighted linear combinations of individual items from one or more clinical scales, where the weightings are determined by the magnitude of progression on each item, with faster progressing items receiving greater weight (7).…”

“…Each patient was randomly assigned to one of ve groups: 1 mg IMM-AD04, 2 mg IMM-AD04, 25 µg AD02 (in two different formulations) and 75 µg AD02 that also contained aluminum oxyhydroxide. The co-primary e cacy outcomes were the adapted ADAS-Cog (aADAS) and adapted Alzheimer's disease cooperative study activities of daily living scale (ADCS-ADL -aADL), which are optimized composite scales speci c to the cognitive and functional domains (9). A composite score (Composite) was the sum of these two scores, and this composite was the prespeci ed primary outcome of the study.…”