Florbetapir F18 PET Amyloid Neuroimaging and Characteristics in Patients With Mild and Moderate Alzheimer Dementia.

BACKGROUND: Clinical diagnosis of Alzheimer disease (AD) is challenging, with a 70.9%-87.3% sensitivity and 44.3%-70.8% specificity, compared with autopsy diagnosis. Florbetapir F18 positron emission tomography (FBP-PET) estimates beta-amyloid plaque density antemortem. METHODS: Of 2052 patients (≥55 years old) clinically diagnosed with mild or moderate AD dementia from 2 solanezumab clinical trials, 390 opted to participate in a FBP-PET study addendum. We analyzed baseline prerandomization characteristics. RESULTS: A total of 22.4% had negative FBP-PET scans, whereas 72.5% of mild and 86.9% of moderate AD patients had positive results. No baseline clinical variable reliably differentiated negative from positive FBP-PET scan groups. CONCLUSIONS: These data confirm the challenges of correctly diagnosing AD without using biomarkers. FBP-PET can aid AD dementia differential diagnosis by detecting amyloid pathology antemortem, even when the diagnosis of AD is made by expert clinicians.

Adverse events and dropouts in Alzheimer's disease studies: what can we learn?

BACKGROUND: Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. METHODS: Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. RESULTS: Median age was 74.2 (interquartile range 67.9-79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6-77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%-24.0%), 8.2% (range 8.1%-8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. CONCLUSIONS: These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety.

Safety profile of Alzheimer's disease populations in Alzheimer's Disease Neuroimaging Initiative and other 18-month studies.

BACKGROUND: Demonstration of a disease-modifying effect of a therapeutic agent on Alzheimer's disease (AD) requires a trial lasting for at least 18 months. An understanding of expected rates of adverse events (AEs), overall discontinuations, and discontinuations due to AEs, serious AEs, and deaths would be useful in planning such trials. METHODS: We examined safety information for patients taking placebo from five published 18-month AD trials and for patients from the Alzheimer's Disease Neuroimaging Initiative study. RESULTS: AEs reported consistently across multiple studies were dyspnea (occurring in 5.3%-5.8% of patients), headache (4.0%-5.5%), constipation (4.3%-4.7%), nausea (2.0%-5.8%), joint swelling (3.6%-3.7%), vomiting (3.6%-3.7%), and anxiety (3.2%-3.6%). Larger multinational studies, as compared with smaller studies with fewer sites and geographies, demonstrated greater overall discontinuations (24.6%-33.0% vs 8.2%-21.0%) and greater discontinuations due to AEs (9.5%-11.6% vs 2.7%-3.2%). Rates of death (1.8%-2.4%) and SAEs (19.9%-21.2%) were consistent across 18 month published studies and in ADNI; fall was the most common SAE (2.6%-4.0%) where SAEs were reported. CONCLUSIONS: In general, comparable types of AEs, frequency of deaths, and serious AEs were seen for patients taking placebo in five randomized, controlled 18-month AD trials and in Alzheimer's Disease Neuroimaging Initiative, whereas rates of discontinuations were more variable. Evaluation across studies was complicated by inconsistent methods of reporting safety information. Evaluation of large databases of placebo patients from therapeutic AD trials is needed to further enhance the understanding of expected safety outcomes in clinical trials of AD patients.

Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline.

BACKGROUND: Alzheimer's disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. OBJECTIVE: This exploratory study aimed to define latent classes from participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. METHODS: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-ß status and follow-up assessments on the Alzheimer's Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. RESULTS: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. CONCLUSIONS: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class.

Alzheimer's disease progression by geographical region in a clinical trial setting.

INTRODUCTION: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. METHODS: Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). RESULTS: Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. CONCLUSIONS: These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00594568 - IDENTITY. Registered 11 January 2008. ClinicalTrials.gov NCT00762411 - IDENTITY2. Registered 26 September 2008 ClinicalTrials.gov NCT00905372 - EXPEDITION. Registered 18 May 2009 ClinicalTrials.gov NCT00904683 - EXPEDITION2. Registered 18 May 2009.

Comparing recruitment, retention, and safety reporting among geographic regions in multinational Alzheimer's disease clinical trials.

INTRODUCTION: Most Alzheimer's disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region. METHODS: We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan. RESULTS: North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan. CONCLUSIONS: These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.

Safety profile of semagacestat, a gamma-secretase inhibitor: IDENTITY trial findings.

OBJECTIVE: Semagacestat, a γ-secretase inhibitor, demonstrated an unfavorable risk-benefit profile in a Phase 3 study of patients with Alzheimer's disease (IDENTITY trials), and clinical development was halted. To assist in future development of γ-secretase inhibitors, we report detailed safety findings from the IDENTITY study, with emphasis on those that might be mechanistically linked to γ-secretase inhibition. RESEARCH DESIGN AND METHODS: The IDENTITY trial was a double-blind, placebo-controlled trial of semagacestat (100 mg and 140 mg), in which 1537 patients age 55 years and older with probable Alzheimer's disease were randomized. Treatment-emergent adverse events (TEAEs) are reported by body system along with pertinent laboratory, vital sign, and ECG findings. RESULTS: Semagacestat treatment was associated with increased reporting of suspected Notch-related adverse events (gastrointestinal, infection, and skin cancer related). Other relevant safety findings associated with semagacestat treatment included cognitive and functional worsening, skin-related TEAEs, renal and hepatic changes, increased QT interval, and weight loss. With few exceptions, differences between semagacestat and placebo treatment groups were no longer significant after cessation of treatment with active drug. CONCLUSIONS: Many of these safety findings can be attributed to γ-secretase inhibition, and may be valuable to researchers developing γ-secretase inhibitors.

Development of semagacestat (LY450139), a functional gamma-secretase inhibitor, for the treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease is thought to be caused by increased formations of neurotoxic amyloid beta (A beta) peptides, which give rise to the hallmark amyloid plaques. Therefore, pharmacological agents that reduce A beta formation may be of therapeutic benefit. OBJECTIVE: This paper reviews the pharmacology and chemical efficacy of an A beta-lowering agent, semagacestat (LY450139). METHODS: A review of the published literature pertaining to semagacestat was obtained using several electronic search engines; unpublished data on file at Eli Lilly and Co. were used as supplementary material. RESULTS/CONCLUSIONS: Semagacestat treatment lowers plasma, cerebrospinal fluid and brain A beta in a dose-dependent manner in animals and plasma and cerebrospinal fluid A beta in humans, compared with placebo-treated patients. On the basis of extant data, semagacestat seems to be well tolerated, with most adverse events related to its actions on inhibition of peripheral Notch cleavage. Thus far, clinical efficacy has not been detectable because of the short duration of the current trials. Phase III trials with 21 months of active treatment are currently underway.

An integrated analysis of olanzapine/fluoxetine combination in clinical trials of treatment-resistant depression.

OBJECTIVE: To evaluate the efficacy of olanzapine/fluoxetine combination (OFC) versus olanzapine or fluoxetine monotherapy across all clinical trials of treatment-resistant depression sponsored by Eli Lilly and Company. METHOD: Efficacy and safety data from 1146 patients with a history of nonresponse during the current depressive episode who subsequently exhibited nonresponse during a 6- to 8-week antidepressant open-label lead-in phase and were randomly assigned to OFC (N = 462), fluoxetine (N = 342), or olanzapine (N = 342) for double-blind treatment were analyzed. All patients had a diagnosis of major depressive disorder as defined by DSM-III or DSM-IV criteria. The dates in which the trials were conducted ranged from May 1997 to July 2005. RESULTS: After 8 weeks, OFC patients demonstrated significantly greater Montgomery-Asberg Depression Rating Scale improvement (mean change = -13.0) than fluoxetine (-8.6, p < .001) or olanzapine (-8.2, p < .001) patients, via a mixed-effects model repeated-measures analysis. Remission rates were 25.5% for OFC, 17.3% (p = .006) for fluoxetine, and 14.0% (p < .001) for olanzapine. Adverse events in >or= 10% of OFC patients were weight gain, increased appetite, dry mouth, somnolence, fatigue, headache, and peripheral edema. Random glucose mean change (mg/dL) was +7.92 for the OFC group, +1.62 for the fluoxetine group (p = .020), and +9.91 for the olanzapine group (p = .485). Random cholesterol mean change (mg/dL) was +12.4 for OFC, +2.3 for fluoxetine (p < .001), and +3.1 for olanzapine (p < .001); incidence of treatment-emergent increase from normal to high cholesterol (baseline < 200 mg/dL and >or= 240 subsequently) was significantly higher for the OFC group (10.2%) than for the fluoxetine group (3.1%, p = .017) but not the olanzapine group (8.0%, p = .569). Mean weight change (kg) was +4.42 for OFC, -0.15 for fluoxetine (p < .001), and +4.63 for olanzapine (p = .381), with 40.4% of OFC patients gaining >or= 7% body weight (vs. olanzapine: 42.9%, p = .515; fluoxetine: 2.3%, p < .001). CONCLUSION: Results of this analysis showed that OFC-treated patients experienced significantly improved depressive symptoms compared with olanzapine- or fluoxetine-treated patients following failure of 2 or more antidepressants within the current depressive episode. Safety results for OFC were generally consistent with those for its component monotherapies. The total cholesterol increase associated with OFC was more pronounced than with olanzapine alone.

A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder.

OBJECTIVE: Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD). METHOD: Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005. RESULTS: After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine. CONCLUSION: Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier: NCT00035321.