Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aß) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 µg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aß positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aß immunoglobulin G titers in 41/42 participants, slower rates of Aß plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid-related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aß active immunotherapies in individuals at risk for AD. HIGHLIGHTS: This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Reversibility of cognitive worsening observed with BACE inhibitor umibecestat in the Alzheimer's Prevention Initiative (API) Generation Studies.

INTRODUCTION: The Alzheimer's Prevention Initiative (API) Generation Studies evaluated the BACE inhibitor umibecestat for Alzheimer's disease (AD) prevention. The studies were terminated early, and the reversibility of umibecestat's side effects was assessed. METHODS: Cognitively unimpaired 60- to 75-year-old apolipoprotein E (APOE) Îµ4 homozygotes and heterozygotes (the latter with elevated brain amyloid deposition) (n = 1556) received umibecestat (50 or 15 mg daily) or placebo for 7 months on average and were followed for a median (interquartile range) of 4 (3 to 6) months after washout. RESULTS: Compared to placebo, umibecestat-treated participants had small, non-progressive, but statistically significant decline in performance on certain cognitive batteries including Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and API Preclinical Composite Cognitive test, but not Clinical Dementia Rating-Sum of Boxes. RBANS differences were no longer significant at the end of follow-up. DISCUSSION: In people at genetic risk for AD, high-dose beta-site amyloid precursor protein cleaving enzyme (BACE) inhibition was associated with early mild cognitive worsening, which reversed shortly after washout, suggesting a symptomatic side effect not associated with neurodegeneration. Fully anonymized data, images, and samples are available upon request for further research on BACE inhibition. HIGHLIGHTS: This is the first trial with blinded assessment of reversibility of BACE inhibitor side effects. Umibecestat was tested in cognitively unimpaired persons at genetic risk for AD. Umibecestat led to early mild cognitive decline that reversed shortly after washout. This suggests a potentially manageable effect not associated with neurodegeneration. Further research may determine the future of BACE inhibition in AD prevention.

Rationale for the selection of dual primary endpoints in prevention studies of cognitively unimpaired individuals at genetic risk for developing symptoms of Alzheimer's disease.

BACKGROUND: There is a critical need for novel primary endpoints designed to detect early and subtle changes in cognition in clinical trials targeting the asymptomatic (preclinical) phase of Alzheimer's disease (AD). The Alzheimer's Prevention Initiative (API) Generation Program, conducted in cognitively unimpaired individuals at risk of developing AD (e.g., enriched by the apolipoprotein E (APOE) genotype), used a novel dual primary endpoints approach, whereby demonstration of treatment effect in one of the two endpoints is sufficient for trial success. The two primary endpoints were (1) time to event (TTE)-with an event defined as a diagnosis of mild cognitive impairment (MCI) due to AD and/or dementia due to AD-and (2) change from baseline to month 60 in the API Preclinical Composite Cognitive (APCC) test score. METHODS: Historical observational data from three sources were used to fit models to describe the TTE and the longitudinal APCC decline, both in people who do and do not progress to MCI or dementia due to AD. Clinical endpoints were simulated based on the TTE and APCC models to assess the performance of the dual endpoints versus each of the two single endpoints, with the selected treatment effect ranging from a hazard ratio (HR) of 0.60 (40% risk reduction) to 1 (no effect). RESULTS: A Weibull model was selected for TTE, and power and linear models were selected to describe the APCC score for progressors and non-progressors, respectively. Derived effect sizes in terms of reduction of the APCC change from baseline to year 5 were low (0.186 for HR = 0.67). The power for the APCC alone was consistently lower compared to the power of TTE alone (58% [APCC] vs 84% [TTE] for HR = 0.67). Also, the overall power was higher for the 80%/20% distribution (82%) of the family-wise type 1 error rate (alpha) between TTE and APCC compared to 20%/80% (74%). CONCLUSIONS: Dual endpoints including TTE and a measure of cognitive decline perform better than the cognitive decline measure as a single primary endpoint in a cognitively unimpaired population at risk of AD (based on the APOE genotype). Clinical trials in this population, however, need to be large, include older age, and have a long follow-up period of at least 5 years to be able to detect treatment effects.

Randomized, double-blind, parallel-group, 48-week study for efficacy and safety of a higher-dose rivastigmine patch (15 vs. 10 cm²) in Alzheimer's disease.

AIM: Determine whether patients with Alzheimer's disease demonstrating functional and cognitive decline, following 24-48 weeks of open-label treatment with 9.5 mg/24 h (10 cm(2)) rivastigmine patch, benefit from a dose increase in a double-blind (DB) comparative trial of two patch doses. METHODS: Patients meeting prespecified decline criteria were randomized to receive 9.5 or 13.3 mg/24 h (15 cm(2)) patch during a 48-week, DB phase. Coprimary outcomes were change from baseline to week 48 on the Instrumental Activities of Daily Living domain of the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-IADL) scale and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Safety and tolerability were assessed. RESULTS: Of 1,584 patients enrolled, 567 met decline criteria and were randomized. At all timepoints, ADCS-IADL and ADAS-cog scores favoured the 13.3 mg/24 h patch. The 13.3 mg/24 h patch was statistically superior to the 9.5 mg/24 h patch on the ADCS-IADL scale from week 16 (p = 0.025) onwards including week 48 (p = 0.002), and ADAS-cog at week 24 (p = 0.027), but not at week 48 (p = 0.227). No unexpected safety concerns were observed. CONCLUSIONS: The 13.3 mg/24 h rivastigmine patch significantly reduced deterioration in IADL, compared with the 9.5 mg/24 h patch, and was well tolerated.

Efficacy and safety of agomelatine in the treatment of major depressive disorder: a multicenter, randomized, double-blind, placebo-controlled trial.

In this 8-week double-blind multicenter trial, we evaluated the efficacy and safety of 2 fixed doses of agomelatine in patients with moderate to severe major depressive disorder. Primary efficacy variable was the change in 17-item Hamilton Depression Rating Scale (HAM-D17) total score from baseline to week 8/end of treatment. Secondary efficacy assessment compared the improvements in clinical response and remission (HAM-D17), Clinical Global Impression--Improvement Score, Clinical Global Impression--Severity Score, Hospital Anxiety and Depression (HAD), sleep (Leeds Sleep Evaluation Questionnaire), disability (Sheehan Disability Scale), and overall Quality of Life in Depression Scale between the agomelatine and placebo groups. Eligible patients (n = 511; baseline mean HAM-D17 score = 27.0) were randomized (1:1:1) to once-daily agomelatine, 25 mg; agomelatine, 50 mg; or placebo. Agomelatine 50 mg provided a statistically significant improvement in HAM-D17 score from first baseline visit through week 8 compared with placebo (week 8 treatment difference, 2.5; P = 0.004), whereas agomelatine 25 mg did not show (P = 0.505) a significant improvement. Treatment differences for all secondary efficacy variables were also statistically significant for agomelatine 50 mg versus placebo: Clinical Global Impression--Improvement (P = 0.012); Clinical Global Impression--Severity difference (P = 0.003); improvement in HAD total score, 2.2 (P = 0.014); patients' ability to get sleep (P < 0.001); quality of sleep (P = 0.002). Both doses of agomelatine were well tolerated relative to placebo. However, clinically notable transient aminotransferase elevations were observed in 4.5% of the patients in the agomelatine 50 mg group. The results showed significant antidepressant efficacy of agomelatine 50 mg/d, including a positive effect on sleep compared with placebo in outpatients with moderate to severe major depressive disorder.

Modelling Decline in Cognition to Decline in Function in Alzheimer's Disease.

OBJECTIVES: The study aimed to evaluate and quantify the temporal link between cognitive and functional decline, and assess the impact of the apolipoprotein E4 (APOE-e4) genotype on Alzheimer's disease (AD) progression. METHODS: A nonlinear mixed-effects Emax model was developed using longitudinal data from 659 patients with dementia due to AD sourced from the Alzheimer's disease neuroimaging initiative (ADNI) database. A cognitive decline model was first built using a cognitive subscale of the AD assessment scale (delayed word recall) as the endpoint, followed by a functional decline model, using the functional assessment questionnaire (FAQ) as the endpoint. Individual and population cognitive decline from the first model drove a functional decline in the second model. The impact of the APOE-e4 genotype status on the dynamics of AD progression was evaluated using the model. RESULTS: Mixed-effects Emax models adequately quantified population average and individual disease trajectories. The model captured a higher initial cognitive impairment and final functional impairment in APOE-e4 carriers than non-carriers. The age at cognitive decline and diagnosis of dementia due to AD was significantly lower in APOE-e4 carriers than that of non-carriers. The average [standard deviation] time shift between cognitive and functional decline, i.e. the time span between half of the maximum cognitive decline and half of the maximum functional decline, was estimated as 1.5 [1.6] years. CONCLUSION: The present analysis quantifies the temporal link between a cognitive and functional decline in AD progression at the population and individual level, and provides information about the potential benefits of pre-clinical AD treatments on both cognition and function.

The Alzheimer's Prevention Initiative Composite Cognitive Test: a practical measure for tracking cognitive decline in preclinical Alzheimer's disease.

BACKGROUND: There is growing interest in identifying sensitive composite cognitive tests to serve as primary endpoints in preclinical Alzheimer's disease (AD) treatment trials. We reported previously a composite cognitive test score sensitive to tracking preclinical AD decline up to 5 years prior to clinical diagnosis. Here we expand upon and refine this work, empirically deriving a composite cognitive test score sensitive to tracking preclinical AD decline up to 11 years prior to diagnosis and suitable for use as a primary endpoint in a preclinical AD trial. METHODS: This study used a longitudinal approach to maximize sensitivity to tracking progressive cognitive decline in people who progressed to the clinical stages of AD (n = 868) compared to those who remained cognitively unimpaired during the same time period (n = 989), thereby correcting for normal aging and practice effects. Specifically, we developed the Alzheimer's Prevention Initiative Preclinical Composite Cognitive test (APCC) to measure very early longitudinal cognitive decline in older adults with preclinical AD. Data from three cohorts from Rush University were analyzed using a partial least squares (PLS) regression model to identify optimal composites within different time periods prior to diagnosis, up to 11 years prior to diagnosis. The mean-to-standard deviation ratio (MSDRs) is an indicator of sensitivity to change and was used to inform the final calculation of the composite score. RESULTS: The optimal composite, the APCC, is calculated: 0.26*Symbol Digit Modalities + 2.24*MMSE Orientation to Time + 2.14*MMSE Orientation to Place + 0.53*Logical Memory Delayed Recall + 1.36* Word List-Delayed Recall + 0.68*Judgment of Line Orientation + 1.39*Raven's Progressive Matrices Matrices (subset of 9 items from A and B). The MSDR of the APCC in a population of preclinical AD individuals who eventually progress to cognitive impairment, compared to those who remained cognitively unimpaired during the same time period, was - 1.10 over 1 year. CONCLUSIONS: The APCC is an empirically derived composite cognitive test score with high face validity that is sensitive to preclinical AD decline up to 11 years prior to diagnosis of the clinical stages of AD. The components of the APCC are supported by theoretical understanding of cognitive decline that occurs during preclinical AD. The APCC was used as a primary outcome in the API Generation Program trials.

The Alzheimer's Prevention Initiative Generation Program: Study design of two randomized controlled trials for individuals at risk for clinical onset of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) pathology, including the accumulation of amyloid beta (Aß) species and tau pathology, begins decades before the onset of cognitive impairment. This long preclinical period provides an opportunity for clinical trials designed to prevent or delay the onset of cognitive impairment due to AD. Under the umbrella of the Alzheimer's Prevention Initiative Generation Program, therapies targeting Aß, including CNP520 (umibecestat), a ß-site-amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibitor, and CAD106, an active Aß immunotherapy, are in clinical development in preclinical AD. METHODS: The Alzheimer's Prevention Initiative Generation Program comprises two pivotal (phase 2/3) studies that assess the efficacy and safety of umibecestat and CAD106 in cognitively unimpaired individuals with high risk for developing symptoms of AD based on their age (60-75 years), APOE4 genotype, and, for heterozygotes (APOE ε2/ε4 or ε3/ε4), elevated brain amyloid. Approximately, 3500 individuals will be enrolled in either Generation Study 1 (randomized to cohort 1 [CAD106 injection or placebo, 5:3] or cohort 2 [oral umibecestat 50 mg or placebo, 3:2]) or Generation Study 2 (randomized to oral umibecestat 50 mg and 15 mg, or placebo [2:1:2]). Participants receive treatment for at least 60 months and up to a maximum of 96 months. Primary outcomes include time to event, with event defined as diagnosis of mild cognitive impairment due to AD and/or dementia due to AD, and the Alzheimer's Prevention Initiative preclinical composite cognitive test battery. Secondary endpoints include the Clinical Dementia Rating Sum of Boxes, Repeatable Battery for the Assessment of Neuropsychological Status total score, Everyday Cognition Scale, biomarkers, and brain imaging. DISCUSSION: The Generation Program is designed to assess the efficacy, safety, and biomarker effects of the two treatments in individuals at high risk for AD. It may also provide a plausible test of the amyloid hypothesis and further accelerate the evaluation of AD prevention therapies.

Clinical response after two cycles compared to HER2, Ki-67, p53, and bcl-2 in independently predicting a pathological complete response after preoperative chemotherapy in patients with operable carcinoma of the breast.

INTRODUCTION: To investigate the predictive value of clinical and biological markers for a pathological complete remission after a preoperative dose-dense regimen of doxorubicin and docetaxel, with or without tamoxifen, in primary operable breast cancer. METHODS: Patients with a histologically confirmed diagnosis of previously untreated, operable, and measurable primary breast cancer (tumour (T), nodes (N) and metastases (M) score: T2-3(> or = 3 cm) N0-2 M0) were treated in a prospectively randomised trial with four cycles of dose-dense (bi-weekly) doxorubicin and docetaxel (ddAT) chemotherapy, with or without tamoxifen, prior to surgery. Clinical and pathological parameters (menopausal status, clinical tumour size and nodal status, grade, and clinical response after two cycles) and a panel of biomarkers (oestrogen and progesterone receptors, Ki-67, human epidermal growth factor receptor 2 (HER2), p53, bcl-2, all detected by immunohistochemistry) were correlated with the detection of a pathological complete response (pCR). RESULTS: A pCR was observed in 9.7% in 248 patients randomised in the study and in 8.6% in the subset of 196 patients with available tumour tissue. Clinically negative axillary lymph nodes, poor tumour differentiation, negative oestrogen receptor status, negative progesterone receptor status, and loss of bcl-2 were significantly predictive for a pCR in a univariate logistic regression model, whereas in a multivariate analysis only the clinical nodal status and hormonal receptor status provided significantly independent information. Backward stepwise logistic regression revealed a response after two cycles, with hormone receptor status and lymph-node status as significant predictors. Patients with a low percentage of cells stained positive for Ki-67 showed a better response when treated with tamoxifen, whereas patients with a high percentage of Ki-67 positive cells did not have an additional benefit when treated with tamoxifen. Tumours overexpressing HER2 showed a similar response to that in HER2-negative patients when treated without tamoxifen, but when HER2-positive tumours were treated with tamoxifen, no pCR was observed. CONCLUSION: Reliable prediction of a pathological complete response after preoperative chemotherapy is not possible with clinical and biological factors routinely determined before start of treatment. The response after two cycles of chemotherapy is a strong but dependent predictor. The only independent factor in this subset of patients was bcl-2.

Evidence from nonrandomized studies: a case study on the estimation of causal effects.

Although randomized controlled trials are regarded as the gold standard for comparison of treatments, evidence from observational studies is still relevant. To cope with the problem of possible confounding in these studies, investigators need methods for analyzing their results which adjust for confounders and lead to unbiased estimation of the treatment effect. In this paper, the authors describe the main principles of three statistical methods for doing this. The first method is the classical approach of a multiple regression model including the effects of treatment and covariates. This considers the relation between prognostic factors and the outcome variable as a relevant criterion for adjustment. The second method is based on the propensity score, focusing on the relation between prognostic factors and treatment assignment. The third method is an ecologic approach using a grouped treatment variable, which may aid in avoiding confounding by indication. These approaches are applied to a partially randomized trial conducted in 720 German breast cancer patients between 1984 and 1997. The study had a comprehensive cohort study design that included recruitment of patients who had consented to participation but not to randomization because of a preference for one of the treatments. This design offers a unique opportunity to contrast results from the nonrandomized portion of a study with those for a randomized subcohort as a reference.

Clinical response by palpation during primary systemic therapy with four dose-dense cycles doxorubicin and docetaxel in patients with operable breast cancer: further results from a randomised controlled trial.

Primary systemic therapy (PST) allows the observation of tumour response under treatment, but little is known regarding the typical course of clinical response during such therapy. The aim of this study is to support decision making in case of insufficient clinical response. Tumour response was assessed by palpation at different times in 436 patients with operable breast cancer from the dose-dense biweekly therapy arm of the GEPARDUO phase III trial. The predictive value of clinical response for pathologic complete response (pCR), prognostic models to assess the prognosis and individual courses of clinical response were investigated. Sensitivity and positive predictive value were low, but comparatively highest after the 3rd cycle. The predictive value of clinical response by palpation for pCR was subsequently limited. The majority of patients (68.1%) experienced a consistent decrease in tumour size during PST. The results indicate that decisions about further treatment should take place at the earliest after the 3rd cycle or 6 weeks of dose-dense PST.

Active Aß immunotherapy CAD106 in Alzheimer's disease: A phase 2b study.

INTRODUCTION: This randomized, double-blind, placebo-controlled, 90-week study assessed safety, tolerability, and immunogenicity of CAD106 with/without adjuvant in patients with mild Alzheimer's disease. METHODS: One hundred twenty-one patients received up to seven intramuscular injections of CAD106 (150 µg or 450 µg) or placebo ± adjuvant over 60 weeks. An amyloid positron emission tomography (PET) substudy was also conducted. RESULTS: CAD106 induced strong serological responses (amyloid-beta [Aß]-Immunoglobuline G[IgG]) in 55.1% (150 µg) and 81.1% (450 µg) of patients (strong serological responders [SSRs]). Serious adverse events (SAEs) were reported in 24.5% (95% confidence interval [CI] 16.7-33.8) of the patients in the active treatment group and in 6.7% (95% CI 0.2-31.9) in the placebo group. Three of the SAEs were classified as possibly related to study drug by the investigators. No evidence of central nervous system inflammation was found. Amyloid-related imaging abnormalities (ARIAs) occurred in six cases, all of them were strong serological responders. None of the ARIAs were symptomatic. Serum Aß-IgG titer area under the curves correlated negatively with amyloid PET standardized uptake value ratio percentage change from baseline to week 78 within the CAD106-treated patients (r = -0.84, P = .0004). Decrease in cortical gray-matter volume from baseline to week 78 was larger in SSRs than in controls (P = .0077). DISCUSSION: Repeated CAD106 administration was generally well tolerated. CAD106 450 µg with alum adjuvant demonstrated the best balance between antibody response and tolerability.

Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group.

PURPOSE: Dose-dense and sequential administration of cytotoxic drugs are current approaches to improve outcomes in patients with early-stage breast cancer. METHODS: This phase III study investigated 913 women with untreated operable breast cancer (T2-3, N0-2, M0) randomly assigned to receive either doxorubicin 50 mg/m2 plus docetaxel 75 mg/m2 every 14 days for four cycles with filgrastim support (ADOC), or doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 21 days followed by docetaxel 100 mg/m2 every 21 days for four cycles each (AC-DOC). The primary end point was the incidence of pathologic complete (invasive and noninvasive) response (pCR) in the breast and axillary nodes. Secondary end points were predictors for pCR, clinical response, rate of breast conservation, and safety. RESULTS: A pCR was achieved in 94 patients (10.6%), but the likelihood was significantly greater with AC-DOC (14.3%; n = 63) than with ADOC (7.0%; n = 31) (odds ratio, 2.22; 90% CI, 1.52 to 3.24; P < .001). Independent predictors of attaining a pCR included the use of sequential therapy, high tumor grade, and negative hormone receptor status. The response rates detected by palpation and by imaging were significantly higher with AC-DOC (85.0% and 78.6%, respectively) than with ADOC (75.2% and 68.6%, respectively; both P values < .001). The rate of breast-conserving surgery was 63.4% for AC-DOC and 58.1% for ADOC (P = .05). Predominant grade 3/4 toxicities were leucopenia (AC-DOC, 74.2%; ADOC, 53.7%) and neutropenia (AC-DOC, 66.4%; ADOC, 44.7%) but were infrequently associated with fever (AC-DOC, 4.6%; ADOC, 3.1%). CONCLUSION: Sequential AC-DOC is more effective at inducing pCR than dose-dense ADOC as preoperative treatment for patients with operable breast cancer.

Long-term treatment with active Aß immunotherapy with CAD106 in mild Alzheimer's disease.

INTRODUCTION: CAD106 is designed to stimulate amyloid-ß (Aß)-specific antibody responses while avoiding T-cell autoimmune responses. The CAD106 first-in-human study demonstrated a favorable safety profile and promising antibody response. We investigated long-term safety, tolerability and antibody response after repeated CAD106 injections. METHODS: Two phase IIa, 52-week, multicenter, randomized, double-blind, placebo-controlled core studies (2201; 2202) and two 66-week open-label extension studies (2201E; 2202E) were conducted in patients with mild Alzheimer's disease (AD) aged 40 to 85 years. Patients were randomized to receive 150µg CAD106 or placebo given as three subcutaneous (2201) or subcutaneous/intramuscular (2202) injections, followed by four injections (150 µg CAD106; subcutaneous, 2201E1; intramuscular, 2202E1). Our primary objective was to evaluate the safety and tolerability of repeated injections, including monitoring cerebral magnetic resonance imaging scans, adverse events (AEs) and serious AEs (SAEs). Further objectives were to assess Aß-specific antibody response in serum and Aß-specific T-cell response (core only). Comparable Aß-immunoglobulin G (IgG) exposure across studies supported pooled immune response assessments. RESULTS: Fifty-eight patients were randomized (CAD106, n = 47; placebo, n = 11). Baseline demographics and characteristics were balanced. Forty-five patients entered extension studies. AEs occurred in 74.5% of CAD106-treated patients versus 63.6% of placebo-treated patients (core), and 82.2% experienced AEs during extension studies. Most AEs were mild to moderate in severity, were not study medication-related and did not require discontinuation. SAEs occurred in 19.1% of CAD106-treated patients and 36.4% of placebo-treated patients (core). One patient (CAD106-treated; 2201) reported a possibly study drug-related SAE of intracerebral hemorrhage. Four patients met criteria for amyloid-related imaging abnormalities (ARIA) corresponding to microhemorrhages: one was CAD106-treated (2201), one placebo-treated (2202) and two open-label CAD106-treated. No ARIA corresponded to vasogenic edema. Two patients discontinued extension studies because of SAEs (rectal neoplasm and rapid AD progression, respectively). Thirty CAD106-treated patients (63.8%) were serological responders. Sustained Aß-IgG titers and prolonged time to decline were observed in extensions versus core studies. Neither Aß1-6 nor Aß1-42 induced specific T-cell responses; however, positive control responses were consistently detected with the CAD106 carrier. CONCLUSIONS: No unexpected safety findings or Aß-specific T-cell responses support the CAD106 favorable tolerability profile. Long-term treatment-induced Aß-specific antibody titers and prolonged time to decline indicate antibody exposure may increase with additional injections. CAD106 may be a valuable therapeutic option in AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00733863, registered 8 August 2008; NCT00795418, registered 10 November 2008; NCT00956410, registered 10 August 2009; NCT01023685, registered 1 December 2009.

Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin/cyclophosphamide/docetaxel in operable breast cancer: second interim analysis.

Timing of systemic treatment in primary operable breast cancer is subject to extensive investigation, suggesting that pathologic complete remission (pCR) might improve survival in this setting. The German Adjuvant Breast Cancer Group previously demonstrated the feasibility of a dose-dense biweekly schedule of 4 cycles doxorubicin 50 mg/m2 and docetaxel 75 mg/m2 (ddAT) +/- tamoxifen in the neoadjuvant setting to yield a pCR of 9.7% (Gepardo trial). Patients assigned to ddAT received prophylactic granulocyte colony-stimulating factor support (5 micro g/kg days 5-10). The current study (GeparDUO) was designed to assess whether the pCR rate, including no viable invasive and preinvasive tumor cells, achieved with ddAT was equivalent to sequential administration of doxorubicin/cyclophosphamide followed by docetaxel (AC-DOC) over 24 weeks in primary operable breast cancer. From June 1999 to September 2001, 913 patients were enrolled in this trial. In total, 395 patients randomized before August 1, 2000, were included in the second interim analysis. Safety data were available from 369 patients (ddAT, n = 191; AC-DOC, n = 178) demonstrating that toxicity of both regimens was tolerable. Grade 3/4 neutropenia occurred in 39.8% of patients receiving ddAT and in 69.3% of patients treated with AC-DOC. Efficacy data were available in 378 patients. A pCR occurred in 14.8% of the primary breast tumors. According to the recommendations of the data monitoring committee, recruitment to the study was halted as of September 2001 (n = 913/1000) due to the significant difference in pCR rates observed between the treatment arms. Surgery was documented in 380 patients. Breast conservation was possible in 288 cases (75.8%). The application of both schedules is safe and feasible in an outpatient setting. Although, results obtained from this interim analysis are encouraging, caution is recommended until the results obtained show statistical difference in pCR.

Undernutrition in Benin-an analysis based on graphical models.

Undernutrition is one of the most important health problems in developing countries. Examining its determinants implies the investigation of a complex association structure including a large number of potential influence variables and different types of influences. A recently developed statistical technique to cope with such situations are graphical chain models. In this paper, this approach is used to investigate the determinants of undernutrition in Benin (West Africa). Since this method also reveals indirect influences, interesting insight is gained into the association structure of all variables incorporated. The analysis identifies mother's education, socioeconomic status, and religion as three variables with particularly strong direct and indirect linkages to undernutrition.

Agomelatine in the treatment of major depressive disorder: an 8-week, multicenter, randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy, safety, and tolerability of fixed-dose agomelatine 25 and 50 mg/d in the treatment of outpatients with moderate-to-severe major depressive disorder (MDD) compared to placebo. METHOD: In this 8-week, multicenter, double-blind, parallel-group trial, patients with DSM-IV-defined MDD were randomly assigned (1:1:1) to receive a once-daily dose of agomelatine 25 mg, agomelatine 50 mg, or placebo. The primary efficacy measure was the change from baseline to week 8 in the clinician-rated 17-item Hamilton Depression Rating Scale (HDRS(17)); other efficacy measures were the clinical remission and response rates (measured by HDRS(17)), Clinical Global Impressions scales, Hospital Anxiety and Depression Scale (HADS) score, subjective measures on sleep, and the overall quality of life. The study was conducted between December 2006 and January 2008. RESULTS: Agomelatine 25 mg/d was more efficacious based on the HDRS(17) total score (P = .01) compared to placebo throughout the treatment period, whereas for agomelatine 50 mg/d, statistically significant reduction in HDRS(17) total score could be observed from weeks 2 to 6 but not at week 8 (P = .144). A higher proportion of patients receiving agomelatine 25 mg/d showed clinical response (P = .013), clinical remission (P = .07), and improvement according to the Clinical Global Impressions-Improvement scale (P = .065) compared to those receiving placebo. No statistically significant difference between patients receiving agomelatine 50 mg/d compared to placebo on clinical response (P = .116) or clinical remission (P =. 457) was observed. HADS score, quality of sleep, and quality of life significantly improved with agomelatine 25 mg/d compared to placebo. Both agomelatine doses were safe and well tolerated, although clinically notable aminotransferase elevations were observed transiently in the agomelatine 50 mg/d group. CONCLUSIONS: Agomelatine 25 mg/d was effective in the treatment of patients with moderate-to-severe MDD and was safe and well tolerated. Agomelatine 50 mg/d provided evidence for its antidepressant efficacy until week 6 and was also safe and well tolerated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00411242.

Stratification for the propensity score compared with linear regression techniques to assess the effect of treatment or exposure.

Stratifying and matching by the propensity score are increasingly popular approaches to deal with confounding in medical studies investigating effects of a treatment or exposure. A more traditional alternative technique is the direct adjustment for confounding in regression models. This paper discusses fundamental differences between the two approaches, with a focus on linear regression and propensity score stratification, and identifies points to be considered for an adequate comparison. The treatment estimators are examined for unbiasedness and efficiency. This is illustrated in an application to real data and supplemented by an investigation on properties of the estimators for a range of underlying linear models. We demonstrate that in specific circumstances the propensity score estimator is identical to the effect estimated from a full linear model, even if it is built on coarser covariate strata than the linear model. As a consequence the coarsening property of the propensity score-adjustment for a one-dimensional confounder instead of a high-dimensional covariate-may be viewed as a way to implement a pre-specified, richly parametrized linear model. We conclude that the propensity score estimator inherits the potential for overfitting and that care should be taken to restrict covariates to those relevant for outcome.

Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement.

OBJECTIVES: Our prospective study tested the hypothesis that the 30-day clinical outcome of elective percutaneous catheter intervention (PCI) differs between strata defined by quartiles of platelet aggregation after loading with 600 mg clopidogrel. BACKGROUND: Platelet responses after loading with clopidogrel are highly variable. The impact of this variability on the peri-interventional risk of patients undergoing PCI has not been investigated prospectively. METHODS: Our study included 802 consecutive patients undergoing elective coronary stent placement. Before PCI, patients received a loading dose of 600 mg clopidogrel followed by 75 mg daily. Primary end point was the 30-day composite of death, myocardial infarction, and target lesion revascularization (major adverse cardiac events [MACE]). Platelet aggregation was assessed immediately before PCI by optical aggregometry (5 micromol/l adenosine diphosphate). RESULTS: During 30-day follow-up, 15 patients (1.9%) incurred MACE (3 deaths, 8 myocardial infarctions, 8 target lesion revascularizations). Quartiles of platelet aggregation were <4%, 4% to 14%, 15% to 32%, and >32%. Thirty-day MACE differed significantly (p = 0.034) between quartiles of platelet aggregation. It was 0.5% in the first quartile, 0.5% in the second, 3.1% in the third, and 3.5% in the fourth. Platelet aggregation above the median carried a 6.7-fold risk (95% confidence interval 1.52 to 29.41; p = 0.003) of 30-day MACE. Multivariable logistic regression analysis, including pertinent covariables, confirmed platelet aggregation as a significant independent predictor of 30-day MACE (adjusted odds ratio per 10% increase in platelet aggregation 1.32, 95% confidence interval 1.04 to 1.61; p = 0.026). CONCLUSIONS: The level of platelet aggregation immediately before elective coronary stenting in patients pre-treated with a high loading dose of clopidogrel is correlated with early outcome after the procedure.