Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

The AHEAD 3-45 Study: Design of a prevention trial for Alzheimer's disease.

INTRODUCTION: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aß) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aß, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc. METHODS: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aß 42/40 ratio (Aß 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results. RESULT: The focus of this article is on the innovative design of the study. DISCUSSION: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans.

A novel cognitive disease progression model for clinical trials in autosomal-dominant Alzheimer's disease.

Clinical trial outcomes for Alzheimer's disease are typically analyzed by using the mixed model for repeated measures (MMRM) or similar models that compare an efficacy scale change from baseline between treatment arms with or without participants' disease stage as a covariate. The MMRM focuses on a single-point fixed follow-up duration regardless of the exposure for each participant. In contrast to these typical models, we have developed a novel semiparametric cognitive disease progression model (DPM) for autosomal dominant Alzheimer's disease based on the Dominantly Inherited Alzheimer Network (DIAN) observational study. This model includes 3 novel features, in which the DPM (1) aligns and compares participants by disease stage, (2) uses a proportional treatment effect similar to the concept of the Cox proportional hazard ratio, and (3) incorporates extended follow-up data from participants with different follow-up durations using all data until last participant visit. We present the DPM model developed by using the DIAN observational study data and demonstrate through simulation that the cognitive DPM used in hypothetical intervention clinical trials produces substantial gains in power compared with the MMRM.

Representativeness of European clinical trial populations in mild Alzheimer's disease dementia: a comparison of 18-month outcomes with real-world data from the GERAS observational study.

BACKGROUND: Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer's disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study. METHODS: Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients. RESULTS: EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (-11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (-25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients. CONCLUSIONS: Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data. TRIAL REGISTRATION: ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009.

Phase 3 solanezumab trials: Secondary outcomes in mild Alzheimer's disease patients.

INTRODUCTION: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-ß peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. METHODS: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. RESULTS: In the mild AD population, less cognitive and functional decline was observed with solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study-Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. DISCUSSION: These findings describe solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate solanezumab's effects in a mild AD population.

Peripheral and central effects of γ-secretase inhibition by semagacestat in Alzheimer's disease.

INTRODUCTION: The negative efficacy study examining the γ-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. METHODS: The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. RESULTS: Assignment to the active treatment arms was associated with reduction in plasma amyloid-ß (Aß) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Aß peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Aß peptide but not AUC, supporting a link to inhibition of γ-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. CONCLUSION: These findings may inform future studies of drugs targeting secretases involved in Aß generation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008.

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.

Delayed-start analysis: Mild Alzheimer's disease patients in solanezumab trials, 3.5 years.

INTRODUCTION: Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD. METHODS: A possible disease-modifying effect of solanezumab was assessed using a new statistical method including noninferiority testing. Performance differences were compared during the placebo-controlled period with performance differences after the placebo patients crossed over to solanezumab in the delayed-start period. RESULTS: Noninferiority of the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog14) and Alzheimer's Disease Cooperative Study Activities of Daily Living inventory instrumental items (ADCS-iADL) differences was met through 132 weeks, indicating that treatment differences observed in the placebo-controlled period remained, within a predefined margin, after the placebo group initiated solanezumab. Solanezumab was well tolerated, and no new safety concerns were identified. DISCUSSION: The results of this secondary analysis show that the mild subgroup of solanezumab-treated patients who initiated treatment early, at the start of the placebo-controlled period, retained an advantage at most time points in the delayed-start period.

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.

Assessment of type I error rate associated with dose-group switching in a longitudinal Alzheimer trial.

In clinical trials, there always is the possibility to use data-driven adaptation at the end of a study. There prevails, however, concern on whether the type I error rate of the trial could be inflated with such design, thus, necessitating multiplicity adjustment. In this project, a simulation experiment was set up to assess type I error rate inflation associated with switching dose group as a function of dropout rate at the end of the study, where the primary analysis is in terms of a longitudinal outcome. This simulation is inspired by a clinical trial in Alzheimer's disease. The type I error rate was assessed under a number of scenarios, in terms of differing correlations between efficacy and tolerance, different missingness mechanisms, and different probabilities of switching. A collection of parameter values was used to assess sensitivity of the analysis. Results from ignorable likelihood analysis show that the type I error rate with and without switching was approximately the posited error rate for the various scenarios. Under last observation carried forward (LOCF), the type I error rate blew up both with and without switching. The type I error inflation is clearly connected to the criterion used for switching. While in general switching, in a way related to the primary endpoint, may impact the type I error, this was not the case for most scenarios in the longitudinal Alzheimer trial setting under consideration, where patients are expected to worsen over time.

A phase 3 trial of semagacestat for treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease is characterized by the presence of cortical amyloid-beta (Aß) protein plaques, which result from the sequential action of ß-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer's disease. METHODS: We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used. RESULTS: The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated. CONCLUSIONS: As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections. (Funded by Eli Lilly; ClinicalTrials.gov number, NCT00594568.)

Enriching amnestic mild cognitive impairment populations for clinical trials: optimal combination of biomarkers to predict conversion to dementia.

The goal of this study was to identify the optimal combination of magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET), and cerebrospinal fluid (CSF) biomarkers to predict conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's disease (AD) dementia within two years, for enriching clinical trial populations. Data from 63 subjects in the Alzheimer's Disease Neuroimaging Initiative aMCI cohort who had MRI and FDG-PET imaging along with CSF data at baseline and at least two years clinical follow-up were used. A Bayesian classification method was used to determine which combination of 31 variables (MRI, FDG-PET, CSF measurements, apolipoprotein E (ApoE) genotype, and cognitive scores) provided the most accurate prediction of aMCI to AD conversion. The cost and time trade-offs for the use of these biomarkers as inclusion criteria in clinical trials were evaluated. Using the combination of all biomarkers, ApoE genotype, and cognitive scores, we achieved an accuracy of 81% in predicting aMCI to AD conversion. With only ApoE genotype and cognitive scores, the prediction accuracy decreased to 62%. By comparing individual modalities, we found that MRI measures had the best predictive power (accuracy = 78%), followed by ApoE, FDG-PET, CSF, and the Alzheimer's disease assessment scale-cognitive subscale. The combination of biomarkers from different modalities, measuring complementary aspects of AD pathology, provided the most accurate prediction of aMCI to AD conversion within two years. This was predominantly driven by MRI measures, which emerged as the single most powerful modality. Overall, the combination of MRI, ApoE, and cognitive scores provided the best trade-off between cost and time compared with other biomarker combinations for patient recruitment in clinical trial.

Safety and biomarker effects of solanezumab in patients with Alzheimer's disease.

OBJECTIVES: To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of 12 weekly infusions of solanezumab, an anti-ß-amyloid (Aß) antibody, in patients with mild-to-moderate Alzheimer's disease. Cognitive measures were also obtained. METHODS: In this phase 2, randomized, double-blind, placebo-controlled clinical trial, 52 patients with Alzheimer's disease received placebo or antibody (100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks, or 400 mg weekly) for 12 weeks. Safety and biomarker evaluations continued until 1 year after randomization. Both magnetic resonance imaging and cerebrospinal fluid (CSF) examinations were conducted at baseline and after the active treatment period. The Aß concentrations were measured in plasma and CSF, and the Alzheimer's Disease Assessment Scale-cognitive portion was administered. RESULTS: Clinical laboratory values, CSF cell counts, and magnetic resonance imaging scans were unchanged by treatment, and no adverse events could be clearly related to antibody administration. Total (bound to antibody and unbound) Aß(1-40) and Aß(1-42) in plasma increased in a dose-dependent manner. Antibody treatment similarly increased total Aß(1-40) and Aß(1-42) in CSF. For patients taking 400 mg weekly, antibody treatment decreased unbound Aß(1-40) in CSF (P < .01), but increased unbound Aß(1-42) in CSF in a dose-dependent manner. The Alzheimer's Disease Assessment Scale-cognitive portion was unchanged after the 12-week antibody administration. CONCLUSIONS: Antibody administration was well tolerated with doses up to 400 mg weekly. The dose-dependent increase in unbound CSF Aß(1-42) suggests that this antibody may shift Aß equilibria sufficiently to mobilize Aß(1-42) from amyloid plaques.

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.

Validation of ELISA methods for quantification of total tau and phosporylated-tau181 in human cerebrospinal fluid with measurement in specimens from two Alzheimer's disease studies.

Tau measurements in cerebrospinal fluid (CSF) are gaining acceptance as aids to diagnosis of Alzheimer's disease (AD) and differentiation from other dementias. Two ELISA assays, the INNOTEST® hTAU Ag and the INNOTEST® PHOSPHO-TAU(181P) for quantification of t-tau and p-tau181 respectively, have been validated to regulatory standards. Validation parameters were determined by repeated testing of human CSF pools. Specimens from Phase 2 studies of the γ-secretase inhibitor semagacestat and the therapeutic antibody solanezumab at baseline and following 12-14 weeks of treatment were also tested. Estimated intra-assay CV for repeated testing of 3 CSF pools were ≤11.5% and RE varied between -14.1% and +6.4%. Inter-assay CV for t-tau was <5% and RE was within ±8%. For p-tau181, inter-assay CV was <9% and RE was within ±2.5%. Total CV (intra-assay plus inter-assay) were below 10% for both analytes. Up to 20-fold dilutional linearity was demonstrated for both analytes. Stability of t-tau and p-tau181 was demonstrated in CSF during five freeze-thaw cycles at ≤-20 °C and ≤-70 °C and at 18-22 °C for up to 24 h. Neither semagacestat nor solanezumab interfered with either assay. Inter-individual t-tau and p-tau181 concentrations were highly variable but intra-individual variations were small. These assays are suitable for analysis of CSF t-tau and p-tau181 in a single laboratory supporting multi-center AD clinical trials. No effect of treatment with semagacestat or solanezumab was observed in response to three months of drug administration.

Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia.

OBJECTIVE: The purpose of the present study was to evaluate the efficacy and tolerability of olanzapine long-acting injection for maintenance treatment of schizophrenia. METHOD: Outpatients with schizophrenia who had maintained stability on an oral regimen of olanzapine (10, 15, or 20 mg/day) for 4 to 8 weeks were randomly assigned to 24 weeks of double-blind treatment with "low" (150 mg every 2 weeks; N=140), "medium" (405 mg every 4 weeks; N=318), or "high" (300 mg every 2 weeks; N=141) doses of olanzapine long-acting injection; a very low reference dose of olanzapine long-acting injection (45 mg every 4 weeks; N=144); or their stabilized dose of oral olanzapine (N=322). Rates of and time to psychotic exacerbation were estimated using Kaplan-Meier methodology. RESULTS: At 24 weeks, the majority of oral olanzapine-treated patients (93%), as well as most olanzapine long-acting injection-treated patients receiving high (95%), medium (90%), low (84%), and very low doses (69%), remained exacerbation free, with the therapeutic 4-week regimen (medium dose) and pooled 2-week regimen (low and high doses) demonstrating efficacy similar to that of oral olanzapine as well as to each other. The three standard long-acting doses were superior to the very low reference dose based on time to exacerbation. Incidence of weight gain > or = 7% of baseline was 21% for oral olanza-pine compared with 21%, 15%, 16%, and 8% for the high, medium, low, and very low olanzapine long-acting treatment groups, respectively. No clinically significant differences were observed between the long-acting injection and oral olanzapine groups in general safety parameters. Few injection-site reactions occurred (3%). Two patients experienced sedation and delirium consistent with olanzapine overdose following possible accidental intravascular injection. CONCLUSIONS: Olanzapine long-acting injection was efficacious in maintenance treatment of schizophrenia for up to 24 weeks, with a safety profile similar to oral olanzapine except for injection-related adverse events.

In search of moderators and mediators of hyperglycemia with atypical antipsychotic treatment.

Signal detection methods were used to identify values of metabolic variables that predict development of prediabetes or diabetes before (moderators) or associated with treatment (mediators), utilizing data from two multi-center clinical trials of patients with schizophrenia, treated for 6 months with olanzapine (OLZ) or ziprasidone (ZIP). At baseline, participants were often overweight/obese (63% with a body mass index >or=25.0kg/m(2)), dyslipidemic [more than one-third had elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations], and prediabetic (20%). Weight gain was significantly greater in OLZ-treated patients, as was accentuation of dyslipidemia. However, there were no significant correlations between weight gain and lipid changes from baseline to weeks 2, 4, 8 or to last observation. Type 2 diabetes developed in 4% and prediabetes in 18% of the population. Significant baseline predictors of diabetes were a HDL-C concentration <28mg/dL, or being >or=58-years-old if HDL-C concentration was >or=28mg/dL. Baseline plasma glucose concentration >or=92mg/dL was the only significant predictor of developing prediabetes, accounting for 60% of cases. Post-treatment increments in plasma TG concentrations >or=145mg/dL or >or=59mg/dL were significant predictors of diabetes (23%) or prediabetes (27%), respectively. If the increase in TG was <145mg/dL, rapid weight gain >or=6.1kg in 2 weeks predicted development of diabetes (18%). These findings provide a quantitative approach to identify those at greatest treatment-associated risk to develop glucose intolerance, and emphasize the need to address co-morbid medical disorders in these patients.

Characteristics of two alternative schizophrenia remission definitions: relationship to clinical and quality of life outcomes.

BACKGROUND: The goal of these secondary analyses of clinical trial data was to characterize clinical outcomes in patients with schizophrenia who met symptom severity or duration thresholds for two alternative definitions of remission, and to explore their relationships to improvement duration and quality of life outcomes. METHODS: Definition 1 used threshold criteria for selected PANSS items sustained over at least 6-months Definition 2 used Brief Psychiatric Rating Scale (BPRS) % change, a threshold score for the Clinical Global Improvement-Severity (CGI-S) maintained for at least 8 weeks, and threshold scores for selected BPRS items. Positive and Negative Symptom Scale (PANSS) and Quality of Life scale (QLS) total scores were pooled from 6 clinical trials. The extent to which the alternative severity thresholds from these two definitions and duration of clinical improvement were associated with different clinical and QLS outcomes was explored. Regression analysis also assessed the relative contribution of each of the components of the two definition severity thresholds to improvements in QLS Total score. RESULTS: Increases in QLS scores were greater for those patients who met either threshold criteria relative to those who met neither (p<.0001). Significantly greater improvements in QLS scores were observed for patients who met either threshold criteria at the 8-, 16- and 24-week visits relative to those who met criteria at weeks 16 and 24, or at week 24 only (p<0.001), as well as for the subset of patients who met threshold criteria at both 24 and 52 weeks relative to those who met criteria at only one of these 2 time points. Only 31% to 47% of patients meeting threshold criteria for either definition at the 8-, 16- or 24-week visits remained in remission at the 52-week visit. Among the severity threshold components analyzed, BPRS total % change from baseline was the strongest predictor of improvement in QLS scores. CONCLUSIONS: Quality of life improved most for patients who achieved severity thresholds associated with either remission criteria and who stayed improved for longer periods. Total BPRS change scores accounted for the greatest percentage of the QLS scores variance. Only a fraction of patients who meet severity criteria for either remission definition early in treatment will remain at that level of improvement within the subsequent 9-12 months.

Rapamycin causes regression of astrocytomas in tuberous sclerosis complex.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the formation of hamartomas in multiple organs. Five to 15% of affected individuals display subependymal giant cell astrocytomas, which can lead to substantial neurological and postoperative morbidity due to the production of hydrocephalus, mass effect, and their typical location adjacent to the foramen of Monro. We sought to see whether therapy with oral rapamycin could affect growth or induce regression in astrocytomas associated with TSC. METHODS: Five subjects with clinically definite TSC and either subependymal giant cell astrocytomas (n = 4) or a pilocytic astrocytoma (n = 1) were treated with oral rapamycin at standard immunosuppressive doses (serum levels 5-15 ng/ml) from 2.5 to 20 months. All lesions demonstrated growth on serial neuroimaging studies. Magnetic resonance imaging scans were performed before and at regular intervals following initiation of therapy. RESULTS: All lesions exhibited regression and, in one case, necrosis. Interruption of therapy resulted in regrowth of subependymal giant cell astrocytomas in one patient. Resumption of therapy resulted in further regression. Treatment was well tolerated. INTERPRETATION: Oral rapamycin therapy can induce regression of astrocytomas associated with TSC and may offer an alternative to operative therapy of these lesions.