Onset of efficacy and tolerability following the initiation dosing of long-acting paliperidone palmitate: post-hoc analyses of a randomized, double-blind clinical trial

<p>Abstract</p> <p>Background</p> <p>Paliperidone palmitate is a long-acting injectable atypical antipsychotic for the acute and maintenance treatment of adults with schizophrenia. The recommended initiation dosing regimen is 234 mg on Day 1 and 156 mg on Day 8 via intramuscular (deltoid) injection; followed by 39 to 234 mg once-monthly thereafter (deltoid or gluteal). These post-hoc analyses addressed two commonly encountered clinical issues regarding the initiation dosing: the time to onset of efficacy and the associated tolerability.</p> <p>Methods</p> <p>In a 13-week double-blind trial, 652 subjects with schizophrenia were randomized to paliperidone palmitate 39, 156, or 234 mg (corresponding to 25, 100, or 150 mg equivalents of paliperidone, respectively) or placebo (NCT#00590577). Subjects randomized to paliperidone palmitate received 234 mg on Day 1, followed by their randomized fixed dose on Day 8, and monthly thereafter, with no oral antipsychotic supplementation. The onset of efficacy was defined as the first timepoint where the paliperidone palmitate group showed significant improvement in the Positive and Negative Syndrome Scale (PANSS) score compared to placebo (Analysis of Covariance [ANCOVA] models and Last Observation Carried Forward [LOCF] methodology without adjusting for multiplicity) using data from the Days 4, 8, 22, and 36 assessments. Adverse event (AE) rates and relative risks (RR) with 95% confidence intervals (CI) versus placebo were determined.</p> <p>Results</p> <p>Paliperidone palmitate 234 mg on Day 1 was associated with greater improvement than placebo on Least Squares (LS) mean PANSS total score at Day 8 (p = 0.037). After the Day 8 injection of 156 mg, there was continued PANSS improvement at Day 22 (p ≤ 0.007 vs. placebo) and Day 36 (p < 0.001). Taken together with results in the 39 mg and 234 mg Day 8 arms, these findings suggest a trend towards a dose-dependent response. During Days 1 to 7, AEs reported in ≥2% of paliperidone palmitate subjects (234 mg) and a greater proportion of paliperidone palmitate than placebo subjects were: agitation (3.2% vs. 1.3%; RR 2.52 [95% CI 0.583, 10.904]), headache (4.0% vs. 3.8%; RR 1.06 [95% CI 0.433, 2.619]), and injection site pain (6.7% vs. 3.8%; RR 1.79 [95% CI 0.764, 4.208]). Days 8 to 36 AEs meeting the same criteria in the 156 mg Day 8 arm were: anxiety (3.1% vs. 2.5%; RR 1.24 [95% CI 0.340, 4.542]), psychotic disorder (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), dizziness (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]), and injection site pain (2.5% vs. 1.3%; RR 1.99 [95% CI 0.369, 10.699]). Corresponding Days 8 to 36 AEs in the 39 mg Day 8 group were: agitation (4.5% vs. 4.4%; RR 1.03 [95% CI 0.371, 2.874]), anxiety (3.9% vs. 2.5%; RR 1.55 [95% CI 0.446, 5.381]), and psychotic disorder (2.6% vs. 1.3%; RR 2.07 [95% CI 0.384, 11.110]) while in the 234 mg Day 8 group it was anxiety (3.1% vs. 2.5%, RR 1.25 [95% CI 0.342, 4.570]).</p> <p>Conclusions</p> <p>Significantly greater symptom improvement was observed by Day 8 with paliperidone palmitate (234 mg on Day 1) compared to placebo; this effect was maintained after the 156 mg Day 8 injection, with a trend towards a dose-dependent response. No unexpected tolerability findings were noted in the first week or month after the initiation dosing.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT#00590577">NCT#00590577</a></p

Predicting progression of mild cognitive impairment to dementia using neuropsychological data: a supervised learning approach using time windows

Background: Predicting progression from a stage of Mild Cognitive Impairment to dementia is a major pursuit in current research. It is broadly accepted that cognition declines with a continuum between MCI and dementia. As such, cohorts of MCI patients are usually heterogeneous, containing patients at different stages of the neurodegenerative process. This hampers the prognostic task. Nevertheless, when learning prognostic models, most studies use the entire cohort of MCI patients regardless of their disease stages. In this paper, we propose a Time Windows approach to predict conversion to dementia, learning with patients stratified using time windows, thus fine-tuning the prognosis regarding the time to conversion. Methods: In the proposed Time Windows approach, we grouped patients based on the clinical information of whether they converted (converter MCI) or remained MCI (stable MCI) within a specific time window. We tested time windows of 2, 3, 4 and 5 years. We developed a prognostic model for each time window using clinical and neuropsychological data and compared this approach with the commonly used in the literature, where all patients are used to learn the models, named as First Last approach. This enables to move from the traditional question "Will a MCI patient convert to dementia somewhere in the future" to the question "Will a MCI patient convert to dementia in a specific time window". Results: The proposed Time Windows approach outperformed the First Last approach. The results showed that we can predict conversion to dementia as early as 5 years before the event with an AUC of 0.88 in the cross-validation set and 0.76 in an independent validation set. Conclusions: Prognostic models using time windows have higher performance when predicting progression from MCI to dementia, when compared to the prognostic approach commonly used in the literature. Furthermore, the proposed Time Windows approach is more relevant from a clinical point of view, predicting conversion within a temporal interval rather than sometime in the future and allowing clinicians to timely adjust treatments and clinical appointments.FCT under the Neuroclinomics2 project [PTDC/EEI-SII/1937/2014, SFRH/BD/95846/2013]; INESC-ID plurianual [UID/CEC/50021/2013]; LASIGE Research Unit [UID/CEC/00408/2013

DALI: Defining Antibiotic Levels in Intensive care unit patients: a multi-centre point of prevalence study to determine whether contemporary antibiotic dosing for critically ill patients is therapeutic

Background: The clinical effects of varying pharmacokinetic exposures of antibiotics (antibacterials and antifungals) on outcome in infected critically ill patients are poorly described. A large-scale multi-centre study (DALI Study) is currently underway describing the clinical outcomes of patients achieving pre-defined antibiotic exposures. This report describes the protocol