Selection of the treatment effect for sample size determination in a superiority clinical trial using a hybrid classical and Bayesian procedure.

Specification of the treatment effect that a clinical trial is designed to detect (θA) plays a critical role in sample size and power calculations. However, no formal method exists for using prior information to guide the choice of θA. This paper presents a hybrid classical and Bayesian procedure for choosing an estimate of the treatment effect to be detected in a clinical trial that formally integrates prior information into this aspect of trial design.

Comparison of Drug Approvals in Europe Versus the United States: An Analysis of Discrepancies Between Drug Products Reviewed by EMA and FDA.

Background: Regulators from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) do not always agree on interpretation of data for a drug's safety and efficacy.

Methods And Results: The authors compared all new molecular entities approved or rejected in a 5-year period from 2007 to 2011, identified where FDA and EMA reviews resulted in different regulatory decisions, and explored potential mechanisms for the discrepancies. Thirteen entities were associated with different regulatory decisions, and 2 drugs were withdrawn from their respective markets in 2010: one from the US (Mylotarg; gemtuzumab ozogamicin) and the other in Europe (Thelin; sitaxentan sodium).

Preterm birth results in alterations in neural connectivity at age 16 years.

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP).

Nicotine dependence as a moderator of a quitline-based message framing intervention.

High nicotine dependence is a reliable predictor of difficulty quitting smoking and remaining smoke-free. Evidence also suggests that the effectiveness of various smoking cessation treatments may vary by nicotine dependence level. Nicotine dependence, as assessed by Heaviness of Smoking Index baseline total scores, was evaluated as a potential moderator of a message-framing intervention provided through the New York State Smokers' Quitline (free telephone based service).

Sample size for post-marketing safety studies based on historical controls.

Purpose: As part of a drug's entire life cycle, post-marketing studies are an important part in the identification of rare, serious adverse events. Recently, the US Food and Drug Administration (FDA) has begun to implement new post-marketing safety mandates as a consequence of increased emphasis on safety. The purpose of this research is to provide exact sample size formula for the proposed hybrid design, based on a two-group cohort study with incorporation of historical external data.

Functional connectivity to a right hemisphere language center in prematurely born adolescents.

Prematurely born children are at increased risk for language deficits at school age and beyond, but the neurobiological basis of these findings remains poorly understood. Thirty-one PT adolescents (600-1250g birth weight) and 36 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children-III (WISC-III), the Peabody Picture Vocabulary Test-Revised (PPVT-R), the Comprehensive Test of Phonological Processing (CTOPP) and the Test of Word Reading Efficiency (TOWRE) at 16years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes.

Alterations in neural connectivity in preterm children at school age.

Converging data suggest recovery from injury in the preterm brain. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that cerebral connectivity involving Wernicke's area and other important cortical language regions would differ between preterm (PT) and term (T) control school age children during performance of an auditory language task. Fifty-four PT children (600-1250 g birth weight) and 24 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children - III (WISC-III), the Peabody Individual Achievement Test - Revised (PIAT-R) and the Peabody Picture Vocabulary Test - Revised (PPVT-R) at 8 years of age.

Longitudinal brain volume changes in preterm and term control subjects during late childhood and adolescence.

Objective: Although preterm very low birth weight infants have a high prevalence of neuroanatomical abnormalities when evaluated at term-equivalent age, patterns of brain growth in prematurely born infants during school age and adolescence remain largely unknown. Our goal was to test the hypothesis that preterm birth results in long-term dynamic changes in the developing brain.

Methods: We performed serial volumetric MRI studies at ages 8 and 12 years in 55 preterm infants born weighing 600 to 1250 g and 20 term control children who participated in the follow-up component of a prospective, randomized, placebo-controlled intraventricular hemorrhage prevention study.

Alterations in functional connectivity for language in prematurely born adolescents.

Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600-1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF).

Risk factors for treatment failure in smokers: relationship to alcohol use and to lifetime history of an alcohol use disorder.

Little is known about the impact of alcohol involvement on smoking cessation relapse or possible mechanisms for these associations. We addressed these issues using data from a randomized clinical trial of two types of framed messages (gain vs. loss) in conjunction with open label sustained-release (SR) bupropion (Toll et al.

Dose-dependent reduction of hazardous alcohol use in a placebo-controlled trial of naltrexone for smoking cessation.

The opiate antagonist naltrexone (Ntx) has demonstrated efficacy in the treatment of alcohol dependence and as a component of treatment to reduce heavy drinking. At present, there are no published dose-ranging clinical trials of the oral preparation for treatment of problem drinking. The present study evaluated the effects of Ntx on alcohol use among the subset of hazardous drinkers (n=102) who participated in a placebo-controlled, dose-ranging trial of oral Ntx (25-mg, 50-mg and 100-mg doses) combined with open-label transdermal nicotine patch for enhancing smoking cessation.

Brain volume reductions within multiple cognitive systems in male preterm children at age twelve.

Objectives: To more precisely examine regional and subregional microstructural brain changes associated with preterm birth.

Study Design: We obtained brain volumes from 29 preterm children, age 12 years, with no ultrasound scanning evidence of intraventricular hemorrhage or cystic periventricular leukomalacia in the newborn period, and 22 age- and sex-matched term control subjects.

Results: Preterm male subjects demonstrated significantly lower white matter volumes in bilateral cingulum, corpus callosum, corticospinal tract, prefrontal cortex, superior and inferior longitudinal fasciculi compared with term male subjects.

Prematurely born children demonstrate white matter microstructural differences at 12 years of age, relative to term control subjects: an investigation of group and gender effects.

Objective: The goal was to use diffusion tensor imaging to test the hypothesis that prematurely born children demonstrate long-term, white matter, microstructural differences, relative to term control subjects.

Methods: Twenty-nine preterm subjects (birth weight: 600-1250 g) without neonatal brain injury and 22 matched, term, control subjects were evaluated at 12 years of age with MRI studies, including diffusion tensor imaging and volumetric imaging; voxel-based morphometric strategies were used to corroborate regional diffusion tensor imaging results. Subjects also underwent neurodevelopmental assessments.

Cortical recruitment patterns in children born prematurely compared with control subjects during a passive listening functional magnetic resonance imaging task.

Objectives: To use functional magnetic resonance imaging (fMRI) to test the hypothesis that subjects who were born prematurely develop alternative systems for processing language.

Study Design: Subjects who were born prematurely (n = 14; 600-1250 g birthweight) without neonatal brain injury and 10 matched term control subjects were examined with a fMRI passive listening task of language, the Clinical Evaluation of Language Fundamentals (CELF) and portions of the Comprehensive Test of Phonological Processing (CTOPP). The fMRI task was evaluated for both phonologic and semantic processing.

A functional magnetic resonance imaging study of the long-term influences of early indomethacin exposure on language processing in the brains of prematurely born children.

Background: Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants.

Objective: The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task.

Methods: Forty-seven prematurely born children (600-1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised.

Control group bias in randomized atypical antipsychotic medication trials for schizophrenia.

Context: It has been suggested that the need for concurrent placebo control groups in new schizophrenia studies might be minimized by making comparisons with external placebo. This strategy requires an assumption of constancy, that the novel medication will perform the same way in a study with only active controls as it would have in a placebo-controlled trial.

Objective: To test this constancy assumption in active- and low dose-controlled trials vs placebo-controlled trials of atypical antipsychotic medications.

Increased temporal lobe gyrification in preterm children.

Preterm birth often results in significant learning disability, and previous magnetic resonance imaging (MRI) studies of preterm children have demonstrated reduction in overall cortical tissue with particular vulnerability in the temporal lobe. We measured cortical gyrification in 73 preterm and 33 term control children at 8 years of age and correlated these findings with tests of language ability to determine the associations among preterm birth, neurodevelopment and functional outcome. Preterm children demonstrated significantly increased bilateral temporal lobe gyrification index compared to term controls.

Prevention of intraventricular hemorrhage by indomethacin in male preterm infants.

Our multicenter Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial demonstrated a reduction of IVH in preterm infants. Analysis of our cohort by sex showed indomethacin halved the incidence of IVH, eliminated parenchymal hemorrhage, and was associated with higher verbal scores at 3 to 8 years in boys.

Volumetric analysis of regional cerebral development in preterm children.

Preterm birth is frequently associated with both neuropathologic and cognitive sequelae. This study examined cortical lobe, subcortical, and lateral ventricle development in association with perinatal variables and cognitive outcome. High-resolution volumetric magnetic resonance imaging scans were acquired and quantified using advanced image processing techniques.

Sex differences in cerebral volumes of 8-year-olds born preterm.

We investigate sex-associated effects of preterm birth on cerebral gray matter (GM) and white matter (WM) volumes. Preterm children (n=65) and 31 healthy, term control children had usable magnetic resonance imaging (MRI) data acquired at 8 years of age. Both GM and WM volumes were significantly reduced in the preterm group compared with controls.

Drug switching patterns among patients with rheumatoid arthritis and osteoarthritis using COX-2 specific inhibitors and non-specific NSAIDs.

Purpose: To compare RA and OA patients' time-to-switch after newly initiating treatment with three most commonly used non-specific (NS)-NSAIDs and two COX-2 inhibitors, celecoxib and rofecoxib.

Methods: Managed care enrollees newly prescribed celecoxib, rofecoxib, ibuprofen, naproxen or diclofenac were identified. Time to switch to a different NS-NSAID or COX-2 specific inhibitor was determined using time-to-event analysis and Cox proportional hazards models were used to estimate the odds ratio (OR) after controlling for potential confounders.

Cardiovascular thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib.

To determine whether the cyclooxygenase-2 (COX-2) inhibitor celecoxib affects cardiovascular thrombotic risk, we analyzed the incidence of cardiovascular events for celecoxib, placebo, and nonsteroidal anti-inflammatory drugs (NSAIDs) in the entire controlled, arthritis clinical trial database for celecoxib. The primary analysis used the Antiplatelet Trialists' Collaboration end points, which include: (1) cardiovascular, hemorrhagic, and unknown deaths, (2) nonfatal myocardial infarction, and (3) nonfatal stroke. Other secondary thrombotic events were also examined.

Systematic review of NSAID-induced adverse reactions in patients with rheumatoid arthritis in Japan.

Abstract A systematic review of randomized controlled clinical trials of nonsteroidal antiinflammatory drugs (NSAIDs) in rheumatoid arthritis (RA) patients was conducted to evaluate the risk of NSAID-induced adverse reactions. Double-blind, randomized, controlled trials with 6-week treatments for RA patients were included in the study. The endpoints for the analysis included any adverse reactions, digestive adverse reactions, and upper gastrointestinal (GI) adverse reactions.