Maternal paracetamol intake and fetal ductus arteriosus constriction/closure: comprehensive signal evaluation using the Austin Bradford Hill criteria.

PURPOSE: Acetaminophen (APAP) is available over-the-counter and widely regarded as safe for use in pregnancy. APAP has been used to close a persistently patent ductus arteriosus. Fetal constriction/closure of the ductus arteriosus (FCCDA), of public health interest given the drug's widespread use during pregnancy, is being monitored globally, including by the European Medicines Agency Pharmacovigilance Risk Assessment Committee. Our objective was to share a comprehensive signal evaluation of FCCDA with in utero APAP exposure to determine if the totality of evidence is sufficiently more consistent with one of the following two possibilities: (1) APAP never contributes to FCCDA (null hypothesis or HO) versus (2) APAP may in some cases be at least a contributory cause of in utero DA narrowing (alternative hypothesis or HA) to justify risk communication. METHODS: To assess the relative support for HO versus HA, we synthesize and interpret within an Austin Bradford Hill criteria framework a comprehensive, cross-disciplinary set of published information and de novo analysis, including toxicology, epidemiology, clinical pharmacology, and clinical and quantitative pharmacovigilance analysis of spontaneous reports. RESULTS: While residual uncertainty remains, the totality of information is more compatible with HA than H0, to the extent that it is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA. CONCLUSION: It is reasonably possible that APAP may sometimes be at least a contributory cause of FCCDA, and this should therefore be communicated to stakeholders. TRIAL REGISTRATION: CLINICALTRIALS. GOV REGISTRATION: NOT APPLICABLE.

A comparative clinical study of PF-06410293, a candidate adalimumab biosimilar, and adalimumab reference product (Humira®) in the treatment of active rheumatoid arthritis.

BACKGROUND: This double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10-25 mg/week). We report results for the first 26 weeks of treatment. METHODS: Patients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (-12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28-4(CRP)], European League Against Rheumatism (EULAR) response, DAS28-4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26. RESULTS: Patients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28-4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was -2.98% and corresponding CIs-95% CI (-10.38%, 4.44%) and 90% CI (-9.25%, 3.28%)-were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU). CONCLUSIONS: The study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02480153 . First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29 . Start date: October 27, 2014.

Long-term safety and tolerability of bapineuzumab in patients with Alzheimer's disease in two phase 3 extension studies.

BACKGROUND: Immunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer's disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols. METHODS: The long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses. RESULTS: Because of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7% of the patients who originally received placebo and 66.9% of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1% and 67.6% of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7% and 64.3% of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11% of placebo + bapineuzumab and 4% of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study. CONCLUSIONS: In these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials. TRIAL REGISTRATION: Noncarriers (Study 3002): ClinicalTrials.gov NCT00996918 . Registered 14 October 2009. Carriers (Study 3003): ClinicalTrials.gov NCT00998764 . Registered 16 October 2009.

Bapineuzumab for mild to moderate Alzheimer's disease in two global, randomized, phase 3 trials.

BACKGROUND: Our objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer's disease (AD). METHODS: Two of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale and the Disability Assessment for Dementia. RESULTS: A total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event. CONCLUSIONS: These phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed. TRIAL REGISTRATION: Noncarriers (3000) ClinicalTrials.gov identifier NCT00667810 ; registered 24 Apr 2008. Carriers (3001) ClinicalTrials.gov identifier NCT00676143 ; registered 2 May 2008.

Cytochrome P450 2D6 phenoconversion is common in patients being treated for depression: implications for personalized medicine.

OBJECTIVE: Determine the point prevalence of phenoconversion to cytochrome P450 2D6 (CYP2D6) poor metabolizer status in clinical practice. METHOD: This multicenter, open-label, single-visit naturalistic study was conducted from October 2008 to July 2009 in adult patients (≥ 18 years) who had been receiving venlafaxine extended-release (ER) (37.5-225 mg/d) treatment for up to 8 weeks. A 15-mL blood sample was drawn 4 to 12 hours after patients' last venlafaxine ER dose. Plasma O-desmethylvenlafaxine and venlafaxine concentrations were determined for each patient. CYP2D6 poor metabolizer phenotype was defined as O-desmethylvenlafaxine to venlafaxine ratio < 1 based on published data. CYP2D6 genotype was determined for each patient; patients were classified as poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultrarapid metabolizer. Agreement between poor metabolizer phenotype and genotype classifications was assessed using the McNemar test. RESULTS: Phenoconversion to CYP2D6 poor metabolizer status occurred in 209 of 865 individuals (24%) with a CYP2D6 non-poor metabolizer genotype. The incidence of CYP2D6 poor metabolizer status based on phenotype was almost 7 times higher than that expected based on genotype: only 4% (35/900) of patients were genotypic CYP2D6 poor metabolizers, but 27% (243/900) were phenotypic CYP2D6 poor metabolizers (McNemar test, P < .0001). CONCLUSIONS: CYP2D6 phenotype conversion is common in patients being treated for depression. These results are important because differences in CYP2D6 drug metabolic capacity, whether genetically determined or due to phenoconversion, can affect clinical outcomes in patients treated with drugs substantially metabolized by CYP2D6. These results demonstrate that personalized medicine based solely on genetics can be misleading and support the need to consider drug-induced variability as well. TRIAL REGISTRATION: ClinicalTrials identifier: NCT00788944.

Targeting Beta amyloid: a clinical review of immunotherapeutic approaches in Alzheimer's disease.

As the societal and economic burdens of Alzheimer's disease (AD) continue to mount, so does the need for therapies that slow the progression of the illness. Beta amyloid has long been recognized as the pathologic hallmark of AD, and the past decade has seen significant progress in the development of various immunotherapeutic approaches targeting beta amyloid. This paper reviews active and passive approaches aimed at beta amyloid, with a focus on clinical trial data.

Patient outcomes with education, drug therapy, and support: a study of venlafaxine ER-treated outpatients with major depressive disorder.

OBJECTIVE: Dialogues Time to Talk (Dialogues) is a care management program that provides additional follow-up care and patient education for outpatients with major depressive disorder (MDD) starting venlafaxine extended release (ER) therapy. This study examined the effect of the Dialogues program on patient treatment satisfaction. METHODS: In this 6-month, open-label study, primary care patients with MDD received usual care and were randomly assigned to venlafaxine ER (75 to 225 mg/d) either alone or in combination with the Dialogues program (venlafaxine ER + D). The primary outcome was patient treatment satisfaction on day 112, measured by the 10- point Satisfaction with Depression Care Scale (SDCS). Secondary efficacy outcomes included the 17-item Hamilton Rating Scale for Depression (HAM-D17) total score, response (≥50% decrease from baseline HAM-D17 score), and remission (HAM-D17 ≤ 7). RESULTS: The modified intent-to-treat population included 263 patients in the venlafaxine ER group and 257 in the venlafaxine ER+D group. The percentage of patients with an SDCS "very satisfied" score (≥8) at day 112 was not significantly different in the venlafaxine ER and venlafaxine ER+D groups (63% and 58%, respectively; P = 0.22). No significant differences were found on any secondary outcomes. CONCLUSION: Among primary care patients starting venlafaxine ER for MDD, participation in the Dialogues program did not have a statistically significant effect on patient treatment satisfaction.

Cytochrome P450 2D6 phenotype predicts antidepressant efficacy of venlafaxine: a secondary analysis of 4 studies in major depressive disorder.

INTRODUCTION: Venlafaxine, a serotonin-norepinephrine reuptake inhibitor antidepressant, is metabolized primarily by the cytochrome P450 2D6 enzyme into O-desmethylvenlafaxine (ODV). The ODV/venlafaxine ratio can be used to distinguish between extensive metabolizers (EMs) and poor metabolizers (PMs). OBJECTIVES: To determine the relative efficacy and tolerability of venlafaxine in EM vs PM patients with major depressive disorder (MDD). METHOD: Data from 4 double-blind, placebo-controlled studies of patients with MDD were pooled. Blood samples were analyzed for plasma concentrations of venlafaxine, ODV, total venlafaxine + ODV, and ODV/venlafaxine ratio. Patients were classified as EMs or PMs on the basis of ODV/venlafaxine ratios. Changes from baseline in depression scale scores were compared between EMs and PMs using t tests. Rates of response, remission, discontinuation, and adverse events (AEs) were compared for EMs and PMs using Fisher exact tests. RESULTS: Compared with PMs, EMs had significantly greater mean changes from baseline on 4 of 5 depression rating scales (all 4 comparisons, P ≤ .020). A significantly greater percentage of EMs achieved response or remission by most measures compared with PMs (4 of 5 comparisons, P ≤ .015). Rates of discontinuation and AEs did not differ significantly between EMs and PMs. Since there were no substantial differences between EMs and PMs in terms of venlafaxine dose or tolerability, these factors are not likely to account for the efficacy findings. CONCLUSIONS: Venlafaxine treatment in EMs was associated with greater efficacy in MDD on virtually all measures compared with PMs, with no important tolerability differences.

Venlafaxine metabolism as a marker of cytochrome P450 enzyme 2D6 metabolizer status.

INTRODUCTION: One of the major enzymes of the cytochrome P450 drug-metabolizing system, CYP2D6, shows a high degree of genetic polymorphism and variability in activity. Based on the degree of CYP2D6 activity, individuals can be broadly classified as poor metabolizers (PMs) or extensive metabolizers (EMs); the metabolism of CYP2D6 substrates differs among PMs and EMs. The metabolism of various drugs that are substrates of CYP2D6 has been used as a marker for metabolic phenotype, calculating the plasma or urinary metabolic ratio of the parent compound to its metabolite. The current analysis evaluates the use of the O-desmethylvenlafaxine-venlafaxine ratio (ODV/VEN) after administration of VEN, a CYP2D6 substrate, for determining CYP2D6 metabolic phenotype in healthy adults receiving VEN. METHODS: The analysis included data from 2 studies in which healthy adults were classified as either EMs or PMs using established methods (1 genotypic and 1 phenotypic) and were then administered VEN at daily dosages ranging from 75 to 150 mg. Blood plasma samples were taken at various time points, and the ODV/VEN ratio was calculated. RESULTS: Blood samples from 28 participants in the 2 studies were available for analysis. The ODV/VEN ratio distinguished the EM and PM phenotypes; ratios were 1 or greater for EMs and less than 1 for PMs at 4 hours after dose administration. CONCLUSIONS: The ratio of ODV/VEN is an effective means of phenotyping individuals according to their CYP2D6 metabolizer status.

Video/EEG monitoring in the evaluation of paroxysmal behavioral events: duration, effectiveness, and limitations.

To establish the number of monitoring days needed to distinguish psychogenic nonepileptic seizures (PNES) from epileptic seizures (ES) in adult patients admitted for video/EEG monitoring (VEM), we performed a retrospective chart review on 199 consecutive admissions for behavioral event diagnosis with VEM. Of the 199 adult patients admitted for VEM, 83.9% (n = 167) had a clinical event during admission, and a definitive diagnosis was made in 75.9% (n = 151). Of patients who had clinical events, 87.7% (n = 143) had their first event on admission day 1 or 2. Factors associated with ES (vs PNES) included an abnormal baseline EEG (P < 0.001), an abnormal brain MRI (P = 0.01), and history of events lasting less than 1minute (P = 0.01). There was no association between time to first event and discharge diagnosis. VEM differentiated between ES and PNES in the majority of adult patients evaluated. Most behavioral events were characterized within 2 days of admission.