Comparative assessment of efficacy and safety of ambrisentan and bosentan in patients with pulmonary arterial hypertension: A meta-analysis.

WHAT IS KNOWN AND OBJECTIVE: Two endothelin receptor antagonists, ambrisentan and bosentan, have been demonstrated to be effective individually compared with placebo in the treatment of patients with pulmonary arterial hypertension (PAH). This network meta-analysis compared the efficacy and safety of ambrisentan and bosentan in patients with PAH. METHODS: Clinical trials were identified from the Cochrane Central Register of Controlled Trials (CENTRAL/CCTR), EMBASE and PubMed databases. Weighted mean differences (MD) with 95% confidence intervals (CI) were calculated for continuous outcomes (6-min walk distance [6MWD] and Borg dyspnoea index [BDI]). Hazard ratio (HR) was calculated for binary outcomes, including clinical worsening, discontinuation due to adverse events (AEs) and liver dysfunction. Surface under cumulative ranking curve (SUCRA) was used to rank the treatments in each index. RESULTS: Five clinical trials from four published studies (total patients: n = 920) were included. Ambrisentan and bosentan showed no significant difference in 6MWD (MD: -1.32; 95% CI: -27.87, 25.31, SUCRA score: ambrisentan 0.73, bosentan 0.77), BDI (MD: -0.16; 95% CI: -0.98, 0.65, SUCRA score: ambrisentan 0.83, bosentan 0.66), clinical worsening (HR: 0.99; 95% CI: 0.33, 2.94, SUCRA score: ambrisentan 0.75, bosentan 0.74) and discontinuation due to AEs (HR: 0.84; 95% CI: 0.11, 5.86, SUCRA score: ambrisentan 0.47, bosentan 0.57). However, ambrisentan was significantly better than bosentan with respect to abnormal liver function (HR: 23.18; 95% CI: 2.24, 377.20, SUCRA score: ambrisentan 0.99, bosentan 0.02). WHAT IS NEW AND CONCLUSION: The results of this network meta-analysis suggest that ambrisentan was similar to bosentan in efficacy, while it exhibited better tolerability with respect to abnormal liver function in comparison with bosentan, in patients with PAH.

Prehospital Ketamine Administration for Excited Delirium with Illicit Substance Co-Ingestion and Subsequent Intubation in the Emergency Department.

INTRODUCTION: Excited delirium, which has been defined as combativeness, agitation, and altered sensorium, requires immediate treatment in prehospital or emergency department (ED) settings for the safety of both patients and caregivers. Prehospital ketamine use is prevalent, although the evidence on safety and efficacy is limited. Many patients with excited delirium are intoxicated with illicit substances. This investigation explores whether patients treated with prehospital ketamine for excited delirium with concomitant substance intoxication have higher rates of subsequent intubation in the ED compared to those without confirmed substance usage. METHODS: Over 28 months at two large community hospitals, all medical records were retrospectively searched for all patients age 18 years or greater with prehospital ketamine intramuscular (IM) administration for excited delirium and identified illicit and prescription substance co-ingestions. Trained abstractors collected demographic characteristics, history of present illness (HPI), urine drug screens (UDS), alcohol levels, and noted additional sedative administrations. Substance intoxication was determined by UDS and alcohol positivity or negativity, as well as physician HPI. Patients without toxicological testing or documentation of substance intoxication, or who may have tested positive due to ED sedation, were excluded from relevant analyses. Subsequent ED intubation was the primary pre-specified outcome. Odds ratios (OR) and 95% confidence intervals (CI) were calculated to compare variables. RESULTS: Among 86 patients given prehospital ketamine IM for excited delirium, baseline characteristics including age, ketamine dose, and body mass index were similar between those who did or did not undergo intubation. Men had higher intubation rates. Patients testing positive for alcohol, amphetamines, barbiturates, benzodiazepines, ecstasy, marijuana, opiates, and synthetic cathinones, both bath salts and flakka, had similar rates of intubation compared to those negative for these substances. Of 27 patients with excited delirium and concomitant cocaine intoxication, nine (33%) were intubated compared with four of 50 (8%) without cocaine intoxication, yielding a 5.75 OR (95%, CI 1.57 to 21.05; P = .009). CONCLUSION: Patients treated with ketamine IM for excited delirium with concomitant cocaine intoxication had a statistically significant 5.75-fold increased rate of subsequent intubation in the ED. Amongst other substances, no other trends with intubation were noted, but further study is warranted.

Rescue Intubation in the Emergency Department After Prehospital Ketamine Administration for Agitation.

OBJECTIVE: Prehospital intramuscular (IM) ketamine is increasingly used for chemical restraint of agitated patients. However, few studies have assessed emergency department (ED) follow-up of patients receiving prehospital ketamine for this indication, with previous reports suggesting a high rate of post-administration intubation. This study examines the rate of and reasons for intubation and other airway interventions in agitated patients who received ketamine by Emergency Medical Services (EMS). METHODS: This retrospective cohort study included patients who received prehospital ketamine for agitation and were transported to two community hospital EDs. Charts were reviewed for demographics, ketamine dose, and airway intervention by EMS or in the ED. Characteristics of patients who were intubated versus those who did not receive airway intervention were analyzed. RESULTS: Over 28 months, 86 patients received ketamine for agitation. Fourteen (16.3%) underwent endotracheal intubation. Patients with a higher temperature and a lower Glasgow Coma Score (GCS) were more likely to require intubation. There was no age or dose-dependent association on intubation rate. Intubated patients averaged 39 years old versus 44 for patients not intubated (negative five-year difference; 95% CI, -16 to 6). The mean ketamine dose was 339.3mg in patients intubated versus 350.7mg in patients not (-11.4mg difference; 95% CI, -72.4 to 49.6). The mean weight-based ketamine dose was 4.44mg/kg in patients intubated versus 4.96mg/kg in patients not (-0.53mg/kg difference; 95% CI, -1.49 to 0.43). CONCLUSIONS: The observed rate of intubation in patients receiving prehospital ketamine for agitation was 16.3%. Study data did not reveal an age or dose-dependent rate of intubation. Further research should be conducted to compare the airway intervention rate of agitated patients receiving ketamine versus other sedatives in a controlled fashion.

Comparative efficacy and safety and dolutegravir and lamivudine in treatment naive HIV patients.

OBJECTIVE: Compare the efficacy and safety of the 2-drug antiretroviral therapy regimen dolutegravir + lamivudine (DTG + 3TC) with traditional 3-drug regimens in treatment-naive patients with HIV-1. DESIGN: Data from double-blind, randomized controlled trials of at least 48 weeks' duration in treatment-naive patients with HIV-1 identified by systematic review were evaluated using a Bayesian network meta-analysis methodology. METHODS: The primary outcome was virologic suppression at Week 48 for 3-drug regimens versus DTG + 3TC (also analyzed in patient subgroup with baseline viral load >100 000 RNA copies/ml). Secondary outcomes included CD4 cell count change from baseline and safety (adverse events, serious adverse events, and drug-related adverse events) at Week 48. RESULTS: The network contains 14 unique regimens from 14 randomized controlled trials based on data from 10 043 patients. The proportional difference for viral suppression at 48 weeks for DTG + 3TC versus the other 13 regimens included in the network ranged from -2.7% (-11.0, 5.6%) versus DTG + tenofovir alafenamide/emtricitabine (FTC) to 7.3% (0.6, 13.8%) versus efavirenz + tenofovir disoproxil fumarate/FTC. DTG + 3TC was found to be significantly better than efavirenz + tenofovir disoproxil fumarate/FTC and similar to all other regimens analysed in terms of viral suppression at 48 weeks. With regard to other outcomes (CD4, adverse event, serious adverse event, drug-related adverse events) at 48 weeks, DTG+3TC was broadly similar to all regimens analysed. CONCLUSION: This network meta-analysis demonstrates similar efficacy and safety outcomes over 48 weeks with DTG + 3TC compared with traditional 3-drug antiretroviral therapy regimens.

Indirect Comparison of Ropinirole and Pramipexole as Levodopa Adjunctive Therapy in Advanced Parkinson's Disease: A Systematic Review and Network Meta-Analysis.

INTRODUCTION: To evaluate the comparative efficacy and safety of ropinirole and pramipexole as adjunctive therapies to levodopa (L-dopa) for the management of advanced Parkinson's disease (PD), via a systematic review and network meta-analysis. METHODS: Twenty-one double-blind randomised controlled trials of patients with advanced PD with motor fluctuations receiving L-dopa comparing ropinirole or pramipexole with comparators were identified from 2550 publications. Bayesian indirect comparison methods were applied to independently review efficacy outcomes including off-time reduction, Unified Parkinson's Disease Rating Scale-Activity of Daily Living (UPDRS-ADL) and UPDRS-motor scores, and safety outcomes including adverse events (AE) and patient withdrawals, to determine indirect treatment comparison mean differences (MD) or hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The indirect efficacy comparison resulted in a statistically nonsignificant off-time reduction difference (hours) of ropinirole-sustained release (SR) versus pramipexole-immediate release (MD - 0.25; 95% CI - 0.71, 0.21) and ropinirole-SR versus pramipexole-extended release (ER) (MD 0.18; 95% CI - 0.40, 0.76). Ropinirole-SR adjunctive treatment showed a tendency towards more improvement in UPDRS-ADL score (MD 1.24; 95% CI 0.23, 2.24) than adjunctive treatment of pramipexole-ER. Pramipexole-ER may be less likely to induce somnolence as an AE compared with ropinirole-SR (HR 0.46; 95% CI 0.23, 0.89). However, there were no statistically significant differences in UPDRS-motor score reduction, incidence of dyskinesia, hallucination, hypotension, insomnia and nausea, or withdrawals due to AE, for any reason. CONCLUSION: Adjunctive therapy with ropinirole-SR or pramipexole appears to offer similar efficacy and tolerability in patients with advanced PD on the basis of this indirect comparison. FUNDING: GSK.

An indirect comparison of intravenous and subcutaneous belimumab efficacy in patients with SLE and high disease activity.

AIM: To compare the efficacy of intravenous (IV) and subcutaneous (SC) belimumab plus standard therapy in patients with active, autoantibody-positive systemic lupus erythematosus and high disease activity (HDA). PATIENTS & METHODS: An indirect treatment comparison using patient-level data of patients with HDA from three belimumab IV Phase III randomized controlled trials (BLISS-52 [BEL110751]; BLISS-76 [BEL110752]; Northeast Asia study [BEL113750]) and one belimumab SC randomized controlled trial (BLISS-SC [BEL112341]). RESULTS: Similar efficacy results were identified between the belimumab formulations and greater improvements in efficacy endpoints were observed for both formulations compared with placebo. CONCLUSION: This indirect treatment comparison provides further evidence of the efficacy of belimumab IV and SC in patients with systemic lupus erythematosus and HDA, compared with standard therapy.

Comparative Meta-Analysis of the Efficacy of Once-Daily Fluticasone Furoate 100 µG Versus Twice-Daily Fluticasone Propionate 250 µG in Adolescents and Adults with Persistent Asthma.

Fluticasone furoate and fluticasone propionate are recommended options for prophylactic maintenance treatment of persistent asthma. Using data from two previous clinical studies (GSK studies: FFA109685/NCT00603278, FFA112059/NCT01159912), this meta-analysis compared change from baseline in clinic visit mean trough forced expiratory volume in 1 s (FEV1) with fluticasone furoate 100 µg once-daily (FF100) versus fluticasone propionate 250 µg twice-daily (FP250) in adolescents and adults with persistent asthma. Using a DerSimonian-Laird random-effects model (primary meta-analysis), there was no statistically significant difference between FF100 and FP250 in change from baseline in trough FEV1 (-1.7 mL [95% CI -80.4, +77.0], p = 0.9664) and FF100 was non-inferior to FP250. Supporting analyses using least squares mean and fixed-effects model approaches produced similar findings. In this analysis, FF100 and FP250 demonstrated a comparable treatment effect on trough FEV1 in patients aged ≥12 years with persistent asthma; however, results interpretation should consider study design and methodological limitations.

Comparative effectiveness of mepolizumab and omalizumab in severe asthma: An indirect treatment comparison.

BACKGROUND: Severe asthma is a heterogeneous disease. Patients with both eosinophilic and allergic asthma phenotypes may be eligible for treatment with mepolizumab and omalizumab. Evidence on the relative effectiveness of these treatments in this 'overlap' population would be informative for clinical and payer decision making. METHODS: A systematic literature review and indirect treatment comparison (Bayesian framework) were performed to assess the comparative effectiveness and tolerability of mepolizumab and omalizumab, as add-ons to standard of care. Studies included in the primary analysis were double-blind, randomized controlled trials, ≥12 weeks' duration enrolling patients with severe asthma with a documented exacerbation history and receiving high-dose inhaled corticosteroids plus ≥1 additional controller. Two populations were examined: patients potentially eligible for 1) both treatments (Overlap population) and 2) either treatment (Trial population). RESULTS: In the Overlap population, no differences between treatments in clinically significant exacerbations and exacerbations requiring hospitalization were found, although trends favored mepolizumab (rate ratio [RR]:0.66 [95% credible intervals (Crl):0.37,1.19]; 0.19[0.02,2.32], respectively). In the Trial population, mepolizumab treatment produced greater reductions in clinically significant exacerbations (RR:0.63 [95% CrI:0.45,0.89]) but not exacerbations requiring hospitalization compared with omalizumab (RR:0.58 [95% Crl: 0.16,2.13]), although the trend favored mepolizumab. Both treatments had broadly comparable effects on lung function, and similar tolerability profiles. CONCLUSIONS: Whilst this analysis has limitations due to a restricted evidence base and residual heterogeneity, it showed that in patients with severe asthma, mepolizumab seems to be at least as effective as omalizumab and that the tolerability profiles of the two treatments did not meaningfully differentiate.

Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors.

Design and optimization of a novel series of imidazo[1,2-b]pyridazine PDE10a inhibitors are described. Compound 31 displays excellent pharmacokinetic properties and was also evaluated as an insulin secretagogue in vitro and in vivo.

An indirect comparison of HbA1c treatment effect with albiglutide and exenatide 2.0 mg QW using the Bucher method.

No head-to-head comparisons exist between once-weekly (QW) glucagon-like peptide-1 receptor agonists; accordingly, this indirect comparison was conducted to evaluate the comparative efficacy of QW albiglutide vs QW exenatide. Following a systematic literature search, it was determined that HARMONY 7 and DURATION 6, Phase III trials for albiglutide and exenatide, respectively, were similar in study design and baseline characteristics and included a common comparator arm, making them suitable for an indirect comparison using the Bucher method. The primary endpoint of change from baseline in glycated hemoglobin (HbA1c) with albiglutide 50 mg QW and exenatide 2.0 mg QW was compared and tested for noninferiority. The indirect comparison showed a treatment difference of 0.0% (95% confidence interval: -0.189% to 0.189%) in mean change in HbA1c from baseline, and albiglutide 50 mg was noninferior to exenatide 2.0 mg QW at the noninferiority margin of 0.3%. In the absence of a head-to-head trial, these results can be used in pharmacoeconomic analysis and to inform health technology assessment and clinical decision making.

Evaluation of partial coherence correction in X-ray ptychography.

Coherent X-ray Diffraction Imaging (CDI) and X-ray ptychography both heavily rely on the high degree of spatial coherence of the X-ray illumination for sufficient experimental data quality for reconstruction convergence. Nevertheless, the majority of the available synchrotron undulator sources have a limited degree of partial coherence, leading to reduced data quality and a lower speckle contrast in the coherent diffraction patterns. It is still an open question whether experimentalists should compromise the coherence properties of an X-ray source in exchange for a higher flux density at a sample, especially when some materials of scientific interest are relatively weak scatterers. A previous study has suggested that in CDI, the best strategy for the study of strong phase objects is to maintain a high degree of coherence of the illuminating X-rays because of the broadening of solution space resulting from the strong phase structures. In this article, we demonstrate the first systematic analysis of the effectiveness of partial coherence correction in ptychography as a function of the coherence properties, degree of complexity of illumination (degree of phase diversity of the probe) and sample phase complexity. We have also performed analysis of how well ptychographic algorithms refine X-ray probe and complex coherence functions when those variables are unknown at the start of reconstructions, for noise-free simulated data, in the case of both real-valued and highly-complex objects.

Incremental Hospital Costs Associated With Comorbidities of Prematurity.

PURPOSE: Preterm birth (PTB), defined as birth at a gestational age (GA) of less than 37 weeks, is associated with increased hospital costs. Lower GA at birth is negatively correlated with the presence of neonatal comorbidities, further increasing costs. This study evaluated incremental costs associated with comorbidities of PTB following spontaneous labor at 24-36 weeks. DESIGN: Birth records from January 2001 to December 2010 at the Medical University of South Carolina were screened to identify infants born at GA 23-37 weeks after uncomplicated singleton pregnancies and surviving to discharge. METHODOLOGY: Comorbidities of interest and incremental costs were analyzed with a partial least squares (PLS) regression model adjusted for comorbidities and GA. Incremental comorbidity-associated costs, as well as total costs, were estimated for infants of GA 24-36 weeks. RESULTS: A total of 4,292 delivery visit records were analyzed. Use of the PLS regression model eliminated issues of multicollinearity and allowed derivation of stable cost estimates. Incremental costs of comorbidities at a mean GA of 34 weeks ranged from $4,529 to $23,121, and exceeded $9,000 in 6 cases. Incremental costs rangedfrom a high of $41,161 for a GA 24-week infant with a comorbidity of retinopathy of prematurity requiring surgery (ROP4) to $3,683 for a GA 36-week infant with a comorbidity of convulsions. Incremental comorbidity costs are additive, so the costs for infants with multiple comorbidities could easily exceed the high of $41,161 seen with ROP4. CONCLUSIONS: The PLS regression model allowed derivation of stable cost estimates from multivariate and highly collinear data and can be used in future cost analyses. Using this data set, predicted costs of all comorbidities, as well as total costs, negatively correlated with GA at birth.

Augmented saliency model using automatic 3D head pose detection and learned gaze following in natural scenes.

Previous studies have shown that gaze direction of actors in a scene influences eye movements of passive observers during free-viewing (Castelhano, Wieth, & Henderson, 2007; Borji, Parks, & Itti, 2014). However, no computational model has been proposed to combine bottom-up saliency with actor's head pose and gaze direction for predicting where observers look. Here, we first learn probability maps that predict fixations leaving head regions (gaze following fixations), as well as fixations on head regions (head fixations), both dependent on the actor's head size and pose angle. We then learn a combination of gaze following, head region, and bottom-up saliency maps with a Markov chain composed of head region and non-head region states. This simple structure allows us to inspect the model and make comments about the nature of eye movements originating from heads as opposed to other regions. Here, we assume perfect knowledge of actor head pose direction (from an oracle). The combined model, which we call the Dynamic Weighting of Cues model (DWOC), explains observers' fixations significantly better than each of the constituent components. Finally, in a fully automatic combined model, we replace the oracle head pose direction data with detections from a computer vision model of head pose. Using these (imperfect) automated detections, we again find that the combined model significantly outperforms its individual components. Our work extends the engineering and scientific applications of saliency models and helps better understand mechanisms of visual attention.

Complementary effects of gaze direction and early saliency in guiding fixations during free viewing.

Gaze direction provides an important and ubiquitous communication channel in daily behavior and social interaction of humans and some animals. While several studies have addressed gaze direction in synthesized simple scenes, few have examined how it can bias observer attention and how it might interact with early saliency during free viewing of natural and realistic scenes. Experiment 1 used a controlled, staged setting in which an actor was asked to look at two different objects in turn, yielding two images that differed only by the actor's gaze direction, to causally assess the effects of actor gaze direction. Over all scenes, the median probability of following an actor's gaze direction was higher than the median probability of looking toward the single most salient location, and higher than chance. Experiment 2 confirmed these findings over a larger set of unconstrained scenes collected from the Web and containing people looking at objects and/or other people. To further compare the strength of saliency versus gaze direction cues, we computed gaze maps by drawing a cone in the direction of gaze of the actors present in the images. Gaze maps predicted observers' fixation locations significantly above chance, although below saliency. Finally, to gauge the relative importance of actor face and eye directions in guiding observer's fixations, in Experiment 3, observers were asked to guess the gaze direction from only an actor's face region (with the rest of the scene masked), in two conditions: actor eyes visible or masked. Median probability of guessing the true gaze direction within ±9° was significantly higher when eyes were visible, suggesting that the eyes contribute significantly to gaze estimation, in addition to face region. Our results highlight that gaze direction is a strong attentional cue in guiding eye movements, complementing low-level saliency cues, and derived from both face and eyes of actors in the scene. Thus gaze direction should be considered in constructing more predictive visual attention models in the future.

Persistence and compliance with pazopanib in patients with advanced renal cell carcinoma within a U.S. administrative claims database.

BACKGROUND: Pazopanib is an oral tyrosine kinase inhibitor with demonstrated efficacy and tolerability in patients with advanced renal cell carcinoma (RCC). OBJECTIVE: To examine pazopanib persistence and compliance (adherence) and other drug utilization patterns in both treatment-naïve (first-line) patients and those previously treated with RCC therapy in the real-world setting. Key factors affecting persistence and compliance were also explored. METHODS: This was a retrospective claims analysis using the Truven Health MarketScan Databases to cover claims activity from October 2007 through March 2012. Patients with advanced RCC aged ≥ 18 years who had received pazopanib with 180 days of follow-up were included. Bivariate comparisons of results from first-line and previously treated patients with RCC were conducted. Pazopanib persistence was measured using (a) estimated level of persistence with therapy (ELPT; i.e., the percentage of patients remaining on therapy at 30, 60, and 90 days [patients were censored at 180 days]); (b) time to discontinuation (i.e., duration of therapy); and (c) proportion of days covered (PDC; i.e., the ratio of [total days drug available minus days' supply of last prescription] to [last prescription date minus first prescription date]). Compliance was measured by medication possession ratio (MPR; i.e., the ratio of [total days' supply minus days' supply of last prescription] to [last prescription date minus first prescription date]). Other drug utilization measures included days' supply, time to initiation, time to switching, and dose-related measures. Random forest models were used to explore key factors of pazopanib persistence and compliance. RESULTS: A total of 143 patients met all inclusion criteria; 43.3% were treated with pazopanib first line (first-line cohort), and 56.6% had ≥ 1 prior lines of therapy (previously treated cohort). The mean (± standard deviation [SD]) age of patients was 62.9 (± 10.3) years, and 71.3% of them were males. Continuous pazopanib therapy for up to 90 days was observed in greater than 50% of patients in both cohorts. In the first-line cohort, ELPT at 30, 60, and 90 days was 98.39%, 70.97%, and 56.45%, respectively; the mean (± SD) number of days to discontinuation was 112.2 (± 62.8); the mean (± SD) PDC was 84.7% (± 16.7%); and the mean (± SD) MPR was 85.2% (± 16.9%). Similar results were observed in the previously treated population: ELPT at 30, 60, and 90 days was 98.77%, 75.31%, and 58.02%, respectively; the mean (± SD) number of days to discontinuation was 118.7 (± 61.4); the mean (± SD) PDC was 87.8% (± 13.5%); and the mean (± SD) MPR was 90.1% (± 13.9%). Differences between the 2 cohorts were not statistically significant. More than 90% of patients in both cohorts had at least a 30-day supply of therapy (91.9% of first-line versus 90.2% of previously treated; P = 0.153). The mean (± SD) time from metastatic diagnosis to start of pazopanib therapy was 104.7 (± 199.3) days in the first-line cohort and 360.9 (± 187.0) days in previously treated patients (P = 0.001). Forty-six patients switched to another therapy: 17 patients in the first-line cohort and 29 patients in the previously treated cohort; the mean (± SD) time to switching therapy from each cohort was 94.7 (± 41.4) days and 87.8 (± 49.6) days (P = 0.146), respectively. Statistically significant differences were observed for the starting and ending doses between the 2 cohorts. The average daily dosage of pazopanib was greater than 700 mg in both cohorts (P = 0.055), with a maximum dose of 800 mg. Random forest models demonstrated that younger age and higher comorbidity predicted both higher persistence and compliance. CONCLUSIONS: In this observational study, greater than 50% of patients with advanced RCC were on pazopanib for almost 4 months, with the majority of both cohorts achieving high persistence and high compliance. Additionally, younger age and higher comorbidity index were the strongest predictors of both greater persistence and compliance. Further studies with larger cohorts and longer follow-up are needed to validate these findings.

A proposed modification to Hy's law and Edish criteria in oncology clinical trials using aggregated historical data.

PURPOSE: Identifying drug-induced liver injury is a critical task in drug development and postapproval real-world care. Severe liver injury is identified by the liver chemistry threshold of alanine aminotransferase (ALT) >3× upper limit of normal (ULN) and bilirubin >2× ULN, termed Hy's law by the Food and Drug Administration. These thresholds require discontinuation of the causative drug and are seldom exceeded in most patient populations. However, because maintenance of therapy is critical in the treatment of advanced cancer, customized thresholds may be useful in oncology patient populations, particularly for those with baseline liver chemistries elevations. METHODS: Liver chemistry data from 31 aggregated oncology clinical trials were modeled through a truncated robust multivariate outlier detection (TRMOD) method to develop the decision boundary or threshold for examining liver injury in oncology clinical trials. RESULTS: The boundary of TRMOD identified outliers with an ALT limit 5.0× ULN and total bilirubin limit 2.7× ULN. In addition, TRMOD was applied to the aggregated oncology data to examine fold-baseline ALT and total bilirubin, revealing limits of ALT 6.9× baseline and bilirubin 6.5× baseline. Similar ALT and bilirubin threshold limits were observed for oncology patients both with and without liver metastases. CONCLUSIONS: These higher liver chemistry thresholds examining fold-ULN and fold-baseline data may be valuable in identifying potential severe liver injury and detecting liver safety signals of clinical concern in oncology clinical trials and postapproval settings while helping to avoid premature discontinuation of curative therapy.

Truncated robust distance for clinical laboratory safety data monitoring and assessment.

Laboratory safety data are routinely collected in clinical studies for safety monitoring and assessment. We have developed a truncated robust multivariate outlier detection method for identifying subjects with clinically relevant abnormal laboratory measurements. The proposed method can be applied to historical clinical data to establish a multivariate decision boundary that can then be used for future clinical trial laboratory safety data monitoring and assessment. Simulations demonstrate that the proposed method has the ability to detect relevant outliers while automatically excluding irrelevant outliers. Two examples from actual clinical studies are used to illustrate the use of this method for identifying clinically relevant outliers.

An integrated analysis of liver safety data from orlistat clinical trials.

OBJECTIVE: Orlistat is an oral gastrointestinal lipase inhibitor and is indicated for treatment of obesity in combination with a hypocaloric diet. Post-marketing reports of adverse reactions revealed hints for possible drug-induced liver injury which has prompted changes to the product information. Orlistat's development program, involving over 30,000 patients, did not indicate a hepatic safety issue. METHODS: We analyzed liver function test data from randomized clinical trials of orlistat, using i) meta-analysis of published study safety data, ii) time-to-event analysis for individual patients, and iii) a novel and more sensitive method derived from the U.S. Food and Drug Administration's (FDA) evaluation of drug-induced serious hepatotoxicity (eDISH) technique. Over 10,000 subjects were included. RESULTS: The combined odds ratio from a simple summary-level fixed-effects meta-analysis of treatment-emergent abnormalities in serum alanine aminotransferase (ALT) (defined as greater than the upper level of normal for 2 successive measurements) was 1.09 (95% CI 0.93-1.28), and in total bilirubin 1.24 (95% CI 1.03-1.49). Part of the small apparent effect was due to longer exposure to orlistat than to placebo, on average. A patient-level display, adjusting for regression towards the mean, and Kaplan-Meier analysis of changes in ALT and bilirubin, taking account of different exposure, showed no significant difference between orlistat and placebo. This shows that there is no signal for hepatic damage in clinical studies of orlistat. CONCLUSION: While idiosyncratic liver injury following exposure to orlistat cannot be excluded, it is likely to be extremely rare.

Validation of multivariate outlier detection analyses used to identify potential drug-induced liver injury in clinical trial populations.

BACKGROUND: Potential severe liver injury is identified in clinical trials by ALT >3 × upper limits of normal (ULN) and total bilirubin >2 × ULN, and termed 'Hy's Law' by the US FDA. However, there is limited evidence or validation of these thresholds in clinical trial populations. Using liver chemistry data from clinical trials, decision boundaries were built empirically with truncated robust multivariate outlier detection (TRMOD), in a statistically robust manner, and then compared with these fixed thresholds. Additionally, as the analysis of liver chemistry change from baseline has been recently suggested for the identification of liver signals, fold-baseline data was also assessed. OBJECTIVE: The aim of the study was to examine and validate the performance of fixed and empirically derived thresholds for severe liver injury in generally healthy clinical trial populations (i.e. populations without underlying renal, haematological or liver disease). METHODS: Using phase II-IV clinical trial data, ALT and total bilirubin data were analysed using outlier detection methods to compare with empirically derived and fixed thresholds of the FDA's Hy's Law limits, which were then assessed graphically with the FDA's evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) assessing fold-ULN, as well as a modified eDISH (mDISH) to assess fold-baseline liver chemistries. Data from 28 phase II-IV clinical trials conducted by GlaxoSmithKline were aggregated and analysed by the TRMOD algorithm to create decision boundaries. The data consisted of 18 672 predominantly female subjects with a mean age of 44 years and without known liver disease. RESULTS: Among generally healthy clinical trial subjects, the empirically-derived TRMOD boundaries were approximately equivalent to 'Hy's Law'. TRMOD boundaries for identifying outliers were an ALT limit of 3.4 × ULN and a bilirubin limit of 2.1 × ULN, compared with the FDA's 'Hy's Law' of 3 × ULN and bilirubin 2 × ULN. Inter-laboratory data variations were observed across the 28 studies, and were diminished by use of baseline-corrected data. By applying TRMOD to baseline-corrected data, these boundaries became ALT limit of 3.8 × baseline and bilirubin limit of 4.8 × baseline. Cumulative incidence plots of liver signals identified over time were examined. TRMOD analyses identified normative boundaries and outliers that provide comparative data to detect liver signals in similar trial populations. CONCLUSIONS: TRMOD liver chemistry analyses of clinical trial data in generally healthy subjects have confirmed the FDA's Hy's Law threshold as a robust means of detecting liver safety outliers. TRMOD evaluation of liver chemistry data, by both fold-ULN and fold-baseline, provides complementary analyses and valuable normative data for comparison in similar patient populations. No liver signal is present when new clinical trial data from similar patient populations lies within these normative boundaries. Use of baseline-corrected data diminishes inter-laboratory variation and may be more sensitive to possible drug effects. We suggest examining liver chemistries using graphical depictions of both ULN-corrected data (eDISH) and baseline-corrected data (mDISH), as complementary methods.

Discovery of vinylcycloalkyl-substituted benzimidazole TRPM8 antagonists effective in the treatment of cold allodynia.

Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described.