Opportunities and challenges with decentralized trials in Neuroscience.

Decentralized clinical trials (DCTs), that is, studies integrating elements of telemedicine and mobile/local healthcare providers allowing for home-based assessments, are an important concept to make studies more resilient and more patient-centric by taking into consideration participant's views and shifting trial activities to better meet the needs of trial participants. There are however, not only advantages but also challenges associated with DCTs. An area to be addressed by appropriate statistical methodology is the integration of data resulting from a possible mix of home and clinic assessments at different visits for the same variable, especially in adjusting for sources of possible systematic differences. One source of systematic bias may be how a participant perceives their disease and treatment in their home versus in a clinical setting. In this paper, we will discuss these issues with a focus on Neuroscience when participants have the choice between home and clinic assessments to illustrate how to identify systematic biases and describe appropriate approaches to maintain clinical trial scientific rigor. We will describe the benefits and challenges of DCTs in Neuroscience and then describe the relevance of home versus clinic assessments using the estimand framework. We outline several options to enable home assessments in a study. Results of simulations will be presented to help deciding between design and analysis options in a simple scenario where there might be differences in response between clinic and home assessments.

Circulating Biomarkers of Inflammation and Endothelial Activation in Diabetic Retinopathy.

Inflammation and endothelial activation play a pivotal role in development and progression of diabetic retinopathy (DR), a vision-threatening complication of diabetes mellitus (DM) and the leading cause of blindness in the working age population. Easily accessible and validated biomarkers for DR early diagnosis and progression are required for use in clinical trials: here, we reviewed the available literature to understand the association of circulating levels of selected markers of inflammation and endothelial activation with the presence of nonproliferative and proliferative DR (NPDR and PDR) and investigate the relationship between their systemic and ocular levels. We additionally provide data synthesis and perform statistical analysis for interpretation of the collected evidence. CRP, IL-1ß, IL-6, TNFα, sICAM1, and sVCAM1 circulating levels were increased in subjects with DM compared to healthy individuals. Moreover, TNFα and sVCAM1 showed increasing systemic levels with DR presence and severity; circulating CRP increased with the transition from no DR to NPDR, whereas IL-6 was increased in PDR compared to NDPR stages. The relationship between ocular and systemic concentrations of these proteins remained unclear due to the low number of studies with matched sampling. In conclusion, the available data supports the use of systemic biomarkers of inflammation and endothelial activation to identify DM status and DR severity. These systemic biomarkers are likely reflecting an overall state of inflammation and vascular activation in different tissues of the body, including the eyes. Prospective, longitudinal datasets are required to validate these biomarkers as predictors of early DR presence, of DR progression, or for disease monitoring.

Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms.

Background: Reduced activation of dopamine D1 receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D2- and D1-dependent signaling. Methods: We assessed whether augmentation of D1 signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms. In a 3-period, double-blind, crossover study, we investigated the effects of RG7203 (5 mg and 15 mg doses) and placebo as adjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia with moderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior were evaluated using the monetary incentive delay task during functional magnetic resonance imaging and the effort-cost-benefit and working memory reinforcement learning tasks. Results: Patients (N = 33; 30 male, mean age ± SD 36.6 ± 7.0 years; Positive and Negative Syndrome Scale negative symptom factor score 23.0 ± 3.5 at screening) were assessed at three study centers in the United States; 24 patients completed the study. RG7203 at 5 mg significantly increased reward expectation-related activity in the monetary incentive delay task, but in the context of significantly decreased overall activity across all task conditions. Conclusions: In contrast to our expectations, RG7203 significantly worsened reward-based effortful behavior and indices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negative symptoms in patients with schizophrenia.

Effects of valganciclovir on spermatogenesis in renal transplant patients - results of a multicenter prospective nonrandomized study.

Ganciclovir (GCV) inhibits spermatogenesis in preclinical studies but long-term effects on fertility in renal transplant patients are unknown. In a prospective, multicenter, open-label, nonrandomized study, male patients were assigned to Cohort A [valganciclovir (VGCV), a prodrug of GCV] (n = 38) or B (no VGCV) (n = 21) by cytomegalovirus prophylaxis requirement. Changes in semen parameters and DNA fragmentation were assessed via a mixed-effects linear regression model accounting for baseline differences. Sperm concentration increased post-transplant, but between baseline and treatment end (mean 164 days Cohort A, 211 days Cohort B), the model-based change was lower in Cohort A (difference: 43.82 × 106 /ml; P = 0.0038). Post-treatment, sperm concentration increased in Cohort A so that by end of follow-up (6 months post-treatment) changes were comparable between cohorts (difference: 2.09 × 106 /ml; P = 0.92). Most patients' sperm concentration improved by end of follow-up; none with normal baseline concentrations (≥20 × 106 /ml) were abnormal at end of follow-up. Changes in seminal volume, sperm motility/morphology, DNA fragmentation, and hormone levels were comparable between cohorts at end of follow-up. Improvement in semen parameters after renal transplant was delayed in men receiving VCGV, but 6 months post-treatment parameters were comparable between cohorts.

Generics in transplantation medicine: Randomized comparison of innovator and substitution products containing mycophenolate mofetil
.

OBJECTIVE: Mycophenolate mofetil (MMF) is widely used as an immunosuppressant for the prophylaxis of acute organ rejection in recipients of solid organ transplants. MATERIALS AND METHODS: We have compared, in healthy subjects, the pharmacokinetics of mycophenolic acid when MMF was administered in the form of the innovator product CellCept (F. Hoffmann-La Roche Ltd.) or one of three commercially available generics, Renodapt (Biocon Ltd.), Mycept (Panacea Biotec), or Cellmune (Cipla Ltd.). The study was powered to detect a 20% difference in mean formulation performance measures, but not to formally evaluate bioequivalence. Geometric mean ratios of maximum concentrations (Cmax) and areas under plasma concentration-time curves were calculated. RESULTS: Comparing generics against each other, the differences in point estimates of the geometric mean ratios of Cmax of two of the comparisons were either borderline within (Renodapt/Cellmune) or clearly outside (Mycept/Cellmune) a region of 80 - 125% around the reference mean, indicating that bioequivalence between these generics may be difficult to show. CONCLUSION: Physicians in the field of transplantation should be aware of the potential risk of altering the therapeutic outcome when switching from one preparation of MMF to another. ClinicalTrials.gov identifier: NCT02981290.

Restricted mean survival time for the analysis of cardiovascular outcome trials assessing non-inferiority: Case studies from antihyperglycemic drug development.

Cardiovascular outcome trials (CVOTs) have been employed in multiple therapeutic areas to explore whether a noncardiovascular drug increases the risk for cardiovascular events. These studies are now a central part of drug development programs for antihyperglycemic drugs. These programs are expected to demonstrate that new antihyperglycemic drugs for patients with Type 2 diabetes do not have unacceptable cardiovascular risk. The hazard ratio, which is usually provided as evidence that patients receiving the investigational treatment are not at statistically significantly greater cardiovascular risk than patients on the control treatment, can be difficult to interpret for various reasons. Therefore, an alternative approach known as the Restricted Mean Survival Time (RMST) or τ-year mean survival time is presented, and its ability to overcome interpretation challenges with the hazard ratio discussed. The RMST approach is applied to five completed CVOTs and is compared with the corresponding hazard ratios. Additionally, detailed considerations are given on how to design a non-inferiority CVOT using the RMST approach. The RMST methodology is shown to be a practical alternative to the hazard ratio methodology for designing a non-inferiority CVOT.

A Framework Proposal to Follow-Up on Preclinical Convulsive Signals of a New Molecular Entity in First-in-Human Studies Using Electroencephalographic Monitoring.

Traditionally, in dose-escalating first-in-human (FiH) studies, a dose cap with a 10-fold safety margin to the no observed effect level in animals is implemented if convulsive events are observed in animals. However, the convulsive risk seen in animals does not generally translate to humans. Several lines of evidence are summarized indicating that in a dose-escalating setting, electroencephalographic epileptiform abnormalities occur at lower doses than clinical convulsive events. Therefore, we propose to consider the occurrence of epileptiform abnormalities in toxicology studies as premonitory signals for convulsions in dose-escalating FiH studies. Compared with the traditional dose-cap approach, this may allow the exploration of higher doses in FiH and, subsequently, phase II studies without compromising human safety. Similarly, the presence or absence of electroencephalographic epileptiform abnormalities may also aid the assessment of proconvulsive risk in situations of increased perpetrator burden as potentially present in pharmacokinetic and/or pharmacodynamic drug-drug interactions.

Effect of Hepatic Impairment on the Pharmacokinetics of Alectinib.

Alectinib is approved and recommended as the preferred first-line treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer. The effect of hepatic impairment on the pharmacokinetics (PK) of alectinib was assessed with physiologically based PK modeling prospectively and in a clinical study. An open-label study (NCT02621047) investigated a single 300-mg dose of alectinib in moderate (n = 8) and severe (n = 8) hepatic impairment (Child-Pugh B/C), and healthy subjects (n = 12) matched for age, sex, and body weight. Physiologically based PK modeling was conducted prospectively to inform the clinical study design and support the use of a lower dose and extended PK sampling in the study. PK parameters were calculated for alectinib, its major similarly active metabolite, M4, and the combined exposure of alectinib and M4. Unbound concentrations were assessed at 6 and 12 hours postdose. Administration of alectinib to subjects with hepatic impairment increased the area under the plasma concentration-time curve from time 0 to infinity of the combined exposure of alectinib and M4 to 136% (90% confidence interval [CI], 94.7-196) and 176% (90%CI 98.4-315), for moderate and severe hepatic impairment, respectively, relative to matched healthy subjects. Unbound concentrations for alectinib and M4 did not appear substantially different between hepatic-impaired and healthy subjects. Moderate hepatic impairment had only a modest, not clinically significant effect on alectinib exposure, while the higher exposure observed in severe hepatic impairment supports a dose adjustment in this population.

Effect of alectinib on cardiac electrophysiology: results from intensive electrocardiogram monitoring from the pivotal phase II NP28761 and NP28673 studies.

PURPOSE: Alectinib, a central nervous system (CNS)-active ALK inhibitor, has demonstrated efficacy and safety in ALK+ non-small-cell lung cancer that has progressed following crizotinib treatment. Other ALK inhibitors have shown concentration-dependent QTc prolongation and treatment-related bradycardia. Therefore, this analysis evaluated alectinib safety in terms of electrophysiologic parameters. METHODS: Intensive triplicate centrally read electrocardiogram (ECG) and matched pharmacokinetic data were collected across two alectinib single-arm trials. Analysis of QTcF included central tendency analysis [mean changes from baseline with one-sided upper 95% confidence intervals (CIs)], categorical analyses, and relationship between change in QTcF and alectinib plasma concentrations. Alectinib effects on other ECG parameters (heart rate, PR interval and QRS duration) were also evaluated. RESULTS: Alectinib did not cause a clinically relevant change in QTcF. The maximum mean QTcF change from baseline was 5.3 ms observed pre-dose at week 2. The upper one-sided 95% CI was <10 ms at all time points. There was no relevant relationship between change in QTcF and alectinib plasma concentrations. Alectinib treatment resulted in a generally asymptomatic exposure-dependent decrease in mean heart rate of ~11 to 13 beats per minute at week 2. No clinically relevant effects were seen on other ECG parameters. Approximately 5% of patients reported cardiac adverse events of bradycardia or sinus bradycardia; however, these were all grade 1-2. CONCLUSIONS: Alectinib does not prolong the QTc interval or cause changes in cardiac function to a clinically relevant extent, with the exception of a decrease in heart rate which was generally asymptomatic.

Bayesian predictive power: choice of prior and some recommendations for its use as probability of success in drug development.

Bayesian predictive power, the expectation of the power function with respect to a prior distribution for the true underlying effect size, is routinely used in drug development to quantify the probability of success of a clinical trial. Choosing the prior is crucial for the properties and interpretability of Bayesian predictive power. We review recommendations on the choice of prior for Bayesian predictive power and explore its features as a function of the prior. The density of power values induced by a given prior is derived analytically and its shape characterized. We find that for a typical clinical trial scenario, this density has a u-shape very similar, but not equal, to a ß-distribution. Alternative priors are discussed, and practical recommendations to assess the sensitivity of Bayesian predictive power to its input parameters are provided. Copyright © 2016 John Wiley & Sons, Ltd.

Does Vascular Calcification Accelerate Inflammation?: A Substudy of the dal-PLAQUE Trial.

BACKGROUND: Atherosclerosis is an inflammatory condition with calcification apparent late in the disease process. The extent and progression of coronary calcification predict cardiovascular events. Relatively little is known about noncoronary vascular calcification. OBJECTIVES: This study investigated noncoronary vascular calcification and its influence on changes in vascular inflammation. METHODS: A total of 130 participants in the dal-PLAQUE (Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging) study underwent fluorodeoxyglucose positron emission tomography/computed tomography at entry and at 6 months. Calcification of the ascending aorta, arch, carotid, and coronary arteries was quantified. Cardiovascular risk factors were related to arterial calcification. The influences of baseline calcification and drug therapy (dalcetrapib vs. placebo) on progression of calcification were determined. Finally, baseline calcification was related to changes in vascular inflammation. RESULTS: Age >65 years old was consistently associated with higher baseline calcium scores. Arch calcification trended to progress more in those with calcification at baseline (p = 0.055). There were no significant differences between progression of vascular calcification with dalcetrapib compared to that with placebo. Average carotid target-to-background ratio indexes declined over 6 months if carotid calcium was absent (single hottest slice [p = 0.037], mean of maximum target-to-background ratio [p = 0.010], and mean most diseased segment [p < 0.001]), but did not significantly change if calcification was present at baseline. CONCLUSIONS: Across multiple arterial regions, higher age is consistently associated with higher calcium scores. The presence of vascular calcification at baseline is associated with progressive calcification; in the carotid arteries, calcification appears to influence vascular inflammation. Dalcetrapib therapy did not affect vascular calcification.

Sequentially updating the likelihood of success of a Phase 3 pivotal time-to-event trial based on interim analyses or external information.

When performing a pivotal clinical trial, it may be of interest to assess the probability of success (PoS) of that trial. Initially evaluated when the trial is designed, PoS can be updated as the trial progresses and new information about the drug effect becomes available. Such information can be external to the trial, such as results from trials conducted in parallel, or internal, such as continuing after an interim analysis. We develop a framework to update PoS based on such internal and external information for a time-to-event endpoint and illustrate it using a realistic development program for a new molecule.

Subcutaneous Bioavailability of Taspoglutide at 3 Different Injection Sites in Healthy Overweight/Obese Subjects.

PURPOSE: Taspoglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist that has >90% homology with the endogenous GLP-1 while retaining equivalent potency. Once-weekly subcutaneous injections with taspoglutide demonstrated meaningful antihyperglycemic and weight loss effects in patients with type 2 diabetes. The present study was performed to compare the relative bioavailability of taspoglutide injected subcutaneously in the abdomen, upper arm, and thigh. METHODS: Healthy overweight/obese subjects were randomized in an open-label, 3-way crossover study. A single 20-mg dose of taspoglutide was injected subcutaneously on 3 occasions in the abdomen, upper arm, or thigh. Each injection was separated by a 12-week washout period. Blood was sampled up to 12 weeks for the pharmacokinetic evaluation of taspoglutide. FINDINGS: Sixty subjects were randomized into the study (mean age, 45.5 years; body weight, 97.6 kg; and body mass index, 31.4 kg/m(2)). AUClast values (geometric mean) for subcutaneous injections in the abdomen, upper arm, and thigh were 44.2, 61.2, and 50.0 ng·h/mL, respectively. The geometric mean ratio (relative bioavailability) for the upper arm versus the abdomen was 1.41 (90% CI: 1.22-1.62) and for the thigh versus the abdomen was 1.13 (90% CI: 0.98-1.31). Corresponding Cmax values for subcutaneous injections in the abdomen, upper arm, and thigh were 0.268, 0.382, and 0.341 ng/mL, respectively, and the geometric mean ratio for the upper arm versus the abdomen was 1.43 (90% CI: 1.24-1.64) and for the thigh versus the abdomen was 1.27 (90% CI: 1.10-1.46). Decreases in taspoglutide exposure were observed with each subsequent period. AUClast values (geometric mean across injections sites) for periods 1, 2, and 3 were 97.2, 42.6, and 31.5 ng·h/mL, respectively. The geometric mean ratio for period 2 versus 1 was 0.44 (90% CI: 0.38-0.50) and for period 3 versus 1 was 0.32 (90% CI: 0.27-0.37). Analysis of pharmacokinetic data after first injection only (period 1) showed comparable AUClast across the 3 injection sites and lower initial Cmax after injection into the abdomen compared with the other 2 injection sites. Overall, taspoglutide was well tolerated by most subjects in all 3 injection sites, with a lower incidence of nausea and vomiting when injected in the abdomen. IMPLICATIONS: Regardless of a pronounced period effect, relative bioavailability of taspoglutide was different across injection sites, with the lowest exposure and incidence of nausea and vomiting seen after administration in the abdomen. In the absence of comparable bioavailability, taspoglutide was recommended to be injected into the abdomen.

Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins.

BACKGROUND: Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES: This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS: Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS: Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p<0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34 to 1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p=0.03), with a hazard ratio of 1.50 [corrected] (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. CONCLUSIONS: Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515).

Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract cholesterol efflux to high-density lipoprotein.

PURPOSE: Cholesterol efflux from macrophages to HDL, measured in vitro, is augmented by treatment with agents which raise HDL cholesterol. In vitro, cholesterol depletion by statins is known to trigger a positive feedback on the cholesterol synthetic pathway via sterol regulatory element-binding protein (SREBP) transcription and changes in expression of SREBP regulated genes including microRNA33 (miR33) which is co-transcribed with SREBP and down-regulates ABCA1 and ABCG1 expression. METHODS: We investigated whether miR33 up-regulation, associated with SREBP increased transcription by statins, reduces macrophage ATP-binding cassette (ABC) transporter expression, thereby decreasing HDL-mediated cholesterol efflux at the tissue level. RESULTS: In human macrophage THP-1 cells cholesterol-loaded with acetylated LDL, incubation with 1 µM atorvastatin increased miR33 by 33 % (P < 0.05), and decreased ABCA1 messenger RNA (mRNA) and ABCG1 mRNA by 47 % (P < 0.05) and 27 % (NS), respectively. In J774A.1 mouse macrophage, labelled with 3H-cholesterol, ABCA1 mRNA and ABCA1-mediated cholesterol efflux were decreased by 1 µM statin: simvastatin > pitavastatin > atorvastatin > rosuvastatin > pravastatin. HDL incubated with rhCETP and dalcetrapib increased ABCA1-mediated cholesterol efflux. However, incremental simvastatin concentrations decreased cholesterol efflux to HDL treated with rhCETP and dalcetrapib. When HDL was incubated with rhCETP, addition of dalcetrapib augmented ABCA1-mediated cholesterol efflux from J774A.1 macrophages. However, simvastatin ≥1 µM virtually eliminated any HDL-ABCA1-mediated cholesterol efflux and any augmentation of that process by dalcetrapib. CONCLUSIONS: In vitro, statins increase miR33 expression, and decrease ABCA1 expression and cholesterol efflux from peripheral tissues; this may counteract the potential benefit of agents that raise HDL and apolipoprotein A-I in statin-treated patients.

Effect of gastric pH on erlotinib pharmacokinetics in healthy individuals: omeprazole and ranitidine.

The aim of this study was to evaluate the effect of coadministration of acid-reducing agents on the pharmacokinetic exposure of orally administered epidermal growth factor receptor inhibitor erlotinib, a drug that displays pH-dependent solubility. Two studies were conducted, the first with the proton pump inhibitor omeprazole and the second with the H2-receptor antagonist ranitidine. Twenty-four healthy male and female volunteers were enrolled in each study. Erlotinib was administered as a single oral 150 mg dose on day 1. After the washout a subsequent study period evaluated 150 mg erlotinib administered with the acid-reducing agent. Omeprazole (40 mg once daily) was given on days 11-14, concomitantly with erlotinib on day 15, and for two additional days (days 16-17). In the ranitidine study, on day 13, participants were randomized to either concomitant dosing (treatment B) or staggered administration (treatment C) of erlotinib and ranitidine and crossed over to the other treatment starting on day 27. For treatment B, ranitidine (300 mg once daily) was administered in the morning for 5 days, 2 h before erlotinib. For treatment C, ranitidine was administered as a divided dose (150 mg twice daily) for 5 days, with erlotinib given 10 h after the previous evening dose and 2 h before the next ranitidine morning dose. Plasma samples were obtained for determination of the concentrations of erlotinib and its metabolite OSI-420, following each erlotinib dose. All participants were monitored for safety and tolerability. The geometric mean ratios of AUC0-∞ and Cmax for erlotinib and AUC0-last and Cmax for OSI-420 were substantially decreased when erlotinib was dosed with omeprazole. The estimated mean ratio (90% confidence interval) for erlotinib was 0.54 (0.49-0.59) for AUC0-∞ and 0.39 (0.32-0.48) for Cmax. For OSI-420, the estimated mean ratio was 0.42 (0.37-0.48) for AUC0-last and 0.31 (0.24-0.41) for Cmax. AUC0-∞ and Cmax for erlotinib were substantially decreased by 33 and 54%, respectively, upon coadministration with ranitidine, but the decrease was only 15 and 17% when ranitidine and erlotinib were given staggered. Similar results were observed for the metabolite OSI-420. Erlotinib was generally well-tolerated alone or in combination with omeprazole or ranitidine. Erlotinib pharmacokinetic exposure was substantially reduced upon coadministration with omeprazole and ranitidine, but not when administered with a staggered dosing approach to ranitidine. Therefore, it is recommended that the concomitant use of erlotinib with proton pump inhibitors be avoided. If treatment with an H2-receptor antagonist such as ranitidine is required, erlotinib must be administered 10 h after the H2-receptor antagonist dosing and at least 2 h before the next dose of the H2-receptor antagonist.

First-in-Man Study With Inclacumab, a Human Monoclonal Antibody Against P-selectin.

Inclacumab, a novel monoclonal antibody against P-selectin in development for the treatment and prevention of atherosclerotic cardiovascular diseases, was administered in an ascending single-dose study as intravenous infusion to evaluate safety, pharmacokinetics, and pharmacodynamics. Fifty-six healthy subjects were enrolled in this randomized, double-blind placebo-controlled study. Each dose level (0.03-20 mg/kg) was investigated in separate groups of 8 subjects (6 on inclacumab, 2 on placebo). Platelet-leukocyte aggregates, free/total soluble P-selectin concentration ratio, drug concentrations, bleeding time, platelet aggregation, antibody formation, and routine laboratory parameters were measured frequently until 32 weeks. Pharmacokinetic profiles were indicative of target-mediated drug disposition. Platelet-leukocyte aggregate inhibition and soluble P-selectin occupancy showed dose dependency and were strongly correlated to inclacumab plasma concentrations, with IC50 of 740 and 4600 ng/mL, respectively. Inclacumab was well tolerated by the majority of subjects and did neither affect bleeding time nor platelet aggregation. These findings allowed the investigation of the potential beneficial therapeutic use of inclacumab in patient study.

Predictors of change in carotid atherosclerotic plaque inflammation and burden as measured by 18-FDG-PET and MRI, respectively, in the dal-PLAQUE study.

Baseline predictors of response to treatment of patients with coronary heart disease (CHD) with respect to vascular inflammation and atherosclerotic plaque burden are poorly understood. From post hoc analysis of the dal-PLAQUE study (NCT00655473), 18F-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) imaging and carotid black blood magnetic resonance imaging (MRI) were used to track changes in these vascular parameters. Baseline demographics, imaging, and biomarkers were collected/measured in 130 patients with CHD or CHD risk-equivalents, and imaging follow-up at 6 months (PET) and 24 months (MRI) was performed. Using stepwise linear regression, predictors of change in carotid plaque inflammation by PET [target-to-background ratio (TBR), n = 92] and plaque burden by MRI [wall area (WA) and total vessel area (TVA), n = 89] were determined. Variables with p < 0.05 in multivariable models were considered independently significant. Interleukin-6, systolic blood pressure and standard deviation of wall thickness (WT) at baseline were independently positively associated with 18-FDG uptake (mean of maximum [MeanMax] TBR change over 6 months). Mean of mean TBR, phospholipase A2, apolipoprotein A-I, and high-sensitivity C-reactive protein at baseline were independently negatively associated with MeanMax TBR change over 6 months. Mean WT and plasminogen activator inhibitor-1 (PAI-1) activity at baseline, and age, were independently associated with change in WA over 24 months. For TVA changes; mean WA and PAI-1 activity at baseline, age, and female gender were independent predictors. These findings may help determine patients most suitable for clinical trials employing plaque inflammation or burden changes as endpoints.

Xanthophylls, phytosterols and pre-ß1-HDL are differentially affected by fenofibrate and niacin HDL-raising in a cross-over study.

Fenofibrate and extended-release (ER) niacin similarly raise high-density lipoprotein cholesterol (HDL-C) concentration but their effects on levels of potent plasma antioxidant xanthophylls (lutein and zeaxanthin) and phytosterols obtained from dietary sources, and any relationship with plasma lipoproteins and pre-ß1-HDL levels, have not been investigated. We studied these parameters in 66 dyslipidemic patients treated for 6 week with fenofibrate (160 mg/day) or ER-niacin (0.5 g/day for 3 week, then 1 g/day) in a cross-over study. Both treatments increased HDL-C (16 %) and apolipoprotein (apo) A-I (7 %) but only fenofibrate increased apoA-II (28 %). Lutein and zeaxanthin levels were unaffected by fenofibrate but inversely correlated with percentage change in apoB and low-density lipoprotein cholesterol and positively correlated with end of treatment apoA-II. ApoA-II in isolated HDL in vitro bound more lutein than apoA-I. Xanthophylls were increased by ER-niacin (each ~30 %) without any correlation to lipoprotein or apo levels. Only fenofibrate markedly decreased plasma markers of cholesterol absorption; pre-ß1-HDL was significantly decreased by fenofibrate (-19 %, p < 0.0001), with little change (3.4 %) for ER-niacin. Although fenofibrate and ER-niacin similarly increased plasma HDL-C and apoA-I, effects on plasma xanthophylls, phytosterols and pre-ß1-HDL differed markedly, suggesting differences in intestinal lipidation of HDL. In addition, the in vitro investigations suggest an important role of plasma apoA-II in xanthophyll metabolism.

Effects of dalcetrapib in patients with a recent acute coronary syndrome.

BACKGROUND: In observational analyses, higher levels of high-density lipoprotein (HDL) cholesterol have been associated with a lower risk of coronary heart disease events. However, whether raising HDL cholesterol levels therapeutically reduces cardiovascular risk remains uncertain. Inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels and might therefore improve cardiovascular outcomes. METHODS: We randomly assigned 15,871 patients who had had a recent acute coronary syndrome to receive the CETP inhibitor dalcetrapib, at a dose of 600 mg daily, or placebo, in addition to the best available evidence-based care. The primary efficacy end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest with resuscitation. RESULTS: At the time of randomization, the mean HDL cholesterol level was 42 mg per deciliter (1.1 mmol per liter), and the mean low-density lipoprotein (LDL) cholesterol level was 76 mg per deciliter (2.0 mmol per liter). Over the course of the trial, HDL cholesterol levels increased from baseline by 4 to 11% in the placebo group and by 31 to 40% in the dalcetrapib group. Dalcetrapib had a minimal effect on LDL cholesterol levels. Patients were followed for a median of 31 months. At a prespecified interim analysis that included 1135 primary end-point events (71% of the projected total number), the independent data and safety monitoring board recommended termination of the trial for futility. As compared with placebo, dalcetrapib did not alter the risk of the primary end point (cumulative event rate, 8.0% and 8.3%, respectively; hazard ratio with dalcetrapib, 1.04; 95% confidence interval, 0.93 to 1.16; P=0.52) and did not have a significant effect on any component of the primary end point or total mortality. The median C-reactive protein level was 0.2 mg per liter higher and the mean systolic blood pressure was 0.6 mm Hg higher with dalcetrapib as compared with placebo (P<0.001 for both comparisons). CONCLUSIONS: In patients who had had a recent acute coronary syndrome, dalcetrapib increased HDL cholesterol levels but did not reduce the risk of recurrent cardiovascular events. (Funded by F. Hoffmann-La Roche; dal-OUTCOMES ClinicalTrials.gov number, NCT00658515.).