Rolling continual reassessment method with overdose control: An efficient and safe dose escalation design.

In phase 1 dose escalation studies, dose limiting toxicities (DLTs) are defined as adverse events of concern occurring during a predefined time window after first dosing of patients. Standard dose escalation designs, such as the continual reassessment method (CRM), only utilize this binary DLT information. Thus, late-onset DLTs are usually not accounted for when CRM guiding the dose escalation and finally defining the maximum tolerated dose (MTD) of the drug, which brings safety concerns for patients. Previously, several extensions of CRMs, such as the time-to-event CRM (TITE-CRM), fractional CRM (fCRM) and the data augmented CRM (DA-CRM), have been proposed to handle this issue without prolonging trial duration. However, among the model-based designs, none of the designs have explicitly controlled the risk of overdosing as in the escalation with overdose control (EWOC) design. Here we propose a novel dose escalation with overdose control design using a two-parameter logistic regression model for the probability of DLT depending on the dose and a piecewise exponential model for the time to DLT distribution, which we call rolling-CRM design. A comprehensive simulation study has been conducted to compare the performance of the rolling-CRM design with other dose escalation designs. Of note, the trial duration is significantly shorter compared to traditional CRM designs. The proposed design also retains overdose control characteristics, but might require a larger sample size compared to traditional CRM designs.

Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy.

The main purpose of dose-escalation trials is to identify the dose(s) that is/are safe and efficacious for further investigations in later studies. In this paper, we introduce dose-escalation designs that incorporate both the dose-limiting events and dose-limiting toxicities (DLTs) and indicative responses of efficacy into the procedure. A flexible nonparametric model is used for modelling the continuous efficacy responses while a logistic model is used for the binary DLTs. Escalation decisions are based on the combination of the probabilities of DLTs and expected efficacy through a gain function. On the basis of this setup, we then introduce 2 types of Bayesian adaptive dose-escalation strategies. The first type of procedures, called "single objective," aims to identify and recommend a single dose, either the maximum tolerated dose, the highest dose that is considered as safe, or the optimal dose, a safe dose that gives optimum benefit risk. The second type, called "dual objective," aims to jointly estimate both the maximum tolerated dose and the optimal dose accurately. The recommended doses obtained under these dose-escalation procedures provide information about the safety and efficacy profile of the novel drug to facilitate later studies. We evaluate different strategies via simulations based on an example constructed from a real trial on patients with type 2 diabetes, and the use of stopping rules is assessed. We find that the nonparametric model estimates the efficacy responses well for different underlying true shapes. The dual-objective designs give better results in terms of identifying the 2 real target doses compared to the single-objective designs.

Objective Bayesian model selection for Cox regression.

There is now a large literature on objective Bayesian model selection in the linear model based on the g-prior. The methodology has been recently extended to generalized linear models using test-based Bayes factors. In this paper, we show that test-based Bayes factors can also be applied to the Cox proportional hazards model. If the goal is to select a single model, then both the maximum a posteriori and the median probability model can be calculated. For clinical prediction of survival, we shrink the model-specific log hazard ratio estimates with subsequent calculation of the Breslow estimate of the cumulative baseline hazard function. A Bayesian model average can also be employed. We illustrate the proposed methodology with the analysis of survival data on primary biliary cirrhosis patients and the development of a clinical prediction model for future cardiovascular events based on data from the Second Manifestations of ARTerial disease (SMART) cohort study. Cross-validation is applied to compare the predictive performance with alternative model selection approaches based on Harrell's c-Index, the calibration slope and the integrated Brier score. Finally, a novel application of Bayesian variable selection to optimal conditional prediction via landmarking is described. Copyright © 2016 John Wiley & Sons, Ltd.

Reduction of thromboembolic events in meningioma surgery: a cohort study of 724 consecutive patients.

BACKGROUND: Meningiomas are associated with the highest postoperative rate of venous thromboembolic events (VTE) among all intracranial tumors. The aim of this study is to compare two entirely different VTE prophylaxis regimens in 724 consecutive patients undergoing meningioma surgery. METHODS: Two cohorts at a single institution treated with different regimens to prevent VTE were reviewed retrospectively. Cohort A (n = 482; 314 females, mean age 57 years, range: 11-87 years) received our institutional regimen during the years 1999-2006, consisting of low-molecular-weight heparin (LMWH) and compression stockings. For cohort B (n = 242; 163 females, mean age 56.8 years, range: 16-90 years), during the years 2008-2010, the management included intraoperative 10°-20° leg elevation with intermittent pneumatic compression (IPC), heparin and LMWH administration. We compared the incidence of the endpoints pulmonary embolism (PE), deep venous thrombosis (DVT), hemorrhage and death, taking into account several known associated risk factors. RESULTS: For all endpoints, we observed a more favorable outcome with the new regimen. The difference in incidence of PEs (cohort A: 38/482, 8%; cohort B: 6/242, 2.5%) reached statistical significance (p = 0.002). In general, patients with skull base meningiomas had a higher risk for PE (OR 2.77). Regarding VTE prophylaxis, an adjusted subgroup analysis suggests that the new regimen is particularly beneficial for patients with skull base meningiomas. CONCLUSIONS: We recommend perioperative prophylaxis using a management composed of intraoperative leg-elevation, IPC, early heparin administration and LMWH to reduce the risk for PE.

Sensitization to common ragweed in southern Bavaria: clinical and geographical risk factors in atopic patients.

BACKGROUND: Sensitization to common ragweed (Ambrosia artemisiifolia) is associated with a variety of risk factors, which are incompletely defined. Our aim was to evaluate the association of a variety of clinical, geographical and demographical variables with ragweed sensitization and also to determine its frequency in southern Bavaria. METHODS: In this cross-sectional multicentre study, we enrolled 977 patients with a documented or suspected atopic disease or food allergy. Data were collected on aeroallergen sensitization, age, sex, type and history of allergic disease, place of residence and potential local ragweed exposure. For this last variable, county ragweed cover was taken as a surrogate variable. Relative rates were calculated with multiple additive logistic regression models. Randomly selected patients with ragweed sensitization had a conjunctival provocation test. RESULTS: According to skin prick tests, 190 patients (19.5%) were sensitized to ragweed. The frequency of this finding increased significantly with a rising number of additional sensitizations. Other less important predictors for a ragweed sensitization were male gender, mugwort sensitization, food allergy and a maximum of complaints in September or October. County of residence, extent of local ragweed cover or type of residential area were without relevance. Of 48 sensitized patients, 26 (54.2%) had a positive conjunctival provocation test. DISCUSSION: Patients with multiple sensitizations may be more readily sensitized to a new aeroallergen. Local geographic or environmental conditions are presumably of minor importance for becoming sensitized to ragweed. The frequency of ragweed allergy among sensitized patients might be high.