Two-stage phase II trials with early stopping for effectiveness and safety as well as ineffectiveness or harm

This article proposes new optimal and minimax designs, which allow early stopping not only for ineffectiveness or toxicity but also for sufficient effectiveness and safety. These designs may facilitate effective drug development by detecting sufficient effectiveness and safety at an early stage or by detecting ineffectiveness or excessive toxicity at an early stage. The proposed design has advantage over other designs in the sense that it can control the type I error rate and is robust against the real association parameter. Comparing to Jin's design, it is always advantageous in terms of expected sample size.     

A Hybrid Geometric Phase II/III Clinical Trial Design based on Treatment Failure Time and Toxicity

The problem of comparing several experimental treatments to a standard arises frequently in medical research. Various multi-stage randomized phase II/III designs have been proposed that select one or more promising experimental treatments and compare them to the standard while controlling overall Type I and Type II error rates. This paper addresses phase II/III settings where the joint goals are to increase the average time to treatment failure and control the probability of toxicity while accounting for patient heterogeneity. We are motivated by the desire to construct a feasible design for a trial of four chemotherapy combinations for treating a family of rare pediatric brain tumors. We present a hybrid two-stage design based on two-dimensional treatment effect parameters. A targeted parameter set is constructed from elicited parameter pairs considered to be equally desirable. Bayesian regression models for failure time and the probability of toxicity as functions of treatment and prognostic covariates are used to define two-dimensional covariate-adjusted treatment effect parameter sets. Decisions at each stage of the trial are based on the ratio of posterior probabilities of the alternative and null covariate-adjusted parameter sets. Design parameters are chosen to minimize expected sample size subject to frequentist error constraints. The design is illustrated by application to the brain tumor trial.     

Adaptive Isotonic Estimation of the Minimum Effective and Peak Doses in the Presence of Covariates

We consider a problem of estimating the minimum effective and peak doses in the presence of covariates. We propose a sequential strategy for subject assignment that includes an adaptive randomization component to balance the allocation to placebo and active doses with respect to covariates. We conclude that either adjusting for covariates in the model or balancing allocation with respect to covariates is required to avoid bias in the target dose estimation. We also compute optimal allocation to estimate the minimum effective and peak doses in discrete dose space using isotonic regression.     

Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone

Aims: To evaluate the cause of failure of sildenafil citrate (Viagra^®) to restore erections in patients with organic erectile dysfunction (ED) associated with type II diabetes mellitus (DM) and receiving oral antidiabetic drugs. Methods: Diabetic ED patients (n = 120), aged 43-74 years, failing to respond at least three times to 100 mg Viagra were evaluated. After at least 2 weeks' treatment with oral testosterone undecanoate (Andriol^®), 100 mg Viagra was used before coitus. ED was assessed with the International Index of Erectile Function (IIEF). Serum total testosterone, prolactin, thyroid stimulating hormone, lipid profile and prostate-specific antigen (PSA) were determined by standard methods and prostate volume by digital rectal examination. Age-matched diabetic ED patients (n = 100) served as controls for baseline values. Results: Viagra non-responders had, at baseline, significantly lower testosterone and more depressed libido than controls. Andriol restored testosterone to normal levels and increased libido. In 84/120 (70%) Viagra non-responders, combined therapy with Andriol induced satisfactory erections, a significant increase in IIEF scale (question (Q) 3 from 2.0 ± 0.2 to 3.7 ± 0.3, Q4 from 1.9 ± 0.1 to 3.4 ± 0.2, Q12 from 1.0 ± 0.1 to 4.2 ± 0.4) and increased sexual contacts from 0.5 to 3-4 per month. No adverse events were noted, and PSA levels remained below 4 ng/ml. Conclusion: Decreased testosterone levels in patients with ED and type II DM receiving oral antidiabetic agents may be responsible for failure to respond to sildenafil citrate therapy. Combination with oral testosterone undecanoate restores sexual function in these patients.     

西班牙法西斯政权的建立及在二战中保持中立的原因

西班牙在一战后二战前建立起了法西斯独裁统治的国家。德、意、日三国结为轴心国在二战中犯下了滔天罪行,然而同为法西斯国家的西班牙却在这场全球三分之二的国家被卷入的世界大战中保持中立,让史学界和国际关系学界诸多学者难以理解。阐述了西班牙内战的经过、结局和影响,在此基础上,探析了西班牙内战的前因后果与佛朗哥法西斯政权在二战中保持中立的原因。     

德国威廉二世“世界政策”探源

探讨了威廉二世“世界政策”存在的国内外因素 ,认为实力外交是诱发第一次世界大战的重要因素 ,对世界和平具有极大的破坏性     

德国和日本对二战不同历史态度的评述

德国和日本同为二战轴心国,战后,它们对于人类历史上最黑暗的一页却表现出完全不同的历史态度。一个认真反省,吸取教训,取信于世;一个百般歪曲,不思悔改,欺骗世人。这是由德、日两国不同的历史和认识所造成的结果,由此形成了迥然不同的国际形象。     

TITE‐BOIN‐ET: Time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on both efficacy and toxicity outcomes

One of the primary purposes of an oncology dose‐finding trial is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent clinical trials. In addition, it is quite important to accelerate early stage trials to shorten the entire period of drug development. However, it is often challenging to make adaptive decisions of dose escalation and de‐escalation in a timely manner because of the fast accrual rate, the difference of outcome evaluation periods for efficacy and toxicity and the late‐onset outcomes. To solve these issues, we propose the time‐to‐event Bayesian optimal interval design to accelerate dose‐finding based on cumulative and pending data of both efficacy and toxicity. The new design, named “TITE‐BOIN‐ET” design, is nonparametric and a model‐assisted design. Thus, it is robust, much simpler, and easier to implement in actual oncology dose‐finding trials compared with the model‐based approaches. These characteristics are quite useful from a practical point of view. A simulation study shows that the TITE‐BOIN‐ET design has advantages compared with the model‐based approaches in both the percentage of correct OD selection and the average number of patients allocated to the ODs across a variety of realistic settings. In addition, the TITE‐BOIN‐ET design significantly shortens the trial duration compared with the designs without sequential enrollment and therefore has the potential to accelerate early stage dose‐finding trials.     

Nuclear Waste Management under Approaching Disaster: A Comparison of Decommissioning Strategies for the German Repository Asse II

This article compares different strategies for handling low‐ and medium‐level nuclear waste buried in a retired potassium mine in Germany (Asse II) that faces significant risk of uncontrollable brine intrusion and, hence, long‐term groundwater contamination. We survey the policy process that has resulted in the identification of three possible so‐called decommissioning options: complete backfilling, relocation of the waste to deeper levels in the mine, and retrieval. The selection of a decommissioning strategy must compare expected investment costs with expected social damage costs (economic, environmental, and health damage costs) caused by flooding and subsequent groundwater contamination. We apply a cost minimization approach that accounts for the uncertainty regarding the stability of the rock formation and the risk of an uncontrollable brine intrusion. Since economic and health impacts stretch out into the far future, we examine the impact of different discounting methods and rates. Due to parameter uncertainty, we conduct a sensitivity analysis concerning key assumptions. We find that retrieval, the currently preferred option by policymakers, has the lowest expected social damage costs for low discount rates. However, this advantage is overcompensated by higher expected investment costs. Considering all costs, backfilling is the best option for all discounting scenarios considered.