The randomized discontinuation trial (RDT) design is an enrichment-type design that has been used in a variety of diseases to evaluate the efficacy of new treatments. The RDT design seeks to select a more homogeneous group of patients, consisting of those who are more likely to show a treatment benefit if one exists. In oncology, the RDT design has been applied to evaluate the effects of cytostatic agents, that is, drugs that act primarily by slowing tumor growth rather than shrinking tumors. In the RDT design, all patients receive treatment during an initial, open-label run-in period of duration T. Patients with objective response (substantial tumor shrinkage) remain on therapy while those with early progressive disease are removed from the trial. Patients with stable disease (SD) are then randomized to either continue active treatment or switched to placebo. The main analysis compares outcomes, for example, progression-free survival (PFS), between the two randomized arms. As a secondary objective, investigators may seek to estimate PFS for all treated patients, measured from the time of entry into the study, by combining information from the run-in and post run-in periods. For t ⩽ T, PFS is estimated by the observed proportion of patients who are progression-free among all patients enrolled. For t > T, the estimate can be expressed as , where is the estimated probability of response during the run-in period, is the estimated probability of SD, and and are the Kaplan–Meier estimates of subsequent PFS in the responders and patients with SD randomized to continue treatment, respectively. In this article, we derive the variance of , enabling the construction of confidence intervals for both S(t) and the median survival time. Simulation results indicate that the method provides accurate coverage rates. An interesting aspect of the design is that outcomes during the run-in phase have a negative multinomial distribution, something not frequently encountered in practice.

中文翻译：

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随机终止试验设计中所有接受治疗患者的无进展生存期估计

随机停药试验 (RDT) 设计是一种富集型设计，已用于多种疾病以评估新疗法的疗效。RDT 设计旨在选择更同质的患者组，包括那些更有可能显示出治疗益处的患者（如果存在）。在肿瘤学中，RDT 设计已被应用于评估细胞生长抑制剂的效果，即主要通过减缓肿瘤生长而不是缩小肿瘤起作用的药物。在 RDT 设计中，所有患者在持续时间为 T 的初始、开放标签磨合期接受治疗。具有客观反应（肿瘤明显缩小）的患者继续接受治疗，而早期进展性疾病的患者则从试验中剔除。然后，疾病稳定 (SD) 的患者被随机分配继续积极治疗或改用安慰剂。主要分析比较了两个随机组之间的结果，例如无进展生存期 (PFS)。作为次要目标，研究人员可能会通过结合来自磨合期和磨合后时期的信息，寻求估计所有接受治疗的患者的 PFS，从进入研究的时间开始测量。对于 t ⩽ T，PFS 是通过观察到的所有入组患者中无进展患者的比例来估计的。对于 t > T，估计值可表示为SD 分别随机分配继续治疗。在本文中，我们推导出 的方差，从而能够构建 S(t) 和中位生存时间的置信区间。仿真结果表明该方法提供了准确的覆盖率。该设计的一个有趣方面是磨合阶段的结果具有负多项式分布，这在实践中并不常见。