Clinical Pharmacology and Therapeutics Group, University College London, London, UK.
PAREXEL International, Durham, NC, USA.
World J Urol. 2020 Feb;38(2):463-472. doi: 10.1007/s00345-019-02783-x. Epub 2019 May 11.
Despite superiority of tamsulosin-dutasteride combination therapy versus monotherapy for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH), patients at risk of disease progression are often initiated on α-blockers. This study evaluated the impact of initiating tamsulosin monotherapy prior to switching to tamsulosin-dutasteride combination therapy versus immediate combination therapy using a longitudinal model describing International Prostate Symptom Score (IPSS) trajectories in moderate/severe LUTS/BPH patients at risk of disease progression.
Clinical trial simulations (CTS) were performed using data from 10,238 patients from Phase III/IV dutasteride trials. The effect of varying disease progression rates was explored by comparing profiles on- and off-treatment. CTS scenarios were investigated, including a reference (immediate combination therapy) and six alternative virtual treatment arms (delayed combination therapy of 1-24 months). Clinical response (≥ 25% IPSS reduction relative to baseline) was analysed using log-rank test. Differences in IPSS relative to baseline at various on-treatment time points were assessed by t tests.
Delayed combination therapy initiation led to significant (p < 0.01) decreases in clinical response. At month 48, clinical response rate was 79.7% versus 74.1%, 70.3% and 71.0% and IPSS was 6.3 versus 7.6, 8.1 and 8.0 (switchers from tamsulosin monotherapy after 6, 12 and 24 months, respectively) with immediate combination therapy. More patients transitioned from severe/moderate to mild severity scores by month 48.
CTS allows systematic evaluation of immediate versus delayed combination therapy. Immediate response to α-blockers is not predictive of long-term symptom improvement. Observed IPSS differences between immediate and delayed combination therapy (6-24 months) are statistically significant.
尽管坦索罗辛-度他雄胺联合治疗在治疗良性前列腺增生（LUTS/BPH）相关下尿路症状方面优于单药治疗，但对于有疾病进展风险的患者，通常会起始使用α受体阻滞剂。本研究采用描述有疾病进展风险的中重度 LUTS/BPH 患者国际前列腺症状评分（IPSS）轨迹的纵向模型，评估在开始坦索罗辛-度他雄胺联合治疗前先转换为坦索罗辛单药治疗与直接起始联合治疗对患者的影响。
采用来自 III 期/IV 期度他雄胺试验的 10238 例患者的数据进行临床模拟试验（CTS）。通过比较治疗和未治疗时的情况，探索不同疾病进展率的影响。研究了 CTS 方案，包括参考方案（直接联合治疗）和 6 种虚拟治疗方案（1-24 个月后延迟联合治疗）。采用对数秩检验分析临床应答（与基线相比 IPSS 降低≥25%）。采用 t 检验评估不同治疗时间点与基线相比 IPSS 的差异。
延迟联合治疗起始导致临床应答显著（p<0.01）降低。在第 48 个月时，临床应答率分别为 79.7%、74.1%、70.3%和 71.0%，IPSS 分别为 6.3、7.6、8.1 和 8.0（分别从坦索罗辛单药治疗后 6、12 和 24 个月转换的患者），而直接联合治疗组分别为 79.7%、74.1%、70.3%和 71.0%，IPSS 分别为 6.3、7.6、8.1 和 8.0。更多患者在第 48 个月时从严重/中度转变为轻度严重评分。
CTS 允许系统评估直接联合治疗与延迟联合治疗。α受体阻滞剂的即刻反应不能预测长期症状改善。观察到的直接联合治疗与延迟联合治疗（6-24 个月）之间的 IPSS 差异具有统计学意义。
