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| Natura: | Preprint |
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2025
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| Accesso online: | https://arxiv.org/abs/2505.06939 |
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| _version_ | 1866910979484286976 |
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| author | Zhan, Tianyu Gu, Yihua |
| author_facet | Zhan, Tianyu Gu, Yihua |
| contents | In confirmatory Phase 3 clinical trials with recruitment over the years, the underlying placebo effect may follow an unknown temporal trend. Taking a clinical trial on Hidradenitis Suppurativa (HS) as an example, fluctuations or variabilities are common in HS-related endpoints, mainly due to the natural disease characteristics, variations of evaluation from different physicians, and standard of care evolvement. The adjustment of time-varying placebo effects receives some attention in adaptive clinical trials and platform trials, but is usually ignored in traditional non-adaptive designs. However, under the impact of such a time drift, some existing methods may not simultaneously control the type I error rate and achieve satisfactory power. In this article, we propose SWSR (Semiparametric Weighted Spline Regression) to estimate the treatment effect with B-splines to accommodate the time-varying placebo effects nonparametrically. Our method aims to achieve the following three objectives: a proper type I error rate control under varying settings, an overall high power to detect a potential treatment effect, and robustness to unknown time-varying placebo effects. Simulation studies and a case study provide supporting evidence. Those three key features make SWSR an appealing option to be pre-specified for practical confirmatory clinical trials. Supplemental materials, including the R code, additional simulation results and theoretical discussion, are available online. |
| format | Preprint |
| id |
arxiv_https___arxiv_org_abs_2505_06939 |
| institution | arXiv |
| publishDate | 2025 |
| record_format | arxiv |
| spellingShingle | Semiparametric Weighted Spline Regression (SWSR) in Confirmatory Clinical Trials with Time-Varying Placebo Effects Zhan, Tianyu Gu, Yihua Methodology In confirmatory Phase 3 clinical trials with recruitment over the years, the underlying placebo effect may follow an unknown temporal trend. Taking a clinical trial on Hidradenitis Suppurativa (HS) as an example, fluctuations or variabilities are common in HS-related endpoints, mainly due to the natural disease characteristics, variations of evaluation from different physicians, and standard of care evolvement. The adjustment of time-varying placebo effects receives some attention in adaptive clinical trials and platform trials, but is usually ignored in traditional non-adaptive designs. However, under the impact of such a time drift, some existing methods may not simultaneously control the type I error rate and achieve satisfactory power. In this article, we propose SWSR (Semiparametric Weighted Spline Regression) to estimate the treatment effect with B-splines to accommodate the time-varying placebo effects nonparametrically. Our method aims to achieve the following three objectives: a proper type I error rate control under varying settings, an overall high power to detect a potential treatment effect, and robustness to unknown time-varying placebo effects. Simulation studies and a case study provide supporting evidence. Those three key features make SWSR an appealing option to be pre-specified for practical confirmatory clinical trials. Supplemental materials, including the R code, additional simulation results and theoretical discussion, are available online. |
| title | Semiparametric Weighted Spline Regression (SWSR) in Confirmatory Clinical Trials with Time-Varying Placebo Effects |
| topic | Methodology |
| url | https://arxiv.org/abs/2505.06939 |