Validation of the Surrogate Threshold Effect for Change in Bone Mineral Density as a Surrogate Endpoint for Fracture Outcomes: The FNIH-ASBMR SABRE Project.
Validation of the Surrogate Threshold Effect for Change in Bone Mineral Density as a Surrogate Endpoint for Fracture Outcomes: The FNIH-ASBMR SABRE Project.
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DOI：
10.1002/jbmr.4433
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发表时间：
2022-01
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替代阈值效应(STE)被定义为对替代治疗的最小治疗效果，其可靠地预测治疗效果对临床结果的影响。它提供了实现具有代理终点的临床试验的框架。这项研究的目的是通过验证STE中全髋关节(TH)骨密度的变化作为降低骨折风险的替代指标来更新我们之前的分析；这项研究的新颖性就是这一验证。为此，我们使用了16项随机对照试验中61,415名参与者的个人患者数据，这些试验评估了双膦酸盐(9项试验)、选择性雌激素受体调节剂(4项试验)、地诺舒单抗(1项试验)、奥达那康(1项试验)和特立帕帝(1项试验)，以评估试验中对TH BMD和ALL、椎体、髋部和非椎体骨折的特定治疗效果。然后，我们进行了对数相对骨折风险降低与24个月TH骨密度变化的随机效应Meta回归，并计算了STE作为该回归的95%预测上限与无骨折复位直线的交集。我们通过检查每个试验中骨折的数量是否提供了80%的动力，并确定骨密度改变的试验中有多大比例≥STE报告骨折风险显著降低来验证STE。我们将这一分析应用于(I)我们估计STE的试验；以及(Ii)我们没有估计STE的试验。ALL、椎体骨折、髋部骨折和非椎体骨折的STES分别为1.83%、1.42%、3.18%和2.13%。在用于评估STE的试验中，28项试验中有27项动力充足，显示骨密度效应超过STE，并显示骨折风险显著降低。在11项验证试验中，有10项符合这些标准。因此，STE因骨折类型不同而不同，并已在未用于开发该方法的试验中得到验证。©2021作者。《骨与矿物研究杂志》由Wiley期刊有限责任公司代表美国骨与矿物研究学会(ASBMR)出版。
The surrogate threshold effect (STE) is defined as the minimum treatment effect on a surrogate that is reliably predictive of a treatment effect on the clinical outcome. It provides a framework for implementing a clinical trial with a surrogate endpoint. The aim of this study was to update our previous analysis by validating the STE for change in total hip (TH) BMD as a surrogate for fracture risk reduction; the novelty of this study was this validation. To do so, we used individual patient data from 61,415 participants in 16 RCTs that evaluated bisphosphonates (nine trials), selective estrogen receptor modulators (four trials), denosumab (one trial), odanacatib (one trial), and teriparatide (one trial) to estimate trial‐specific treatment effects on TH BMD and all, vertebral, hip, and nonvertebral fractures. We then conducted a random effects meta‐regression of the log relative fracture risk reduction against 24‐month change in TH BMD, and computed the STE as the intersection of the upper 95% prediction limit of this regression with the line of no fracture reduction. We validated the STE by checking whether the number of fractures in each trial provided 80% power and determining what proportion of trials with BMD changes ≥ STE reported significant reductions in fracture risk. We applied this analysis to (i) the trials on which we estimated the STE; and (ii) trials on which we did not estimate the STE. We found that the STEs for all, vertebral, hip, and nonvertebral fractures were 1.83%, 1.42%, 3.18%, and 2.13%, respectively. Among trials used to estimate STE, 27 of 28 were adequately powered, showed BMD effects exceeding the STE, and showed significant reductions in fracture risk. Among the validation set of 11 trials, 10 met these criteria. Thus STE differs by fracture type and has been validated in trials not used to develop the approach. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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