Mather Kieren J, Tjaden Ashley H, Hoehn Adam, Nadeau Kristen J, Buchanan Thomas A, Kahn Steven E, Arslanian Silva A, Caprio Sonia, Atkinson Karen M, Cree-Green Melanie, Utzschneider Kristina M, Edelstein Sharon L
Department of Medicine, School of Medicine, Indiana University, Indianapolis, Indiana.
The Biostatistics Center, Milken Institute School of Public Health, George Washington University, Washington, DC.
Am J Physiol Endocrinol Metab. 2021 Apr 1;320(4):E797-E807. doi: 10.1152/ajpendo.00598.2020. Epub 2021 Mar 1.
Application of glucose clamp methodologies in multicenter studies brings challenges for standardization. The Restoring Insulin Secretion (RISE) Consortium implemented a hyperglycemic clamp protocol across seven centers using a combination of technical and management approaches to achieve standardization. Two-stage hyperglycemic clamps with glucose targets of 200 mg/dL and >450 mg/dL were performed utilizing a centralized spreadsheet-based algorithm that guided dextrose infusion rates using bedside plasma glucose measurements. Clamp operators received initial and repeated training with ongoing feedback based on surveillance of clamp performance. The precision and accuracy of the achieved stage-specific glucose targets were evaluated, including differences by study center. We also evaluated robustness of the method to baseline physiologic differences and on-study treatment effects. The RISE approach produced high overall precision (3%-9% variance in achieved plasma glucose from target at various times across the procedure) and accuracy (SD < 10% overall). Statistically significant but numerically small differences in achieved target glucose concentrations were observed across study centers, within the magnitude of the observed technical variability. Variation of the achieved target glucose over time in placebo-treated individuals was low (<3% variation), and the method was robust to differences in baseline physiology (youth vs. adult, IGT vs. diabetes status) and differences in physiology induced by study treatments. The RISE approach to standardization of the hyperglycemic clamp methodology across multiple study centers produced technically excellent standardization of achieved glucose concentrations. This approach provides a reliable method for implementing glucose clamp methodology across multiple study centers. The Restoring Insulin Secretion (RISE) study centers undertook hyperglycemic clamps using a simplified methodology and a decision guidance algorithm implemented in an easy-to-use spreadsheet. This approach, combined with active management including ongoing central data surveillance and routine feedback to study centers, produced technically excellent standardization of achieved glucose concentrations on repeat studies within and across study centers.
在多中心研究中应用葡萄糖钳夹技术面临标准化方面的挑战。恢复胰岛素分泌（RISE）联盟在七个中心实施了高血糖钳夹方案，采用技术和管理相结合的方法来实现标准化。利用基于电子表格的集中算法，以200mg/dL和>450mg/dL的血糖目标进行两阶段高血糖钳夹，该算法根据床旁血浆葡萄糖测量值指导葡萄糖输注速率。钳夹操作人员接受了初始培训和反复培训，并根据钳夹性能监测获得持续反馈。评估了所达到的特定阶段血糖目标的精度和准确性，包括各研究中心之间的差异。我们还评估了该方法对基线生理差异和研究期间治疗效果的稳健性。RISE方法产生了较高的总体精度（在整个过程的不同时间点，所达到的血浆葡萄糖与目标值的差异为3%-9%）和准确性（总体标准差<10%）。在各研究中心观察到所达到的目标葡萄糖浓度存在统计学上显著但数值较小的差异，处于所观察到的技术变异性范围内。安慰剂治疗个体中所达到的目标葡萄糖随时间的变化较低（<3%的变化），并且该方法对基线生理差异（青年与成人、糖耐量受损与糖尿病状态）以及研究治疗引起的生理差异具有稳健性。RISE方法在多个研究中心对高血糖钳夹技术进行标准化，在所达到的葡萄糖浓度方面产生了技术上出色的标准化。这种方法为在多个研究中心实施葡萄糖钳夹技术提供了一种可靠的方法。恢复胰岛素分泌（RISE）研究中心采用简化方法和在易于使用的电子表格中实施的决策指导算法进行高血糖钳夹。这种方法与积极管理相结合，包括持续的中央数据监测和对研究中心的常规反馈，在研究中心内部和跨研究中心的重复研究中，在所达到的葡萄糖浓度方面产生了技术上出色的标准化。
