Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial
Achieving Milestones as a Prerequisite for Proceeding With a Clinical Trial
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DOI：
10.1213/ane.0000000000002680
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发表时间：
2018-06-01
影响因子：
5.7
通讯作者：
Wildes, Troy S.
中科院分区：
文献类型：
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作者：
Mickle, Angela M.;Maybrier, Hannah R.;Wildes, Troy S.
背景技术背景：尽管美国国立卫生研究院（NIH）每年在研究上投资300亿美元，但许多受资助的研究未能产生可以指导实践的结果。美国国立卫生研究院引入了分阶段资助机制作为一种潜在的解决方案。为初始试验阶段建立研究特定里程碑。我们通过正在进行的脑电图（EEG）指导麻醉减轻老年性晕厥（ENGAGES）实用临床试验评估这种分阶段方法的实用性。该试验的假设是，脑电图指导全身麻醉，通过预防脑电图抑制，可以减少术后谵妄和其下游的负面后遗症.METHODS：在与研究利益相关者合作，我们确定了关键的里程碑为ENGAGES研究，与许多临床试验的共同主题。这些主题包括：监管任务;招生目标;研究干预的可行性和影响;主要结局发生率;主要结局的测量可靠性;以及随访。在实现里程碑的进展进行了评估，在试点阶段定期由ENGAGES调查，国家研究所老龄化项目官员，和无党派的研究组织（Westat）。结果：监管任务，包括机构审查委员会批准，基础设施建设和试验注册，如期完成。共有117名患者接受了随机化，超过目标51名。成功实施了EEG引导方案，并证明了对麻醉实践的相关影响（年龄调整的最低肺泡麻醉药浓度中位数从0.93降至0.78 [P < .001]，零EEG抑制时间中位数比例从87%增至94% [P < .01]）。几乎所有患者（115/117，98.3%）均使用意识模糊评估方法评估了谵妄，谵妄发生率（28.1%; 95% CI，20%-37%）与用于样本量计算的估计值（25%）相似。证实了谵妄评估的良好评定者间可靠性（= 0.94 [95% CI，0.86-1]）。最后，获得了96.9%的患者的1个月随访生命状态数据，85.7%的患者至少完成了1次surveillance.CONCLUSIONS：与ENGAGES试验，我们证明了关键的里程碑，可以确定和逐步评估在试点阶段。假设成功达到适当的里程碑可预测研究的有意义的完成，并可为在试验阶段之后继续进行提供依据。这一分阶段办法对投资回报和科学产出的影响需要进一步研究。
BACKGROUND: Although the National Institutes of Health (NIH) invests $30 billion in research annually, many funded studies fail to generate results that can inform practice. The National Institutes of Health introduced a phased funding mechanism as one potential solution. Study-specific milestones are established for an initial pilot phase. We assess the utility of this phased approach through the ongoing Electroencephalography (EEG) Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) pragmatic clinical trial. The hypothesis of the trial is that EEG guidance of general anesthesia, through prevention of EEG suppression, can decrease postoperative delirium and its downstream negative sequelae.METHODS: In collaboration with study stakeholders, we identified critical milestones for the ENGAGES study, with themes common to many clinical trials. These themes include: regulatory tasks; enrollment targets; feasibility and impact of study intervention; primary outcome incidence; measurement reliability of primary outcome; and follow-up. Progress in achieving the milestones was assessed at regular intervals during the pilot phase by ENGAGES investigators, a National Institute on Aging program officer, and a nonpartisan research organization (Westat).RESULTS: Regulatory tasks, including institutional review board approval, infrastructure establishment, and trial registration, were completed on schedule. A total of 117 patients were randomized, exceeding the target by 51. The EEG-guided protocol was successfully implemented, and a relevant effect on anesthetic practice was demonstrated (decrease in median age-adjusted minimum alveolar anesthetic concentration from 0.93 to 0.78 [P < .001] and increase in median proportion of zero EEG suppression time from 87% to 94% [P < .01]). Nearly all patients (115 of 117, 98.3%) were assessed for delirium using the Confusion Assessment Method, and the delirium incidence was similar (28.1%; 95% CI, 20%-37%) to the estimate (25%) used for the sample size calculation. Good interrater reliability of delirium assessment was demonstrated ( = 0.94 [95% CI, 0.86-1]). Finally, 1-month follow-up vital status data were obtained for 96.9% of patients, with 85.7% of patients completing at least 1 survey.CONCLUSIONS: With the ENGAGES trial, we demonstrated that key milestones can be identified and progressively assessed during a pilot phase. Success in attaining appropriate milestones hypothetically predicts meaningful completion of a study, and can provide justification for proceeding beyond a pilot phase. The impact of this phased approach on return on investment and scientific yield requires additional study.