A Prospective, Randomized, Controlled Trial of Rectal Indomethacin in the Prevent

描述（由申请人提供）：胰腺炎是内镜逆行胰胆管造影术（ERCP）最常见的并发症，导致大量发病率、偶尔死亡率和医疗保健费用增加。许多药物已被研究，在预防ERCP术后胰腺炎（PEP），但临床试验结果一直令人失望，无论是由于样本量不足或缺乏效益。最近，已经发表了几项评价非甾体抗炎药（NSAID）保护作用的研究。我们最近报告的荟萃分析表明，实质性的好处。然而，连续的前瞻性临床数据对影响当前的临床实践是必要的。目的：确定建立多中心临床试验的可行性，以研究预防性直肠给药吲哚美辛对高危患者ERCP术后胰腺炎发生率的有效性。研究方法：本研究设计为一项多中心、前瞻性、随机、安慰剂对照、双盲临床试验，共入组948例连续接受ERCP的高危患者。将根据经确认的患者和手术相关风险因素选择高风险受试者。入组的受试者将在ERCP时随机接受安慰剂或吲哚美辛栓剂。将在ERCP时记录患者和手术特征。将在术后5天内和30天内收集研究结局，包括ERCP术后胰腺炎的存在和严重程度。对于主要终点的分析，将使用双尾Fisher精确检验分析吲哚美辛组和安慰剂组之间发生ERCP后胰腺炎的患者比例的差异。在资助期间，我们的目标是在两个医疗中心建立必要的研究基础设施，最终可以扩展到其他中心，以成功完成这项关键的临床试验。我们的目标是在试点资助期的16个月内累积256名受试者，允许进行中期分析（沿着现有受试者数据），其结果将用于申请额外资助。重要性：如果阳性，这项明确的临床试验的结果将立即影响临床实践，支持在ERCP时广泛使用预防性吲哚美辛。在美国，这可能导致手术相关发病率的大幅降低以及每年超过75，000，000美元的医疗保健成本节省。一项阴性研究也将是有益的，因为它为这一至关重要的临床问题提供了答案，并为将来在PEP中进行药物预防试验制定了标准。R21试点和可行性补助金将用于资助这项最终临床试验的试点阶段，在此期间将确定这项研究的可行性，并进行基础设施调整。 公共卫生相关性：胰腺炎或胰腺炎症是内镜逆行胰胆管造影术（ERCP）最常见和最具破坏性的并发症，ERCP是一种重要的诊断和治疗程序。从临床和经济的角度来看，预防ERCP后胰腺炎的有效方法将是非常有益的。基于大量的初步数据，我们认为在ERCP时给予单剂量的广泛使用的抗炎药吲哚美辛将有效预防ERCP后的胰腺炎。本研究的目的是建立一个基础设施的医疗中心，可以确定，在科学严谨的方式，如果吲哚美辛降低胰腺炎的风险后ERCP。

DESCRIPTION (provided by applicant): Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), accounting for substantial morbidity, occasional mortality, and increased health care expenditures. Many pharmacologic agents have been studied in the prevention of post-ERCP pancreatitis (PEP), however clinical trial results have been disappointing either due to inadequate sample sizes or absence of benefit. Recently, several studies evaluating the protective effect of non-steroidal anti- inflammatory drugs (NSAIDs) have been published. Our recently reported meta-analysis suggests substantial benefit. Definitive prospective clinical data, however, are necessary to impact current clinical practice. Objective: To determine the feasibility of establishing a multi-center clinical trial to study the efficacy of prophylactic rectally-administered indomethacin on the incidence of post-ERCP pancreatitis in high risk patients. Methods: The study is designed as a multi-center, prospective, randomized, placebo-controlled, double-blind clinical trial, enrolling a total 948 consecutive high risk patients undergoing ERCP. High risk subjects will be selected on the basis of validated patient and procedure-related risk factors. Enrolled subjects will be randomized to receive either placebo or indomethacin suppositories at the time of ERCP. Patient and procedure characteristics will be recorded at the time of the ERCP. Study outcomes, including the presence and severity of post-ERCP pancreatitis, will be collected within 5 days and at 30 days after the procedure. For analysis of the primary endpoint, the difference in the proportion of patients developing post-ERCP pancreatitis between the indomethacin group and placebo group will be analyzed using a two-tailed Fisher's exact test. Our objective during the funding period is to establish, at two medical centers, the necessary study infrastructure that can ultimately be extended to additional centers to successfully complete this pivotal clinical trial. Our target is to accrue 256 subjects within 16 months into the pilot funding period, allowing for an interim analysis (along with existing subject data), the results of which will be used to apply for additional funding. Significance: If positive, the results of this definitive clinical trial will immediately impact clinical practice by supporting the widespread use of prophylactic indomethacin at the time of ERCP. This may result in a substantial reduction of procedure-related morbidity as well as healthcare cost savings in excess of $75,000,000 annually in the United States. A negative study would also be beneficial by providing an answer to this critically important clinical question and setting the standard by which future trials of pharmacoprevention in PEP should be conducted. The R21 pilot and feasibility grant will serve to fund the pilot phase of this definitive clinical trial, during which the feasibility of this study will be determined and infrastructure adjustments will be made. PUBLIC HEALTH RELEVANCE: Pancreatitis, or inflammation of the pancreas, is the most common and devastating complication of endoscopic retrograde cholangiopancreatography (ERCP), an important diagnostic and therapeutic procedure. An effective way of preventing pancreatitis after ERCP would be highly beneficial, both from clinical and economic standpoints. Based on substantial preliminary data, we believe that a single dose of a widely available anti- inflammatory drug, indomethacin, given at the time of ERCP will be effective in preventing pancreatitis after ERCP. The objective of this study is to set up an infrastructure of medical centers that can determine, in a scientifically rigorous fashion, if indomethacin reduces the risk of pancreatitis after ERCP.