首页 > 分享 > IDWeek直击现场丨Thomas L. Holland：选择临床结局时深思熟虑，为细菌性疾病的临床试验带来更多可能

IDWeek直击现场丨Thomas L. Holland：选择临床结局时深思熟虑，为细菌性疾病的临床试验带来更多可能

花匠小妙招
2024-11-30 19:45

编者按：金黄色葡萄球菌菌血症是血流感染的主要原因，同时医院获得性细菌性肺炎也通常由多重耐药菌引起。而开发新的抗生素需要以患者为中心的临床结局，如何对临床试验的设计、分析和解释进行以患者为中心的获益风险评估，从而让更多细菌临床研究获得预期疗效？在近日举办的2023年美国感染病周（IDWeek 2023）大会现场，《感染医线》特邀美国杜克大学医学中心的Thomas L. Holland教授介绍了关于临床结局顺序的DOOR研究的实际应用和潜在挑战，并分享了临床结局顺序的重要性及其对未来临床试验和治疗方案的重要影响。

专家简介

Thomas L. Holland, MD

美国杜克大学医学中心

医学系传染病科副教授

研究方向包括抗菌试验，特别是针对金黄色葡萄球菌菌血症和抗生素耐药病原体的试验，以及新型临床试验终点的设计和实施，包括临床结局顺序和生活质量指标。同时积极参与新冠肺炎临床护理、研究以及新型诊断学研究。

《感染医线》：您最近公布了医院获得性细菌性肺炎和复杂腹腔内感染的结局期望排名（DOOR）的研究终点，您认为DOOR将如何改变细菌性疾病临床试验格局？您能否分享下它的实际应用和潜在挑战？

Holland教授：谢谢你提出这个问题。DOOR是一种逐渐为人们所熟知的结局排序。我认为在新冠试验时代，对结局进行排序是标准流程。众所周知，患者的治疗方案会根据最理想的结局进行排序，这也是DOOR对于细菌试验或任何其他试验的作用。我认为DOOR的挑战和吸引力在于，它真正将所有相关的结局整合为一个终点，这样你就可以将结局有效性、安全性结局、不良事件结局整合到一起进行分析。治疗后最理想的结局是什么？最不理想的结局通常是死亡。因此，在这些试验使用DOOR很有吸引力，并可给出一种直观的结局排序。

我认为挑战可能有两个，一是应该如何就排序顺序达成一致，从而真正获得参与试验的科学家、患者和其他利益相关者的认同，进而了解该排序结局中包含了哪些有意义的内容。第二个挑战可能是让监管机构在整个过程中接受新的终点，我们希望有关皮内感染的工作将有助于推动这一进程。

Infectious Disease Frontline：Good afternoon, Dr. Holland. In the context of your studies involving the Desirability of Outcome Ranking (DOOR) endpoints for Hospital-Acquired Bacterial Pneumonia and Complicated Intra-Abdominal Infections, how do you envision DOOR methodology altering the landscape of clinical trials in bacterial diseases? Can you provide insights on its practical application and the potential challenges?

Dr. Holland：Yeah, thanks for that question. The DOOR is an ordinal outcome, right? And so ordinal outcomes have become a lot more familiar. I think in the era of COVID trials where ordinal outcomes were standard. You know patients were ranked according to the most desirable outcome. And that's what DOOR does for bacterial trials or any trials as well. I think that the challenge of DOOR, the appeal of DOOR is that it really integrates all of your relevant outcomes into one endpoint, so you can integrate efficacy outcomes, and safety outcomes, adverse event outcomes, all into one thing that really makes sense. What's the most desirable way to end up after a treatment? down to the least desirable which is usually death. So there's a lot of appeal and using a sort of an intuitive ordinal outcome for these trials.

I think the challenge probably is two. One is agreeing on what that ranking should look like, so really getting consensus from both scientists in trial list, but also patients and other stakeholders as to what makes sense to include in that ordinal endpoint. That's one challenge. Probably the second challenge is Regulators to accept or embrace a novel endpoint as a whole process, but we hope that the work on intradermal infections will help move that forward.

《感染医线》：基于会议焦点及发展趋势，您如何评价下一代测序对金黄色葡萄球菌菌血症个体化治疗的临床试验与细菌性疾病临床试验的影响，其将会如何影响治疗方案和实践？

Holland教授：谢谢你的提问。我们借此机会考虑在CMI上发表一篇文章，探讨哪些试验可能会在葡萄球菌感染方面取得进展。我在最近的会议上谈到，患者的死亡率仍然很高，90天死亡率仍然高达20%、25%，我们需要采取措施来改变这一状况。一方面，通过更好的药物或药物组合；但我们认为另一种更具优势的方案是，能否使用菌血症或血液DNA的持续时间作为个体化治疗的方式。提出该方案的依据是目前qPCR或下一代测序等工具较为成熟。这种测试灵敏度很高，当患者需要时就接受抗葡萄球菌菌血症的治疗，一旦不再检测不到细菌DNA则停止治疗。对于那些不需要继续治疗的患者来说，这可能是一种缩短治疗时间的方法；或者对于那些没有如期痊愈的患者来说，可以延长治疗时间，或寻找其他原因。因此这将是一种个性化治疗的方案，如果我们能够真正应用于临床，患者葡萄球菌菌血症的死亡率或许能够取得更大进展。

Infectious Disease Frontline：Considering the conference’s focus, how does your proposal of a clinical trial evaluating next-generation sequencing for individualizing therapy in Staphylococcus aureus bacteraemia align with the evolving trends in clinical trials for bacterial diseases? How might this influence treatment protocols and practices?

Dr. Holland：Thanks for that question as well. Yeah, we took the chance to think about a publication in CMI as to what would be a trial that might move the needle in staph infections. I was just talking in the recent session about mortality in patient is still terrible. It's still 20%, 25% at 90 days. And we need ways to change that and move that. One round is to have better drugs or better combinations of drugs, but another that we think has some merit as an idea is could you use personalized duration of bacteraemia or DNA in the blood as a way to tailor therapy. So the idea there is because you get a test like a qPCR or a next generation sequencing test. That's really sensitive and then once a patient is on treatment for staph bacteraemia, once they're no longer a detectable DNA, that's when you stop therapy. That might be a way to shorten therapy for people that don't need it to go on any longer or to extend therapy for people who aren't clearing like you think they should be or to go looking for other sources. So it'd be a way to personalize duration and approach to therapy that hopefully if we can actually manage to test that and our patients can move the needle on the staph orious mortality.

《感染医线》：ERADICATE研究结果表明，头孢吡普在治疗复杂性金黄色葡萄球菌菌血症方面具有非劣效性，这一结局会对未来类似细菌感染的临床试验和治疗方法产生怎样的影响？对临床实践将会产生哪些影响？

Holland教授：ERADICATE试验着眼于头孢吡普，一种新的抗生素。它在欧洲的某些国家已经获得批准，但目前尚未在美国获得批准。因此我们在美国的葡萄球菌菌血症患者中进行了临床试验，并将其与达托霉素进行了比较，这项非劣效性研究结果表明头孢吡普非劣效于达托霉素。目前FDA已经接受了新药申请但尚未获批。它是否能获得葡萄球菌菌血症的批准，我们拭目以待。我认为这可能是一种前线疗法，特别是对于具有β-内酰胺酶活性的MRSA。头孢吡普对耐甲氧西林葡萄球菌具有活性，拥有较高效价是一件令人兴奋的事情，并且可能被用作MRSA的一线疗法用于菌血症或挽救性治疗。

Infectious Disease Frontline：Okay. And with the ERADICATE Study findings indicating Ceftobiprole's noninferiority in treating complicated Staphylococcus aureus bacteraemia, how might this outcome influence future clinical trials and treatment approaches in similar bacterial infections? What are the anticipated implications for clinical practice?

Dr. Holland：Yeah. So the ERADICATE trial looked at Cepthibrioprol which is a new antibiotic. It's approved in some countries in Europe not currently approved in the US. So it was tested in staph orious bacteraemia, and it was compared to Daptomycin. It was not inferiority trial and Cepthibrioprol was not inferior. So the next steps for that antibiotic, it'll go to the FDA for a decision. The FDA has already accepted the new drug application, hasn't ruled on it as accepted the application. And we'll see if it becomes an approved treatment option for staph bacteraemia. I think ultimately we'll see where it ends up getting used. I think it will potentially be an upfront therapy especially for MRSA having a beta-lactam, that's active against methicillin resistant staph orious would be an exciting thing to have high-quality data, and might get either used as a first-line therapy for MRSA bacteraemia or in salvage therapy treatments.

《感染医线》：最后一个问题，鉴于您在细菌和病毒感染方面的深入工作，特别是您最近使用地塞米松治疗COVID-19患者的研究，抗病毒治疗的经验教训如何为细菌性疾病治疗和临床试验的进步和创新提供借鉴？

Holland教授：是的，我们从新冠疫情中学到了很多东西。过去几年，我也有机会参加了新冠肺炎临床试验。我认为可能会转化为细菌性疾病的重要教训有两个，首先是终点的选择绝对至关重要。在新冠疫情早期，我们不知道最佳结局是死亡率结局还是恢复结局或恢复时间结局。我认为真正仔细关注正确的终点，可以帮助我们了解如何选择治疗策略，这是普遍挑战。我们必须更加敏锐地思考试验的结局。第二个，我认为我们从新冠疫情中学到的另一件事，可以快速启动并运行试验网络和站点网络来应对问题。适应性临床试验和平台型临床试验确实出现了爆炸式增长，可以快速测试不同的治疗方法。在细菌性疾病中我们也应进行借鉴。

Infectious Disease Frontline：Thank you. The last question. Given your extensive work in both bacterial and viral infections, specifically your recent study on dexamethasone for COVID-19 patients, how can learnings from antiviral treatments inform advancements and innovations in bacterial disease treatments and clinical trials?

Dr. Holland：Yeah, we've learned a lot of things from COVID. I've had the chance to participate in COVID trials in the last few years as well. I think probably two big picture lessons that would translate to bacterial diseases are one, your endpoint that you choose is absolutely critical. Early in COVID, we didn't know if the best endpoint was a mortality endpoint or a recovery or time to recovery endpoint. And I think really careful attention to the right endpoint that helps you understand how a treatment strategy works. That's a universal challenge in trials. And we've got to be sharper in our thinking about endpoints for trials. And the second is that it, I think the other thing we've learned from COVID is it is possible to get trial networks and networks of sites up and running quickly to answer questions. And there's been a real explosion of adaptive and platform trials that can rapidly test different treatments. We need that in bacterial diseases as well.