<Internaitonal Circulation>: In your presentation， you mentioned the EPITHET trial， which showed that there is no significant difference in the primary outcome， but it has a trend. The secondary endpoint shows statistical significance. What are the possible reasons for the non-significance of the primary outcome? Do you think the result of EPITHET trial has enough power to change the current therapeutic window for intravenous thrombolysis?
《国际循环》：您在演讲时提到了EPITHET试验，其主要临床结果有差异，但差异无显著性，次级终点有显著差异。您认为主要终点没有显著差异的可能原因是什么？您认为EPITHET试验的结果是否会改变静脉溶栓的治疗窗？

Prof. Donnan: A very good question. Firstly， it was probably a bit underpowered and it should have been a bigger trial. It was a phase two trial. So it showed as you were saying enough trends and enough positive secondary outcome measures for us to be very encouraged about the time window and it encouraged us to plan the phase three study. But because it is a phase two study it was never designed to change practice. When you run a phase two trial， the idea is to show that it is feasible and it is safe and the end it might have surrogate outcome measures that are positive. We showed it is feasible， it’s safe and some of the surrogate outcome measures were positive， so that was enough for us to say that it’s good. We can now go on to the phase three study.
Donnan教授：首先，这项研究不具备足够的效力，还需要大规模临床试验来验证。这项二期试验结果显示的趋势和阳性的次级终点，使我们有足够的信心计划三期试验。但是因为二期试验的目的并不是改变现有的治疗方案，而是为了证实其可行性和安全性，以及替代的终点结果。在这些方面我们都已经得到了良好的结果，我们正着手准备三期试验。

<Internaitonal Circulation>: Include more patients?
《国际循环》：包含更多患者？

Prof. Donnan: Include more patients， yes. So it’s encouraging.
Donnan教授：对。

<Internaitonal Circulation>: In EPITHET， what kind of method did you use to monitor the reperfusion?
《国际循环》：EPITHET试验采用什么方法监测再灌注？

Prof. Donnan: We used the MR - PWI perfusion weighted imaging. So， it was the number of patients who achieved 90% perfusion on the repeat study at 3~5 days. We got the initial perfusion scan and then the repeat perfusion scan at 3~5 days. It was the difference in the number of patients who had almost completely reperfused.
Donnan教授：我们采用磁共振灌注加权成像技术（MR-PWI），3~5天时有相当多患者的梗死部位得到90%的灌注，我们一开始对患者进行灌注扫描，3~5天时重复扫描梗死部位。几乎达到完全再灌注的患者数量也有差异。

<Internaitonal Circulation>: According to the studies in the past， how about the correlation of the reperfusion with all these imaging techniques， do you think that this is a good technique to study reperfusion?
《国际循环》：根据过去的研究，再灌注和各种成像技术之间有什么相关性？您是否认为这是适合研究再灌注的成像技术？

Prof. Donnan: That’s reperfusion of the tissue. Also， there is recanalization of the artery itself， the big artery. That， we measured by MRI but because MRI is difficult， the image quality was often not good enough for us to determine the outcome so our measure was always going to be the perfusion image.
Donnan教授：对于组织再灌注，血管再通，大动脉再通的研究，我们用MRI扫描，但是图像质量有时候不理想，没有办法分辨结果，所以基本上都用灌注成像。

<Internaitonal Circulation>: rt-PA is a traditional thrombolytic agent. It has been used by clinicians all around the world for a long time. Are there any new thrombolytic agents under development or in clinical trials that have shown promise for the intravenous thrombolysis? So all these new drugs work in the same mechanism? What about the agents versus rtPA?《国际循环》：rt-PA是常规溶栓药物，全世界医生使用该药已经有很长时间了。现在是否有新的静脉溶栓药在开发中或者在进行临床试验？这些新药的作用机制都一样吗？这些药物跟rtPA相比如何？

Prof. Donnan: Yes， there’s one called tenecteplase， which is in trial in Australia and a few other countries. There’s another one called desmoteplase， and that was the ECASS-3 study， which was negative， but they are going to run it again because there were lots of technical problems with the trial. So they are the main two that are being developed--tenecteplase and desmoteplase. Similar mechanism in that they dissolve clots， but both of those have a theoretical advantage in that they may not have as much hemorrhagic side effect， particularly desmoteplase. We didn’t study those agents， but certainly the safety of desmoteplase in all the desmoteplase studies that have been done， there have now been three studies， have shown each time that they are probably as safe， if not safer than tPA.
Donnan教授：一种新的溶栓药——替奈普酶正在澳大利亚和其他一些国家进行临床试验。ECASS-3研究中使用了去氨普酶，其研究结果是阴性的，但是由于该研究存在很多技术问题，所以正准备重新进行。替奈普酶和去氨普酶是目前正在进行研究的两种主要溶栓药。作用机制相差不大，但理论上新药，尤其替奈普酶，导致出血的副作用应该少于传统的溶栓药。
替奈普酶的安全性已为多数研究所证实，目前研究结果显示替奈普酶的安全性不劣于tPA。

<Internaitonal Circulation>: We often take neurological examinations to see if patients improve after thrombolytic therapy and there are other measures which we can use to see if the patients improve. But are there any studies that observe the long term outcome of thrombolytic therapy? If you take reperfusion as a secondary endpoint， but reperfusion can by harmful sometimes. So what do you think of the long term outcome?
《国际循环》：我们经常采用神经系统检查确定患者在接受溶栓治疗后是否有好转，同时还有其他观察患者是否改善的方法。但是，有没有关于溶栓治疗的长期结果的研究？如果将再灌注作为次级终点，但是再灌注有时可能是有害的，那么，您对长期临床结果有什么看法呢？

Prof. Donnan: I think it’s absolutely critical that you have hard clinical outcomes for the phase three studies. If you are going to change clinical practice， you must have clinical outcome measures. So， ECASS-3， for example， the one I have mentioned before， was a clinical outcome measure at three months and traditionally it is done at three months. So all the trials that have been phase three trials have used a three-month outcome measure and it’s been a clinical outcome measure， usually a disability score like the Modified Rankin Score， is the most commonly used.
Donnan教授：我认为三期试验的临床硬终点绝对是非常重要的。如果要改变临床治疗方案，就必须有临床试验结果支持。例如我刚才提到的ECASS-3研究设定了3个月的结果评价，这与其他研究通常设定的时间一致。所有的三期临床试验都是采用3个月的临床结果，应用最常用的评分标准，如改良的Rankin评分，有利于试验结果的评估。

<Internaitonal Circulation>: According to the results of clinical studies，should progressive ischemic stroke patients receive thrombolytic therapy?
《国际循环》：根据临床研究的结果，进展性缺血性脑卒中患者是否应该接受溶栓治疗？

Prof. Donnan: Yes， if it is within the time window of 3.3 hours or 4.5 hours. If they are progressing within that period， yes. However， if they have had a stroke， recovered， and then progress—no.
Donnan教授：如果在3.3或4.5小时的时间窗内病情持续进展，就应该接受溶栓治疗。

<Internaitonal Circulation>: