Lynn is the research director at the cardiology department at Boston Children's Hospital, where I work, Harvard Medical School. And she's going to talk to us today about chasing the dream of equipoise, design and execution challenges of multi-center trial design in pediatric ECMO. Thanks so much for being here. Thank you for having me. My disclosures. So I'd like to discuss today trying to achieve equipoise and the processes and the challenges with regard to that in regards to finding a study intervention in that context, some of the trade-offs in study site selection, and the progress of the TITRE trial. The TITRE trial will be used as a primary example here for this talk. This is a 20-center North American multi-center randomized trial that's funded by a four-year grant from the US Department of Defense. And one of the challenges and exciting parts of ECMO research is that there are multiple stakeholders, even within each and every one of the 20 sites that we have participating. There are intensivists. There are multiple ICUs. There are surgeons. There are regulatory aspects. And this is all the things that contribute to chasing that dream of equipoise and really launching a trial and getting it off the ground that we've learned a lot about over the last year and a half. Our overarching goal for TITRE is to determine whether restricting blood transfusion results in less organ impairment and whether it improves long-term one-year outcomes for neurodevelopmental outcomes for children on ECMO. Some of the aspects of the trial are going to be described in greater detail by Dr. Theogarajan in about 10 minutes. So getting to yes. So this is just a definition of what is equipoise if you look it up. It's a balance of forces or interests. And in a trial, a randomized trial, which most till recently at least have been considered the gold standard to answer research hypotheses, you need to have clinical equipoise. So that really needs to be a balancing act between holding across all those stakeholders that we talked about sufficient belief to justifying exposing a subject to treatment and sufficient doubt to justify withholding that. And you need to be somewhere in the middle and confident in order to be able to randomly assign patients. So very briefly with the tighter rationale just to give you context for the equipoise challenges in this study, but these will be talked about again in the next talk, is that you all know that ECMO patients require frequent red blood cell transfusions both for management of ECMO and because of bleeding. But it has also been shown that there has not really been an optimal, or it hasn't been shown what an optimal hematocrit hemoglobin threshold is really in this situation. There is research that shows that only a very small percentage of red blood cell transfusions actually results in an increase in SpO2. And on the other side of the coin, despite needing RBC transfusions in ECMO, there is evidence that as the total volume of blood increases in terms of what's been received, that there is an increased mortality risk. So this sort of set the stage for the trial is that there's a trade-off between necessary red blood cell transfusion and optimizing ECMO outcomes. But it may, in fact, be that reducing unnecessary red blood cell transfusions is a good thing. And this is what the tighter trial was designed to test. There are two aims. The first is the shorter term across the course duration of ECMO, which is to test whether there is a greater improvement in organ function between two strategies, an indication-based red blood cell transfusion strategy versus a center-specific, typically threshold-based strategy. And the second is a one-year aim looking at neurodevelopmental outcomes in those two groups. Our original plan and our original protocol for titer was to have the indication-based strategy be compared against the center-specific one. And the indication-based one meant that there would be transfusion occurring if any one of the bullets here on the bottom were met, if there was monotrous severe bleeding, if there was reduced DO2, or for bleeding if hemoglobin was below 8 or hematocrit below 25%. So that was what we originally proposed to our sites. We started with 18 proposed sites that we wrote in the grant and started to work with when we got funding. In terms of whether we could adopt that protocol and have everyone on board, it really required a very in-depth communication with each potential study site, both from the leadership team at Boston with each of those sites and then asking each of those site PIs or joint PIs to go back and talk with all of their stakeholders internally across all disciplines. And it seems like just a couple of bullets here. It is very time intensive, both as a group and at the sites. Secondly, so part of it is whether they could accept the algorithm for the indication-based. But in contrast, there are also additional sites who, because there's a window of opportunity for equipoise, some sites actually have already adopted that. So those sites also would be a challenge to have them in our trial, because they basically would be randomizing patients to two arms that were the same strategy. So for that point, rapid mobilization of a trial is really important, because that window of opportunity for equipoise can be closing month by month. We talked with all the sites, and they really ended up in these three groups amongst those who hadn't already adopted the strategy that we wanted to test. So some centers were not able to join our trial. Others were. Others were with a fair bit of discussion and amongst themselves. What are the consequences of lack of equipoise? Well, one of the biggest ones is if everyone just joined and said, yes, we want to be in the trial, we'll randomize. But then they actually are not able to support the randomization assignment, that there could be treatment crossover. And so from a statistical perspective, when a trial lives and dies by its intention to treat primary analysis, there'll be a very diluted treatment effect if there's a lot of crossover. So it's really important in terms of getting equipoise and having protocol compliance. So what would have been some alternatives to what we had originally proposed? One would have been to exclude some of those fragile subgroups in the trial. Other would be to have sites to come on board, but only have some of their ICUs and not other ICUs. Those are all things that were discussed in the process of us developing the protocol. Or we could be inclusive and modify the trial intervention. The trade-off there is whether or not we have separation of treatment arms. So they're tough decisions, both scientifically and clinically, really, for care. In the end, we ended up modifying the protocol so that those most fragile subgroups had a different threshold for blood transfusion that's going to be discussed a bit in the next talk. So what would have happened if we had excluded the neonates entirely? This on the left is actually a little bit of descriptive information about where we are right now. But you can see from this, we have 52 patients randomized out of a target of 228. But then nearly half our patients are neonates. So if we had decided, instead of modifying the algorithm to exclude them, we would be doubling our recruitment duration on a time-limited grant, et cetera. And the generalizability of our results would be limited. So the altered threshold was really a subset for a subset of the patients was really a compromise that I've discussed now. Feasibility of the trial, getting it off the ground, and hopefully answering the questions we set out to answer versus a separation of treatment arms. So they both have a little bit of jeopardy and trade-offs there. Finding that balance between having trial that is perfect versus one that's feasible is a real reality. I wanted to talk briefly about other trade-offs. These are about study site selection. And what we did is, in order to engage sites and also understand really the full spectrum of a site's background, is we had a very detailed site survey with regard to their practices. And really, there's a trade-off for most sites. These are just some things to think about if you're doing a multi-center trial. Is it helpful to have a site that has high volume but mediocre data quality in the end? Smaller volume, but they always deliver. Is enthusiastic, but doesn't have experience, et cetera, et cetera. So these are all factors that go into site selection and that need to be considered and how they fit into the success of your particular trial. Some of these items, the ones I have in blue, are somewhat less modifiable. And the ones in green are more modifiable and can work with sites. And in general, for the field of pediatric ECMO research, we really want to engage and have an engaged full community of research. So we're trying to work with everyone. I think this I've already talked about. So this is just a brief summary of TITER on its way. We have now 218 patients screened. The 52 consented. We are a little bit behind our target, which would be up in the blue region. But we're very excited to be getting there. And we now have the 20 sites, which I thank everyone for participating in all the hard work that has gone into this to date. And so in summary, really open communication and a lot of time and effort interacting, both at the site level and amongst all parties, is really critical to launch a trial. And the goal is to have some compromise where needed, but to preserve scientific rigor to deliver quality, rigorous research in pediatric ECMO. Thank you.

pediatric ECMO trials

TITRE trial

blood transfusion

protocol compliance

stakeholder engagement