97 - Harlan Krumholz - Listen Study & Paxlovid Trial

Episode 97 of the Long Covid Podcast is a chat with Dr Harlan Krumholz, Cardiologist, leading research scientist at Yale and also the co-lead of the Paxlovid Trial.

We chat around the research into Long Covid at Yale - the Listen Study as well as the Paxlovid Trial which are collaborations with Akiko Iwasaki, as well as the way that these studies are being run - in a decentralised way.

More info & sign up for the Listen Study

More info & how to sign up for the Paxlovid Trial

For more information about Long Covid Breathing courses & workshops, please check out LongCovidBreathing.com

(music credit - Brock Hewitt, Rule of Life)

Transcript

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Jackie Baxter  
Hello, and welcome to this episode of the long COVID Podcast. I am absolutely delighted to be joined today by Harlan Krumholz, who is a cardiologist and leading research scientist at Yale, and also the Co-lead of the Yale Paxlovid trial. So I'm really, really excited to get into all of this today, a very warm welcome to the podcast. 

Harlan Krumholz  
Oh, thanks so much, Jackie. Thanks for inviting me to be on.

Jackie Baxter  
So I'm really excited to dive all into all of this. But maybe before we do that, would you mind just saying, maybe just a little bit more about yourself and what it is that you do?

Harlan Krumholz  
So as you said, I'm a cardiologist, I still see patients, although much less than I used to. But my major focus is as director of the Center for outcomes research and evaluation that we have at Yale, a group of people who are intent on trying to make healthcare and healthcare outcomes better, and a group that really measures our success, not in number of papers or grants, but actually whether we've been able to contribute substantively to tangible benefits for people. 

So, you know, we do a lot of different things. We have people working with the government and on policies, we have people working on clinical research studies, we're trying to understand how we can be better accountable for what it is we're spending in health care, in the kind of services we're providing. We're trying to understand over time, whether we're really making any progress, that's meaningful. 

We look at effectiveness and efficiency and equity in patient centeredness, safety, timeliness of healthcare delivery, but also whether or not there's actual evidence that that people are getting healthier, better, you know, that people are able to live longer and healthier lives. So it's a great group, and it's a group and still with that kind of mission to actually try to make the world better.

Jackie Baxter  
Yeah, definitely. I think that's like, the point of health care is to make people healthier... 

Harlan Krumholz  
Is it? Is it? I don't know? 

Jackie Baxter  
Well, it should be,

Harlan Krumholz  
Look, I was socialized to the system, I would say our health care system, which has extraordinary heroes, you know, in every different nook and cranny, and lots of people who are truly dedicated. But they're locked in a system that's primarily reactionary, and also very hierarchical, not one in which we try to instill a sense of, of, you know, what's the perspective of the people who are ill, or trying to get help. I mean, it's still more like a battle zone triage, which is, you know, everyone's lucky to get whatever they get and, you know, in, it can be extended time for appointments, or sitting in a waiting room, or just the way people are sometimes dismissed. Again, not because people aren't well meaning or dedicated. But, but the structure the system isn't set up. 

And that's why you're seeing the burnout on the healthcare provider side and, and on the patients. I mean, in a way, there's just a sense of acceptance for like, this is just the way that the system is, and instead, we can be driving to delight people by their experiences in healthcare, to try to understand what is it that truly makes a difference for them with regard to their interactions. To move away from transactions to relationships? How can we help people to anchor to individuals who truly know them and are invested in their success? 

And yes, I mean, you know, there's sometimes not always alignment between the person you're seeing and the person who's seeking care, but then we should seek where there is alignment, or people can have honest conversations. But increasingly, in healthcare, I mean, I think you feel lucky if things work out. And you know, that NHS is, of course, experiencing, you know, a real crisis, you know, of funding, but more than that, of organization. 

And we have it too, I mean, you know, we pay per thing done, you know, there's an intense drive, to actually just do tests and procedures rather than actually have conversations and develop relationships, which aren't reimbursed to the same extent, and, and, in fact, are diminished with regard to their importance. So, you know, this isn't in any way to undermine, you know, the intent and in the hopes of all the people who are working in the system, but just to say, there's got to be better ways to do this.

Jackie Baxter  
Yeah, I mean, this is something that I've noticed with long COVID. I mean, I was lucky to never really need health care, until I had long COVID. So then, it was a bit of a kind of an eye opener, that you know, that there didn't seem to be overall thinking between sort of specialties. There wasn't people that were looking at the bigger picture. And actually, it was kind of the opposite, that actually, a lot of people seem to be experiencing things like gaslighting, you know, where they won't even be believed. And this isn't everybody by any means. You know, there are huge numbers of extremely capable and empathetic and amazing health care providers out there. But it was definitely a bit of an eye opener that there were so many that weren't. So there are things that could be better, I think,

Harlan Krumholz  
Well, I think Long Covid stressed the system in a kind of a little bit of a different way. So here you have a system that is set up for short interactions, transactions, trying to move people to exactly what they need, rapid pattern recognition and moving people into wherever it is that whatever they have ought to be treated, and so forth. And then all of a sudden, you have the emergence of something which doesn't fit a pattern, and a bunch of people who actually need time and investment to understand what they're experiencing, to catalogue the set of symptoms they have, to be able to try and in some ways, even individually experiment with different strategies that might make them feel a little bit better, while other work is going on to try to understand the underlying basis for what it is that's affecting them. 

And when you have a system that, again, is like everyone's on the edge, there's no margin, you know, people are feeling already stressed out. And in the course of long COVID, it fell into a moment where acute COVID was already again stressing a fragile system, you know, then people with long COVID were often brushed aside. And I always say, you know, not that the healthcare professionals like I am, you know, deserve more, or even an ounce of sympathy compared to the people who are actually suffering from the disease. But there's an intense sense of inadequacy, you know, when people show up. 

And the inadequacy manifests in multiple ways, I mean, in lack of evidence, in lack of knowledge, but also lack of time, I mean, people are showing up  with mystery conditions; mystery, in the sense, never really well characterized before. And it's not like you're given an hour and a half to really ponder it with them, and to catalogue it. You're being pushed to move them in and out of the clinics. And so, you know, it's just, it's a moment where, yeah, the doctors and nurses and health care providers are feeling inadequate, and people who have the conditions are wondering what the heck just happened. I mean, you know, I saw somebody and they had little to offer, they didn't even spend that much time, and I have the feeling that they think it's all in my head. 

And you know, that that becomes then insult to injury to people who are suffering. And on the healthcare side, I think it's, it's a sense of feeling overwhelmed by the problem, because, you know, until someone starts to provide some evidence, just about what to do, what might be the next steps, you know, all you have are anecdotes, and people and experiments that they're running on themselves, and really little reliable information. It's a setup for what we saw, which is everybody being dissatisfied, and no one being happy, and people suffering without relief, and feeling dismissed.

Jackie Baxter  
Yeah, I think that's a really good point. You know, there's the sheer pressure on the healthcare system. And although there's not really any excuse for gaslighting, I think, you know, yeah, the healthcare professionals are really, really struggling, even if they do have the best will in the world, which many of them do. 

So what brought you specifically into long COVID research?

Harlan Krumholz  
Yeah, it's not an area that's natural to me. I spent most of my career in cardiology, our group actually does look at a wide range of issues. And, again, you know, worked with the government and other groups around a whole range of conditions. But, you know, Immunology and Infectious Disease wasn't an area that I was spending much time in. You know, maybe when I was in high school, I worked in an immunology lab, that was my last exposure. 

You know, what happened was that when the pandemic emerged, a lot of us who had skills, you know, tried to figure out where could we apply our skills, and for me, you know, I have clinical skills, but maybe my best unique skills are in clinical research, I mean, trying to apply creative energy to seeing if we can generate evidence that might help us move forward in rational ways. And so, you know, I began to get involved in clinical research and in public health research around the pandemic, around its spread, its toll, disparities, who was being infected, you know, how best to mitigate. 

I got on like, in Connecticut, the state I live in we, the governor put together a panel about, you know, how do we reopen Connecticut, and so I was beginning to get - it was pulling me in new directions. And then, in the course of that, it became aware that there was this long tail for some people with regard to the pandemic, so while we were working on on studies on the acute phase, I became aware that there was a large number of people who were suffering without end, and that this was a real, a real mystery. 

And by the way, I'm also looking at people who are reporting vaccine injuries. There are some people with a chronic condition long term that, you know, the vaccine I believe, was a great modern miracle, saved millions of lives, but there may be some people who in fact had harms as a result of it, like most vaccines, like most interventions, and medicine, you know, things can be very positive for on average, but there still can be people affected. 

And then  I was on a panel with Akiko Iwasaki and we began talking, of course, I have such great admiration for her she's remarkable person as well as a scientist. And we started having some discussions, and I had been tinkering with approaches to accelerate science in ways that would be partnered with people, that really wouldn't call them subjects anymore, but really partners and participants, and that we could be using digital and decentralized - decentralized, meaning they didn't have to go to a site. 

You know, because many people it's fatiguing to go somewhere or for those who have hourly jobs, giving up hours to go attend research visits, I mean, all these things can be burdensome. And so I was starting to develop approaches that might be able to speed research and make it more efficient and participant-friendly and partner it. Partner it, you know, and Akiko was very intrigued by this, her research had largely been with animals before, you know, and then she was starting to turn towards actually human studies. 

And so we started talking about what would happen if we took a world renowned immunologist, and paired that person with a clinical scientist, and we sort of started working in ways that, for example, you know, we start characterizing the computational phenotypes, the organization, the way I started talking about is the map, if you can think conceptually, that there's a big Atlas. And now I'm trying to understand the geography and by the geography, I mean, people under the umbrella of long COVID have, it's not just one conditions, as you know so well, it's many different conditions, it's a family of conditions. 

So if we can start saying, well, there's this town where these people are manifesting it like this, and there's, you know, this is what the map looks like, and people are aggregating in different areas. And some people are in the middle. And some people are unique, they live in, like, they live in a rural area by themselves, like no one else is like them, but a lot of other people are like lots of other people with long COVID, and different from other people. And we start creating that Atlas. 

And then on the biology side, if Akiko's 1000s of measurements and the kind of deep immune phenotyping that she and her lab does so well, her lab is terrific. You know, there's so many bright and energetic folks who are working hard on this problem. And if we can create a map on that side, and then see if it overlays, like, can we see how certain manifestations correlate with certain biological signals, and we can start moving all the way towards diagnostics and targets for therapeutics and even therapeutics themselves, you know, we can start to make some progress. 

So that that was sort of the kind of stuff that we were hatching together, of course, it's so nice for me to be able to work with somebody on that side. And someone so smart, so kind, so generous, you know. So that was a very much of a unique opportunity for me to branch out from what I've been doing. And it was also a chance to test - could we show proof of concept for the kind of study that would respect and honor the people who are in the study, listen intently to their contributions and suggestions, try to make it easy for them. 

And to learn together and do things like always guarantee we're going to return results, when we learn things, we're going to share back. If we can share into the research data back, we'll share it back, we'll have town halls, where people in the study get access to the investors, I've never done that before. And it's been like amazing to do that. And work hard, so that people don't have to travel anywhere, or they don't have to, you know, they can do everything from their home if they want to participate. And so, you know, that's how I ended up doing this. 

I mean, a lot of my other work continues, but I'm really energized by the possibility and I have met so many people along this journey, who so inspire me just because they get up and keep going and have hope that we will be able to figure this out, and that their lives can be better even as every day they're facing intense challenges.

Jackie Baxter  
Yeah, I mean, I have to say that this is one of the - I don't know if Silver Linings is the right word. But you know, one maybe positive to have come out of this whole awful experience of long COVID, is that I have spoken and connected with so many incredible people, you know, people with long COVID, people who are looking into it. And obviously there is a massive crossover between those two groups as well. And the fact that I am sitting here speaking to somebody like you this afternoon is just like, it's such a wonderful experience,

Harlan Krumholz  
or I'm sitting here talking to somebody like you.

Jackie Baxter  
Exactly. It's a really cool thing. But I love what you're saying about you know, the feeding back to people with long COVID and people who are involved in the research, because so often you know, you use your time and your energy and you participate in this research study and you put your data in and you send it off and that's that. And you don't really hear anything back for you know, quite a long time. And I think when you're giving up time and energy that you maybe don't really have, it could be quite frustrating.

Harlan Krumholz  
Oh my gosh. It's more than frustrating. It's disrespectful. But you know, to be fair, I was socialized in the system of hierarchy and not really talking to the people in the studies, calling them subjects, treating them like subjects like that. And not only that, I mean, treating the data as if it's mine, I get to do whatever I want with it. But I don't have to share it with anybody. And I'm embarrassed to say in a studies I ran, I didn't tell people what the result was, you know, they were just in the studies. I mean, it's horrible now to think about. 

But, you know, I underwent a, I guess, a transformation through the course, I was running a training program. And part of the training program, and part of one of the renewals to get funding, was to say you had to start thinking about teaching community based participatory research. And I'd never heard about that before. But that kind of Research is the research in which you really partner with people, you go out and understand their perspective. And the joint product is better than what it would have been if you would have just done it the old way. 

And we have lots of evidence about the problems with the traditional way. I mean, here are people who are suffering from conditions who joined studies in the hopes there's going to be breakthroughs, and they drop out, they don't stay with it, or it's hard to recruit them. And why is that? That's because we make these studies toxic and noxious. We don't respect the people in them. We don't make it easy for people to participate, we don't think about what is it like to be them, and to be participating in the studies. And so we're, I'm on a journey to improve, let me say, I don't think I've perfected this. It's not optimized yet. I have lots to learn. But that's what we're aspiring to. 

And there are, by the way, some patient citizen scientists, I think, who do this really, really well, because they intrinsically are on both sides, you know, and so, those people in you know, like patient led group, for example, you know, Hannah Davis, Lisa McCorkle, that group, you know, all of them and more and more, many more people out there who are contributing, I mean, they they have a foot in each camp, and they they really do it well. For those of us who grew up on the, on the traditional research side, you know, it's a constant effort and aspiration to get better and better and figure out how to make this work. And that's the hope. And that's really what we've tried to do.

Jackie Baxter  
Yeah, yeah. And from what I know of it, it definitely seems to be doing that, which  I think is wonderful. And this is all kind of feeding into the LISTEN study, isn't it?

Harlan Krumholz  
Yeah. So it started with with the Listen study. And so there's really two major things going on - the listen study is a longitudinal observational study that anyone in the world can join. It was about surveys, and for a subset of people, which right now, in the United States, we are getting biospecimens, blood and saliva and then combining it with the information. But for others, we're just trying to continue to give voice to people's experience to, in some ways I see it, we can use our credibility to legitimize this. So to make it that, that this is a legitimate form of research, that these these patients are authentically feeling, what they feel, they're authentically suffering. 

There's another thing in part, this is a disclosure, which is, you know, for a long time, I've been trying to crack this. And another important piece of this, I felt was to be able to efficiently gain access to medical records, but I call it ethically source them. You know, it's sort of like, you talk about, like, how do you do this, with very highest ethics? And a lot of studies and a lot of things that are going on in medicine, and healthcare these days, our data about you is floating around without your knowledge. And it's not clear to you exactly what's going on. What I did was eventually, I couldn't find any other way to do it. So created a startup, which is still in process, whose intent purpose - Hugo Health - which was the purpose was to give people agency over their data. 

So the principles would be, with this you could gain access to your data, you could link to it digitally, and it would be coming into your cloud based account and being refreshed. And then you could give permission for that to go into a study. And that's what we're using in Listen. And, of course, the idea is you can cut that off anytime, the study has to be worthy of your trust. And it's always your data, your data that you're sharing, not you gave me permission to go into the medical records and pull all your data and you never have any, you know, access to that data. But it's really the dream was eventually that that data could turn into something you can use and it could be used for the research. 

So Listen, was a idea of a digital decentralized, democratized study, one that gave broad access, was all all digital, either you could fill out surveys on your your devices, you could connect your medical records to your wearables, to your pharmacies, to your, in the US, we we have these companies that are payers, you know, and all of that data could be coming in and your data assets would grow over time. And then if you're giving consent to being in the Listen study, you're saying I'm willing to share that data. But again, you're willing to share your data, not just signing a consent, where I'm going out and scraping your data from different places. And that was part of the idea. 

And like I said, so the big part was really trying to characterize symptoms and end the suffering, legitimize and give voice to it, combine it with the medical records to give insight as to what's happening on the healthcare side. And then work with Akiko to combine sort of the architecture of long COVID, the sort of how are people being organized by their symptoms and experiences? How do we correlate that with what seems to be going on biologically? And so we're working hard to kind of bring all of that together. 

And in this sort of, I think the Listen study is, it's going it we've got about 2200 people, and it's still, you know, growing, I hope people listening here will be interested in joining and see, and we'll work hard, like I said, to be worthy of their trust, if they join. But I still think of it as a prototype. You know, it's like, Okay, now, what can we do better? How does this work even better, more efficiently, more participant centric, faster, you know, all these things we've got to figure out.

Jackie Baxter  
Yeah, but it's so exciting. And being able to collect that much data from that many people, I think, you know, it's gonna give you something useful, I think, hopefully,

Harlan Krumholz  
Well, give give *us* something. I mean, that's why I wanted to it's like, you know, I'm a big open science person, too. So how do we make sure that if we can de-identify it, so security is safe, how do we get as many smart people as possible working on this problem. And if we can start creating datasets, then it takes away the need for somebody to do what we're doing, which is spent a couple years and really pulling together people. That all has to be permissioned. People have to say it's okay. And we have to make sure that their identities are protected. But again, we should be trying to get as many smart people as possible onto this. And the easier we can make it for people to do research, then I think the better off we're going to be.

Jackie Baxter  
Yeah, definitely. I'd love to talk a bit more specifically about the Paxlovid trial, because I think this is not just started, but it's just been expanded recently into more areas. Is that right?

Harlan Krumholz  
Yeah. So I'm trying to think about the principles that we've used in Listen and say, can we apply this in clinical trials? Can we create a clinical trial that's digital, decentralized and democratized. So that basically, anybody can join, they can join from home, everything is done from home, they don't have to travel anywhere. We can do surveys at home, we can call them if we need to, we can ship drugs, we can draw bloods and collect biospecimens from their home or a place convenient to them. And by the way, we can compensate them for their time, we can actually respect and honor that this is taking effort to be able to do this. 

And so we - Akiko and I - sort of tried to conceptualize, you know, could this again, be a means by which we could start to create a platform that could be highly efficient for doing this again? Right now, it's United States only, in part, because the way that the shipping of the meds and the way the biospecimen collection has to occur, you know, it's hard to go across country lines, but I think that the model could work in lots of different places. 

And we got a little delayed in part because Yale, bless them, you know, they've never seen a trial like this before. So between the IRB and a lot of the mechanics of trying to get this through everything, it delayed us a bit as we tried to set all this up. But I think we're in really good shape with regard to all of the regulatory and mechanics of the trial. We started rolling just a couple weeks ago. 

And then I was trying to work hard on how do we expand across the entire country, and Yale was a little gun shy about shipping drugs to states where I as the PI didn't have a license. Now, our FDA says if you have an investigational new drug, and you get approved by them, which we are, you can ship across state lines, but there's ambiguity about whether or not the state laws will entangle us. I mean, this is how I knew all this - nobody really knows this. Most people think it won't be a problem, but it hasn't truly been tested. 

So Yale said you need somebody with a license in each state that you're going to include. We began working with some other colleagues. And then there's an organization called Trusted Medical, which has clinical clinics in many different states. A terrific guy Kevin Carr's friend of mine, started talking to Kevin, they came on board with us, and now we're going to be able to offer it in 41 states, and we're going to try to go even more. But I'm really happy because we can now talk about a national decentralized digital study. 

The other thing is in a lot of trials, it depends a lot on the clinician. So clinicians may know about this, if they forget about it, or they get too busy. They're not enrolling people so they don't enroll very quickly. But but they're also making implicit judgments. Is this a good person for the trial, even if you meet criteria, if they're behind or they think he wouldn't be a good subject? I don't know. There's lots of ways that it ends up creating barriers. 

In this study, it's the people who step forward. I mean, we try to raise awareness. Anyone can take the survey to see if they qualify. If they do that, they connect their records, we make sure that they're fit based on the criteria, based on records. And if it works, they're in. And then we're just basically sign them up. They're using their devices for surveys, so we're sending them like I said, medications,we're drawing blood at their house, bang, we're off to the races. And we've already got people through and it's working really well. 

The only other thing that we have to make sure is that we're fully accessible to all populations, you know, we want to be able to make sure that we have diversity in the trial, that we're welcoming groups of all different health literacy and that we're not letting a digital divide make it difficult. And so we're working hard to try to figure out, you know, how did we do this. Our previous work with this kind of platform is that actually, traditionally underrepresented groups, minoritized populations, actually feel really strengthened by this sort of tipping of the balance of power, by they're being put in this position. And the idea that we're making it convenient for them also gets rid of this problem about hourly working, and having take time off work, where that's not going to be covered. 

But we've got a lot to learn still about, again, being worthy of the trust, getting to people, the right populations, and meaning the right populations, ensuring that it's not just certain populations, well educated and in well off groups, but that we're able to reach all sorts of different folks. But it's so far, it's moving quickly. Lots of people are interested. I'm happy to be on this program to to promote and invite people paxlcstudy@yale.edu, or we'll give you the links to accompany the notes, but I'm even more excited about what it can show about future studies, if this platform works, then we can just keep reloading with new things to try. 

Because in lung COVID, honestly, we're gonna need to try a lot of things to figure out what works for whom. And Akiko is doing a lot of deep phenotyping in this study, because on average, there may not be a benefit, but there may be responders. And we need to then understand, okay, who responded in this study? And can we then do another study where we really pick out those responders and demonstrate it. So it's not only about average effects. And I think that's going to be true throughout long covid , which is why we keep re-iterate, iterate, iterate, to generate the evidence that people need.

Jackie Baxter  
Yeah, man, this is so exciting. Are you able to talk a little bit about what Paxlovid actually is? I feel like this is something that we keep hearing about. But I'd love to know just a little bit more about what is it? And what does it do? Or what are you hoping that it might do?

Harlan Krumholz  
So the idea - people may wonder, you know, why did we go to Paxlovid? You know, because there are lots of people who are interested in, you know, a lot of different therapies. And to be honest, you know, one thing is these trials have to be funded. And there was a company that had a product that was somewhat interested in this, you know, and Paxlovid many people have heard about it, because it's the pill that , you know, people use to treat acute COVID, you know, and it was recently in the US granted full approval by the Food and Drug Administration. For a long time it was under an emergency use authorization. 

And, you know, it's an oral antiviral pill, that, you know, people can take it in their home, and it was shown in lots of studies that it was associated with a pretty dramatic reduction in the risk of hospitalization and death in unvaccinated people. And that was the clinical trial that supported the EUA. And, you know, subsequently, lots of people still think even if you've been vaccinated, this is the thing to do, you know, to try to treat and both more quickly reduce symptoms, but even more importantly, that it can reduce this risk of hospitalization and death, you know. 

So Paxlovid consists of two separate medications that are packaged together. And so you generally, you know, when you do this, you take three pills, you know, two of the pills are Nirmatrelvir, and the other is ritonavir, and the ritonavir potentiates the action of the Nirmatrelvir. And, you know, this is a drug that interferes with the mechanisms of viral replication, and helps to help the body to overcome the virus. 

And so, you know, what we thought was one of the central hypotheses around long COVID - it's not the only one - but one of them is viral persistence. And there's continuing to be evidence emerging, that for many people, they continue to carry around the virus after they've gotten over the acute infection. And so, the idea is that this treatment, which has been shown to so that when the COVID virus that's released from cells can't enter uninfected cells in the body, like it's sort of neutralizes the infection, that maybe if we use this for an extended dose, so that the acute care dose is five days as you know, but this is in the trial, we're testing 15 days. 

So people ask us, Why did you choose 15, it was just out of recognition that lots of people have rebound after five. And that, you know, that might not be enough to kick the virus out, you know, for some people. We didn't really have, it had been tested and 10 and a little bit and 15 in more in the lab situations and for safety. And we also were aware that Paxlovid for some people can cause metallic taste, and, you know, some nuisance symptoms, and to ask people to try that for more than two weeks when we haven't tried the two weeks yet, you know, seemed excessive. 

So we thought, well, let's go to two weeks first, and see what happens, we think people can bear up and manage their symptoms over that period of time. And then we you know, we're formally sort of testing this viral persistence theory and see whether or not it kicks the virus out. And there's lots of issues, you know, whether or not the virus might be hiding in places that it's hard for Paxlovid to get to and so forth. But it's, you know, it's a beginning. 

Like, again, I said, this is a platform, let's get this done. Let's see where it leaves us. Let's see for Akiko's study can provide insight into who are responders, but this shouldn't be the be all and end all trial, it should be the beginning. And then let's test 10 things, let's test 20 things, you know, let's start getting ramping up. And getting in a position where we can learn rapidly about what works.

Jackie Baxter  
I think this is something that I again, I've never been involved or even really known anything about research until long COVID. So coming into this kind of world, and speaking to people who are involved in research, it was quite an exciting moment for me, when I realized that actually, each research study is not like going to solve everything on its own. It's that each research study is like a piece of a bigger jigsaw, or it's a springboard for another study, or, you know, it's like building up, you know, building blocks, isn't it, to sort of whatever the quote unquote answer is. And I think it's probably quite frustrating as a patient, but it's also quite exciting, seeing all of these kind of pieces being put together over time. 

Harlan Krumholz  
Well I'm kind of hopeful that this represents something, you know, it's just like Kitty Hawk, you know, it's, you're showing that this approach works that you can actually do these studies, you can, you know, like I said, what are the features that are very participants centric, decentralized, very convenient, you know, potentially faster, because you can roll from across the entire country. I don't have to depend on three sites or four sites enrolling or 10 sites, or 20 sites. Actually, I've got the whole country, anyone who hears about it, who wants to be involved can be involved. 

Like in Listen, and those who want to be involved and can pass the screens, the exclusion criteria, can get into Pax LC, and then we can before you know, we'll be flying, you know, we'll be flying fleets, you know, it'll change the nature of the way we're doing research, philosophically and culturally, and technologically, that combination, right. It's not technology by itself, culturally too, its this embracing of wisdom, you know, it's not the hierarchical approach. It's one in which we're all colleagues together, we each have different skills, different knowledge, we're trying to make progress. It's not about its superstars. It's about the team. 

And, you know, that's my dream about this is that this starts to crack open a new approach to doing the culturally and technologically, you know. And that this will expand to other places, other places for mystery diseases, like MECFS, or vaccine injury, other cases like that. But then also, across all the spectrum of medicine, there's no reason we can't be doing this. 

One thing I wanted to say about, just because people may wonder about on our placebo arm, we do give Ritonavir. So the active agent, you know, really is Nirmatrelvir, but it's the ritonavir is a potentiater, but it also can be the cause of that metallic taste. So we want to stay blinded. I mean, you know, I just say this, because you mentioned, because this is new to you, and research. And it is really important that people don't know which one they're on. 

By the way, another feature of the decentricity here was the study goes on for 24 weeks after randomization. But we talked to a lot of people as we designed the study, and people said that they really didn't want to wait that long to know which one they were on - placebo or Paxlovid. Because if they were on placebo, and it looked like there was any evidence of benefit, they wanted to take the Paxlovid. So we said, you know, as soon as we get the final result on the 28 day endpoint, which should be about 90 days after the last person has finished that 28 days, and much shorter than it would have been if we waited till everyone finished the entire study, then we'll crack the code and we'll tell everybody what they were on and, and help people to you know, think about what that means. 

But, you know, again, that's another feature of saying like, you know, people want to know that, in creating the design for this study we spent a lot of time you know, say hey, what do you think about this? What do you think about that? People with long COVID, you know, like, we're going to study you guys. You guys are going to be part of this. What should we do to make sure that this trial is ultimately friendly? You know, inviting and sensitive to the ideas and feelings that people have who are facing this disease every day.

Jackie Baxter  
Yeah, yeah, definitely. I think, yeah, the idea of having patients involved, it's something that seems to me as an outsider, like a complete no-brainer, but it's kind of realizing that this hasn't really been that central to research until sort of more recently, but I think it's just such a cool thing.

Harlan Krumholz  
But don't be fooled to think it's easy, or that we're great at it. I mean, what do you do when someone who's got the disease expresses a strong opinion about something you should do. And 10 other people express another opinion, but you want to honor everybody's contribution? You know, how do you manage conflict, you know, and the conflict does not necessarily between researcher and the patient or participant, it could be that you're having trouble reaching consensus, you're hearing different things from different people. And you don't want anyone to feel dissed by us because you didn't follow what they recommended. 

You know, I'm still finding it challenging sometimes, you know, to make everyone feel whole, and also people with this condition. Many people are angry, and understandably so, you know, they're frustrated. And so, you know, that comes out in lots of different ways to I mean, you know, trying to handle people gently, respectfully, and help them know that you believe in them. But also, you're not always following what everybody's telling you. Because you can't do it. You're, you know, lots of different opinions.

Jackie Baxter  
Yes, yeah, exactly. It's not possible to, well, you can listen to everybody, but you can't necessarily follow exactly what everybody wants. Must be really difficult. 

Harlan Krumholz  
Yeah. 

Jackie Baxter  
So I suppose this this is the question everybody wants to know the answer to isn't it? When do you get results from the trial, and when might that be able to feed into either the next phase or rolling it out more, or you know what, whatever the next step looks like?

Harlan Krumholz  
Well we will go faster, the more people who step up and want to be part of it. So everybody, everybody can help by by stepping forward. This is a study, though, of only 100. And we're, you know, already enrolling at a good pace. We have some limitations of throughput, because everybody's getting the deep immune phenotyping. So in some ways, the capacity of the lab, but also is controlling how many people you can bring through in a week. 

We are hopeful that we'll finish the enrollment toward the end of November. And then early in the new year, maybe February, you know, we will be able to have results. But even more than that, what I hope is that we're proving out whether this kind of strategy, the digital decentralized, democratized approach works, because then we can, okay, let's go to scale, let's really try to start testing a lot of different things and figure out, you know, how they can all best work. But yeah, I mean, I say this sheepishly because I really wish I could say, you know, next week or the week after, but it's really going to probably be after the first of the year, you know, that we'll be able to get those results, I'm hoping

Jackie Baxter  
Yeah, fantastic.

Harlan Krumholz  
I want to convey to your listeners, the deep gratitude I have for all of my teachers, because every single person I've interacted with, with this condition has taught me something, and they're making me better, you know, they're making me a better researcher, they're making me a better a better person, honestly, because so many people are struggling through this with courage and are facing such extreme challenges in their life, I mean, how they feel, but also how it's affecting their relationships, how it's affecting their economic well being. And, you know, I'm honored to be part of an effort, you know, that includes so many of them. 

And anyway, just because people are listening, I just want to convey that because it's a humbling experience on on our side on the research side, because every day we're seeing these super people, who don't feel very super, don't feel very energized, you know, but truly, they are because of just getting through their days, and there's ups and downs, unpredictability of their days, some days, better, some days not, and having to manage people around them who may or may not believe what's going on or, just fatigued having to, you know, by the lack of progress, not just the people who are suffering, but the people around them are fatigued too. And that's just hard. It's just hard. So I'm hopeful that together, you know, as a group, we can forge progress, but that's what I'd want to convey.

Jackie Baxter  
Oh, thank you so much for joining me today. And thank you for all that you're doing. Maybe you'll come back and talk to me in the new year when you've got some of your results. That would be amazing.

Harlan Krumholz  
I would love to do that. And I would love to report really good results and it's been so nice, delightful to meet you. So appreciate being on, and really it is a true team effort including everyone who's participating in these studies, deserves a ton of credit for stepping up

Jackie Baxter  
yeah, absolutely, well thank you so much

Harlan Krumholz  
thank you, thank you so much Jackie

Transcribed by https://otter.ai