Jason Weatherald, MD - phaware® interview 500

In our 500th episode, Dr. Jason Weatherald, a pulmonologist at the University of Alberta in Canada, discusses a project called CRAVE (Canadian Right Ventricular Failure Adaptive Platform) to address the lack of treatments for right heart failure in patients with pulmonary hypertension. 

He explains that platform trials, which allow for multiple interventions to be tested simultaneously, are more efficient and offer a higher chance of receiving a potential therapy compared to traditional clinical trials. 

Dr. Weatherald emphasizes the importance of patient involvement in research and highlights the use of phaware’s HeartWorks mobile app, which allows patients to measure their walking distance at home, as a potential endpoint in the trial.

My name is Jason Weatherald. I'm a pulmonologist in Edmonton in Canada at the University of Alberta. My main area is pulmonary hypertension in terms of my clinical focus and my research program. I also practice as a lung transplant physician in Edmonton. I've been pretty involved in pulmonary hypertension research since about 2016 and was practicing before that for a couple of years. So, I'm coming up on 10 years of being in this area.

I'm starting to work on a really exciting project called CRAVE, which is the Canadian Right Ventricular Failure Adaptive Platform. CRAVE is sort of a response to, I guess a gap identified by some of us in the pulmonary hypertension space that we've been really researching treatments for the blood vessel disease in the lungs, but there haven't been a lot of treatments for the consequences of it, which is stress on the right side of the heart and right heart failure.

As opposed to left heart failure, which is a very common problem for which there are many treatments that have improved the prognosis of that disease, there really haven't been a lot of therapies that target the right heart and restore right heart function or help people who have developed a dysfunction or failure of the right side of the heart. So, one of the problems we identified was that, this is a less common problem and it's harder to study rare conditions. In PAH, we've done a pretty good job of that as a community developing multicenter trials across many countries, but that hasn't been done for right heart failure yet.

We learned a lot of lessons through COVID-19 about how to conduct efficient clinical trials on a large scale. We identified that there's a type of clinical trial called a platform trial, and that's where you have sort of one common infrastructure for running a trial, but you can look at multiple interventions simultaneously, and you compare them to the control arm in the trial. From a patient's point of view, this is potentially more interesting, because there's a higher chance that you get on a new potential therapy rather than being on a placebo or the control. If, for instance, if you have four treatments of interest in your platform trial, there's a four out of five chance that any given patient gets randomly assigned to being on treatment.

The other advantage of this is that because these treatments share the same control arm, it's actually more efficient to run a trial. What I mean by efficient is that you can arrive at an answer quicker, and if treatments don't work, you expose fewer people to a potentially futile therapy. I became really interested in this idea and this design of clinical trials during the COVID-19 pandemic, because these were rolled out on a very large scale. In fact, much of what we learned about how to treat COVID-19 and hospitalized patients came from these platform trials. So I was really impressed by our ability to do them and to arrive at answers efficiently.

My colleague and partner on this project, Lisa Mielniczuk and I sort of talked about this idea. In fact, it's been almost two years that we've been working on this idea of the CRAVE platform trial. We've managed to kickstart it a little bit and sort of develop a mini version of this trial called a pilot trial where we just make sure that we can run such a trial and we can recruit participants into this trial to make sure that it's feasible to do this on a larger scale. That's the stage that we're at right now in the CRAVE Program, with a vision in the coming months to years to develop this project across Canada and probably also into the United States, so that people who develop right heart dysfunction due to many potential causes of pulmonary hypertension may have access to this type of a research program.

Recently we held a meeting here in Edmonton, called the CRAVE Planning Meeting. The purpose of this was twofold. Number one was to engage people who are important stakeholders in this type of research, specifically the patients, but also the doctors and nurses who take care of the patients that would go into this trial, to understand a bit better about how they felt about how we were designing the trial, whether it aligned with their ideas of what was important to them. In terms of the things we're measuring in the trial, what do they think would be important for us to collect. We gathered with almost 40 people to talk about different aspects of how such a trial would be designed and conducted. In the Canadian context, we wanted to make sure that it was addressing specific barriers that some people have in this country to participating in research for a variety of reasons, whether they be sort of cultural or geographic.

We want to make sure that people who are underrepresented in clinical trials and who have difficulty accessing clinical trials may have better access to this trial. There's a variety of things that we can do to sort of increase accessibility for people to participating in research if they want to. We wanted to engage patients and clinicians to understand those barriers a little bit better and think about ways that we can improve accessibility to the CRAVE trial, hoping to develop ways to minimize those barriers. So whether they be making some aspects of the clinical trial conducted remotely or virtually, and doing some of the assessments outside of the hospital. Also thinking about ways that we can let people outside of the big academic institutions even know about the trial. So, getting the word out there and making it easier for people to get access to the trial. So those are some of the types of things that we've been discussing before and after the meeting, and particularly during the meeting.

The timeline for this whole project can conceivably last several years. What we're working on right now is this feasibility trial. So that's like a mini version of the trial that we're aiming to get going and complete within two years. We would recruit 30 people in that trial across several sites just to show what the problems are or the solutions could be to recruiting people. What are the some of the barriers from the patient perspective, and can we capture the data and identify people with this condition and get them into a trial and run it. That timeline, although two years sounds like a long time, it's really not a long time to design and start a clinical trial from scratch and to recruit and analyze the data from 30 patients.

In parallel, we will be working on a couple of other things to inform and design the larger CRAVE trial. That's a platform trial that could involve several hundred patients and could run over several years. The important thing about platform trials is that they don't necessarily have a definite ending to them as long as new therapies are identified, they can be added to the trial and sort of plugged in as like a module in this larger trial perpetually. So, it could go on for many years as long as you have patients and funding to do the trial. I think it's a really exciting way to potentially look at multiple promising treatments for people with right heart failure and pulmonary hypertension.

This CRAVE trial I think is unique and innovative in several ways in that we really aim to have patients embedded in the trial as partners and not just subjects of the trial. I think that is an important example of what we call patient-oriented research, where research really has to be meaningful to patients. I think the best way to ensure that research is meaningful, is to have them as colleagues and collaborators, having meaningful input from them at all stages of the research. Even before CRAVE, this actually comes from a project we did in Canada where we asked patients and their families, what do they think are the most important priorities for future research?

CRAVE kind of spawned from that exercise where we identified from the patient's perspective, what are the top 10 problems that you think future research should focus on? Things that had to do with the right ventricle and right heart failure, there were two sort of questions in the top 10 questions that had to do with the right heart. So, I think involving patients even from the beginning about what is important to you that we focus on, and then getting patient input into the design of research and how we should conduct it, makes the results more meaningful to patients.

It builds a partnership so that it's not kind of us and them, but it's us together developing research and conducting it. I think ultimately that will improve interest and buy-in from patients to make sure that they think that this research is important for them.

One of the things that's important to highlight is, one of the aspects of this trial that we'd like to include, and it's directly relevant to phaware, of course, is one of the things that is typically measured in clinical trials is the six-minute walking distance. We know that this is an endpoint that's used in clinical trials that regulatory agencies like the FDA and Health Canada will accept in terms of a drug or an intervention needs to show benefit on the six-minute walk distance because that's meaningful to patients, it's a measure of how they function in regular life. That's why we care about it in the clinic and in research.

Of course, there's been this app developed from phaware called HeartWorks™, which among its features includes the ability for patients to do their walk test at home and to do it more frequently. To me this is a really interesting endpoint in a trial that we could look at. So, one of our plans is to validate this app, HeartWorks™, and its measurements further in the context of a clinical trial so that hopefully it can be something that we can record in the larger CRAVE trial and look at how these interventions affect people not just at their clinic visits six months down the road, but how does it affect their walking time and distance day-to-day.

I think this app that phaware has developed and that our colleagues and friends in Stanford have worked on, looking in the research area, I think it's a really exciting innovation. It's a good example of what I mean about trying to decentralize clinical trial activities as much as possible to record as much of the information that you need in a clinical trial outside of the hospital, making it more convenient for patients, but actually more representative of what's going on in their day-to-day life.

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