Cardiac Imaging in the VALOR-HCM Trial

Podcast Transcript

Announcer:

Welcome to Cleveland Clinic Cardiac Consult, brought to you by the Sydell and Arnold Miller Family Heart, Vascular and Thoracic Institute at Cleveland Clinic.

Milind Desai, MD, MBA:

Hello, everybody. I'm Milind Desai. I'm the Vice Chair for Heart, Vascular and Thoracic Institute at Cleveland Clinic and also, I direct the Hypertrophic Cardiomyopathy Center.

Today, I am extremely happy to do this podcast, a unique podcast with my very good friends and colleagues in arms from C5Research, which is our academic research organization. They're run out of HVTI at the Cleveland Clinic, and my good friends in the Cardiac Imaging Core Lab. We have an exciting podcast ahead of us where we discuss a lot of things related to the functioning of our C5Research Echo Core Lab in the context of clinical trials. Especially today, we are going to talk about the VALOR-HCM trial, which was run out of Cleveland Clinic in many ways, more than one.

So let's get started. I hope everybody has fun with this podcast and learns something out of it, not just the results of the trial, but also how we got from point A to point B.

So background. First and foremost, why hypertrophic cardiomyopathy? It's an important disease. This is prevalent worldwide, one in 500 patients, which means if you do the math for the world, it is 15, 20 million patients, maybe more. The problem is about 85% of these patients are, we think, undiagnosed, underdiagnosed, or misdiagnosed. So that's an important thing. We can spend the next hour with my expert imaging sonographer Core Lab colleagues just talking about how we can change that, how we can move the needle.

But I think there's more to the story. For 60 years since its initial discovery, the therapies have been limited in terms of drug therapies and majority of the patients, once they get past a certain level of symptoms, drugs don't work. You send them for invasive procedures like cardiac surgery. And the problem with cardiac surgery is yes, Cleveland Clinic is one of the world's biggest centers for this type of surgery. In fact, it is the biggest center for cardiac surgery in North America by far. But not everybody has access to Cleveland Clinic. Not everybody decides to come to Cleveland Clinic. So there are unmet needs of doing something more in terms of medical therapies, less invasive therapies.

Then, along comes a drug called Mavacamten. It is a precision drug that was developed specifically to help take care of symptomatic hypertrophic cardiomyopathy patients. This drug works directly on the heart muscle and it impacts the hypercontractility of the heart to make it normal contractile. It makes the heart function efficiently and use energy in a nice, sustainable way. Of course, for a new drug, it has to go through the process of regulatory approvals and the key part of that is a Phase III randomized controlled trial where the drug is compared against placebo for a chosen primary and a host of secondary endpoints.

A trial like this typically is done in a multi-center format, and the best-run trials like these are run under an independent umbrella of an academic research organization similar to C5Research. C5RResearch stands for Cleveland Clinic Coordinating Center for Cardiovascular Research, and this is an independent research organization where the sponsor contracts with them. The organization then contracts with various recruitment sites and we execute the study.

VALOR-HCM was a Phase III randomized control trial, which looked at Mavacamten versus placebo in patients with severe hypertrophic obstructive cardiomyopathy. Every patient was referred for cardiac surgery or invasive procedures. So everybody was symptomatic at their wits end, needed something aggressive done. The study was done in United States, about 19 sites, all major HCM centers and coordinated by our C5Research Group led by Ruth Cannata and program managers who help execute the study, statistical help who are experts in doing these advanced statistical analysis.

For this drug, this trial, a very important decision that we made was the drug titration was, for the first time, basically made through echocardiography measurements. In real life, this is how we manage these patients. So an important part of the trial was to use a Core Lab to do these blinded echocardiography reads. Why, one asks, do we do Core Lab? To maintain the sanctity of a trial where the investigator is blinded, the sonographer who is doing the measurements or the Core Lab personnel who is doing the measurement is blinded. Patient is blinded, the sponsor, everybody's blinded. Okay? So they are just doing the echo measurements and we are taking care of the patients and conducting the trial.

So for this trial, the titration of the drug up and down was entirely done through guidance from Core Lab reads. So in hypertrophic obstructive cardiomyopathy in the context of Mavacamten, there are two things important that we need to ascertain from an imaging perspective. What is their outflow tract gradient, which suggests how much obstruction do they have to the flow of blood, and what is their ejection fraction, heart function? Heart function is a safety monitor. Outflow tract gradient is an efficacy monitor. So everything was measured by an experienced sonographer. Then the studies were loaded to our Core Lab. They did independent reads, and then we titrated the medicine and ran the trial in a double-blind manner.

So extremely important. We will come to the end results and what this has resulted in, et cetera, in a little bit. But before we go there, I want to introduce our colleagues from C5Research and the Imaging Core Lab: Jeanne Drinko, she's a highly experienced sonographer, Amy Kanta and Annie Campbell. All three are highly experienced sonographers and play crucial role in our Imaging Core Lab.

So Jeanne, once we got awarded the Core Lab Project for this, from the moment we got awarded the Core Lab to the time the first echo rolled in and you guys drew the first set of circles or traced the first set of Doppler, what were the operational things that you needed to achieve to make that a reality?

Jeanne Drinko:

Well, as far as the execution, we were working around 20 US sites and that we had to analyze over 2,600 echoes and half of these were expedited. We needed to set up some processes in order to make this work. What I mean by expedited reviews is that if the studies came in before 2:00, the studies were checked in, analyzed by the imaging specialist, reviewed and verified by the physicians and entered into the database all on the same day, which was unheard of before. I mean, we never had a one-day turnaround.

So of course, it took excellent teamwork and dedication to meet our goals, especially from our front line who checked in the cases and did the first QA pass, make sure that there were no queries that needed to be sorted out with the site and also with the imaging specialist teams who analyzed the studies and did second reviews. What they do is, they do the second reviews. The first imaging specialist would do the initial analysis. The second reviewer would look at the endpoint, study endpoints and make sure everything made sense. Then the studies were forwarded to the physicians and they were read and verified and then these studies were entered into database all within the same day.

Milind Desai, MD, MBA:

So a few important things you have brought up is high quality work that is checked and double-checked, analyzed, and if the site were to upload the images at or before 2:00 P.M. Eastern Standard Time, we guaranteed a signed, finalized report uploaded to the blinded data set for the investigator across the United States to make their decision of titrating the dose same day. Or if you raise the safety signal concern and alarming signal, potentially, they had time to react the same day.

Jeanne Drinko:

Correct.

Milind Desai, MD, MBA:

So that is incredible, but I'm going to want to talk a little bit more upstream.

Amy, you are on deck. So what do I mean by that? So in terms of we got the contract for the Core Lab. What are the things, the standard operating procedure?

Amy Kanta:

Sure.

Milind Desai, MD, MBA:

The binder, the contract, the training, the transfer logistics. This is not a pony mail where the echoes are delivered. Electronic transfer and the safety, the safeguarding of HIPAA, walk us through those.

Amy Kanta:

Right. Sure. So as we approached or started VALOR, there were two things top of mind as already mentioned. We had to do expedited reviews, and we knew going into this that the knowledge base around HCM is not widespread. So training was going to be of utmost importance. So in preparation, first of all, we had weekly meetings with the sponsor and this went on throughout the duration of the trial and on the meetings, we discussed expectations. We were sure to align to make sure that between the Core Lab, the sponsor, and sites, everyone was on the same page and could meet the deadlines of the same day turnaround.

So for training and preparation, we prepared a manual of procedures, which is a document that outlines all the necessary tasks we need from a site and it also outlines the imaging protocol. We created a sonographer training PowerPoint, a coordinator training PowerPoint. We created checklists which are essentially reference guides for the sonographers. And in addition to all of these site-facing training documents, we hosted over 100 live training sessions, which really proved to be successful because the image quality that we received from over 20 US sites was excellent, which really helped with the results.

So training was very important, and not only did we do external training, but we did internal training. So internally, we, as Jeanne... and I don't know if she mentioned this yet, but we measure things in a standardized way. So we have analysis definitions, and we follow these definitions to ensure that all measurements are alike. So we measure the LV in a similar way. We train internally to ensure that all of the imaging specialists measuring on this trial measure similar and are aware of what they're getting into.

In addition to all this, a big piece in preparation was our quality control processes. So for VALOR, we had a qualification process. So not only did all sonographers and coordinators need to be trained, but all sonographers participating in this trial needed to submit a qualification echo before they could scan study subjects. The qualification, the purpose of this was multifold. It served to ensure that the site could upload their images successfully, but also to ensure that they understood the protocol and they could capture good images. Because as mentioned, study drug being titrated based on echo, we've needed high quality images.

Milind Desai, MD, MBA:

I mean, and that's a crucial point that has to be underscored. This is not just an analysis that some scientist is going to look at six months down the road to put in a manuscript. We are making, we were making, we are making live decisions based on what you were telling, right? So we had plans. We had to put contingency plans in place for what happens if there's a delay, et cetera.

Amy Kanta:

So in addition, for our quality control processes, in addition to the qualification, we also critique each study that comes in. So whether it be a qualification or on study visit, we provide feedback to the site and this is how we communicate to ensure the sites don't miss anything on future echoes and we also can give the sonographers kudos for doing a good job as well.

Milind Desai, MD, MBA:

And important... one thing, all of us would like to forget that era in all of our lives. But VALOR study was started, initiated at the height of the pandemic, COVID-19 pandemic, and it was run through the pandemic. We got done recruiting, in spite of all the challenges, a month or two ahead of schedule. And how many echoes did we not deliver on? This is open to all.

Amy Kanta:

We delivered on everything.

Milind Desai, MD, MBA:

We delivered on everybody. You need to say that out loud, right? Every echo, we had a contingency plan to deliver on every promise we can, right?

Jeanne Drinko:

Yeah, it was definitely teamwork.

Milind Desai, MD, MBA:

It was teamwork.

Jeanne Drinko:

For sure.

Milind Desai, MD, MBA:

During the most challenging of circumstances where people were working from home, working here, patient's visits. I can remember the patient visits and everything to go along.

What else do you want to add, your insights about that?

Amy Kanta:

So a few additional pieces for quality control. We have the quality control piece for the sites, but also for ourselves internally. We have the second review process, which Jeanne briefly mentioned. So each at VALOR Echo that we received was analyzed by an imaging specialist and then it was second reviewed by another imaging specialist.

Milind Desai, MD, MBA:

So what does an imaging specialist mean for a layperson?

Amy Kanta:

An imaging specialist is an advanced cardiac sonographer.

Milind Desai, MD, MBA:

So these are highly trained sonographers, most of whom, if not all, used to work in our main clinical echocardiography laboratory. For reference in 2024, we are on deck to do more than 100,000 echoes in Northeast Ohio. That's a big number. So everybody that works in our Core Lab has had their hands and feet wet in the clinical laboratory. So these are folks who are highly experienced. Before they talked the talk, they have walked the walk.

Amy Kanta:

Right. So in addition to our second review process, we also have reviewer team set up to ensure or to limit variability in the reads. So what that means is when subject A came into the Core Lab, a reader team was assigned. So the same imaging specialist and physician reviewer stuck with that patient throughout the duration of the trial, again, to limit variability in the reads. And then also, we participated in intra- and inter-observer processes throughout the duration of the trial to ensure that we were all measuring alike.

Milind Desai, MD, MBA:

Excellent. So the processes were put in place during extremely challenging times. And then we ran the trial and as I gave away the punch line, we started in the middle of the Covid pandemic and we got done recruiting ahead of schedule and not just imaging data flowing in fast and furious, but also clinical data, adverse events data, et cetera.

Now something important happened along this, which almost never has happened, is as we got done analyzing the data and presenting the first set of results, and we will talk about it, the drug also got approved, first ever drug in this space approved in April of 2022. So all of us, at least on the clinical side, we have the research patients. We have clinical patients. We now also had research patients that were transitioning to clinical care. So this required a very choreographed, orchestrated approach to taking care of these patients.

There's a lot of results we want to talk about. The thrill of hard work is not thrilling unless you see the fruits of your labor, right? And the fruits of the labor basically is the impactful results that you're going to see. So I will recap some of the results.

So I was the principal investigator and Dr. Steve Nissen was the study chair representing C5. And basically, this was 112 patient study, 112 sick obstructive HCM patients who had referred for advanced invasive therapies, mostly surgery. We approached them and say, "You want to try this drug or you want to go for an operation?" So 112 brave souls agreed to participate. Half got placebo. Half got Mavacamten. So the primary question we asked was, "You need surgery or you need alcohol ablation. After we give you 16 weeks of Mavacamten, how many patients no longer need surgery or alcohol ablation?" 16 weeks. That was a primary fundamental question we asked, plus how many required or how many improved their gradients and what happened to their safety signals, ejection fraction, heart failure, et cetera. How many had their quality of life improved, NYHA class improved.

16 weeks was the adjudication of primary endpoints, and we agreed to enroll or offer patients at 16, 32, 56, and 128 weeks. Every step of the way, we would go and ask the patients, "Do you want to continue or do you want to go to surgery?" Every step of the way. So for the first 16 weeks, it was placebo controlled. After 16 weeks, everybody got the goods. That's what I say. Everybody got the real drug and they got into the long-term extension plan.

So what did we show? At 16 weeks, remember baseline, 100% patients met criteria for advanced invasive therapies. At 16 weeks, eight out of 10, 82%, no longer qualified, met criteria for invasive therapy. A drug doing that against an invasive procedure. Generally, it has never been shown before, right?

So the critics could say, "Anybody can suck it up for 16 weeks for therapy. Maybe everybody will choose surgery in the longer term." That didn't happen. So at 16 weeks, what did we see is along with the primary endpoint, the gradients, the diastolic function, the MR, we are going to talk more about it. Then we said, "Maybe some things will wither off at 32 weeks." Not really. Same things. At one year, at 56 weeks, again, nine out of 10 patients continue to choose Mavacamten over invasive therapy. Nine out of 10. So sustained effect. The study was designed for 128 week of follow-up. So at 128 weeks, surely, they're going to get sick of taking Mavacamten and they'll go to surgery. No, it didn't happen. Even today, nine out of 10 patients transitioned to commercial Mavacamten. As I told you, it got approved in between the trial.

So patients have a very strong preference to medical therapy over invasive therapies. Okay? It was not just based on what we told them. They were feeling awesome. Their symptoms were gone. Their quality of life was significantly improved. That's why they made the decision. But along with that, what happened to all these 2,600 echoes? We learned a lot of things from these echoes, right?

So Annie, we learned an awful lot of things, good things from all the 2,600 echoes that were done. As a sonographer, as a card-carrying member of our clinical sonography laboratory for a long time and a recent export to the Core laboratory, can you highlight some of the things and what were your emotions? How did you feel when you saw a lot of the fruits of your hard labor pan out?

Anne Campbell:

Yeah, so it was actually, I have an interesting perspective because I wasn't here for the start of the trial and I didn't have to do a lot of the hard work, but I got to see all the exciting results. So from a sonographer standpoint, obviously, you're thinking that the LVOT gradient is all you kind of care about, thinking that that gets better, then the patient's getting better. But looking at these echoes towards the end of the trial, seeing obviously the gradient dropped, but their diastology improved, their LV, their LA strain both improved and significant reductions in their mitral regurgitation. So I think seeing all those things together for me was more surprising. I thought it would just sort of be the LVOT gradient, which I think is expected.

Milind Desai, MD, MBA:

And these measurements till the very end were done in a blinded manner. So the sonographers who were analyzing this data had no understanding of whether this was placebo or the drugs, right? Completely unbiased. So I think what you are describing is all of us who deal with hundreds of patients a year in the clinical laboratory, yeah, we see gradients go down after what have you, but the walls shrinking, the LA shrinking, the strain improving, the holy grail of everything in echocardiography, everybody and their grandmother talks about strain and diastology. A placebo-controlled randomized trial showing improvement in strain, I'm not aware of too many other programs that have done that, if any. Right? So it's sort of a feel-good situation where you are analyzing the data and when you are analyzing a single echo, you may not appreciate the difference, but the totality of the evidence is pointing in the right direction.

So anything else you guys want to add?

Jeanne Drinko:

Just that, like Amy said earlier, so when you're assigned at the beginning of the trial, you're assigned a physician and imaging specialist team for that patient subject from screening all the way to the end of the trial. So it's very dynamic, the changes. So it was very exciting.

Milind Desai, MD, MBA:

And I think you raised an extremely important point is the Core Lab has how many sonographers? How many imaging specialists out there in the Core lab?

Jeanne Drinko:

11.

Milind Desai, MD, MBA:

11 imaging specialists in the Core Lab. Okay? And about how many physicians read? Four or five in a given trial?

Jeanne Drinko:

Think we have five or six.

Milind Desai, MD, MBA:

Yeah, five or six. So that's important. It's kind of like any sport you play, football or what have you. If you work closely with the same group of people, you understand, you iteratively get better, you understand each other, the peculiarities, what they're looking for, how they interpret, et cetera. But here, we are doing it in a blinded manner. So they are used to seeing the same quality, the same progression of imaging, the same way you analyze it, et cetera. So I think that also adds a layer of reliability and also reduces a fair bit of heterogeneity.

What else, Annie? What else did you find exciting?

Anne Campbell:

I mean, actually just seeing such the change from one echo to the next, but it's all the things that we nerdily care about and look for and all the main factors like you were saying. Yeah, it was pretty impressive to see it on the other side.

Milind Desai, MD, MBA:

And then the important thing, though, about this and I alluded to is this is not your esoteric drug that is being tested in a trial and you present your data and then the drug may be approved five, seven years down the road and you forget. No, this is happening live. Basically, everybody, as I said, nine out of 10 patients in VALOR trial got transitioned to commercial Mavacamten, so they did not miss a beat. And you were part of a journey that started during very challenging times of the pandemic. You persevered. You showed that the drug makes a difference. You showed that your work helped the drug show that it makes a difference and now, it is hit mainstream.

Jeanne Drinko:

That's very satisfying to see.

Milind Desai, MD, MBA:

Exactly. I mean, the last Super Bowl, I'm seeing my texts started blowing up because for the first time I'm seeing commercials on TV. I had nothing to do with the commercial, but all of us had something to do with these commercials showing up.

Anne Campbell:

What about from a patient aspect as you were seeing them throughout?

Milind Desai, MD, MBA:

Yeah, so the patients, look, the patients, these are advanced symptoms patients. They had agreed to have a surgical procedure or an invasive procedure. From there, walks in this guy trying to convince them to try a drug. And with some trepidation, obviously, there's some who say, "I don't want surgery." The others say, "Okay, I'm willing to try" and they start experiencing how good they feel. That was very satisfying. I mean, they start seeing their symptoms feel better, their quality of life. They would do the Kansas City score. Their quality of life is better. "I was not able to do XYZ. Now, I planted a whole yard in the summer." So that kind of things. We have stories galore.

Anne Campbell:

That's huge. Yeah.

Milind Desai, MD, MBA:

We have stories galore and many patients, echo normalizes, but EKG normalizes. I mean, that is also things that we had never seen before. And what has the trial done? This is sort of that Little Engine That Could kind of a situation. It has elevated the echo game. It has recognized that across the world, how we are doing, approaching echoes, especially in the context of HCM and gradients and this and that were fairly heterogeneous and often frankly suboptimal. So the company that makes the drug, the community, HCM community of physicians has recognized. In fact, in the middle of all this, we even wrote guidelines for how to image HCM patients for American Society of Echo. And that is basically a lot of lessons that people have learned from experiences like this. A trial like this showed, yes, we can do something like this. Yes, we can deliver same day results. So I mean, so many things we have learned along the way and, of course, the big picture is the patients.

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