Lew Romer, MD - phaware® interview 420

Jun 20, 2023

Lew Romer, MD is a Professor of Anesthesiology and Critical Care Medicine, Johns Hopkins Medicine in Baltimore, Maryland.

Dr. Romer discusses the importance of clinical trials in the pediatric pulmonary hypertension population and his work on the PPHNet's Kids MoD PAH Trial: Mono- vs. Duo-Therapy for Pediatric PAH patients.

My name is Lew Romer. I am a pediatric intensivist at Johns Hopkins. I have a longstanding interest in problems that children have with various types of circulation issues specific to various kinds of blood vessels and what happens when they don't work and how to help them do the best they can despite those challenges. I have a basic science laboratory where we do work on cells and try to figure out different kinds of pathways and ways we can make things better. I also take care of children in the intensive care unit. I've had an interest in pulmonary hypertension for a very long time. I think the things that have kept me going in the ICU are the very amazing ways in which children rise to the occasion no matter what's put in their way. That's very inspiring to me. I really appreciate the kids and their families and the fact that we make a team. We make an alliance. We work together to try to overcome challenges.

I think it's fair to say that the medical world is on a bit of a seesaw. On the one hand, people think of doctors as having a sense that they know everything. One has to be confident in what one has to offer, especially in emergency circumstances. But on the other hand, there are an awful lot of things that we do not understand. We don't know how they work. We don't know what's the best way to go about trying to approach them. Thankfully, that doesn't apply so much to the things we do in a resuscitation situation, in an acute circumstance. But many of the longer term challenges involve processes that we really don't know the answers to. Because of that, all of medicine from surgical to the medical, from pediatrics to geriatrics, care for all kinds of problems and all kinds of aged people all over the world depend on testing hypotheses.

We think we have an idea of how something might work. So if we try this, or we try to do things a bit differently, or we combine approaches, we might have more to offer people that have those kinds of challenges. On a very global way of looking at things, those are called trials. They are experiments. They are the way in which we find out the answers to things. What's the best way to proceed?

They are a final bridge to practice. Meaning that before a trial is done, before we're going to try a new approach or a combination of approaches on people, there's a lot of data that support trying that because otherwise we wouldn't try it on children and not adults. There are experiments that are done; chemistry, cell biology, animal models of disease, things that lead up to those clinical trials of medications or combinations of medications, different kinds of therapies to see if they're going to work.

Historically, right up until the current day, those are much more plentiful in adult medicine than they are in pediatric medicine. They're very good reasons for that. People feel very protective of children. They don’t want to try things out unless they're have a very high level of confidence that they are safe to try. It's a much more complicated process to do a clinical trial with a child. We have a whole family that's involved in the trial. That means there are a lot of people thinking day-to-day whether they really want to continue this and whether this is a good idea. The process of consent obviously involves talking with the child, talking with their family, talking with their parents who talk with their parents and their colleagues and their friends. So it's a very involved process. I think for that reason it has again, right up until the current day been a challenge to accomplish trials in kids, meaning to get to the point where we have asked the question enough times, have enough children participating in the trial to be able to answer the question at hand.

I think it's a really important thing to do. In the case of the trial that I'd like to tell you about, my interest is driven by many things. I like to share the insight that when an intensive care physician is sitting at the bedside of a very sick child with pulmonary hypertension at three o'clock in the morning and one has tried everything that one knows how and things are still really difficult, one wishes one had more answers. One wishes one had a better way to answer those questions. That's one reason to do clinical trials. I've been close to families over the years that have unfortunately had children very sick with pulmonary hypertension that have not been able to make it, have not survived. That leaves one with just a feeling that we've got to do better.

When I first became an active member of the Pediatric Pulmonary Hypertension Network of North America, the PPHNet, it became clear that as I had known some of the busier and more accomplished and more experienced, well-known members of the group (who) had worked with drug companies on various types of trials of medications that those drug companies had developed. Did this work? What was the right dose? When should it be started? Which aged children under what circumstances were right for this kind of therapy?

We had not as the PPHNet ever done… in fact, it's never been done in North America, an investigator initiated trial. In other words, where the physicians taking care of children with pulmonary hypertension got together and said, what are the questions we want to ask? What are the things that would be most helpful for us to answer in our practice? All of those things are what led to the current clinical trial.

Certainly, as soon as children are of an age where they can understand and ask questions, we engage them directly in understanding what it is we're going to do. We require ascent for our study from kids, depending upon which site, with the university that they're being cared for at, kids from eight or older are giving us ascent. They're clearly not of legal age to give formal consent. Their families are involved as well. There are circumstances under which one needs to really explain things to a child or answer a child's questions individually as opposed to in the whole group. We certainly try to address things in a group, at least for part of this process, because we want the parents, the child to feel that they're in this together. This is a team effort. It’s never going to work if anybody is really not comfortable with going forward. We wouldn't want to put them in that situation. We want to feel that we have a team here that's on board.

In general because this is a trial that is of initial therapy; we're talking with families and children who have just heard about their new diagnosis. So it's a lot to deal with all at once. We try to give them time to adjust and come back and have additional discussions as needed before they make a decision about getting involved in the trial or not, and make sure that their questions are answered along the way. But we definitely try to involve the whole group.

I have a very high opinion of people I think in general. The people that come to the clinics that we see patients at have, I don't think it's an unfair generalization to say they have an altruistic sense to them. They want to contribute. If I can help other kids with what I do with my treatment, then that makes it even better. We do make it clear that there's not a definite answer to what's the best starting therapy for children. That's why we have this trial. We're trying to figure that out.

There are pediatric trials that have gone into building the data that we have to base our decision making and therapies on today. Some of them have been done as collaborative studies looking at patients and how they've responded to medication with European centers and American centers. Some have been drug company trials, work that was done on Sildenafil, for instance. Some of it is in the context of people that take care of both children and adults with pulmonary hypertension saying we should try this medicine in kids, because it worked in adults. Those pioneers also contributed a lot to where we are today in various tools that we have to use.

The PPHNet registry is really a treasure trove of collected information about kids that have presented to the PPHNet centers with pulmonary hypertension and how they've done over time. It stands as really an unmatched, certainly on this side of the ocean, collection of information about pediatric pulmonary hypertension. It's not specific to any drug company trial, but the medicines people have been on, how they've done, what their symptoms and levels of disease or challenges or disabilities coming in were and how they did over time. All of those things are measured and stored in the database, their echo cardiograms, their laboratory tests over time, and their catheterization data. We are hoping to use that as a benchmark, what has been up until this point, and compare where we might go with a trial like the one that I'm helping to move forward with the next chapter. How do those kids do with this new combination of therapy, a new approach based on all the different kinds of metrics and things that we're looking at, their quality of life, their echoes, how they feel, how they function, and compare those with what's in the register.

The study is called the Kids MoD PAH study. I'd love to share some of the specifics of this trial that we've put together, this multicenter randomized clinical trial of initial therapy for children with pulmonary hypertension. It's called the Kids MoD PAH Trial, and that means kids, we're looking at children between the ages of four months and 18 years, and MoD means mono or duo meaning one drug or two, and PAH stands for pulmonary arterial hypertension, so Kids MoD PAH. Children, whether one or two drugs as an initial therapy for pulmonary arterial hypertension.

This is a two-year study. We are looking to enroll children who have Group I or Group III type pulmonary arterial hypertension, meaning that they're in an idiopathic or hereditary cause for the problem or it's associated with lung disease. We are either using Sildenafil alone as the initial drug therapy or Sildenafil plus Bosentan as the initial drug therapy, a dual approach. The rationale for that is that these are two different medicines that work in different ways. They have potentially added effects and benefits. Our hypothesis is that if we start both at the same time as initial upfront first therapy kids have been on for pulmonary hypertension, kids might do better going forward and have a better trajectory.

Our primary endpoint for the study is the World Health Organizational, WHO functional class, meaning how well kids are functioning. We specifically are looking for kids at the get-go, at entry into the study are at functional class II or III. Meaning that they have some issue with exercise tolerance and fatigue and so forth, getting through the day and so forth, but not to the degree that they're in heart failure. Those two ends of the spectrum; no symptoms at all and heart failure are not eligible for this study at this point in time. We are trying to figure out whether we can change the course of the disease, improve things in the early going, delay worsening, potentially help kids to function better, feel better as they go forward.

We're looking at many different kinds of things as kids go through the study. In addition to WHO functional class, we're following the usual things that kids have followed when they have pulmonary hypertension, echo cardiograms and proBNPs, the biomarker for pulmonary hypertension. We're also looking at a quality of life scale, which is essentially a survey that kids and their parents take about what's life like with pulmonary hypertension. We're following that longitudinally over time. We're looking at actigraphy, which is a monitor that we try to get four days’ worth of good recording over a week period of time. It tells us how active kids actually are, how much are they moving. Actigraphy has actually been used in infants as well as in bigger people and adolescents, so it fits nicely with the range of ages that we're looking at.

We're looking at certain biomarkers, there is a biomarker aspect of the study. We are also trying to test ways in which the study team can stay in touch with the family. There's an app called MyCap, which is a way for the family to ask questions of the study team on a regular basis, record their medication diary all on their phone, how's the kid feeling, what are the things they want to ask, and stay in touch with the study team on a more frequent basis than the every three month visits that they have coming into clinic. Those are some of the things we're doing in the study.

We have screened about a hundred kids, but we have not enrolled that many yet. We're really early in the process, behind our goals, which is, as I mentioned, unfortunately the rule rather than the exception for pediatric trials. It's tough. We are trying to make actually some modifications in our criteria to relax some of our requirements for getting into the study to include more kids so that we can be more successful in enrolling.

There are many things that come up. Very few are situations where the family says, we don't want to get involved in research. That has happened very, very seldom. Sometimes there are complicating factors. The child has another kind of a disease process, which makes it tough for them to get around to consider participating in a clinical trial. There are exclusion criteria with regard to other kinds of disease.

One of the things that we've been running into fairly commonly is that although just a few years ago, most of the time, kids who are on medicine for pulmonary hypertension had that medicine prescribed by pulmonary hypertension experts at pulmonary hypertension centers. More pediatric cardiologists and general pediatricians are feeling comfortable getting something started, so they feel like, okay, I'm going to refer this child to a center, but while they're waiting for an appointment over there, I might as well get them started on some medicine. We're not able to enroll them in the study if they're already on something, so that's been a barrier, as well.

My name is Lew Romer. I'm a pediatric intensivist in Baltimore, and I am very aware that my patients are extremely special and very rare.

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Learn more about the Kids MoD PAH Trial: https://clinicaltrials.gov/ct2/show/NCT04039464