The Minefields Ahead in Long COVID Treatment Development

— "For the people hurting and suffering, they need treatment yesterday," says long COVID expert

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    Jeremy Faust is editor-in-chief of ľֱ, an emergency medicine physician at Brigham and Women's Hospital in Boston, and a public health researcher. He is author of the Substack column Inside Medicine.

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    Emily Hutto is an Associate Video Producer & Editor for ľֱ. She is based in Manhattan.

In this Instagram Live clip, Jeremy Faust, MD, editor-in-chief of ľֱ, and Ziyad Al-Aly, MD, chief of the Research and Education Service at the VA St. Louis Health Care System in Missouri, discuss treating long COVID patients and what needs to happen to more thoroughly study treatment options for them.

Watch Part 1 and Part 2 of this interview.

The following is a transcript of their remarks:

Faust: Somebody asked a question about how do you advise doctors who are treating long COVID?

I think that's really difficult, because people want to do something and they want to acknowledge that something's happening. Then I think that they get creative, and that's not in the patient's interest, even though their heart is in the right place.

How hard is it to tell our colleagues, even for you when they come to you as an expert on this, to tell them, "Actually, don't do much." I mean, what do you tell them?

Al-Aly: It is really hard because management at this time is symptomatic, right? Somebody comes in with tachycardia and you'd treat them with beta-blockers, right? You're not getting at the root cause of it; you're literally treating the tachycardia with a drug that slows heart rates.

And it is hard. It is hard. For example, there's also no treatment for fatigue. Like, what do you do for fatigue? What do you do for brain fog? How do you improve brain fog? So there is literally not much there in our toolbox to offer these patients and the providers who are caring for them.

It's a difficult conversation because there are many of them. These people are hurting, and some people actually have profound fatigue that is limiting and post-exertional malaise that leaves them literally bed bound for days or even longer than that. Even after very, very mild exertion, they get this crash and are really wiped out for days. And there's really no validated treatment that we could offer.

It's a difficult conversation, but this is why the field needs to move to offering solutions as soon as possible, because for the people who are hurting and suffering, they need treatment yesterday.

Faust: Yeah. I think that one of the barriers in good research is sorting out who should be in which trial. Because if you're, as I used the analogy before, if you're doing a clinical trial studying multiple myeloma -- blood cancer -- you don't want to include cancer patients, because lung cancer and multiple myeloma are going to respond to different things. By being too inclusive, ironically, you actually end up having a higher risk of dismissing something that might work.

Al-Aly: Oh, yes.

Faust: Yeah. So how do you balance the advocacy of wanting people to feel like they can get a diagnosis so they can get the support they need, with the possible downside that people might be enrolling in trials that they shouldn't be in because they need to be in the other one, not this one?

Al-Aly: I think the two main barriers to entry into trials -- and maybe I'll add a third component to your question: Why is pharma not doing more trials on long COVID where they could get a new indication? So, there are two major barriers.

One is lack of clarity, exactly what you said, for the entry criteria. What are the phenotypes? Let's say I'm doing a trial for low-dose naloxone. What are the entry criteria for the phenotype that I'm looking for to actually include in this trial so I can test whether therapeutic A works better than placebo?

And two -- also very, very importantly -- is validated clinical endpoints. We talk about brain fog, we talk about PAM, we talk about fatigue, but how do you measure those things? Let's say I do it using a fatigue scale or cognitive scale X or cognitive scale Y, will that also be acceptable to the FDA, to regulators here and regulators in Europe -- the European Medicines Agency?

So, those things need to be solved. Two key things need to be solved to accelerate the development of trials. One is really getting some consensus about the phenotypes of long COVID and entry criteria under the different trials. And B, and very, very importantly, cultivating buy-in between regulators and pharma on what are the clinical endpoints that would be acceptable.

Because Pfizer for example... I talk to these people a lot -- no drug-maker is going to invest millions in a trial with an endpoint for a fatigue scale or something and then they go to the FDA and they say, "Oh, it's not acceptable to us. We wanted endpoint B, you did A, but we want B in the trial." So some consensus about how do we evaluate improvement in brain fog, how do we evaluate improvement in post-exertional malaise, what the scales are that will be acceptable to regulators. Some consensus around those things is going to be very, very important.

So that's where the field is moving, to build consensus around entry criteria for phenotypes, entry criteria for clustering or phenotypes, entry criteria into trials, and also very importantly, clinical endpoints for those trials.

Faust: Okay. I think that's extremely important.

I like the idea of kind of you look in the back of the book for the answers first, like what would be the answer that would be acceptable before you start asking the question. Because like you said, there are some conditions that -- we know that for asthma and emphysema, a pulmonary function test is actually acceptable.

On the other hand, there's a lot of data showing that there's a lot of bias in those tests, and there can be discrimination too. So you have to really be careful even with validated markers or validated outcomes that you're not leaving some people behind, right?

It's an incredibly fertile area for progress. It's also, I imagine, a minefield for folly. And so having more support, more minds on this is so critical.