SCCM Pod-463 CCM: Clazakizumab for COVID-19: Friend or Foe?

Clazakizumab is a monoclonal antibody against human interleukin-6 that may benefit patients hospitalized with severe or critical COVID-19 accompanied by hyperinflammation. Although not yet FDA approved, clinical trials of clazakizumab for treatment of COVID-19 are underway worldwide. Samantha Gambles Farr, MSN, NP-C, CCRN, RNFA, is joined by Bonnie E. Lonze, MD, PhD, to discuss the article, “A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation,” published in the September 2022 issue of Critical Care Medicine (Lonze B, et al. Crit Care Med. 2022;50:1348-1359). Dr. Lonze is a faculty transplant surgeon at NYU Langone in New York, New York, USA, focusing primarily on kidney transplants. As vice chair for research of the NYU Langone Transplant Institute, she leads the research group on clinical trials and regulatory oversight.

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Category: CCM Podcast

Transcript:

Samantha Gambles Farr: Hello, and welcome to another edition of the Society of Critical Care Medicine’s podcast. I’m your host, Samantha Gambles Farr. Today I will be speaking to Bonnie E. Lonze, MD, PhD, about the article, “A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.” Dr. Lonze is a faculty transplant surgeon at NYU Langone in New York, New York. She’s been in practice for eight years and focuses primarily on kidney transplant. Serving as the vice chair for research in the Transplant Institute at NYU Langone, she leads the research group focusing on clinical trials and regulatory oversight. Welcome, Dr. Lonze, and thank you for joining us. Before we begin, do you have any disclosures to report?

Bonnie Lonze: Thank you for having me. No, I don’t have any disclosures that are related to the work we’ll be discussing today.

Samantha Gambles Farr: Thank you so much. We are very excited to have you here to discuss your research article today. We are all aware of the impact COVID-19 has had on the United States and globally, resulting in greater than 5.7 million deaths. With manifestations of no symptoms to overt acute respiratory distress syndrome, one of the key factors associated with the disease is hyperinflammation. As such, identification of recommended treatments has been a hot topic in critical care since COVID began in 2020. Your study focuses on clazakizumab, an interleukin-6 inhibitor. How did you and the other medical centers develop the idea to study this topic?

Bonnie Lonze: This came about as a combination of necessity, opportunity, and maybe a little bit of desperation. As you mentioned, I’m a transplant surgeon, I’m not a critical care physician. You may be curious as to how a transplant surgeon ended up getting involved in a COVID-19 trial of this nature. It has everything to do with what the situation looked like that was unfolding in New York in late March of 2020, when the pandemic first hit. It’s kind of surreal thinking back on it now, what we lived through at that time, but what was happening was patients were coming into the hospital, getting very sick very fast, dying, and there really were no therapies, no treatments that were known to be effective for patients who had the most severe disease. What was coming out of China was the only data we had to rely on at that time to help guide us. There was some early evidence that many of the patients, in particular the sickest patients, were having these hyperinflammatory states, which were manifested by several serum markers of inflammation, as well as all the stuff that we later came to see that many of these patients displayed, the venous thrombosis, all these other manifestations of hyperinflammation.

There were trials, and by that I mean not formal rigorous randomized controlled trials but just empiric give-the-medication-to-the-sick-patients trials, of antiinflammatory agents in China, that early reports in the literature seemed to suggest were having a benefit. The one drug that was most readily available was a drug called tocilizumab, which is an IL-6 receptor inhibitor, which actually has an FDA-approved indication for treating other disease processes. That was the drug that was administered and reported on, but it turned out in our pharmacy there were a handful of doses of that drug, I think it was on the order of six or seven. They were given to patients who presented early on and then that drug was no longer available.

This trial came out of a conversation between me, the director of transplantation, Dr. Robert Montgomery, and our infectious diseases hospital director at the time, who was overseeing how we were helping to treat these patients. We pitched the idea of proposing to give this drug, clazakizumab, which we had unique access to in transplantation by way of some clinical trials that we were about to get started with using this drug. We pitched the idea: If we could figure out a way to get this medication for some of the patients, would you be interested in us doing that? The answer to that was a resounding yes, and things moved forward very quickly from there. That being said, there were a lot of steps between this conversation and actually being able to administer this drug to patients in this fashion by way of the trial. That’s a long-winded answer, but that’s how it all came about.

Samantha Gambles Farr: From a practical aspect, I work in a large academic level 1 trauma center in San Diego. You also work at a large academic institution. I was wondering, prior to COVID-19, was the utilization of interleukin-6 inhibitors something common for your specific institution? I think you already touched on that a little bit, or was that something specifically new to your institution?

Bonnie Lonze: I can elaborate on that a little bit more. I think rheumatologists and other specialists probably have some more experience than we did in transplant with this class of drugs. However, there are some transplantation trials that have utilized tocilizumab in various transplant applications, in particular antibody-mediated rejection. But this was a medication that I had never prescribed. In fact, clazakizumab is not a commercially available drug. It’s an investigational agent, and our access to it was purely by way of participating in a clinical trial that the company that manufactured clazakizumab, which at that time was Vitaeris, had asked us to participate in. When COVID hit, we were in the process of putting this trial in place at our site. We hadn’t actually started the trial, we hadn’t actually enrolled any patients in this trial, but it was a clinical trial of this drug for the treatment of antibody-mediated rejection in kidney transplantations. That’s how we ended up having our level of familiarity with this drug. It led to conversations between us and the leadership at Vitaeris that produced this drug to be able to pivot and generate this clinical trial where one hadn’t existed before.

Samantha Gambles Farr: Your study had an interesting design. After reading it, I was wondering if you can tell us how you came up with the methods used in your study and what they are specifically.

Bonnie Lonze: That’s an insightful comment. It does have an interesting design and I thank you for using the word “interesting” because that has a bit more positive connotation. It’s very atypical, the way this study unfolded. The way the manuscript described it is how it happened. This was a trial that was in evolution and it all starts with how we ended up initiating this effort in the first place. Our goal was to try to just give the drug to patients. I recognize that that’s not really a scientifically rigorous thing to do, but there were patients that were dying in the hospital and there was a therapy that we thought might work. What we initially set out to do was to get permission to give basically compassionate care use of this drug to the patients that were dying and there was nothing more that could be done in terms of supporting them.

So we went to the FDA with this request. Could we use this investigational agent open label for individual patients? They gave us, I would say with reticence, as I remember these conversations, a very conditional yes. What they told us specifically was that we could apply for three single-patient INDs, no more than that, but with the agreement that, if we were going to pursue using this drug any more extensively than that, they would require us to write and conduct a formal clinical trial where we could test this and actually just get some information as to whether this was going to be an effective therapy or not because I think, in the interest of the greater good, that’s the right thing to do.

Giving patients open-label drugs in a single-patient setup doesn’t really inform at all or doesn’t give us the ability to interpret at all whether that drug had any benefit or not. That’s exactly what we did. We went to the FDA with three single-patient IND requests; all of these were granted. We enrolled three patients in three single-subject studies, and we gave the drug to these patients. In the meantime, we started to write this clinical trial, and we designed it as a single-center study initially because we had our own site and we were focused on what we could do. We designed it as a randomized controlled trial that would give us the ability to gather some dose-finding information.

The initial study was a three-arm trial, where we randomized to one of two clazakizumab doses versus placebo. We aimed to enroll, I think it was 30 subjects in that trial. What happened was, within two weeks, we had completed enrollment in that trial. That’s how significant the volumes of these critically ill patients were at the time. It became very clear relatively quickly that we had the opportunity to expand this to a trial that enrolled a larger number of patients and might actually have some statistical power to make some inferences about two parts. Could we identify a dose that was effective or more effective than another dose? And was there some ability to ascertain efficacy of this drug in this patient population?

That’s how it evolved and how it turned into a multicenter study. As the wave of COVID spread from New York City across the country, we found ourselves in communication with colleagues. Generally, these were transplant connections that were in similar situations in their hospital where they didn’t have access to drugs. There were other clinical trials that were being rolled out at those sites that were formal company-sponsored trials. I should mention that this was a fully investigator-initiated trial. This was not a study that was put together by the drug company. This was a study that was written by us and put in place by us and all the regulatory work, all the interfacing with the FDA, all the INDs, this was all done by us. There were other sites and colleagues of ours that had interest in being able to offer a trial like this to the patients at their sites. So we then turned this into a collaborative multicenter study. That’s how it all came about.

Samantha Gambles Farr: Reflecting in talking about everything that you just spoke of and reflecting of the time and what was happening, particularly when COVID really set into America, prior to that, consents for patient in a trial were performed face to face. I would imagine that there was some adjustment that was needed to obtain consent. Can you describe some of the challenges that you faced as a researcher in this study as it relates to consent?

Bonnie Lonze: Absolutely. That is a very important question and one that gets taken for granted when we look at a final product such as a manuscript that comes out in a journal, which is to say that the patients who were enrolled, there was some consenting process for getting them to become study subjects. It was very difficult in this case because the inclusion and exclusion criteria that we designed for this trial were written to capture patients who were the sickest of the sick. As you know, the patients who are the sickest with COVID are intubated and incapacitated and unable to sign consent. As we all know, having lived through this pandemic, hospitals closed their doors to visitors. There were no families allowed. There were no consent designees allowed in our hospital. There was no one who was going to be able to sign consent as a proxy for any patient who was intubated or otherwise unable to make the determination that they could enroll themselves in a clinical trial. This was a huge issue. I’m speaking as someone with a fair bit of experience conducting clinical trials prior to this. All of the consents that we had ever done were on paper. There was no mechanism for electronic consent. There was really no mechanism for telephone consent in an interventional trial like this. It just didn’t exist within the parameters of what was acceptable from a regulatory standpoint from the IRB.

These were processes that we had to put in place in real time in order to be able to do this. The consent process was extremely complicated, but we worked very hard and very fast, in particular with tremendous support from our IRB to help adapt the processes that were in place at our institution to come up with a mechanism that was going to be acceptable and ethically aboveboard in a way that we felt that the patients, even if they didn’t have the capacity to consent, that the person who was closest to them that would have the ability to do that was making that decision on their behalf. This involved, in our case, after the patients regained capacity in the instances where they did, we then, as the study team, had to reapproach the patients and actually ask them to sign the consent themselves retrospectively and tell them, During this time that you were intubated and you were sedated, your family member enrolled you in this trial because they felt it was in your best interest. This is what happened. Obviously, you can’t change what happened, but do you agree to continue to participate in the trial? We gave the patients the opportunity to say, I don’t want anything to do with this trial. I withdraw my consent to participate. Please remove my data from everything you’ve collected. No one actually did that. Everyone was grateful for the opportunity to have been able to participate, but the consent process was a fluid continual process. That was again just by virtue of the way this all unfolded. We found ourselves in a scenario that was very, very different from how we had conducted clinical research in the past.

Samantha Gambles Farr: That was definitely something that was felt throughout the country and globally, as people were trying to come up with as much evidence based in the time of that fluidity answers to help save patients’ lives.

Bonnie Lonze: I would say just on this topic, not a lot of great things came out of COVID, but there are some good things that came out of COVID. One thing, from this standpoint, that is really, I think, very beneficial that came out of this is now the processes for doing this are very, very streamlined. We can do electronic consents where we can actually email a consent form to somebody, get a digital signature, and all of this stuff that we sort of had to figure out how to do before because it didn’t exist exists now in a way that honestly makes research easier. I think it’s important to take away from what was obviously a tragic and desperate and scary situation the fact that we were able to move some things forward in a way that will benefit researchers and clinicians in the future and not just having to do with treating COVID and treating critically ill patients.

Samantha Gambles Farr: Yeah, I think it’s interesting that technology at the time was meeting us there, whereas if this had happened 50 or 60 years ago, I don’t feel the technology would have met us at that place.

Bonnie Lonze: Agree.

Samantha Gambles Farr: I’d like to shift gears right now and discuss the utilization of CRP in your research. We all know that CRP can be utilized to identify inflammatory disease processes. Can you discuss how CRP played a role or definition within your research?

Bonnie Lonze: Absolutely. It’s a great question because C-reactive protein, or CRP, as you indicated, is a marker of inflammation. No one knows what it means, but it just is one way for us to tell that the patients may or may not be in a hyperinflammatory state. It was critical to us that we enroll a group of patients that we thought would likely benefit from the drug that we were proposing to give. The mechanism of the drug is that it is an interleukin-6 inhibitor, meaning it blocks all the proinflammatory cytokine activities that are driven by interleukin-6. Interleukin-6 is elevated in patients with hyperinflammation or inflammatory states. CRP is a marker for these hyperinflammatory states. One would postulate that if a patient didn’t have the hyperinflammation, then there would be no benefit to giving a drug like this. So we really needed to identify the patient population that we hypothesized was likely to benefit. Those were patients with hyperinflammation, and we used CRP as a marker for the hyperinflammatory state.

Our inclusion/exclusion criteria that we designed for the trial specified that patients had to have at least two serum markers of hyperinflammation. CRP was one; every single patient in the hospital was basically getting a CRP every day. That was one that was readily available, and it’s quick and easy for us to pull out of the electronic medical record for screening. Then we included some other markers of inflammation, like ferritin and fibrinogen, listed in our inclusion criteria in the study itself. You may ask, Did we test whether IL-6 levels were elevated in these patients, and did we use that as an inclusion criterion? The answer is no, and that may sound surprising, but there’s just a practical reason for that, which is that this is a highly specialized test that not all clinical laboratories are able to run and turn around, including the NYU Langone Clinical Laboratory.

I think tests get sent out to a third-party lab and the turnaround time for this was two to three days, which would have been very problematic in terms of being able to enroll patients in our trial since there’s often not a lot of stability in these patients. You couldn’t expect that someone in two to three days looked the way they looked at the time that we were trying to enroll them in the trial. So while we did capture that data for purposes of analysis, we couldn’t use the IL-6 level as an inclusion criterion formally for the trial, so we used other markers, CRP being primarily the one that basically every single patient had.

Samantha Gambles Farr: I think it’s important also to mention during that time of dealing with send-out labs and labs that required two to three days before COVID, those times could have even been longer than those two to three days, given staffing issues and things that were going on as well. Talking about the protocols and the different phases of your research, I noticed that there was a revision of the protocol after phase 2. Can you describe that revision and directly speak to the impact that this had on your statistical methods?

Bonnie Lonze: Yes. This was a pivot that we made after interim data analysis indicated that, in the three-arm phase of the trial, there was likely to be some efficacy to one of the doses of clazakizumab, not both. We had a data safety and monitoring board, a DSMB, that was convened specifically for the purpose of COVID-related trials at NYU Langone. I would say our institutional leadership was just incredible at mobilizing resources to be able to do this. People who worked on other studies and other things that got shut down were very rapidly reassigned to do things that they do best in the interest of helping researchers like our team be able to do what we were proposing to do in the interest of helping the patients.

A DSMB was convened. It consisted of a number of experts, statistical experts, clinical experts. They weren’t all faculty here, it was a multidisciplinary group that was representative of faculty at outside sites. So it was extremely impartial, and that DSMB had very stringent requirements for us to provide them data. Initially, it was once a week, we were providing them with the raw data from our study on a weekly basis for them to do interim safety analyses and efficacy analyses because clearly we were doing something that was outside the box, clearly we were doing something that was put together very fast. The most important focus on studies like this and all the other studies that rolled out at that time was safety. We needed to make sure that what we were doing wasn’t going to harm patients, first and foremost. Second, they wanted the ability to pick up very rapidly on therapies that actually did have some promise and that would allow us to focus resources institutionally. One DSMB was monitoring all of the new COVID trials that were being rolled out at our institution and that really allowed other institutions to focus resources where they were probably best served.

After some of the early interim analyses, it was probably a couple of weeks into the study at most, I don’t remember the exact timeline, but the DSMB were unblinded. We, as the study team, were blinded. I didn’t know who was getting what drug, the patients didn’t know, the nurses who were giving it didn’t know. But the DSMB was doing unblinded interim data analyses in order to be able to answer these questions about safety and efficacy. Very early on, there were some signals in the preliminary data analyses that the low-dose clazakizumab arm was no different from placebo and that there was some benefit to the high-dose regimen.

At their request, we redesigned the trial to drop that low-dose arm and then focus on randomizing patients into the placebo arm versus the high-dose arm in the interest of being able to populate those arms with enough patients to be able to draw some conclusions about efficacy. And that’s what happened. At that point, this trial evolved from a phase 2 into a phase 3 efficacy study. There were a number of regulatory tasks that were required to do that. We needed to get approval for this significant protocol amendment, both from our own IRB, as well as from the FDA. So all of those conversations and exchanges of information and protocols took place. We needed to change our consents. There was a lot of work that needed to be done again very rapidly in that transition. But that’s what we did and that’s how it came about.

Samantha Gambles Farr: One of the charts within your research talked about the utilization of the World Health Organization score. I was wondering how that assisted in gathering the information as you moved into analysis phasing of this research.

Bonnie Lonze: That was critical for a couple of reasons. One, it’s very objective and it’s very discreet. There was a manuscript that was published that outlined this scoring scale. It has very, very clear objective criteria about how you assign the scores. Basically what it is is a scoring scale that goes from zero to 10, that describes the level of clinical illness of a given patient. Zero is an uninfected patient, someone who’s totally healthy, and 10 is a patient who is deceased. One through nine are stepwise increases in the level of clinical acuity from a respiratory standpoint.

The things that we look at are basically oxygen requirements. Are they on room air? Are they on nasal cannula? Are they on high flow? Are they intubated? Are they intubated with P/F ratios that are less than 200? Are they on ECMO? Or up to number 10, has the patient passed away? This scale allowed us the ability to categorize our patients according to clinical acuity, which ended up being very important for data analysis. It also ended up being something that was very widely adopted among the clinical trials that were enrolling COVID patients at the time. In the literature, this is a very, very commonly used scale to assess the clinical status of a patient. It’s a way of comparing apples to apples. If you want to know what type of clinical acuity level patients were enrolled in trial A versus trial B, this scale affords you the way to do that and put the patients into those categories that you can understand who exactly you’re enrolling and who you’re treating. For multiple reasons, it ended up being very central to our ability to conduct this trial and get data out of this trial that we could actually analyze.

I might add to that, again, adding to the challenges of trying to conduct a trial in these circumstances, we were a small group. I don’t want to falsely suggest that we had a whole army of patients that were working on this. It was a small number of us that were doing this. The majority of our research staff was at home. A couple of us were in the hospital facing the patients, getting the consent in person face to face, doing our best with the PPE, but most of the research staff that helped in data collection and all of the bookkeeping that’s required in document preparation, they were at home. There was no reason to unnecessarily expose people to COVID if they didn’t have to be here. Clearly, some of us did. But this sort of a scale allowed those staff working from home to log in to our EMR and collect this information. It was very objective. It was in a place that was very easy to find. And it’s all backed up by source documentation, which is obviously very critical for proper conduct of a trial. This very simple scoring system was really key to what we did.

Samantha Gambles Farr: I think that you touched on something that was very important, the amount of people that were actually in the hospital versus we started seeing a transition of people working from home at that time. That was the beginning of stay-at-home orders around the country. I only mention that to reiterate all the things that you’ve said because, fast forward, we’re now in 2022. Sometimes if you’re living in that, it’s hard to forget, but it just is a reminder of what was actually happening in that moment of time. Further continuing our discussion about the analysis, one of the things you talked about moving forward was outcomes. You had a primary outcome of ventilator-free days at 28 days. You also had secondary outcomes. Can you enlighten us with some of those?

Bonnie Lonze: Our primary outcome was 28-day ventilator-free survival. We really wanted to know: Did this drug afford a benefit in terms of keeping people both alive and off the ventilator at one month after the drug was administered? All the outcomes that we chose were chosen because, number one, we thought they were clinically relevant, that’s the most important. Number two, they involved collecting data measures, data points, that we had access to. Critical to us was that we designed a trial that we could actually do. This continuation of my response to the prior question, which is to say that the people that were collecting a lot of this information, apart from me, were doing this from home. The clinical measures that we captured were data points that were readily available in the electronic medical record and were documented in a way that was unambiguous.

That having been said, the overarching objective of the outcomes was to pick outcomes that were clinically relevant. We were interested in who was alive and off the ventilator at 28 days. We were interested in overall survival. We were interested in the incidence of renal failure and recovery from renal failure. Then, we did actually at the end of the day do some post hoc analyses here, which weren’t prospectively designed in the trial, but a critical question was: Is there a subset of patients that benefits from this drug? I’m getting a little bit of ahead of ourselves, but we did find that, with respect to our primary outcome, there was a statistically significant improvement in patients who received the drug as opposed to receiving a placebo.

The next question was patients who are clinically ill with COVID, as you know, it’s a sliding scale, and some of them are on high-flow nasal canula, and some of them are on ECMO. That’s, in many of these cases, a continuum of the disease process. The question is: At what point do you intervene and give them some antiinflammatory drug that’s hopefully going to help interrupt these processes that are making the patient sicker and sicker? Is there a point at which it’s too late, that if you administer whatever you have that may be effective, patients are already too far down that path of respiratory failure, ARDS, end-stage respiratory failure, are they no longer salvageable? So we ended up doing some post hoc analyses, which are more exploratory outcomes, looking at subgroups of patients and how ill they were at the time of enrollment, trying to tease out, Was there some subgroup that benefited and another subgroup that didn’t benefit? We actually were able to get some information with respect to that too, which I think is one of the strengths of our study.

Samantha Gambles Farr: Following with the theme that went all the way through your paper and our discussion today, we’ve been talking about how things were changing so rapidly. Safety is always our primary concern as providers and as researchers. With that new information being discovered in the midst of your research, can you describe your safety outcome?

Bonnie Lonze: We focused on two categories of safety events. One, we called COVID-expected events; these were things like pneumonias or superinfections or venous thromboembolic events, as we all were learning in real time that these patients were susceptible to. We wanted to know whether administering clazakizumab versus placebo made any difference in terms of the patients experiencing those COVID-expected adverse events. Then obviously, as it pertains to safety of the drug itself, we needed to make sure, you could imagine a scenario where we’re potentially making the patients better from a respiratory standpoint from a drug that’s effective. But this drug has some other toxicities that are making patients much worse, so you have to weigh the risks and the benefits of the potential side effects or adverse effects of the drug itself or off-target effects.

We characterized a group of what we considered clazakizumab-expected adverse events; these were based on what was known about the drug having been administered to patients in other clinical trials in other settings. The drug was an investigational product, but it had been trialed in various rheumatologic conditions. There were some significant data on safety of giving this drug to clearly non-COVID patients. We were looking out for things like increased rates of infection, because theoretically blocking cytokines could be potentiating an immunosuppressive state. In some of the early studies of clazakizumab, there were some patients that experienced bowel perforations; these were patients that were at higher risk to do so, but it’s unclear whether clazakizumab is really associated with the greater risk of bowel perforation or not. Nonetheless, we wanted to make sure that there weren’t any incidences of that that were disproportionate in the clazakizumab group.

Some of the patients in the phase 2 studies developed elevated liver enzyme tests, so we wanted to make sure that we were monitoring liver enzyme tests and liver function. So basically, everything that had been attributed to clazakizumab as a potential toxicity, we made sure that we were capturing. What we found basically was no difference in the frequency of these safety events, not the COVID-expected events, not the clazakizumab-expected events when we ultimately looked at our blinded data. We were happy to have that be the case.

Samantha Gambles Farr: Then there were additional adverse effects that developed as a result of just having COVID, that developed over time that providers weren’t necessarily aware of. Patients coming in with DVTs was one of them, until that sequelae of information was passed from one center to the next. People were starting to notice that as they were treating these patient. That’s an additional thing that was an adverse effect of just having COVID at times for the patients.

Bonnie Lonze: Absolutely. There were a large number of AEs that were collected in these patients. They were very ill. An AE is basically anything that goes wrong, as those of us in clinical trials know, and there were a large number of these. Some of the patients had 10, 20, 30 AEs, depending on the duration of their hospital stay and the acuity of their condition. But importantly, these were things that we captured blinded. Again, we didn’t know who had received the drug, who had received the placebo. We were just capturing these events and trying to be as comprehensive as we possibly can. Then, ultimately with the unblinded comparisons, you get to make a determination of whether it looks like the drug is associated with more of these or not.

Samantha Gambles Farr: As you have moved through everything and you’ve gone through the analyses and everything got completed, what are your big takeaways?

Bonnie Lonze: Clearly, this study, as with all studies, has some limitations. I want to make sure I talk about that. But as it pertains to this study in this patient population, what we did find was that this drug does improve 28-day ventilator survival. It does improve 28-day and 60-day overall survival. It improved the rate of intubation. By that, I mean it decreased the probability that someone would need to become newly intubated after they were diagnosed with COVID. Likewise, it decreased the likelihood that they would need to be newly transferred to the ICU. These were statistically significant findings. But I would say, with the caveat that that was in this patient population with this strain of COVID, and in all clinical research, this included, needs to be taken in the context of who is the patient population that has been treated.

I think what we can’t do is make inferences about how this drug works on all strains of COVID. Fortunately, I think what we have seen is that people are getting a little less critically ill from some of the variants of COVID that have evolved over time, which is excellent. But hopefully, there’s still some applicability to those patients who do develop severe pulmonary manifestations of the disease. Again, these are patients who had COVID and severe hyperinflammation. I think we did, with this study, provide evidence to suggest that there is a therapy that probably is effective for this.

That having been said, the post hoc analyses that I alluded to before, what they pretty clearly demonstrated to us was that the time to intervene is early. If we get to patients and we administer this treatment, and by that time they have progressed to ARDS end-stage respiratory failure, it’s too late. We found that there was absolutely no benefit to giving the drug to patients who were already that far along the trajectory of respiratory decompensation. Those were the takeaway points, that this drug does appear to help. Does it fix everybody? Nope. Were there some patients who got clazakizumab who still eventually expired? Yes, there were. But there were fewer that got the drug than got the placebo that died. So, in the context of potential therapies for patients who are the sickest of the sick, we think we have some evidence that this class of drugs is probably beneficial.

Samantha Gambles Farr: Those are very important and poignant takeaways. I think the fact that you mentioned that the particular strain of COVID that you were dealing with in the very beginning is a very relevant point to the discussion that we’re having. You had mentioned earlier that this was a multicenter study; primarily a lot of the hospitals that participated in this study were in New York City. I would be remiss not to acknowledge the fact that New York City was one of the first epicenters for the disease in the U.S. that resulted in thousands upon thousands of deaths. I would, at this moment, like to offer you an opportunity to acknowledge your coauthors, understanding that providers around the globe continue to seek evidence, answers as it relates to COVID-19. I’m sure we’ll be talking about COVID-19 from now moving forward. I wanted to give you an opportunity to acknowledge those that were in the depths with you.

Bonnie Lonze: You couldn’t describe it any better because it was a very surreal time and it was a small number of us who just went full steam ahead trying to make this work in the interest of trying to be able to do something that we thought could help. I think that’s the situation that we were all in; there was a sense that everyone felt desperate and what could we possibly do to help? This is how this came about. People that just poured everything they had into this.

Samantha Gambles Farr: I highly recommend, if you haven’t had an opportunity to read it before listening to this podcast, to engage and read the article. We thank you and all those who assisted in this research article and those who continue to work toward the greater good and health of all of our patients. This concludes another session of the Society of Critical Care Medicine’s podcast. Dr. Lonze, it’s been a pleasure speaking with you. I want to thank you for being here today, and thank you everyone for tuning in. Until next time.

Samantha Gambles Farr, MSN, NP-C, CCRN, RNFA, is a nurse practitioner intensivist at University of California San Diego Health in the Department of Trauma, Burns, Surgical Critical Care, and Acute Care Surgery. She also serves as adjunct faculty at University of San Diego Hahn School of Nursing and Health Science in its nurse practitioner program.

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