When I was trying to imagine the landscape of this trial I never thought it would be a failure, even after it was stopped early. I thought we'd end up with half a success and half a failure and that the failed half would reinforce the successful half in terms of reinforcing the cells' MOA. We'd know when the cells worked and when they didn't, which is what clinicians want to know. I thought we'd have a chance of an EUA because our results would be realistic in real-world patients and you can’t get any more real world than a pandemic where SoC changed so dramatically in two key respects.
In mortality, we've ended up with a successful first half and an unsuccessful second half, but not in the way I thought. My opinion is that we have quite a good chance of an EUA.
60 Day SE
MSB has reported on 60 day mortality SE. Even before the FDA changed guidance, based on the reading I've done, my view is that anyone who quibbled about 30 day PE would have no credibility in the ARDS community. Mortality is well known to be a courageous endpoint. Most patients survive the acute phase and most haven't died by 30 days and I provided evidence of this in this post:
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I was worried by the ambitious choice of PE right in the beginning. Josh Farkas, whose blog Pulmcrit is well known, says it’s a ‘fool’s errand’. I don't see, though, how we could have gone for any other PE in the emotive environment of a pandemic.
That they got such good results for mortality at 60 days in under 65s is amazing in itself. If the MOA of MSCs is similar to MPCs in that they set off a healing cascade where treatment group goes on to improve over time, combine that with the terribly sad trend of survivors who continue to die up to a year, even two, after discharge and I'd expect SOc + Remestecel_L and SoC + placebo groups to further separate out.
MSB has not yet reported on mortality for over 65s for the second half of the trial. That's understandable in the context of the patients we were getting. The consensus is that older patients with comorbidities tend to die from the underlying condition, rather than the ARDS. We could get exciting results for biomarkers and positive results in preventing fibrosis and sequelae.
The main issues in ARDS are longer-term mortality and bad survival. Survivors are discharged to skilled nursing facilities or visited at home by nursing staff. You can see confronting recent photos in journals of muscle wastage in people who are relatively young. They are heavy users of healthcare resources such as nursing, physiotherapy and psychiatry. They’re particularly at risk of pneumonia. We're hearing reports of Covid seq
uelae such as heart and kidney damage in young people. If corticosteroids are doing a good job, why are we hearing such things?
Steroids in ARDS
After the trial was stopped early. I listened to the CC: Use early. Our cells are potent anti-inflammatory agents that respond to peak inflammation and use the IL-6 pathway. Dex is a potent anti-inflammatory agent that uses the IL-6 pathway. In the beginning it was going so well. The narrative was finally in our favour and there was a buzz surrounding stem cells. MSCs and Covid ARDS seemed perfect for each other. When the trial was stopped and intelligent posters here, one previously supportive, said it was proof Remestemcel-L didn’t work, I was confused. It didn't make sense. If our trial was a failure then my big picture was all wrong. I decided to trust my big picture. The answer therefore had to be that the trial wasn't a failure. The bad luck would somehow work in our favour. The bad luck, however, was not the one I expected. In fact, I couldn't have been more wrong. What caused our trial to be stopped was that we started to get patients who were a decade older with comorbidities.
If I recall right, during the CC (where the 60% mortality was mentioned?) SI referred to older patients who were refractory to Dex. The older age was a bit of a red flag (How would we know whether or not they died from the ARDS?) but the 60% mortality and the being refractory to dex I took to mean our cells were still making a difference, as I thought at that point the trial was still going well.
The 60% mortality was the one issue I had with MSB at the time the media was reporting improved survival; however, older patients with comorbidities do account for most deaths in ARDS, so if the death in SoC in the earlier stage was 45% then it could be that in the later stage of the trial it was 60% in the highly refractory cohort we were treating.
Bottom line is not only did the unexpected arrival of Dex as Soc not negatively affect our cells as I feared, there appeared to be an unexpected synergy. How serendipitous in this respect!
In this post
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, I referred to one study in concomitant use of steroids and MSCs that concluded Dex would be the least likely to affect MSCs; however there were two others that found Dex strongly affected and abrogated MSC effect. With respect to potential synergy, I've since found a study by Michelo et al (2016) that suggests Dex augments MSCs’ effect on NK cells. I don’t know if this is relevant. It was way beyond me as a non scientist and actually seemed contradictory but no doubt we’ll hear more about the synergy in the future.
If I didn't know about a potential synergy and I looked at these results in under 65s, my layperson's view would be that Remestemcel-L works well and Dex doesn't at all. I based my view on the EAP where the doctor appeared to be in awe and what I learned about Mount Sinai cutting edge work re. predictive and response biomarkers. I'd also base my view on my reading up of corticosteroids in ARDS, a condition where after decades, there's still no consensus as to whether or not they provide mortality benefit; the rushed trials in corticosteroids in Covid where open-label Recovery trial in Dex provided most of the data and had important information missing; the Recovery Trial showing no great benefit in overall mortality (Overall, 454 (21.6%) patients allocated dexamethasone and 1065 (24.6%) patients allocated usual care died within 28 days); the high mortality of 45% mortality in our RCT in the SoC +Dex arm.
ARDS is overseen by the ARDS network. In her YT presentation Dr Calfee reports on 25 years of failed pharmacological agents with corticosteroids at the top of the list. There are doctors who favour using corticosteroids but there's disagreement as to dosage, timing, selection of patients, and which steroid. One doctor commenting on the published Recovery trial said that Dex isn't the corticosteroid they used for lung injury. What he said is supported by Caroline L Hough MD, whose review is reflective of the frank and balanced discussion in ARDS. She reports on the rigorous ARDS Network RCT in methylprednisolone that found no benefit in mortality:
"The primary outcome was 60 day mortality. It was estimated that the intervention would decrease mortality from 40% to 20%, with a sample size of 180 and 85% power. Sixty day mortality was lower than anticipated—29%—and was equal in both study groups.There were interesting differences between the treatment groups, however. Patients randomized to steroids liberated from mechanical ventilation sooner than those on placebo (14 days versus 23 days, p=0.006) and had significantly more ventilator free days at both 28 and 180 days. Yet, there was no difference in ICU length of stay between the groups, and return to mechanical ventilation was significantly more likely among patients randomized to steroids (20 versus 6, p=0.008)"
Dexa Ards
I'm no expert in analysing clinical trials but I've checked with people who are and they think the Dexa ARDS randomized trial was a well designed and well run; the patients were very well matched. Patients with comorbidities were excluded. The trial was stopped early because of slow recruitment.
“We observed a reduction in the number ventilator-free days of more than 4 days and a 15% increase in the 60-day survival compared with patients in the control group”.
This trial used a high dose of Dex. High doses of steroids (including Dex) were associated with adverse events such a long-lasting sequelae of pulmonary fibrosis, AVN and diabetes in survivors of MERS and SARS1 who received corticosteroids. It would be important to know if there were any associated adverse effects in the DEXA ARDS cohort. Also, as Dex is long- lasting, if there was a rebound in inflammation after stopping this steroid. The trial completed in 2018, so I'd also be interested to know long-term mortality and sequelae. I haven't been able to find any information on follow-up and would appreciate it if anyone could refer me to it.
Corticosteroids in Covid
Albani et al (Nature, 2021) found corticosteroid treatment had no effect on hospital mortality in 1,403 Covid19 patients:
"559 patients (39%) were exposed to corticosteroids during hospital stay, 844 (61%) were not exposed to corticosteroids. In the cohort of patients exposed to corticosteroids, 171 (30.6%) died. In the cohort of patients not exposed to corticosteroids, 183 (21.7%) died (unadjusted p < 0.001"
After adjustment, authors, however, did not find mortality was associated with steroids.
Budhatoki et al 2020 did their own meta analysis of 40 Covid studies:
"Though the non-randomized nature of the included study and risk of bias is there, we need to rethink the use of corticosteroid in such COVID-19 patients because of no added benefit rather than having a poor outcome".
Our study concludes that more severe and critically ill patients tend to get corticosteroids, and the mortality risk increases with the use of corticosteroids. With the use of corticosteroids, delayed recovery and a longer hospital stay were observed”.
In an editorial (Jama, 2020), Prescott et al discuss the meta analysis of corticosteroids in severe Covid:
"While early observational data from China suggested a potential mortality benefit of corticosteroids in COVID-19,10 previous studies of corticosteroids in other viral pneumonias, especially severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), found an association with delayed viral clearance, and reinforced concerns that corticosteroids may impair host response to SARS-CoV-2.11,12 Furthermore, a meta-analysis of observational studies suggested increased mortality with corticosteroid treatment in influenza"
Authors discuss the Codex trial which used a high dose of Dex:
"The CoDEX trial randomized 299 patients in 41 ICUs in Brazil with moderate or severe ARDS and COVID-19 to open label high-dose dexamethasone (20 mg/d for 5 days, then 10 mg/d for 5 days) vs usual care alone.15 The primary outcome was ventilator-free days through day 28, which were greater in patients randomized to dexamethasone (6.6 vs 4.0,P = .04).15 Two-thirds of patients (66.9%) were receiving vasopressors at the time of randomization, and 35% of the patients randomized to usual care received at least 1 dose of corticosteroids, potentially reducing the effect size between the study groups.While 28-day mortality was not significantly different between patients randomized to corticosteroids vs usual care (56.3% vs 61.5%, P = .83), stopping the study early when RECOVERY results were announced resulted in a sample size that was underpowered to adequately evaluate the effect of corticosteroids on mortality".
Authors discuss the open label Recovery Trial in Dex that supplied the bulk of the data:
"Although the meta-analysis suggests the benefit may be higher in those not receiving mechanical ventilation, imprecision in this result is high due to enrollment of relatively few patients not mechanically ventilated in most of the trials and the inclusion of all patients receiving oxygen from the RECOVERY trial in this comparison (due to ambiguity over which patients enrolled in RECOVERY were truly critically ill)
This criticism of the Recovery trial of what is meant by "critically ill" is important because it relates to criteria for mechanical ventilation.
Dr Matthay also discusses the limitations of the Recovery trial. In addition to lack of information about viral loading:
"A second limitation of the RECOVERY trial is that no data are available on the level of oxygen support. In retrospect, this was an important omission from the database".
(Perhaps this information is available now? I haven't checked for updates but I've been looking for 6 month follow up and haven't been able to find it. I'd be interested if anyone can direct me to this.)
My understanding is that Dex is only for patients receiving high flow oxygen or mechanical ventilation? It showed no mortality benefit in patients not requiring supplemental oxygen and harm could not be ruled out.
IL-6 and CRP
SoC changed dramatically between the early and later stage of the pandemic. Patients were put on ventilators early because of advice from China. I recall at the time listening to doctors and nurses who were critical of this, saying the ventilators were doing more harm than good.
My questions for the scientists and medical experts:
Is it possible that in the early stage of the pandemic patients were put on ventilators according to oxygen levels and CRP but may not have been in such a severe cytokine storm as the later stage (when Dex became SoC)?
As the pandemic progressed, did IL-6 emerge as a more commonly used biomarker of poor outcome?
By the time Dex became SoC was there interest in its effect on IL-6 suppression?
There was huge pressure from the WHO to use corticosteroids, particularly Dex. Re. concomitant use, how did doctors know that the MSCs wouldn’t interfere with Dex action? Or was it the case that Dex was administered and if there was no improvement in biomarkers, Remestemcel- was administered? My perception was that our candidate, being for the most severe disease, came to be used as salvage therapy. I’m wondering how that came to be.
I note some conflicting reports as to whether CRP or IL-6 are more accurate predictors of poor outcome. I have read that both are; however, Wu et al; Sabaska et al; Santa-Cruz et al report that IL-6 is a more accurate biomarker predicting poior outcomes. I'm not sure about the exact sequence of events but as the pandemic progressed, from the reading I did, I thought IL-6 emerged as a biomarker (The reason IL-6 blocker Actemra was trialled)
Santa-Cruz et al (2021) say:
"IL-6 level was the most significant predictor of the non-survivors group, when compared to age and CRP. Herein, we present IL-6 as a relevant tool for prognostic evaluation, mainly as a predictor of outcome".
(Please note my confirmation bias for Remestemcel-L in that I've long seen it as a secret weapon in cytokine storms and I keep thinking about the dramatic results in the EAP. I also have a bias against steroids in certain conditions because I believe they're responsible for turning acute cases into chronic ones in that they suppress the inflammation that leads to cure. In one organ (skin) in the condition of chronic severe eczema, I think we have enough evidence to be proof.)
DEX and IL-6
Awasthi et al (Nature, 2021) report on their study in plasma IL-6 levels following corticosteroid therapy as an indicator of ICU length of stay in critically ill Covid-19 patients:
“The precise mechanisms by which dexamethasone mediates clinical improvement in severe COVID-19 patients are not well understood. Indeed, the success of dexamethasone in treating COVID-19 was somewhat unexpected in light of an early report during this pandemic urging clinicians to not prescribe corticosteroids for lung injury in COVID-19 patients, based on the lack of efficacy as well as an elevated risk of adverse events associated with steroid use in the previous SARS and MERS epidemics”
"Among the COVID19 patients that were admitted to ICU at some point during their hospital stay and had undergone an IL6 test, the patients that were on corticosteroids (n = 43) experienced longer durations on higher levels of respiratory support compared to the patients that were not on corticosteroids (n = 56)"
“We also observed that IL-6 levels did not correlate with levels of the inflammatory markers C-reactive protein and erythrocyte sedimentation rate in the COVID patients”.
“If suppression of IL-6 production by corticosteroids like dexamethasone is indeed confirmed to be responsible for mitigating the respiratory and vascular onslaught of SARS-CoV-2 in severely ill COVID-19 patients, then longitudinal monitoring of plasma IL-6 levels before and after initiation of steroids may be warranted in clinical practice. We speculate that such practice will help determine whether a patient is likely to respond to corticosteroid therapy alone or if they should be considered as candidates for alternative intervention..."
Authors go on to suggest that corticosteroids could be combined with other therapies such as Actemra, an IL-6 blocker, that failed in severe Covid. I think because IL-6 can be good or bad and requires regulation rather than blockade.
Authors say the size of their studies was small and larger follow-up studies could help shed light on the mechanisms underlying heterogeneity in patient responsiveness to corticosteroids.
The biggest confirmation bias I have is my opinion of doctors and researchers in ARDS. I never read such high quality discussion and honest assessment as to the reality of this condition. Unlike the selective reporting in GvHD, researchers in ARDS don't hold back on reporting bad results. Dex is a cheap, potent drug doctors are very familiar with and there have been 25 years of striving to improve outcomes for patients. I doubt that in a pandemic such impressive people could have come up with anything they couldn't have before.
ARDS is a significant area in which pharma have no agents. I don't know where the scaremongering about Novartis walking away came from. I think that's unlikely, but in the light of this data, if they do I'll view that as so peculiar as to be bizarre. I'll be most interested to see what happens next.
Please feel free to make any corrections as I don't have a science background and my intention is as much to learn.
(20min delay)