REMAP-CAP and RECOVERY trials...a little background...
So, the REMAP-CAP study published on January 9th set out to determine if the IL-6 receptor antagonists, tocilizumab and Sarilumab, compared with standard care, improve respiratory and cardiovascular organ support free days up to day 21 in critically ill patients with COVID-19. The critically ill patient is the emphasis here as the first 5 studies looking at Tocilizumab were fairly negative studies and for the most part (with the exception of the EMPACTA trial), excluded anyone on High Flow Nasal Cannula (HFNC) or higher support. Results of this study were published January 9th.
The RECOVERY trial, which was published February 11th set out to determine if Tocilizumab decreased 28-day mortality when compared to usual care.
Let’s highlight a couple of important features about these studies to set the stage. The REMAP-CAP trial initially started in 2016 to evaluate various interventions in patients with community acquired pneumonia. It branched out in early 2020 to target patients with COVID-19. Therefore, the newly named REMAP-COVID group is really a group of trials with different domains within the larger REMAP-CAP trial. Each domain also has several arms, which can get quite difficult to keep track of.
Current ongoing study domains include….
This is important to point out as patients were allowed to be enrolled in multiple domains at once. Further, the REMAP-CAP/REMAP-COVID trial also coordinates patients with the RECOVERY trial, which also includes several domains (i.e. azithromycin, tocolizumab, convalescent plasma, monoclonal antibodies and aspirin). A statement on the coordinated effort of these two trials can be found here.
The focus of this discussion is pertinent to the immunomodulation domain in these trials. In the REMAP-CAP study, this included 5 interventions (see table below), but Tocilizumab and usual care overwhelmingly had the vast majority of patients. So, this study is really a study on Tocilizumab vs usual care only. Similarly, the immunomoduation domain of the RECOVERY trial only looked at Tocilizumab vs standard care.
The Tocilizumab arm of the REMAP-CAP trial started April 19, 2020 and the Tocilizumab arm of the RECOVERY trial started April 23, 2020. This timing is important, as they both compared Tocilizumab to usual care, and the definition of “usual care” changed frequently throughout the summer. While Tocilizumab patients were able to be enrolled concurrently in the steroid domain as well, usual care at the time these studies started enrolling did not necessarily include steroids and in-hospital mortality was much higher than it was when these studies concluded (Nov 19th for the REMAP-CAP study and Jan 24th for the RECOVERY trail). The steroid domain of the REMAP-CAP trial stopped enrolling June 17th following preliminary results of the steroid domain of the RECOVERY trial showing benefit from steroids and steroids were considered usual care in all arms from that point on.
In the REMAP-CAP trial, there were 399 patients in the Tocilizumab group and 412 in the usual care group at study completion. 158 patients were recruited before steroids were considered usual care and 107 of them were also included in the steroid domain of the REMAP-CAP trial. 707 patients were randomized after June 17th. In total, 93% of all patients in this study were also treated with steroids within 48 hours of enrollment with 88% of patients in the Tocilizumab group receiving steroids.
For the RECOVERY trial, 82% of patients enrolled in the Tocilizumab group were also treated with steroids before June 17th and this increased to 97% of patients after steroids became usual care. Keep these number in mind when I review the other studies on Tocilizumab later on.
So what role does IL-6 really play?
I really had high hopes early last year when people started to theorize that IL-6 was a key player in the cytokine storm phenomenon. However, I don’t know if the data in favor of IL-6 as the only player is as robust as people think.
A systematic review and meta-analysis of cytokine elevation was published in the Lancet on Dec 8th. They essentially reviewed different cytokine concentrations in COVID compared to other non-COVID inflammatory conditions including non-severe COVID, severe COVID, critical COVID, hypo and hyper-inflammatory ARDS, Sepsis in general and cytokine release syndrome (which was described in literature years before COVID was a thing). The bottom line is, while IL-6 levels are elevated in COVID, they aren’t the only cytokine on the playing field and IL-6 levels are actually much higher in non-COVID related illnesses as well and these results question the role of a cytokine storm in COVID-19 induced organ dysfunction.
Following results of the RECOVERY trial steroid arm and the WHO meta-analysis, steroids have been the only medication shown to improve mortality. The way in which steroids were included in previous trials of Tocilizumab is significantly different and likely significant, as well as the population of patients that were included.
Let’s quickly review the available studies assessing Tocilizumab and how they vary in regards to steroid usage and respiratory support…
Final points to highlight...
The REMAP-CAP trial is a trial within a trial within a trial. Patients were not only also allowed to be enrolled in any domain of the REMAP-CAP trial, they could potentially be included in pre-ICU arms of the RECOVERY trial and be subsequently included in the REMAP-CAP trial if they require transfer to the ICU. I can’t find a break-down of the concentration of any of these patients in other trial arms.
Tocilizumab appears to generally be very safe suggesting little downside to giving it from this standpoint. So far, no studies have shown a significant increase in harm with the drug. There were 3 serious adverse events reported in the RECOVERY trial, all of which were successfully treated with standard therapy. Up to 15% of patients will get neutropenic, but this wasn’t associated with a higher rate of infection. If anything, those in the Tocilizumab group had fewer subsequent bacterial infections than those that weren’t, even in those that became neutropenic.
Cost and supply may be an issue. I am not entirely certain of the cost. My google search suggests an 800 mg dose could cost upwards of $5,000 for the brand name Actemra injectable solution. Further, Tocilizumab is certainly not available to all hospital systems. Supply was an issue even in the REMAP-CAP trial, which is why they started using Sarilumab. These issues are likely to limit Tocilizumab as a standard treatment option for most patients.
Timing when to use Tocilizumab is still not entirely certain, in my opinion. These studies (with the exception of the COVACTA trial) mainly focused on patients early in the disease process, before requiring more than nasal cannula and did not show benefit in these groups. However, the RECOVERY trial showed no significant difference in patients who received Tocilizumab < 2 days or > 2 days of hospitalization which contradicts earlier studies.
There does not seem to be any robust evidence that Tocilizumab has any benefit in patients outside of the ICU. This is interesting because in the theory of IL-6 induced cytokine storm, you would think blocking this cascade before it occurs would offer the best outcome, and that doesn’t seem to be the case. The REMAP-CAP trial excluded patients in the ICU for > 24 hours, so we can’t really conclude that the timing of administration of the drug is what leads to favorable outcomes. However, both the CONVACTA trial and now the RECOVERY trial, has shown a decrease in requiring mechanical ventilation. It is important to note that patients included in the RECOVERY trial had very high CRP levels, suggesting that perhaps this may be a better target for identifying patients who may benefit outside of the ICU.
Only 1 study (RCT-TCZ-COVID-19) measured and reported measured IL-6 levels, which were higher in the Tocilizumab cohort of that study which still doesn’t answer the question if IL-6 levels are really the cause of clinical severity. Perhaps steroids (which block multiple inflammatory processes) combined with IL-6 specific inhibition is more beneficial. The RECOVERY trial only included hypoxemic patients with a CRP > 75 mg/L. The data from both this trial and the REMAP-CAP trial suggest the greatest benefit is seen as CRP levels increase.
The REMAP-CAP Tocilizumab arm (published January 9th) and the REMAP-CAP steroid arm (published September 2nd) used the same study design. While no statistical triggers were reached in the steroid arm of this study, using the Bayesian approach, the authors suggest a high probability (80-93%) of superiority of corticosteroid use (compared to no steroids) in organ support free days within 21 days and an increased probability of lower mortality (54-62%). Given the endpoints and study design are identical, it would be nice to see some sort of subgroup analysis between the 2 studies to see how much of a factor steroids really play. One thing that has been consistent between all studies is that patients do not benefit from Tocilizumab alone. The benefit is only seen when combined with steroid therapy.
IDSA Guidelines (last updated 2/17/2021)
“Among hospitalized adults with progressive severe* or critical** COVID-19 who have elevated markers of systemic inflammation, the IDSA guideline panel suggests tocilizumab in addition to standard of care (i.e., steroids) rather than standard of care alone. (Conditional recommendation, Low certainty of evidence)”
Remarks:
- “Patients, particularly those who respond to steroids alone, who put a high value on avoiding possible adverse events of tocilizumab and a low value on the uncertain mortality reduction, would reasonably decline tocilizumab.”
- “In the largest trial on the treatment of tocilizumab, criterion for systemic inflammation was defined as CRP ≥75 mg/L.”
Severity definitions:
*Severe illness is defined as patients with SpO2 ≤94% on room air, including patients on supplemental oxygen
**Critical illness is defined as patients on mechanical ventilation and ECMO. Critical illness includes end organ dysfunction as is seen in sepsis/septic shock. In COVID-19, the most commonly reported form of end organ dysfunction is ARDS.
You can view the full discussion of IDSA recommendations for all treatments in COVID-19 here.
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