IL-6 agonists tocilizumab and sarilumab reduces mortality in severe COVID-19: interim results from REMAP-CAP study

Simon Collins, HIV i-Base

On 7 January 2021, preliminary results were published ahead of peer review from the international randomised adaptive platform REMAP-CAP study. This used two open label IL-6 agonists in adults withsevere pneumonia in intensive care from COVID-19 and already needing organ support. [1, 2]

This led to announcements that both treatments would be immediately available for use in the UK.

Randomisation occurred within 24 of organ support with a primary outcome using an ordinal scale combining mortality in hospital and days without needing respiratory or cardiovascular support (up to day 21).

The study had a complicated design that included randomization, if eligible, to more than type of treatment (with each type referred to as a domain). It included predefined criteria for efficacy using routine interim analyses, and adapted based on changing standards of care.

Baseline characteristics were similar to cohorts hospitalised with COVID-19 and importantly ere balanced between active and control arms. Mean age was approximately 61 years (+/–12); 70% male; 73% white, 17% Asian, 4% black; with median BMI: 30 kg/m²(IQR: 27 to 35). Comorbidities were common (including diabetes mellitus 35%, respiratory 24% and kidney and severe cardiovascular each 10%).

High flow nasal oxygen was used by 28%, non-intensive ventilation by 41% and invasive mechanical ventilation by 30%.

The latest results, are based on outcomes from 803 participants from six countries, randomised to either of the monoclonal antibodies: initially to tocilizumab (n=353, 8 mg/kg) or later to sarilumab (n=48, 400 mg) – or to standard of care control (n=402).  Tocilizumab was given twice (for 29%), 12-24 hours apart, but sarilumab could only be infused once. Corticosteroids were routinely included as part of standard of care by the majority of participants (610/654, 93%) although use was randomised for 158 of the earliest participants. Approximately one-third used remdesivir.

Other compounds in the immune modulator domain included an IL-1 receptor antagonist (anakinra) and interferon beta-1a. The results from these 69 participants are not included.

Statistical modelling was used to decide whether any effect was likely to be better or worse that other interventions or the control arm, based on posterior probability >99% or <0.25%, respectively. Differences were reported as odds ratios (with 95% credible interval) that were superior, equivalent or inferior,

An interim analysis on 28 October the DMSB reported that tocilizumab met the trigger to be superior to control (posterior probability 99.75%, OR: 1.87, 95%CrI: 1.20 to 2.76). Further randomisation to the control arm stopped on 19 November but continued to other immune modulators. At this time, 2,046 participants had been randomised to the study overall.

The median number of days without organ support were 10 (IQR: –1 to 16), 11 (IQR: 0 to 16) and 0 (IQR: –1 to 15) for tocilizumab, sarilumab and control, respectively.

The median adjusted OR were 1.64 (95% CrI: 1.25 to 2.14) for tocilizumab and 1.76 (95%CrI: 1.17 to  2.91) for sarilumab, with >99.9% and 99.5% posterior probabilities of superiority compared with control.

Mortality was 28.0% (98/350) for tocilizumab and 22.2% (10/45) for sarilumab compared to 35.8% (142/397) for control. Median OR for survival was 1.64 (95%CrI: 1.14 to 2.35) for tocilizumab and 2.01 (95% CrI: 1.18 to 4.71) for sarilumab.

All further outcomes and secondary and sensitivity analyses supported efficacy of these IL-6 receptor antagonists. 

comment

The peer-review version of this paper will be important given the complex statistical models. Also because of the choice of an unusual combined endpoint – mortality and time on organ support – even though mortality was independently associated with benefits.

These results, however, don’t mean there will be activity in earlier COVID-19.

Also, while the approximately 8% benefit compared to control was reportedly in addition to the protective impact of dexamethasone, the overall mortality still remained high.

Earlier reports in HTB have included many studies showing positive results although in August 2020 a lack of benefit in the phase 3 COVACTA led to an NIH recommendation against using tocilizumab, other than as part of a clinical trial.

References

1. REMAP-CAP investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19–preliminary report. MedRxiv. Pre-peer review. (7 January 2021).
   https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1
2. Randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP) study website.
   https://www.remapcap.org
3. Tocilizumab fails to meet clinical endpoints in randomised COVACTA study: other studies continue. HTB (14 October 2020).
   https://i-base.info/htb/38965
4. Slama C et al. Tocilizumab in patients hospitalized with Covid-19 pneumonia. N Engl J Med 2021; 384:20-30. DOI: 10.1056/NEJMoa2030340. (7 January 2021).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2030340