{"id":39759,"date":"2021-01-22T07:21:39","date_gmt":"2021-01-22T07:21:39","guid":{"rendered":"https:\/\/i-base.info\/htb\/?p=39759"},"modified":"2021-01-26T16:24:37","modified_gmt":"2021-01-26T16:24:37","slug":"il-6-agonists-tocilizumab-and-sarilumab-reduces-mortality-in-severe-covid-19-interim-results-from-remap-cap-study","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/39759","title":{"rendered":"IL-6 agonists tocilizumab and sarilumab reduces mortality in severe COVID-19: interim results from REMAP-CAP study"},"content":{"rendered":"
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Simon Collins, HIV i-Base<\/span><\/strong><\/p>\n<\/div>\n

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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 with<\/span>severe pneumonia in intensive care from COVID-19 and already needing organ support. [1, 2]<\/span><\/strong><\/p>\n<\/div>\n

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This led to announcements that both treatments would be immediately available for use in the UK.<\/span><\/p>\n<\/div>\n

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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).<\/span><\/p>\n<\/div>\n

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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.<\/span><\/p>\n<\/div>\n

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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 (+\/\u201312); 70% male; 73% white, 17% Asian, 4% black; with median BMI: 30 kg\/m2<\/sup>(IQR: 27 to 35). Comorbidities were common (including diabetes mellitus 35%, respiratory 24% and kidney and severe cardiovascular each 10%).<\/span><\/p>\n<\/div>\n

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High flow nasal oxygen was used by 28%, non-intensive ventilation by 41% and invasive mechanical ventilation by 30%. <\/span><\/p>\n<\/div>\n

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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). \u00a0Tocilizumab 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.<\/span><\/p>\n<\/div>\n

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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.<\/span><\/p>\n<\/div>\n

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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,<\/span><\/p>\n<\/div>\n

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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.<\/span><\/p>\n<\/div>\n

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The median number of days without organ support were 10 (IQR: \u20131 to 16), 11 (IQR: 0 to 16) and 0 (IQR: \u20131 to 15) for tocilizumab, sarilumab and control, respectively. <\/span><\/p>\n<\/div>\n

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The median adjusted OR were 1.64 (95% CrI: 1.25 to 2.14) for tocilizumab and 1.76 (95%CrI: 1.17 to \u00a02.91) for sarilumab, with >99.9% and 99.5% posterior probabilities of superiority compared with control. <\/span><\/p>\n<\/div>\n

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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.<\/span><\/p>\n<\/div>\n

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All further outcomes and secondary and sensitivity analyses supported efficacy of these IL-6 receptor antagonists.\u00a0<\/span><\/p>\n<\/div>\n

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comment<\/h3>\n<\/div>\n
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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.<\/span><\/strong><\/p>\n<\/div>\n

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These results, however, don\u2019t mean there will be activity in earlier COVID-19.<\/span><\/strong><\/p>\n<\/div>\n

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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.<\/span><\/strong><\/p>\n<\/div>\n

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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.<\/span><\/strong><\/p>\n<\/div>\n

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References<\/p>\n<\/div>\n

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  1. REMAP-CAP investigators. Interleukin-6 receptor antagonists in critically ill patients with Covid-19\u2013preliminary report. MedRxiv. Pre-peer review. (7 January 2021).
    \nhttps:\/\/www.medrxiv.org\/content\/10.1101\/2021.01.07.21249390v1<\/a><\/li>\n
  2. Randomized, embedded, multifactorial adaptive platform trial for community-acquired pneumonia (REMAP-CAP) study website.
    \n    https:\/\/www.remapcap.org<\/a><\/li>\n
  3. Tocilizumab fails to meet clinical endpoints in randomised COVACTA study: other studies continue. HTB (14 October 2020).
    \n    https:\/\/i-base.info\/htb\/38965<\/a><\/li>\n
  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).
    \n    https:\/\/www.nejm.org\/doi\/full\/10.1056\/NEJMoa2030340<\/a><\/li>\n<\/ol>\n<\/div>\n","protected":false},"excerpt":{"rendered":"

    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 …<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[283,278],"tags":[],"class_list":["post-39759","post","type-post","status-publish","format-standard","hentry","category-covid-19-investigational-drugs","category-covid-19"],"_links":{"self":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/39759","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/comments?post=39759"}],"version-history":[{"count":0,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/posts\/39759\/revisions"}],"wp:attachment":[{"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/media?parent=39759"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/categories?post=39759"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/i-base.info\/htb\/wp-json\/wp\/v2\/tags?post=39759"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}