Canakinumab to reduce deterioration of cardiac and respiratory function in SARS-CoV-2 associated myocardial injury with heightened inflammation (canakinumab in Covid-19 cardiac injury: The three C study)

Abstract

Background: In patients with Covid-19, myocardial injury and increased inflammation are associated with morbidity and mortality. We designed a proof-of-concept randomized controlled trial to evaluate whether treatment with canakinumab prevents progressive respiratory failure and worsening cardiac dysfunction in patients with SARS-CoV2 infection, myocardial injury, and high levels of inflammation.

Hypothesis: The primary hypothesis is that canakiumab will shorten time to recovery.

Methods: The three C study (canakinumab in Covid-19 Cardiac Injury, NCT04365153) is a double-blind, randomized controlled trial comparing canakinumab 300 mg IV, 600 mg IV, or placebo in a 1:1:1 ratio in hospitalized Covid-19 patients with elevations in troponin and C-reactive protein (CRP). The primary endpoint is defined as the time in days from randomization to either an improvement of two points on a seven category ordinal scale or discharge from the hospital, whichever occurs first up to 14 days postrandomization. The secondary endpoint is mortality at day 28. A total of 45 patients will be enrolled with an anticipated 5 month follow up period.

Results: Baseline characteristics for the first 20 randomized patients reveal a predominantly male (75%), elderly population (median 67 years) with a high prevalence of hypertension (80%) and hyperlipidemia (75%). CRPs have been markedly elevated (median 16.2 mg/dL) with modest elevations in high-sensitivity troponin T (median 21 ng/L), in keeping with the concept of enrolling patients with early myocardial injury.

Conclusions: The three C study will provide insights regarding whether IL-1β inhibition may improve outcomes in patients with SARS-CoV2 associated myocardial injury and increased inflammation.

Keywords: Covid-19; SARS-CoV-2; canakinumab; myocardial injury.

FIGURE 1

Trial design

FIGURE 2

Putative mechanism of SARS‐CoV2 associated myocardial injury with increased inflammation and possible beneficial effect of canakinumab. SARS‐CoV2 acts as an initial PAMP recognized by innate immunity receptors at the cell surface or inside the cell. These receptors are integrated into the inflammasome. Signaling via ROS also leads to NF‐κB activation with increased transcription of pro‐IL‐1β. Inflammasome‐mediated cleavage of pro‐IL‐1β leads to systemic release of active IL‐1β. IL‐1β drives its own expression and production of other chemokines and cytokines, including IL‐6, all resulting in further macrophage activation and potentially contributing to vascular inflammation, endothelial dysfunction, and myocardial injury. Canakinumab may attenuate this response by blocking IL‐1β. ATP, adenosine triphosphate, CARD, caspase activation and recruitment domain, IL, interleukin, JNK, Jun amino‐terminal kinase, K+, potassium ion, NF‐κB, nuclear factor‐kappa B, NLRP3, nucleotide‐binding oligomerization domain‐like receptor pyrin domain‐containing 3, PAMP, pathogen‐associated molecular patterns, ROS, reactive oxygen species, TLR, Toll‐like receptors