Adding Colchicine to Tocilizumab in Hospitalized Patients With Severe COVID-19 Pneumonia: An Open-Label Randomized Controlled Trial

The novel coronavirus infection (COVID-19) significantly contributes to increased mortality in many countries, with a continuously increasing number of infected cases worldwide.1 As of the end of February 2021, there have been over 112 million confirmed cases of COVID-19, including 2.5 million deaths globally.2 The leading cause of mortality due to COVID-19 is respiratory failure from acute respiratory distress syndrome (ARDS).3 The mechanisms by which COVID-19 induces ARDS is currently thought to be due to the activation of the innate immune system leading to hypercytokinemia and hence cytokine storm.

COVID-19 disease course can be divided into three phases; (1) early infection phase, where the virus penetrates host cells in the lung parenchyma; (2) pulmonary phase, in which the viral propagation causes lung tissue injury and hence the host immune response is activated; and (3) the inflammatory cascade, which is triggered by the viral RNA and it is comprised of inflammasome activation that drives the cytokine storm.4,5 SARS-CoV-2 acts on the macrophages to release the nod-like receptor protein 3 (NLRP3) inflammasome, leading to the conversion of pro-interleukin (IL)-1 and pro-IL-18 to their active forms.6,7 The production of IL-1 leads to IL-6 synthesis which is a cytokine that induces C reactive protein (CRP) and has been considered a major proinflammatory agent in the COVID-19 cytokine storm.8-11 Consequently, a few biological therapies that have been studied and used for the treatment of COVID-19 to target specific cytokines augmented by the disease, including anakinra for IL-1, and tocilizumab for IL-6.

Early in the COVID-19 pandemic, the therapeutic efficacy of IL-6 antagonists was evaluated. So far, the results of the evidence assessing the use of IL-6 antagonists are somewhat controversial. A meta-analysis of seven retrospective observational studies using tocilizumab in patients with severe COVID-19 found that tocilizumab resulted in lower all-cause mortality compared to placebo without achieving statistical significance. Furthermore, the risk of ICU admission and the need for mechanical ventilation were similar between the two groups. Recently, the REMAP-CAP trial evaluated the use of a single injection of an IL-6 receptor blocker, tocilizumab or sarilumab, compared to placebo among 800 patients in need of respiratory or blood-pressure support or both. It showed that IL-6 antagonist resulted in an in-hospital mortality of 27%, as compared with 36% in the control group. On the contrary, the COVACTA trial evaluated the use of tocilizumab versus placebo among 452 patients with severe COVID-19 pneumonia and it showed that the mortality rate was 19.7% in the tocilizumab group versus 19.4% in the control group. Therefore, in the absence of potent antiviral therapies to block SARS-CoV-2 replication, it remains unclear whether blocking IL-6 alone is effective.

Colchicine is one of the oldest anti-inflammatory therapies that is approved for treating and preventing acute gout attacks and familial Mediterranean fever. Colchicine has been shown to interfere with the activation of the NLRP3 inflammasome, reducing IL-1 production, which in turn prevents IL-6 release and neutrophils and macrophages activation. Consequently, colchicine targets multiple cytokines in the inflammatory cascade of the cytokine storm induced by COVID-19, which makes it a potential anti-inflammatory therapy for COVID-19. Colchicine differs from IL-6 receptor blockers by having pleotropic mechanisms of action, acting upstream of the cascade of cytokines, and being an oral agent. A few studies have evaluated the use of colchicine in hospitalized patients with COVID-19. The GRECO-19 trial was the first open-label randomized trial that evaluated the efficacy of colchicine versus usual care in non-critically ill hospitalized patients. The study included 105 patients and found a significant reduction in the primary outcome of a two-point deterioration on World Health Organization disease severity scale. Additionally, in a single center cohort study in Italy, the use of colchicine in 122 hospitalized patients with COVID-19 compared with 140 patients who received hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir, resulted in a significantly better survival rate at 21 days (84.2% versus 63.6% respectively, p=0.001).22 Moreover, there are a few ongoing trials in different countries evaluating the use of colchicine in COVID-19 in comparison to standard care, while excluding the concurrent use of IL-6 antagonists: Given its ease of use, low cost, good safety profile, having different anti-inflammatory mechanism of action than other IL-6 blockade, and the lack of an effective therapy for COVID-19 so far, colchicine might serve as a potential anti-inflammatory agent among patients with severe COVID-19 pneumonia. Colchicine acts upstream in the cytokines cascade by inhibiting the NLRP3 inflammasome while IL-6 receptor antagonists block the end result of the cytokines cascade. The latter might be the reason behind the controversies surrounding tocilizumab efficacy in treating COVID-19 as it has been thought that the ongoing replication of the virus overwhelms the drug capacity to control the disease burden. Given the lack of potent anti-viral agents against SARS-CoV-2, adding colchicine to tocilizumab with the aim of blocking the early and end products of the cytokines cascade, might reduce the risk of developing cytokine storm and hence the need for invasive mechanical ventilation and eventually death. Therefore, investigators aim to conduct an open-label randomized controlled trial to evaluate the efficacy and safety of adding colchicine to tocilizumab among patients with severe COVID-19 pneumonia in an attempt to reduce the rate of invasive mechanical ventilation and mortality.