This week the RECOVERY trial has released the first results from the Colchicine arm of the trial. We await the pre-print and the peer reviewed paper, but we are already very familiar with the trial and it’s processes having reported the results on the blog already. We are therefore pretty confident about the methodology.
To briefly summarise the trial so far
Eligibility: Hospitalised patients with COVID19.
- Drugs shown to work
- Drugs shown to have no benefit
- Drugs still being randomised
- Aspirin
- Baricitinib
- REGN monoclonal antibodies
- Dimethyl Fumarate
Colchicine was in the trial until this morning but has been removed following a decision from the data monitoring committee.
To quote the RECOVERY team
The DMC reviewed data on patients randomised to colchicine vs. usual care alone. The preliminary analysis is based on 2178 reported deaths among 11,162 randomised patients, 94% of whom were being treated with a corticosteroid such as dexamethasone. There is no significant difference in the primary endpoint of 28-day mortality (20% colchicine vs. 19% usual care alone; risk ratio 1.02 [95% confidence interval 0.94-1.11]; p=0.63). Follow-up of patients is ongoing and final results will be published as soon as possible.
RECOVERY TRIAL TEAM
It’s important to note that the majority of patients were also treated with dexamethasone so this result is in keeping with current practice. Although recruitment closed today we will still be following up patients for 28 days, which will of course include some randomised in the last month and so we can expect the final numbers in the trial to be slightly larger.
We also need to see a lot more data on this as it’s unclear how many were randomised to Colchicine. I suspect it’s a 1:2 ratio, but I don’t know at the moment. Hopefully we will see a pre-print soon.
Why was Colchicine in the study?
Colchicine is a drug that many of us will know from the treatment of gout, and so it was interesting to see it recommended by the UK COVID-19 Therapeutics Advisory Panel for inclusion in the study but there good reason to do so.
The protocol states that Colchicine inhibits cellular transport and mitosis by binding to tubulin and preventing its polymerisation as part of the cytoskeleton transport system. As a consequence, colchicine has a wide range of anti-inflammatory effects, including inhibition of certain inflammasomes (cytosolic pattern recognition receptor systems that are activated in response to detection of pathogens in the cytosol). There is evidence that inflammasomes are activated in COVID-19, and the degree of activation is correlated with disease severity. Colchicine has been widely used for treatment of gout and pericarditis, and there is evidence of cardiovascular benefit in patients with coronary artery disease.
Should we abandon Colchicine?
For hospitalised patients outside of clinical trials then the answer on the basis of these results is yes. However, Colchicine is still included in the UK platform trial for non-hospitalised patients (PRINCIPLE) and we look forward to the results of that study. We should also be mindful that this is very little data and we do need to see the pre-print/peer reviewed paper.
Where next for RECOVERY?
The trial continues with the addition of Dimethyl Fumarate (DMF) into the study this week. DMF is included in the trial based on the following (from the latest protocol)
Dimethyl fumarate (DMF) is thought to prevent NLRP3 inflammasome activation and the process of pyroptosis (inflammatory cell death) through its action on the protein gasdermin D.27 SARS-CoV-2 induces inflammasome activation and the degree of activation is thought to correlate with disease severity.28 DMF has demonstrated anti-viral and anti-inflammatory effects against SARS-CoV-2 in vitro. 29 Other inflammasome-modulating drugs, such as colchicine, have demonstrated provisionally promising results in small randomised trials. 30,31 DMF is licensed to treat relapsing remitting
multiple sclerosis and plaque psoriasis as a long-term immunomodulatory agent and is generally well-tolerated with no major safety concerns.
32,33 The UK COVID-19 Therapeutics Advisory Panel has recommended that RECOVERY investigate the safety and efficacy of DMF in an early phase assessment among patients hospitalised with COVID-19.
The inclusion of DMF in the study is interesting from a practical perspective as previously RECOVERY has acted as a large scale, pragmatic and arguably fairly ‘light touch’ RCT in terms of monitoring and data collection, even for a phase 3 trial. DMF will be different and is arguably has much more of a phase 2 trial process with much closer monitoring of patients receiving the drug. It will only be offered in a limited number of UK sites, and only for 500 patients. I’m glad that my hospital will be recruiting to the DMF arm.
Final thoughts
These results show that Colchicine is ineffective in the treatment of hospitalised patients with COVID19.
It’s also interesting to reflect on how rewarding it has been for many of us involved in the trial. To be part of the leading therapeutic trial for COVID19 in the world, to learn so much about a new disease, the immunology, the pathology, and a whole range of new drugs has been a silver lining in a very dark year. Let’s hope there is more positive news to come from the drugs still being tested.
We will update the post when the pre-print/paper become available.
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References
RECOVERY trial closes recruitment to colchicine treatment for patients hospitalised with COVID-19 https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19
Simon Carley, “JC: RECOVERY trial shows Tocilizumab effective for COVID19. St Emlyn’s,” in St.Emlyn’s, February 11, 2021, https://www.stemlynsblog.org/jc-recovery-trial-shows-tocilizumab-effective-for-covid19-st-emlyns/.
Simon Carley, “The RECOVERY platform trial: No benefit to Hydroxychloroquine in Covid-19. St Emlyn’s,” in St.Emlyn’s, June 6, 2020, https://www.stemlynsblog.org/the-recovery-platform-trial-no-benefit-to-hydroxychloroquine-in-covid-19-st-emlyns/.
Simon Carley, “Dexamethasone, COVID-19 and the RECOVERY trial. St Emlyn’s,” in St.Emlyn’s, June 28, 2020, https://www.stemlynsblog.org/dexamethasone-covid-19-and-the-recovery-trial-st-emlyns/.
Simon Carley, “JC: Lopinavir/Ritonavir in the treatment of COVID-19,” in St.Emlyn’s, December 23, 2020, https://www.stemlynsblog.org/jc-lopinavir-ritonavir-in-the-treatment-of-covid-19/.
Simon Carley, “JC: Convalescent plasma in COVID 19 patients.,” in St.Emlyn’s, November 21, 2020, https://www.stemlynsblog.org/jc-convalescent-plasma-in-covid-19-patients/.
Broz P, Dixit VM. Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol 2016;16:407-20.
Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther 2014;36:1465-79.
Rodrigues TS, Keyla SG, Ishimoto AY, et al. Inflammasome activation in COVID-19 patients. medRxiv 2020.
Rodrigues TS, de Sá KSG, Ishimoto AY, et al. Inflammasomes are activated in response to SARSCoV-2 infection and are associated with COVID-19 severity in patients. Journal of Experimental Medicine 2020;218.
Olagnier D, Farahani E, Thyrsted J, et al. SARS-CoV2-mediated suppression of NRF2-signaling reveals potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate. Nature Communications 2020;11:4938.
Deftereos SG, Giannopoulos G, Vrachatis DA, et al. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019:
The GRECCO-19 Randomized Clinical Trial. JAMA Network Open 2020;3:e2013136-e.
Lopes MIF, Bonjorno LP, Giannini MC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial. medRxiv
2020:2020.08.06.20169573.
Bomprezzi R. Dimethyl fumarate in the treatment of relapsing-remitting multiple sclerosis: an overview. Ther Adv Neurol Disord 2015;8:20-30
