Background Colchicine has been proposed as a treatment for COVID-19 based on its anti-inflammatory actions.
Methods
In this randomized, controlled, open-label trial, several possible treatments were compared with usual care in patients hospitalized with COVID-19. Eligible and consenting adults were randomly allocated in a 1:1 ratio to either usual standard of care alone or usual standard of care plus colchicine twice daily for 10 days or until discharge (or one of the other treatment arms) using web-based simple (unstratified) randomization with allocation concealment. The primary outcome was 28-day mortality. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
Findings Between 27 November 2020 and 4 March 2021, 5610 patients were randomly allocated to receive colchicine and 5730 patients to receive usual care alone. Overall, 1173 (21%) patients allocated to colchicine and 1190 (21%) patients allocated to usual care died within 28 days (rate ratio 1.01; 95% confidence interval [CI] 0.93-1.10; p=0.77). Consistent results were seen in all pre-specified subgroups of patients. There was no significant difference in duration of hospitalization (median 10 days vs. 10 days) or the proportion of patients discharged from hospital alive within 28 days (70% vs. 70%; rate ratio 0.98; 95% CI 0.94-1.03; p=0.44). Among those not on invasive mechanical ventilation at baseline, there was no significant difference in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (25% vs. 25%; risk ratio 1.02; 95% CI 0.96-1.09; p=0.47).
Interpretation In adults hospitalized with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.
Funding
UK Research and Innovation (Medical Research Council) and National Institute of Health Research (Grant ref: MC_PC_19056). Wellcome Trust (Grant Ref: 222406/Z/20/Z) through the COVID-19 Therapeutics Accelerator.
INTRODUCTION
Inflammation is a key feature of severe COVID-19. Markedly raised levels of inflammatory markers such as C-reactive protein (CRP), ferritin, interleukin-6 (IL-6), and other cytokines are observed in severe cases and are associated with poor outcomes.1-5 Inflammation is particularly prominent in the lung and vascular endothelium and is commonly associated with extensive alveolar damage and thrombosis of large and small pulmonary vessels.6 Corticosteroids and interleukin-6 inhibitors have both been shown to reduce mortality in patients with severe COVID-19, while Janus kinase (JAK) inhibitors accelerate improvement in clinical status.7-10 Together these results show that inflammation is modifiable and anti-inflammatory therapy can improve clinical
Outcomes.
Inflammasomes are a key part of the innate immune response to SARS-CoV-2 infection. These cytosolic pattern recognition receptor systems are activated in response to the detection of pathogens in the cytosol and stimulate the release of proinflammatory cytokines.11 In COVID-19, the degree of inflammasome activation, particularly the nucleotide-binding domain (NOD)-like pyrin domain 3 (NLRP3) inflammasome, correlates with disease severity.12 Colchicine, a readily available, safe, and inexpensive drug, has a wide range of anti-inflammatory effects, including inhibition of the NLRP3 inflammasome.13 In addition to its role in treating acute gout and pericarditis, there is emerging evidence that colchicine may inhibit endovascular inflammation and provide clinical benefits in patients with coronary artery disease.14-17 Given the activation of NLRP3 in COVID-19 and the presence of vascular endothelial inflammation, colchicine has been proposed as a treatment for SARS-CoV-2 associated inflammatory disease.
However, only three small randomized controlled trials have assessed the effects of colchicine in hospitalized patients and, with a total of only seven deaths across these studies combined, none were adequately powered to identify any impact on mortality.18-20 Here we report the results of a large randomized controlled trial of colchicine in patients hospitalized with COVID-19.
METHODS
Study design and participants
The Randomised Evaluation of COVID-19 therapy (RECOVERY) trial is an investigator-initiated, individually randomized, controlled, open-label, platform trial to evaluate the effects of potential treatments in patients hospitalized with COVID-19. Details of the trial design and results for other possible treatments (dexamethasone, hydroxychloroquine, lopinavir-ritonavir, azithromycin, tocilizumab, and convalescent plasma) have been published previously.7,9,21-24 The trial is underway at 177 hospitals in the United Kingdom supported by the National Institute for Health Research Clinical Research Network, two hospitals in Indonesia, and two hospitals in Nepal (appendix pp 3-25). The trial is coordinated by the Nuffield Department of Population Health at the University of Oxford (Oxford, UK), the trial sponsor. The trial is conducted by the principles of the International Conference on Harmonisation–Good Clinical Practice guidelines and approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) and the Cambridge East Research Ethics Committee (ref: 20/EE/0101). The protocol, statistical analysis plan, and additional information are available on the study website www.recoverytrial.net. Patients admitted to the hospital were eligible for the study if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attending clinician, put the patient at significant risk if they were to participate in the trial. Children and pregnant women were not eligible for randomization to colchicine. Patients with severe liver impairment, significant cytopaenia, concomitant use of strong CYP3A4 or P-glycoprotein inhibitors, or hypersensitivity to lactose were excluded (further details in appendix p 80). Written informed consent was obtained from all patients, or a legal representative if patients were too unwell or unable to provide consent.
Randomization and masking
Baseline data were collected using a web-based case report form that included demographics, level of respiratory support, major comorbidities, suitability of the study treatment for a particular patient, and treatment availability at the study site (appendix pp 32-34). Eligible and consenting, non-pregnant adult patients were assigned in a 1:1 ratio to either usual standard of care or usual standard of care plus colchicine or one of the other available RECOVERY treatment arms using web-based simple (unstratified) randomization with allocation concealed until after randomization (appendix pp 30-31). For some patients, colchicine was unavailable at the hospital at the time of enrolment or was considered by the managing physician to be either indicated or contraindicated. These patients were excluded from the randomized comparison between colchicine and usual care. Patients allocated to colchicine were to receive 1 mg after randomization followed by 500 mcg 12 hours later and then 500 mcg twice daily by mouth or nasogastric tube for 10 days in total or until discharge, whichever occurred earlier. Dose frequency was halved for patients receiving a moderate CYP3A4 inhibitor or who had renal impairment (estimated glomerular filtration rate <30 ml/min/1.73m2) or estimated body weight <70 kg (appendix p 80).
As a platform trial, and in a factorial design, patients could be simultaneously randomized to other treatment groups: i) convalescent plasma versus monoclonal antibody (REGN-CoV2) versus usual care, ii) aspirin versus usual care, and iii) baricitinib versus usual care (appendix pp 31). Until 24 January 2021, the trial also allowed subsequent randomization for patients with progressive COVID-19 (evidence of hypoxia and a hyper-inflammatory state) to tocilizumab versus usual care. Participants and local study staff were not masked to the allocated treatment. The trial steering committee, investigators, and all other individuals involved in the trial were masked to outcome data during the trial.
Procedures
A single online follow-up form was completed when participants were discharged, had died, or at 28 days after randomization, whichever occurred earliest (appendix pp 35-41). Information was recorded on adherence to allocated study treatment, receipt of other COVID-19 treatments, duration of admission, receipt of respiratory or renal support, and vital status (including the cause of death). In addition, in the UK, routine healthcare and registry data were obtained including information on vital status (with date and cause of death), discharge from hospital, receipt of respiratory support, or renal replacement therapy.
Outcomes
Outcomes were assessed at 28 days after randomization, with further analyses specified at 6 months. The primary outcome was all-cause mortality. Secondary outcomes were time to discharge from hospital, and, among patients not on invasive mechanical ventilation at randomization, invasive mechanical ventilation (including extra-corporal membrane oxygenation) or death. Prespecified subsidiary clinical outcomes were the use of non-invasive respiratory support, time to successful cessation of invasive mechanical ventilation (defined as cessation of invasive mechanical ventilation within, and survival to, 28 days), use of renal dialysis or haemofiltration, cause-specific mortality, bleeding events, thrombotic events, and major cardiac arrhythmias. Information on suspected serious adverse reactions was collected in an expedited fashion to comply with regulatory requirements.
Statistical Analysis
The primary analysis for all outcomes was by intention-to-treat comparing patients randomized to colchicine with patients randomized to usual care but for whom colchicine was both available and suitable as a treatment. For the primary outcome of 28-day mortality, the log-rank observed minus expected statistic and its variance were used to both test the null hypothesis of equal survival curves (i.e., the log-rank test) and to calculate the one-step estimate of the average mortality rate ratio. We constructed Kaplan-Meier survival curves to display cumulative mortality over the 28 days. We used the same method to analyze time to hospital discharge and successful cessation of invasive mechanical ventilation, with patients who died in hospital right-censored on day 29. Median time to discharge was derived from Kaplan-Meier estimates. For the pre-specified composite secondary outcome of progression to invasive mechanical ventilation or death within 28 days (among those not receiving invasive mechanical ventilation at randomization), and the subsidiary clinical outcomes of receipt of ventilation and use of hemodialysis or haemofiltration, the precise dates were not available and so the risk ratio was estimated instead.
Prespecified analyses were performed for the primary outcome using the statistical test of interaction (test for heterogeneity or trend), by the prespecified analysis plan, defined by characteristics at randomization: age, sex, ethnicity, level of respiratory support, days since symptom onset, and use of corticosteroids (appendix p 114).
Estimates of rate and risk ratios are shown with 95% confidence intervals. All p-values are 2-sided and are shown without adjustment for multiple testing. The full database is held by the study team which collected the data from study sites and performed the analyses at the Nuffield Department of Population Health, University of Oxford (Oxford, UK) As stated in the protocol, appropriate sample sizes could not be estimated when the trial was being planned at the start of the COVID-19 pandemic (appendix p 54). As the trial progressed, the trial steering committee, whose members were unaware of the results of the trial comparisons, determined that sufficient patients should be enrolled to provide at least 90% power at a two-sided significance level of 0.01 to detect a clinically relevant proportional reduction in 28-day mortality of 12.5% between the two groups. On 4 March 2021, the independent data monitoring committee (DMC) conducted a routine review of the available safety and efficacy data. The DMC notified the chief investigators that there was no convincing evidence that further recruitment to the colchicine comparison would provide conclusive proof of worthwhile mortality benefit either overall or in any pre-specified subgroup. Consequently, recruitment to the colchicine comparison was closed on 5 March 2021 and preliminary results were made available to the public. Analyses were performed using SAS version 9.4 and R version 3.4. The trial is registered with ISRCTN (50189673) and clinicaltrials.gov (NCT04381936).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. Credited to Peter W Horby
1Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom, and International Severe Acute Respiratory and Emerging Infections Consortium (ISIC), University of Oxford, Oxford, United King
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