Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial
Maria Isabel Lopes, Leticia P Bonjorno, Marcela C Giannini1, Natalia B Amaral, Pamella Indira Menezes, Saulo Musse Dib, Samara Libich Gigante, Maira N Benatti, Uebe C Rezek, Laerte L Emrich-Filho, Betania A A Sousa, Sergio C L Almeida, Rodrigo Luppino Assad, Flavio P Veras, Ayda Schneider, Tamara S Rodrigues, Luiz O S Leiria, Larissa D Cunha, Jose C Alves-Filho, Thiago M Cunha, Eurico Arruda, Carlos H Miranda, Antonio Pazin-Filho, Maria Auxiliadora-Martins, Marcos C Borges, Benedito A L Fonseca, Valdes R Bollela, Cristina M Del-Ben, Fernando Q Cunha, Dario S Zamboni, Rodrigo C Santana, Fernando C Vilar, Paulo Louzada-Junior and Rene D R Oliveira
Objective To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes.
Design We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate.
Results Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0–6.0) days for the colchicine group and 6.5 (4.0–9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0–9.0) days for the colchicine group and 9.0 (7.0–12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26).
Conclusion Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19.
Systemic inflammation is the hallmark of moderate to severe cases of COVID-19.1 Its outbreak has already sent millions to infirmaries and intensive care units (ICUs) throughout the world, mainly due to pulmonary infiltrates resulting in the severe acute respiratory syndrome (SARS).2 High levels of interleukin (IL)-1β, IL-6, IL-18 and tumour necrosis factor (TNF) are some of the many immunological disturbances in the pathophysiology of the high inflammatory status of COVID-19,3 which counts, moreover, with markedly elevation of serum C reactive protein (CRP) and uncommon neutrophilia and lymphopaenia.4 5 Neutrophils release neutrophil extracellular traps (NETs), which were found to be toxic to lung epithelial cells in vitro. Furthermore, high levels of NETs were present in the plasma of patients with COVID-19 compared with healthy controls, and the presence of these cellular components was at least 10 times higher in tracheal aspirates than in plasma of the same patients, raising the question whether they have a role in the lung lesions.6
The inflammasome of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) may be important in certain antiviral responses.7 After viral activation of the protein complex, mainly in monocytes and antigen-presenting tissue cells, its constituent pro-caspase-1 suffers autocleavage and, by its turn, cleaves pro-IL-1β and pro-IL-18 to their active form: IL-1β and IL-18.8 Both products activate B, T and NK cells in addition to stimulating the release of other inflammatory cytokines.9It seems appropriate to infer that an aberrant activation of inflammasome underlies the ‘hyper’ inflammation found in hospitalised patients with COVID-19.
For decades, colchicine has been successfully used for the treatment and prevention of crystal-induced arthritis, for example, gout. Systemic autoinflammatory diseases such as familial Mediterranean fever and Behçet’s disease are conditions in which colchicine use may be necessary continuously.10 Much of this success comes from its direct effect on phagocytes residing or migrating into the synovial joints, vessel walls or other tissues, leading to inflammasome inhibition and impaired production and release of IL-1β11 and NETs.12 In all of these situations, the drug is well tolerated, and its adverse effects are broadly recognised.
Piantoni et al13 discussed the rationale of its use for the treatment of COVID-19, with focus on the control of the systemic inflammation caused by SARS-CoV-2 infection. A case–control study14 and an open-label clinical trial15 of colchicine for COVID-19 have results published hitherto.
We conducted a randomised, double-blinded, placebo-controlled clinical trial to evaluate the use of colchicine for the treatment of hospitalised patients with moderate to severe COVID-19. The randomisation was performed 1:1 for placebo or colchicine by using the online tool at https://www.randomizer.org/.
To estimate the sample size, we took into account the parallelism of the groups and the 1:1 randomisation, with a minimal difference of effect of 0.30 attributed to the intervention on the primary endpoints. Alpha and beta errors of, respectively, 0.05 and 0.10, were predetermined, which resulted in a minimal number of 27 participants per group. Considering the prominent need of efficient therapies for COVID-19, besides limitations to conduct a clinical trial in a single centre, a minimal number of 60 patients seemed to be appropriate whether randomised into two groups of 30 patients.
The trial is registered on the National Registry under the alphanumeric code RBR-8jyhxh (http://www.ensaiosclinicos.gov.br/rg/RBR-8jyhxh/). All patients signed the consent form.
Patients of the intervention arm received colchicine 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days; if body weight ≥80 kg, the first dose was 1.0 mg. Whether a patient had chronic kidney disease, with glomerular filtration rate under 30 mL/min/1.73 m2, colchicine dose was reduced to 0.25 mg thrice daily for 5 days, then 0.25 mg twice daily for 5 days, no matter the body weight.
All participants received the institutional treatment for COVID-19 with azithromycin 500 mg once daily for up to 7 days, hydroxychloroquine 400 mg twice daily for 2 days, then 400 mg once daily for up to 8 days and unfractionated heparin 5000 UI thrice daily until the end of hospitalisation. During the study conduction, the first results of the RECOVERY Collaborative Group were launched,16 showing the benefits of adding a glucocorticoid to the treatment of COVID-19. Then, methylprednisolone 0.5 mg/kg/day for 5 days was added to the institutional protocol, for use if the patient’s need for supplemental oxygen was equal to 6 L/min or more. Study and institutional protocol drugs were suspended when participants reached good clinical and laboratory parameters and could be discharged.
For a matter of selection criteria, we classified patients according to the severity of COVID-19: the mild form of the disease was defined in patients with flu-like symptoms without dyspnoea and imaging findings of pneumonia; the moderate form was defined in patients with fever, dyspnoea and imaging findings of pneumonia; the severe form in those with the same findings of moderate form plus respiratory rate ≥30 times per minute or oxygen saturation (SatO2) ≤92%; and the critical form was defined when patients presented respiratory failure or shock.17 18 The inclusion criteria were: individuals hospitalised with moderate or severe forms of COVID-19 diagnosed by RT-PCR in nasopharyngeal swab specimens and lung CT scan involvement compatible with COVID-19 pneumonia; older than 18 years; body weight >50 kg; normal levels of serum Ca2+ and K+; QT interval <450 ms at 12 derivations ECG (according to the Bazett formula) and negative serum or urinary β-HCG if woman under 50 years. The exclusion criteria were defined as: mild form of COVID-19 or in need for ICU admission; diarrhoea resulting in dehydration; known allergy to colchicine; diagnosis of porphyria, myasthenia gravis or uncontrolled arrhythmia at enrolment; pregnancy or lactation; metastatic cancer or immunosuppressive chemotherapy; regular use of digoxin, amiodarone, verapamil or protease inhibitors; chronic liver disease with hepatic failure; and inability to understand the consent Form.
Patients were evaluated daily, and blood collection for general laboratory tests were performed at days 0, 2, 4 and 7 if discharge did not happen before. Twelve derivations ECG were performed each 24–48 hours. The definition of requirement of oxygen supply was a measure of SatO2 ≤92% at rest. The criteria for discharging patients from the hospital were the absence of dyspnoea and SatO2 >92%, both for at least 48 consecutive hours.
The primary endpoints were clinical parameters, such as the time of need for supplemental oxygen; time of hospitalisation; need for admission and length of stay in ICU; and death rate and causes of mortality. As secondary endpoints, we assessed clinical and laboratory parameters: measures of serum CRP, serum lactate dehydrogenase (LDH) and relation neutrophil to lymphocyte of peripheral blood samples from day 0 to day 7; the number, type and severity of adverse events; frequency of interruption of the study protocol due to adverse events; and frequency of QT interval above 450 ms.
We present descriptive statistics as absolute numbers and percentage or median and IQR. Absolute numbers and percentage were compared with Fisher’s exact test. Comparisons of clinical and laboratory parameters expressed in median and IQR were done through Mann-Whitney test. Additionally, Kaplan-Meier survival curves were performed, with analysis by Mantel-Haenszel log rank test, to compare the time to abandon supplemental oxygen and time to discharge between the groups. Kruskall-Wallis test was used for comparisons of laboratory exams at the four blood collection times, followed by Dunn’s Multiple Comparison test. For all tests, p<0.05 was considered for statistical significance.
The enrolment started on 11 April and stopped on 31 August 2020. We assessed 131 patients and included 75 for randomisation as shown in figure 1.The baseline laboratory and clinical characteristics of the 72 patients who completed the study are presented in table 1. All patients received the institutional protocol treatment with hydroxychloroquine, azithromycin and heparin. Twenty-five and 24 patients, respectively, for colchicine and placebo groups received methylprednisolone. No treatment, institutional or interventional, was interrupted due to adverse events. The groups were similar in terms of demographic characteristics, clinical status and laboratory evaluation at baseline. There was a slight predominance of men in the colchicine group. Moreover, 35 out of 36 patients in the colchicine group had body mass index (BMI) above 25.0 kg/m2 (data not shown) and the group median arterial oxygen partial pressure (PaO2)/fractional inspired oxygen (FiO2) was 50.0 lower, for both parameters with no statistical difference.
At least half of the patients receiving colchicine stopped using supplemental oxygen for the fourth day (median 4.0; IQR 2.0–6.0 days) of intervention, while the same happened to the patients receiving placebo on the seventh day (median 6.5; IQR 4.0–9.0 days; p<0.001). Significant difference (p=0.003) between the groups was found for the time of hospitalisation, in detriment of the placebo group (median 7.0; IQR 5.0–9.0 days vs median 9.0; IQR 7.0–12.0 days).
Two and four patients, respectively, for colchicine and placebo groups needed admission to ICU. The ICU assistant team preferred to stop the study intervention for one patient per group. For this reason, these two patients were taken off the final analysis. Although the interventions were stopped, both patients were followed for some main outcomes: the time of treatment before ICU admission was 2 and 3 days, the length of stay in ICU was 12 and 11 days and the time of hospitalisation was 23 and 26 days, respectively, for colchicine and placebo groups. Two patients of the placebo group died (two male; death rate of 6%) and none of the colchicine group. The cause of death was ventilator-associated pneumonia in both cases. No statistical analysis was performed for the need for admission in ICU and the death rate due to the small number of events for each group.
Kaplan-Meier survival curves for the need for supplemental oxygen and the maintenance of hospitalisation are depicted in figures 2 and 3, respectively. At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, these values were 9% versus 42%, in the colchicine and placebo groups, respectively (log rank test, 10.6; p=0.001). Hospitalisation was maintained for 42% versus 72% of patients at day 7 and 9% versus 39% at day 10, in the colchicine and placebo groups, respectively (log rank test, 9.2; p=0.002). Both outcomes presented similar behaviour, once the last is at large extension a consequence of the first one.