|Year : 2022 | Volume
| Issue : 2 | Page : 136-141
Effectiveness of colchicine among patients with COVID-19 infection: A randomized, open-labeled, clinical trial
Aryan Mohamadfatih Jalal1, Sheelan Faroz Aref1, Dashty Abbas Albustany2
1 Department of Rheumatology, Rizgari Teaching Hospital, Kurdistan Board for Medical Specialities, Erbil, Iraq
2 Department of Medicine, Rizgary Teaching Hospital, Erbil, Iraq
|Date of Submission||26-Nov-2021|
|Date of Acceptance||21-Feb-2022|
|Date of Web Publication||03-May-2022|
Dr. Aryan Mohamadfatih Jalal
Department of Rheumatology, Rizgari Teaching Hospital, Kurdistan Board for Medical Specialities, Erbil
Source of Support: None, Conflict of Interest: None
Background and Objective: In November 2019, there were abundant cases of COVID-19 which first case was reported in Wuhan, China. Colchicine has an important role in inhibiting activation of NLRP3 inflammasome that predispose to decrease cytokine production. This study aimed to evaluate whether colchicine is effective in treatment of corona virus disease of 2019 (COVID-19) patients or not.
Patients and Methods: A randomized, open-labeled, clinical trial of Colchicine for the treatment of COVID-19, allocated between May 8, and June 18, 2021. The colchicine tablet dosage was 0.5 mg twice daily for 14 days added to the standard treatment versus control group who receive standard treatment without colchicine, with the trial registration ID: NCT04867226. The study was conducted in Erbil city-Iraq with the endpoints being clinical, laboratory parameters and duration of hospitalization.
Results: Eighty patients participated in the study. Fewer patients in the colchicine group had musculoskeletal symptoms (17.5%, P = 0.001) in comparison to the patients, who received control treatment. The serum ferritin level in most of patients who treated with colchicine returned to normal in contrast to the control group, whose serum ferritin level was still high (P = 0.041). Similarly, the average of C-reactive protein and D-dimer after treatment among the colchicine group participants was significantly lower than the control group, the P values were 0.011 and 0.043 consecutively. The colchicine group patients stayed for a shorter duration at the hospital (18.4 days) compared to the control group (24.24 days). P value was 0.009. In addition to that the response and cure rate were higher in the colchicine group (56%) in the comparison to control group (43.1%).
Conclusion: The colchicine drug can be effective in treating patients with COVID-19 infection by improving musculoskeletal symptoms and inhibiting inflammatory biomarkers; it is also effective in reducing duration of hospitalization.
Keywords: Colchicine, COVID-19, Erbil-Iraq, randomized controlled trial
|How to cite this article:|
Jalal AM, Aref SF, Albustany DA. Effectiveness of colchicine among patients with COVID-19 infection: A randomized, open-labeled, clinical trial. Indian J Rheumatol 2022;17:136-41
|How to cite this URL:|
Jalal AM, Aref SF, Albustany DA. Effectiveness of colchicine among patients with COVID-19 infection: A randomized, open-labeled, clinical trial. Indian J Rheumatol [serial online] 2022 [cited 2022 Jul 4];17:136-41. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/2/136/344591
| Introduction|| |
In November 2019, there were abundant cases of an acute respiratory illness (then the International Committee on Taxonomy of Viruses (ICTV) named it corona virus disease of 2019 (COVID-19) on February 11, 2020 that the first case was reported in Wuhan, China. The severe acute respiratory syndrome coronavirus 2 was spread so fast that it had involved the whole world about 1 year after the first case was reported on 31 December 2019. As of May 25, 2021, the corona virus has resulted in over 166,352,007 confirmed cases of COVID-19, including 3,449,189 fatalities globally since the COVID-19 pandemic outbreak.
Up to date, no obvious proof exist how the disease occurs and what its pathophysiology is; however, several studies show that it is owing to overreaction of the immune system in response to the virus, which lead to emergence of the disease's clinical features. Cytokine storm syndrome is the severe immune reaction that may cause a severe tissue response in the COVID-19 patients. Clinical experience underlines the role of inflammation in the pathophysiology of the disease and suggests a potential role for colchicine, which has pleiotropic effects.
The interleukin 1 β (IL-1 β) cytokine and other types of cytokines enhance large numbers of leukocytes from the marrow, and then undergo activation and production of cytokine. The production of IL-1 β lead to the synthesis of IL-6, is a cytokine that induce C-reactive protein (CRP) and has been regarded as a vital pro-inflammatory agent in the COVID-19 cytokine storm.,
Colchicine is a medication that is commonly used to prevent and treat acute Gout, Familial Mediterranean fever More Details and Behcet's disease.
More recently, colchicine is found to have an important role in inhibiting activation of NLRP3 inflammasome that predisposes to decrease cytokine production.
According to it is anti-inflammatory effect, it seems that colchicine has an important role in reducing symptoms, inflammatory markers, and severity of disease. Therefore, this open-labeled clinical trial conducted to know whether colchicine is effective in treatment of COVID-19 patients or not, also to measure the effectiveness of colchicine in alleviating and controlling pulmonary and extra pulmonary complications of the virus.
| Patients and Methods|| |
A randomized, open-labeled, clinical trial conducted among patients, who were infected with COVID-19; they were either treated at home with healthcare advises and follow-up, or at the COVID-19 care centers in Erbil city, such as West Erbil Emergency Hospital and Erbil International Private Hospital. Our study conducted between May 8, and June 18, 2021. The study registered in public page before enrolment at clinicaltrial.gov, with the trial registration ID: NCT04867226.
The randomization was performed 1:1 control and colchicine using the online tool. To estimate the sample size by online ClinCalc.com statistic, we considered into account the parallelism of the groups and the 1:1 randomization, has been calculated using a significance level of 0.05 (one-sided) and 80% power for the event of an average deterioration/improvement of 1 point in favor of the intervention group, with odds ratio of 5 the estimated sample size was 45 patients per group (90 in total), besides limitations to conduct a clinical trial in a multicenter, a minimal number of 100 patients seemed to be appropriate whether randomized into two groups of 50 patients.
Study Investigators, Research coordinators and principal investigator enrolled participants and assigned participants into the intervention.
For choosing patients for enrolments, we classified the participants according to the severity of COVID-19: the mild form of the disease were the patients who had flu-like symptoms without dyspnea and imaging findings; the moderate form of disease was defined in patients with fever, dyspnea, and imaging findings of pneumonia; the severe form in those with the same findings of moderate plus oxygen saturation ≤92%.,
The inclusion criteria were
The patients with mild, moderate, or severe COVID-19 infection; either hospitalized or at home, confirmed by A real time of polymerase chain reaction in nasopharyngeal swab specimens and/or lung involvement confirmed by computed tomography scan compatible with COVID-19, patient's age between 18 and 70 years old.
The exclusion criteria were
Known allergy to colchicine, pregnancy, malignancy, estimated glomerular filtration rate <30, and those who already taken colchicine for another disease.
Patients were randomly assigned in to two groups; in group A, 40 patients were treated with colchicine tablet added to their current standard care treatment in a dose of 0.5 mg dose of colchicine twice a day (reduced to 0.5 mg/day, in patients with low body weight or developed side effects) for 14 days. Meanwhile the patients in the control group (group B) were receive standard care treatment without colchicine.
All participants received the institutional standard treatment for COVID-19 with azithromycin 500 mg once daily for up to 6 days, subcutaneous low molecular weight heparin daily until the end of hospitalization. Antiviral (remdesivir and favipiravir) and corticosteroid were added to the protocol according to the severity of the disease.
End points the endpoints were clinical and laboratory parameters: the respiratory symptoms with SpO2 measurement, musculoskeletal symptoms measured by visual analogue scale of pain, and time of hospitalization. The clinical parameters follow-up done as a baseline then every 3 days until the end of the treatment. The laboratory measures of serum CRP (mg/ml), serum ferritin (ng/ml), D-dimer (mg/ml), and serum lactate dehydrogenase (LDH) by (U/L) checked as a baseline when the patients confirmed with COVID-19 diagnosis and the last day of treatment. The endpoints also include the number of the patients who developed adverse effects due to colchicine tablet.
A well-organized questionnaire (case sheet) was used to gather the patients' demographic data, their current COVID-19 symptoms, musculoskeletal symptoms, chronic diseases, current treatments for COVID-19 well-arranged table to assess patients at baseline, then follow-up their conditions (through clinical symptoms of respiratory and musculoskeletal symptoms by visual analogue scale, with SpO2 measurement and laboratory follow-up) every 3 days until the end of a 14-day treatment course. The questionnaire was reviewed, validated, and pilot-tested by 10 academic researchers at Kurdistan Board for Medical Specialties and a 12-member academic research committee from the Iraq or Kurdistan Regional Government Ministry of Health edited before starting the study.
Approval was obtained from Kurdistan Board for Medical Specialties for scientific and ethical committee, on February 8, 2021, approval no. 403 participating patient was provided with an explanation of the study objective. Those patients, who didn't provide consent, were excluded from the study. The data confidentiality is ensured; the local Ethics was obtained from the KRG Ministry of Health on December 8, 2020 approval no. 14219. The current controlled prospective trial registration ID approved by ICMJE and WHO registry at clinicaltials.gov is (NCT04867226), the date of registration is April 30, 2021.
The study analysis compared the results of the primary and secondary findings between the colchicine group (group A) and the control group (group B). The respiratory and musculoskeletal signs and symptoms, SpO2 monitoring were also reported. The data recorded on a specially designed questionnaire, collected, and entered on computer via the Microsoft Excel worksheet (Excel 2010).
Then the recorded data were analyzed using an appropriate data analysis system called statistical Package for the social sciences (SPSS)version 25.0 (IBM Corp, Armonk, NY, USA) and the results were compared among patients who had different variables, with a statistical significance level of ≤0.05. The results were presented as rates, ratio, frequencies, percentages in tables and figures, and were analyzed using t-test and Chi-square test.
| Results|| |
Out of one hundred patients, 20 participants were excluded: six didn't meet inclusion criteria, another six refused enrolment, and eight patients met exclusion criteria. Hence, eighty patients were enrolled in the study [Figure 1].
A total eighty patients with COVID-19 infection were enrolled and participated in this study; they were equally and randomly assigned into either colchicine or control group. The findings in [Table 1] reveal nonsignificant statistical association between the study (colchicine or control) groups and the background variables.
In both the colchicine and control groups, the percentage of various variables and categories were close to each other. The segregation of gender, smoking, disease severity, chronic diseases, treatment venues, and symptoms were approximately equal in both groups. Both studied groups were in the same degree of severity, although mild form were more in home treated patients.
After receiving treatment whether it was colchicine intervention, or the usual protocol (control) the association with ferritin was significant. The ferritin level in most of the patients treated with colchicine returned to normal in contrast to the control group participants, whose ferritin level was still high (p-0.041). Similarly, the average CRP and D-dimer after treatment among the colchicine group participants was significantly lower than the control group patients; T-test was performed, and P values were 0.011 and 0.043 consecutively. Although the mean LDH after treatment of colchicine group was lower than the control group, it was not statistically significant (P = 0.063).
At the end of the study, fewer patients in the colchicine group had musculoskeletal (17.5%, P = 0.001) and respiratory symptoms (25%, P = 0.006) in comparison to the patients, who received control treatment. The average SpO2 with oxygen (94.05%) among the colchicine group participants was higher than the control group patients (SpO2: 90.46%) with P = 0.029. The colchicine group cases stayed for a shorter duration at hospitals (18.40 days) compared to longer duration (24.24 days) among the control group; t-test was significant, and P = 0.009 [Table 2].
|Table 2: Musculoskeletal, respiratory, SpO2 after therapy, and duration of hospitalization of both colchicine and control groups|
Click here to view
The results of [Table 3] shows that the outcomes of patients who treated with colchicine was generally better than those treated with standard protocol; as the response and cure rate were higher in the colchicine group (56%) in comparison to the control group (43.1%), the nonresponsiveness to therapy was five patients out of eighty. A patient was succumbed to death in each study group, and the admission to the respiratory care unit was 8 out of 80 patients (in the control group 75% was three times higher than the colchicine group 25%), P = 0.041. Among 65 (81.3%) responded patients (35.4%, 30.8%, 33.8%) in mild, moderate, and severe degree respectively, P = 0.007. The place of treatment in association to outcome; the study showed that 65 patients out of 80 responded to the medications regardless the place of treatment. The patients who responded at home 34 (52.3%) slightly higher in comparison to the hospitalized patients 31 (47.7), and the P = 0.003, which is statistically significant.
|Table 3: Comparison of outcomes with study group, severity of disease, place of treatment|
Click here to view
Out of the 40 participating patients, who received colchicine therapy, only eight developed side effects: three of them had diarrhea, two had nausea and vomiting, another two had only epigastric pain, and one case alone reported skin rash [Figure 2].
| Discussion|| |
Positive results from the COLCORONA trial show that colchicine is the only effective oral medication for treating nonhospitalized patients, clinically providing persuasive results of colchicine's efficacy to treat COVID-19. The study also shows that colchicine has reduced the risk of death or hospitalization in patients with COVID-19 by 21% compared to placebo treatment.
COLCORONA study show the treatment efficacy of colchicine in reducing the complications associated with COVID-19; in that study as the first large scale study at home with the first oral medication in the world, whose use could have a significant impact on public health and potentially prevent COVID-19 complications for millions of patients, these positive result shows a promising support in the findings of our study that the patients treated at home had earlier response to colchicine with shorter duration of symptoms. Our report can be considered a proof-of-concept study supporting the possible use of colchicine in the treatment of the early phase of COVID-19 [Table 1].
A randomized trial conducted by Deftereos et al. was the first open label randomized prospective trial to evaluate the colchicine effect versus the usual care in early hospitalized patients. The patients who received colchicine were less prone to clinical deterioration despite the fact that their serum levels of CRP showed no significant difference between the two groups compared to the control group;,, in contrast, our study has shown a significant difference of decreasing CRP level in the colchicine group and the P value was significant (P = 0.011) [Table 4].
For evaluating patients with COVID-19, clinicians can use biomarkers in approaching their treatment and in close monitoring. Biomarkers may help improve outcome and prognosis. Inflammatory markers such as D-dimer, CRP, LDH, and serum ferritin have been used to predict the risk of progression to severe COVID-19 infection as follow-up for patients as a baseline and after treatment. In our study, we've measured all these inflammatory markers in both groups, the results show that CRP, D-Dimer, and serum ferritin reduction respectively were statistically significant in the colchicine group (P value: 0.01, 0.043, 0.04) while LDH did not show significant reduction [Table 4].
The study conducted by Arlene et al., which showed a lower level of inflammatory markers including D-dimer, LDH, CRP, and serum ferritin had faster normalization the results found in our study were close to Arlene et al. study although LDH findings in our study were not statistically significant. Our study has shown a difference between the two groups and a decrease in LDH level after treatment in the colchicine group. The role of albumin in the progression of COVID-19 remains unclear, which may be associated with the progression of COVID-19. Albumin level on admission can predict the outcome of COVID-19 as an independent indicator from other indicators, such as lymphocyte count or comorbidities. Among the 80 participating patients whose data were entered in the analysis, twelve patients who were on noninvasive ventilation in the hospital were sent for albumin and procalcitonin levels; all of them had showed low serum albumin range between (2 and 2.5 g/dl) and they received albumin: six of them had high procalcitonin levels, four had low levels, and other two patients had normal levels. These incidental findings may need further research.
The limitations of the study, it was an open-labeled trial, which was initially developed as an improvement objective for those patients with COVID-19 showing improving outcomes during a critical period of the pandemic; another limitation was the selection of a small-sized sample since the curve of COVID-19 infection was decreasing during our research time.
| Conclusion|| |
The colchicine drug can be effective in treating patients with COVID-19 infection by improving musculoskeletal symptoms and inhibiting inflammatory biomarkers; it is also effective in reducing duration of hospitalization.
In conducting this study, there are several people and government entities that extended their assistance and support so we could effectively implement our study project. Hence, we would like to extend our gratitude and appreciation to internist Doctor. Ali A. Barzanji, M. B. CH. B, C. A. B. M, and the KRG Ministry of Health for granting us permission to collect data in their affiliated health facilities as well as for the participating patients who agreed to be a significant part in our study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]