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RESEARCH ARTICLE
Efficacy of colchicine in patients with
moderate COVID-19: A double-blinded,
randomized, placebo-controlled trial
Motlabur Rahman
1
, Ponkaj K. DattaID
1
*, Khairul Islam
1
, Mahfuzul HaqueID
1
,
Reaz Mahmud
2
, Uzzwal Mallik
1
, Pratyay HasanID
1
, Manjurul Haque
1
, Imtiaz Faruq
1
,
Mohiuddin Sharif
1
, Rifat H. Ratul
1
, Khan Abul Kalam Azad
1¤a
, Titu Miah
3
, Md.
Mujibur RahmanID
1¤b
1Department of Medicine, Dhaka Medical College, Dhaka, Bangladesh, 2Department of Neurology, Dhaka
Medical College, Dhaka, Bangladesh, 3Department of Medicine and Principal, Dhaka Medical College,
Dhaka, Bangladesh
¤a Current address: Department of Medicine, Popular Medical College, Dhaka, Bangladesh
¤b Current address: Faculty of medicine, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
*ponkajdatta@yahoo.com
Abstract
Background
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may cause
severe life-threatening diseases called acute respiratory distress syndrome (ARDS) owing
to cytokine storms. The mortality rate of COVID-19-related ARDS is as high as 40% to 50%.
However, effective treatment for the extensive release of acute inflammatory mediators
induced by hyperactive and inappropriate immune responses is very limited. Many anti-
inflammatory drugs with variable efficacies have been investigated. Colchicine inhibits inter-
leukin 1 beta (IL-1β) and its subsequent inflammatory cascade by primarily blocking pyrin
and nucleotide-binding domain leucine-rich repeat and pyrin domain containing receptor 3
(NLRP3) activation. Therefore, this cheap, widely available, oral drug might provide an
added benefit in combating the cytokine storm in COVID-19. Here, we sought to determine
whether adding colchicine to other standards of care could be beneficial for moderate
COVID-19 pneumonia in terms of the requirement for advanced respiratory support and
mortality.
Methods and findings
This blinded placebo-controlled drug trial was conducted at the Dhaka Medical College Hos-
pital, Dhaka, Bangladesh. A total of 300 patients with moderate COVID-19 based on a posi-
tive RT-PCR result were enrolled based on strict selection criteria from June 2020 to
November 2020. Patients were randomly assigned to either treatment group in a 1:1 ratio.
Patients were administered 1.2 mg of colchicine on day 1 followed by daily treatment with
0.6 mg of colchicine for 13 days or placebo along with the standard of care. The primary out-
come was the time to clinical deterioration from randomization to two or more points on a
seven-category ordinal scale within the 14 days post-randomization. Clinical outcomes
PLOS ONE
PLOS ONE | https://doi.org/10.1371/journal.pone.0277790 November 16, 2022 1 / 15
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OPEN ACCESS
Citation: Rahman M, Datta PK, Islam K, Haque M,
Mahmud R, Mallik U, et al. (2022) Efficacy of
colchicine in patients with moderate COVID-19: A
double-blinded, randomized, placebo-controlled
trial. PLoS ONE 17(11): e0277790. https://doi.org/
10.1371/journal.pone.0277790
Editor: James Mockridge, PLOS: Public Library of
Science, UNITED KINGDOM
Received: October 8, 2021
Accepted: October 21, 2022
Published: November 16, 2022
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
process; therefore, we enable the publication of
all of the content of peer review and author
responses alongside final, published articles. The
editorial history of this article is available here:
https://doi.org/10.1371/journal.pone.0277790
Copyright: ©2022 Rahman et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All data set files are
available from the https://figshare.com/articles/
dataset/Colchicine_in_COVID-19_BD_trial_data_
were also recorded on day 28. The primary endpoint was met by 9 (6.2%) patients in the pla-
cebo group and 4 (2.7%) patients in the colchicine group (P = 0.171), which corresponds to
a hazard ratio (95% CI) of 0.44 (0.13–1.43). Additional analysis of the outcomes on day 28
revealed significantly lower clinical deterioration (defined as a decrease by two or more
points) in the colchicine group, with a hazard ratio [95%CI] of 0.29 [0.098–0.917], (P =
0.035). Despite a 56% reduction in the need for mechanical ventilation and death with col-
chicine treatment on day 14, the reduction was not statistically significant. On day 28, colchi-
cine significantly reduced clinical deterioration measured as the need for mechanical
ventilation and all-cause mortality.
Conclusion
Colchicine was not found to have a significant beneficial effect on reducing mortality and the
need for mechanical ventilation. However, a delayed beneficial effect was observed. There-
fore, further studies should be conducted to evaluate the late benefits of colchicine.
Clinical trial registration
Clinical trial registration no: ClinicalTrials.gov Identifier: NCT04527562 https://www.
google.com/search?client=firefox-b-d&q=NCT04527562.
Introduction
The World Health Organization (WHO) formally notified the pneumonia case cluster in
Wuhan City, China on December 31, 2019 [1]. By mid-January 2020, the virus and its genome
sequence were identified. The novel coronavirus, severe acute respiratory syndrome coronavi-
rus 2 (SARS-CoV-2), was isolated and the disease was later named coronavirus disease-19
(COVID- 19) [2].
SARS-CoV-2 infection may cause an asymptomatic, mild-to-severe, life-threatening disease
[3]. Death is mainly caused by acute respiratory distress syndrome (ARDS), which involves a
cytokine storm. The mortality rate of COVID-19-related ARDS is between 40% and 50% [4].
The cytokine storm syndrome indicates a hyperactive and inappropriate immune response
characterized by the release of widespread acute inflammatory mediators, such as interferon,
interleukins, tumor necrosis factors, and chemokines [5]. This syndrome can also occur in a
patient with a diminishing viral load, which indicates that it may be caused by an exuberant
host immune response [6]. Effective treatments to reduce this hyperactive immune response
are limited. However, many anti-inflammatory drugs with variable efficacy have been investi-
gated, including targeted anti-inflammatory therapy, such as interleukin 1 (IL 1) inhibitors, IL
6 inhibitors, interferon-gamma, tumor necrosis factor alpha (TNF-α) inhibitors, and non-tar-
geted anti-inflammatory agents, such as corticosteroids, hydroxychloroquine, Janus kinase
(JAK) inhibitors, and colchicine. Among them, corticosteroids, such as dexamethasone, have
been found to have beneficial effects in hospitalized patients requiring supplemental oxygen
[7]. Colchicine has long been used as an anti-inflammatory agent for Bechet’s disease, Lepra
reaction, gout, and familial Mediterranean fever. Colchicine inhibits IL-1βand its subsequent
inflammatory cascade by primarily blocking pyrin and nucleotide-binding domain leucine-
rich repeat and pyrin domain containing receptor 3 (NLRP3) activation. As NLRP3 is likely
activated following viral entry into cells, colchicine might provide an added benefit in combat-
ing the cytokine storm in COVID-19. Colchicine is also inexpensive, widely available, and can
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Colchicine in moderate COVID-19: A double-blinded, randomized, placebo-controlled trial
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set/16734640 database DOI: 10.6084/m9.figshare.
16734640.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
be administered orally. Further, its side effect profile is well known and limited. Therefore, col-
chicine has a widespread advantage over other costly and parenteral anti-inflammatory drugs,
such as tocilizumab and anakinra [8]. One case series, retrospective observational studies, and
randomized control trials revealed variable efficacies of colchicine in COVID-19 [9–13].
Among several systematic reviews on COVID-19 and colchicine, the most recent
COCHRANE review is identified as a comprehensive and rigorous assessment. This review
included three randomized controlled trials with 11,525 hospitalized participants and one ran-
domized controlled trial with 4,488 non-hospitalized participants. According to the study, col-
chicine might have little to no influence on mortality or clinical progression in hospitalized
patients with moderate-to-severe COVID-19. However, there is uncertain evidence of the
effect of colchicine on mortality in people with asymptomatic infection or mild disease. Fur-
ther, colchicine might cause a slight reduction in hospital admissions or deaths within 28 days
and the rate of serious adverse events compared with placebo [14]. Here, we sought to deter-
mine whether adding colchicine to other standard of care treatments could be beneficial for
patients with moderate COVID-19 pneumonia in terms of the requirement for advanced
respiratory support and mortality.
Patients and methods
Ethics approval
The trial was conducted in accordance with the principles of the Good Clinical Practice Guide-
lines of the International Conference on Harmonization-2016 and was approved by the ethical
review committee of Dhaka Medical College Hospital (ERC-DMC/ECC/2020/128, dated June
08, 2020). This trial was registered at ClinicalTrials.gov (identifier: NCT04527562). The trial
protocol was published, and the full text is available at https://dx.doi.org/10.18203/2349-3259.
ijct2021xxxx (Rahman et al). Written informed consent was obtained from all patients. The
study was conducted in accordance with the Equator Network Guidelines.
This was an investigator-initiated, blinded, and placebo-controlled trial. Treatment safety
and efficacy were monitored by an independent data safety monitoring board at the Dhaka
Medical College. Routine investigations were performed in the pathology laboratory of the
Dhaka Medical College. Polymerase chain reaction (PCR) tests were performed, free of charge,
in the virology laboratory of the Dhaka Medical College. Colchicine and placebo were supplied
by Incepta Pharmaceuticals Ltd. Shahid Tajuddin Ahmed Srani, Tejgaon industrial area,
Dhaka, Bangladesh. A random number was generated and maintained by an independent bio-
statistician from Incepta Pharmaceuticals Limited, Dhaka, Bangladesh. The company had no
role in the planning, data collection, analysis, or interpretation of the study results.
Patients
The study was conducted at Dhaka Medical College Hospital, Dhaka, Bangladesh. A total of
300 patients were enrolled between June 2020 and November 2020. These patients had moder-
ate COVID-19 confirmed by positive RT-PCR (within 3 days of positivity) results and were
older than 18 years; both sexes were included in the trial. In this study, moderate disease was
defined clinically as fever or history of fever, cough and/or shortness of breath, respiratory rate
<30 breaths/minute, oxygen saturation 94% or more without any supplemental oxygen, and
pulmonary consolidations involving less than 50% of lungs based on chest imaging (chest x
ray or CT scan of chest) (i.e., all patients in both arms had radiologically confirmed pneumonia
at enrolment). Pregnant and lactating mothers; patients with known hypersensitivity to colchi-
cine; known chronic illnesses such as hepatic failure, chronic kidney disease (eGFR<30 ml/
min), decompensated heart failure, long QT syndrome (QTc >450 msec), inflammatory
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bowel disease, chronic diarrhea, or malabsorption; patients taking colchicine for other indica-
tions (mainly chronic indications represented by familial Mediterranean fever or gout); and
patients undergoing chemotherapy for cancer were excluded from the study. All patients
enrolled in this study were assigned to category 3, were hospitalized, and did not require sup-
plemental oxygen, according to a seven-category ordinal scale (as defined in the Outcome
Measures section). Patients in other categories were excluded from the study.
Trial design
Random assignment. On day 1 of enrolment, patients were randomly assigned to either
of the treatment groups at a 1:1 ratio. A random number was generated and maintained by an
independent biostatistician from Incepta Pharmaceuticals Limited, Dhaka, Bangladesh. Group
assignment was concealed using an identical opaque envelope. Colchicine and placebo blisters
within each envelope were identical in size and labelling. A total of 300 identical cards num-
bered 1–300 were prepared. After signing the informed consent form, each participant ran-
domly took a card from the investigator. The study nurse then supplied a sealed envelope with
the corresponding number. Neither the investigators nor the patients were aware of the group
assignment.
Decoding was performed at the end of the trial under the supervision of the Data Safety
Monitoring Board of the Dhaka Medical College, Dhaka, Bangladesh.
Interventions
Active drug group. The treatment group received a starting dose of 1.2 mg of colchicine
(2 tablets of 0.6 mg) 12 h divided doses on day 1 followed by daily treatment with 0.6 mg of col-
chicine for 13 days. Paracetamol, antihistamines, and oxygen therapy were also administered
as part of the standard care according to the National Guidelines of Bangladesh and Clinical
Management of COVID-19, Interim Guidance of World Health Organization [15,16]. Low
molecular weight heparin, according to the indication, appropriate broad-spectrum antibiot-
ics, if needed, remdesivir injection, and other drugs for associated comorbid conditions were
prescribed by the attending physicians.
Placebo group. The placebo group received standard care and placebo tablets that
appeared similar to the study drugs (i.e., the placebo resembled a colchicine tablet). Colchicine
has a bitter taste. As the placebo tablets only contained excipients, the bitter taste could not be
replicated in the placebo.
Experimental procedures
The baseline demographic and clinical characteristics of patients were collected using data col-
lectors in a case-record form. The date of random assignment was considered day 1, and all
patients received their initial treatment dose on day 1. Patients were followed up from day 1
through day 28 until discharge from the hospital due to clinical recovery and at the COVID-19
Details of blinding in this randomized trial of colchicine for the treatment of adult patients with moderate COVID-19
Individual blinded Information withheld Method of blinding Blinding maintained
Person assigning participants to groups Group assignment opaque envelops Yes
Participants Group assignment Placebo medications Yes
Care providers Group assignment Placebo medications Yes
Data collectors and managers Group assignment Not informed of group assignment Yes
https://doi.org/10.1371/journal.pone.0277790.t001
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clinic of the hospital. Patients who failed to attend the clinic were followed up via telephone
calls. Clinical recovery was defined as a normal body temperature of 36.1˚C–37.2˚C main-
tained for at least 3 days, significantly improved respiratory symptoms (respiratory rate <25/
min, no dyspnea), and oxygen saturation greater than 93% without supplemental oxygen inha-
lation, as recommended by the national guideline of Bangladesh and the World Health Orga-
nization [15,16]. The clinical status and vital signs (including respiratory status) were recorded
daily. Any adverse events defined by the Medical Dictionary for Regulatory Activities (Med-
DRA) were documented.
Laboratory tests were performed on day 1 and included the following: complete blood
count; concentrations of random blood glucose, creatinine, alanine transaminase, C-reactive
protein, serum ferritin, D-dimer, lactate dehydrogenase, and either a chest radiograph or chest
CT scan, whichever was feasible or needed. Complete blood count was repeated on days 3, 7,
10, and 14, and random blood glucose, serum creatinine, and serum alanine transaminase
tests were repeated on days 7 and 14. Real-time polymerase chain reaction for COVID-19 was
scheduled to be performed at least twice; however, due to changes in national policy and
resource constraints, only one run was performed for each patient during their hospital stay
(i.e., after the initial positive test).
Outcome measures
The primary outcome was the time to clinical deterioration, defined as the time from randomi-
zation to a change of two or more points (from the status at randomization) on a seven-cate-
gory ordinal scale. The scale was recommended by the WHO R&D Blueprint expert group.
The seven-category ordinal scale consisted of the following categories: 1) not hospitalized with
the resumption of normal activities; 2) not hospitalized, but unable to resume normal activi-
ties; 3) hospitalized, not requiring supplemental oxygen; 4) hospitalized, requiring supplemen-
tal oxygen; 5) hospitalized, requiring nasal high-flow oxygen therapy or noninvasive
mechanical ventilation, or both; 6) hospitalized, requiring ECMO or invasive mechanical ven-
tilation, or both; and 7) death [17–19]. The secondary outcomes were: 1) length of hospital
stay defined by the total number of days from enrolment to discharge from hospital or death
in hospital; 2) proportion of participants requiring supplemental oxygen (any amount or by
any device such as nasal cannula, face mask, high-flow nasal cannula, invasive or non-invasive
mechanical ventilation); 3) proportion of participants requiring mechanical ventilation; and 4)
proportion of all-cause mortality among the participants. The timeframe for all outcomes was
14 days post-randomization. Clinical outcomes on day 28 were also recorded.
Statistical methods
The estimated sample size was 292 (146 in each arm). The following formula [20] was used to
calculate the sample size:
n¼ðZ/=2þZbÞ2XP1ð1P1Þ þ P2ð1P2Þ
ðP1P2Þ
where n = sample size required in each group, P
1
= proportion of participants with a change in
the placebo group at day 14 = 0.50, P
2
= proportion of participants with a change in the colchi-
cine group at day 14 = 0.34, P
1
-P
2
= clinically significant difference = 0.16, Z
α/2
: this is depen-
dent on the level of significance; 5% = 1.96, Z
β
: this is dependent on power; 80% = 0.84.
Due to the lack of data at the time of study initiation, we assumed that 50% of the hospital-
ized patients will have deteriorated with standard treatment plus placebo, and a difference of
16% between the colchicine and placebo would be sufficient. Therefore, a sample size of 292
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patients, 146 in each arm, was sufficient to detect a clinically important difference of 16%
between groups in the prevention of deterioration in moderate COVID-19 patients using a
two-tailed Z-test of proportions between two groups, with 80% power and a 5% level of signifi-
cance. Later, a study that reported 29% deterioration among hospitalized patients was found
[21]. Using the same difference in efficacy, power, and level of significance, we obtained a sam-
ple size of 202, with 101 patients in each arm. In addition, we assumed a higher loss to follow-
up rate during this pandemic; therefore, a total of 300 patients were recruited, 150 patients in
the colchicine treatment group and 150 patients in the placebo group.
Primary efficacy analysis was performed on an intention-to-treat basis. Continuous param-
eters are reported as median and interquartile range (IQR) and were compared using the non-
parametric test (Mann-Whitney U). For comparisons of the biochemical laboratory test values
on days 1, 7, and 14, the Wilcoxon signed rank test was used. Categorical variables are reported
as counts and percentages and were compared using the χ2 test. A Cox proportional hazards
model was used for the final outcome analysis. A survival analysis for clinical deterioration
was performed. The Kaplan-Meier curve and log-rank tests were performed to determine sig-
nificance. Statistical significance was set at P = <0.05; all tests were 2-tailed. IBM SPSS statisti-
cal software (version 23.0) was used for all statistical analyses. Subgroup analysis was
performed for the different sexes, age subgroups (18–40 years, 41–60 years, and >60 years),
comorbidities (diabetes mellitus, hypertension, asthma, and COPD), and duration of symp-
toms before enrolment (10 days vs. >10 days). Odds ratios with a 95% confidence interval
for the clinical endpoint were measured and a forest plot was constructed to identify any
differences in the primary outcomes among the different subgroups. Additional analysis was
performed using day 28 outcomes with the same statistical methods used for the day 14
outcomes.
Results
Study enrolment began on July 14, 2020, and was completed on November 15, 2020. The last
follow-up date was December 15, 2020. A total of 366 patients were screened for eligibility and
299 patients were included for randomization (Fig 1). After group allocation, 1 patient in the
colchicine group and 2 patients in the placebo group withdrew their consent and did not
receive the drug. Thus, 296 participants received the allocated treatment. The median [IQR]
age of the participants was 47 [35–55] years. The baseline clinical characteristics and baseline
blood biomarkers (Table 1) of the patients administered the allocated treatment were analyzed.
The colchicine and placebo groups were similar in terms of demographic characteristics, clini-
cal status, and laboratory evaluations at baseline. The baseline clinical score was 3 on a seven-
category ordinal scale in both groups. All patients received additional treatment according to
the national guidelines of Bangladesh and the WHO guidelines. An analysis was performed for
low-molecular-weight heparin and dexamethasone among the treatment groups; however, no
significant difference was found.
Outcomes
The primary endpoint was met by nine (6.2%) patients in the placebo group and four (2.7%)
patients in the colchicine group (P = 0.171), which corresponds to a hazard ratio (95% CI) of
0.44 (0.13–1.43) (Table 2). The median (IQR) time of a 2-point deterioration on the seven-cat-
egory ordinal scale was 3 (2.2–10.5) days in the placebo group and 4 (3.0–9.5) days in the col-
chicine group (P = 0.604). The Kaplan-Meier curve revealed no difference in terms of clinical
deterioration on day 14 (log-rank: P-value = 0.159) (Fig 2). Of the 9 patients who met the pri-
mary endpoint in the placebo group within 14 days, 5 required transfer to the ICU and
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Colchicine in moderate COVID-19: A double-blinded, randomized, placebo-controlled trial
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mechanical support but died thereafter. The remaining four patients required respiratory
support with HFNC at the HDU. A total of 4 participants in the colchicine group met the pri-
mary endpoints. Of them, 2 patients who died were transferred to the ICU and received
mechanical ventilation. The other two patients needed respiratory support with HFNC in the
HDU.
Among the secondary outcomes, the length of hospital stay after enrolment and the propor-
tion of participants requiring supplemental oxygen were not found to significantly differ
between the treatment groups. Colchicine might reduce the need mechanical ventilation [haz-
ard ratio, (95% CI) - 0.49, (0.09 to 2.68)] and death [hazard ratio, (95% CI) - 0.39, (0.08 to
2.02)]; however, the values were not found to be statistically significant (Table 2).
The baseline blood biomarkers were compared with those found on days 7 and 14 of fol-
low-up for patients in the colchicine and placebo groups. Both groups had statistically signifi-
cant reductions in serum CRP levels. The changes in mean serum ferritin and D-dimer levels
were not statistically significant (S1 Table).
Fig 1. Study flow diagram.
https://doi.org/10.1371/journal.pone.0277790.g001
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Table 1. Baseline characteristics of the study participants.
Characteristics Total (n = 296)
N (%)
Colchicine (n = 148)
N (%)
Placebo (n = 148)
N (%)
Age (Years)
18–40 109 (36.8) 57 (38.5) 52 (35.1)
41–60 154 (52.0) 75 (50.6) 79 (53.4)
61 33 (11.2) 16 (10.8) 17 (11.5)
Gender
Female 106 (35.8) 53 (35.8) 53 (35.8)
Male 190 (64.2) 95 (64.2) 95 (64.2)
Duration (Day) of symptoms before enrolment Median (IQR) 9 (7–12) 9 (7–11) 9 (6.25–12)
Clinical features
Fever 287 (97.0) 143 (96.6) 144 (97.3)
Cough 177 (59.8) 96 (64.9) 81 (54.7)
Shortness of breath (SOB) 134 (45.3) 64 (43.2) 70 (47.3)
Sore throat 104 (35.1) 48 (32.4) 56 (37.8)
Diarrhea 26 (8.8) 13 (8.8) 13 (8.8)
Anosmia 1 (0.3) 0 (0.0) 1 (0.7)
Duration (Day) of symptoms before admission Median (IQR) 6 (4–8) 6 (4–8) 6(3–9)
Duration (Day) of fever at the time of Enrolment Median (IQR)
$
9 (6–11) 9 (7–11) 8(6–12)
Presence of Co-morbidity 148 (50.0) 69 (48.6) 79 (51.3)
Diabetes mellitus 100 (33.8) 52 (35.1) 48 (32.4)
Hypertension 79 (26.7) 32 (21.6) 47 (31.8)
Chronic obstructive pulmonary disease (COPD)/Bronchial asthma 23 (7.8) 12 (8.1) 11 (7.4)
Chronic kidney disease (CKD) 3 (1.0) 0 (0.0) 3 (2.0)
Ischemic heart disease 14 (4.8) 4 (2.7) 10 (6.8)
Chronic liver disease (CLD) 2 (0.7) 0 (0.0) 2 (1.3)
Other Treatment
Low molecular weight heparin (LMWH) 260 (87.8) 130 (87.8) 130 (87.8)
Dexamethasone 182 (61.5) 97 (65.5) 85 (57.4)
Ramdesivir 27 (9.1) 13 (8.7) 14 (9.4)
Ceftriaxone 73 (24.6) 37 (25) 36 (24.3)
Meropenem 36 (12.2) 16 (10.8) 20 (13.5)
Baseline blood parameters Median (IQR)
Hemoglobin12.2(11.0–13.5) 12.10(11.00–13.4) 12.25(10.90–13.70)
Total count of WBC8.5(6.2–11.8) 8.5(6.4–12.2) 8.4(6.1–11.1)
Neutrophil(%) 71.70(60.8–83.0) 73.2(61.0–83.7) 70.0(60.5–82.4)
Lymphocyte(%) 21.7(12.8–30.8) 20.4(12.2–30.0) 24.6(12.8–31.0)
Platelet count247.0(188.5–324.0) 245.0(191.5–328.5) 249.0(185.2–315.0)
Serum Creatinine 1.0(0.8–1.1) 0.93(0.80–1.10) 0.99(0.81–1.12)
Random blood sugar (RBS)
$
8.4(6.2–14.0) 8.3(6.3–17.2) 9(6.91–13.7)
Alanine aminotransferase (ALT)
#
40.0(24.0–59.0) 49.0(29.0–71.0) 34.5(22.0–60.0)
Serum C-reactive protein (CRP)
@
12.0(6.0–36.3) 10(6–28.20) 15.24(6.00–25.02)
Serum Ferritin
#
297.0(121.5–672.0) 301.0(175.0–758.0) 256.0(95.04–642.0)
Lactate dehydrogenase (LDH)
$
451.5(351.5–594.5) 483.0(372.0–619.0) 446.0(331.5–583.0)
(Continued )
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Subgroup analysis
Subgroup analysis of sex (male vs. female), age (18–40 years, 41–60 years, >60 years), comor-
bidities (diabetes mellitus, hypertension, asthma, and COPD), and duration of symptoms
before enrolment (10 days or less vs. more than 10 days) did not reveal any credible subgroup
effects (S1 Fig).
Additional analysis
The outcomes were analyzed on day 28 of follow-up. Two-point deterioration at the 28-day
follow-up was found in 13 (8.9%) patients in the placebo group and 4 (2.7%) patients in the
colchicine group. The rate of deterioration was significantly lower in colchicine group, with a
hazard ratio [95%CI] of 0.29 [0.098–0.917], (P = 0.035). A Kaplan-Meier curve was con-
structed for this exploratory outcome on day 28, and the log-rank test revealed significance
(P = 0.025) (Fig 3). This additional outcome is the same as all-cause mortality at day 28 because
all patients who deteriorated by two or more points on the seven-category ordinal scale had a
score of 7 (i.e., death). A total of 131 (89.7%) participants in the placebo group were at home
on day 28 compared to 137 (93.8%) in the colchicine group (odds ratio [95%CI], 0.57 [0.24–
1.35] P = 0.200).
Safety outcome
We actively searched for three well-known side effects of colchicine, including diarrhea, nau-
sea/vomiting, and abdominal pain. Further, we collected self-reported adverse events
Table 1. (Continued)
Characteristics Total (n = 296)
N (%)
Colchicine (n = 148)
N (%)
Placebo (n = 148)
N (%)
D-dimer
&
0.5(0.3–1.1) 0.43(0.26–0.83) 0.51(0.28–1.50)
$ median Duration (Days) of fever at the time of Enrolment for 288 records (144 in placebo and 144 in colchicine); ivermectin 1 patient in the placebo group.
mean baseline levels for 294 records (148 in placebo and 148 in colchicine group); unit-gm/dl.
mean baseline Serum creatinine for 284 records (140 in placebo and 144 colchicine).
$ mean baseline Random blood sugar (RBS) for 270 records (135 in placebo and 135 in colchicine); unit: mmol/Lt.
# mean baseline Alanine amino transferase (ALT) for 281 records (138 in placebo and 143 in colchicine).
@ mean baseline Serum Serum C-reactive protein (CRP) for 182 records (87 in placebo and 95 in colchicine).
# mean baseline Serum ferritin for 161 records (75 in placebo and 86 in colchicine).
$ mean baseline Lactate dehydrogenase (LDH) for 252 records (126 in placebo and 126 in colchicine).
& mean baseline d-Dimer for 191 records (99 in placebo and 92 in colchicine).
IQR = Inter quartile range.
https://doi.org/10.1371/journal.pone.0277790.t002
Table 2. Clinical outcomes of patients administered colchicine compared with those administered placebo on day 14 of follow-up.
Outcomes Colchicine (N = 146)
n (%)
Placebo (N = 146)
n(%)
Hazard Ratio
(95% CI)
P-value
Decrease of 2 or more points in the ordinal outcome 4 (2.7) 9 (6.2) 0.44 (0.13–1.43) 0.171
Participants requiring Supplemental oxygen (any device) 7(4.8) 7(4.8) 0.98 (0.34–2.78) 0.96
Participants requiring mechanical ventilation (both non-invasive and invasive) 2(1.4) 4(2.7) 0.49(0.09–2.68) 0.41
Death (all-cause mortality) 2(1.4) 5 (3.4) 0.39(0.08–2.02) 0.26
Length of hospital stay Median (IQR) 10 (7–15) 9 (6–15) 0.59
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according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Among the adverse events, diarrhea (18.5% in the colchicine group and 4.1% in the placebo
group; P<0.001) and nausea/vomiting (8.2% in the colchicine group and 2.7% in the placebo
group; P = 0.040) were significantly more frequent in the colchicine group than the control
group (Table 3). However, these side effects were generally mild, self-limiting, and did not lead
to drug discontinuation. None of the patients experienced dehydration, and diarrhea was con-
trolled via oral ingestion of saline only. Omeprazole and domperidone were prescribed for
nausea and vomiting. In addition, one patient in the colchicine group developed a macular
skin rash on the trunk on day 3; however, this rash was ameliorated after 2 days with an oral
antihistamine. At baseline, 20 (7.1%) patients had elevated serum ALT levels that exceeded
three times the upper limit of normal: 11 (3.9%) in the colchicine group and 9 (3.2%) in the
placebo group. The elevated serum ALT levels of 19 patients were close to normal at 14 days of
follow-up. One patient (placebo group) with elevated serum ALT level at baseline showed a
reduction at 10 days of follow-up but unfortunately died on day 11 in the intensive care unit
due to acute respiratory distress syndrome. During treatment, patients with normal ALT levels
at baseline did not show an elevation that would exceed three times the upper limit of normal.
Among the 4 patients who died in the colchicine group within the 28-day follow-up, 3 died
at the hospital. The fourth patient clinically recovered and was discharged on day 14, but died
suddenly on day 24. This patient was a 45 years old male with no chronic illness; however, his
blood test revealed pancytopenia before enrolment. His pancytopenia did not improve during
discharge from a specialized COVID-19 unit. As a result, this patient was referred to a hema-
tology team. During the evaluation process, the patient died at home before a diagnosis was
given. In the placebo group, 13 patients died within the 28 days of follow-up, 5 of whom died
before day 14 of follow-up. Two patients who had a change in score of 5 on day 14 of follow-
up died in the intensive care unit. Another patient who had a change in score of 5 on day 14 of
Fig 2. Kaplan-meier survival curves based on the primary clinical endpoint on day 14 using the log rank test.
https://doi.org/10.1371/journal.pone.0277790.g002
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follow-up recovered clinically and was discharged from the hospital. Four patients whose clini-
cal score was 3 or 4 during the day 14 follow-up deteriorated subsequently and died at the
HDU or ICU; the other 2 patients showed clinical improvement and were discharged but died
on days 20 and 25. One of these patients was a 37 years old female who was treated for breast
cancer 2 years ago, and the other patient was a 60 years old male with diabetes mellitus.
Discussion
Based on the findings of our study, there was a 56% reduction in the need for mechanical ven-
tilation and death on day-14 in the colchicine arm, which was not statistically significant.
Fig 3. Kaplan-meier survival curve on Day 28 of follow-up using the log-rank test.
https://doi.org/10.1371/journal.pone.0277790.g003
Table 3. Comparison of adverse events between colchicine and placebo.
Adverse events Colchicine (n = 146) Placebo (n = 146) P-value
Diarrhea, n(%) 27 (18.5) 6 (4.1) <0.001
Nausea/ vomiting, n(%) 12 (8.2) 4 (2.7) 0.040
Abdominal pain or burning, n(%) 11 (7.5) 6 (4.1) 0.211
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There was no significant difference in the length of hospital stay between groups. However, on
day-28, colchicine significantly reduced the clinical deterioration by two or more points from
baseline and all-cause mortality.
The open-level GRECCO trial suggested a significant clinical benefit of colchicine in hospi-
talized COVID-19 patients. The patient group in this trial had different severities of disease,
ranging from categories 3 to 5, with a sample size of 105. The timeframe for the primary end-
point was 21 days [11]. In the COLCORONA trial, the outcome of patients with a positive
RT-PCR test on day 30 following randomization revealed a significant reduction in the com-
posite outcome of hospitalization and death [22]. The results of our study differed when the
outcomes at day 14 were compared but were similar when the outcomes at day 28 of follow-up
were compared. This finding indicates that the primary outcome may have been measured
early, and the beneficial effect of colchicine during the cytokine storm may continue for the
next two–three weeks.
Based on a recent meta-analysis of three RCTs, a benefit might exist in mortality that is not
statistically significant among patients receiving colchicine versus non-colchicine regimens
[23]. In our study, the same trends were found in the 14-day follow-up; however, in the 28 day
follow-up, colchicine had a significant benefit.
In our study, the C-reactive protein (CRP) level was significantly reduced from the baseline
on days 7 and 14 in both groups. Our result is similar to that of a previous study that revealed a
significant reduction in serum CRP levels on days 4 and 7 compared to the baseline [13]. How-
ever, when we compared the median CRP level of the placebo group with that of the colchicine
group on day 7, no significant difference was found. This was also true for the median CPR
level on day 14. Our findings are consistent with those of the GRECCO trial [11]. However, it
is not clear from this study whether the CRP decrease is related to the use of anti-inflammatory
drugs, such as colchicine and dexamethasone, or just to the natural recovery of patients.
We enrolled hospitalized patients with moderate COVID-19 infection. In this patient
group, colchicine did not have a beneficial effect on day 14 of treatment; however, a late benefi-
cial effect was observed on day 28. Although this result can be generalized to this patient group
in the population, this result may not be applicable to hospitalized patients with different
severities and non-hospitalized patients.
Limitations
This clinical trial had several limitations. This single-center study was conducted over a short
period. Colchicine has a bitter taste that cannot be replicated in a placebo. Although patients
were advised to swallow the tablets immediately after putting them into the mouth, the bitter
taste of colchicine could have compromised the blinding to some extent. The patients were not
hospitalized during the observation period. Accordingly, telecon follow-up was required,
which has inherent drawbacks. Due to the limitations of the investigation facilities, in some
instances, follow-up RT-PCR could not be performed for all participants at the scheduled
time. Moreover, a follow-up investigation of the patient after discharge was not possible in
most cases.
Conclusion
Colchicine was not found to have a significant early beneficial effect on the reduction of mor-
tality and the need for mechanical ventilation by hospitalized patients with moderate COVID-
19; however, a late beneficial effect was observed. Further studies should be carried out to eval-
uate the late benefits.
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Colchicine in moderate COVID-19: A double-blinded, randomized, placebo-controlled trial
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Supporting information
S1 Checklist.
(DOC)
S1 Fig. Forest plot: Showing sub group effect at day 14.
(DOCX)
S1 Table. Comparison of baseline and follow up blood biomarkers between colchicine and
placebo.
(DOCX)
S2 Table. Clinical outcome at day 14.
(DOCX)
S3 Table. Clinical outcome at day 28.
(DOCX)
S1 Protocol.
(DOCX)
Acknowledgments
The authors would like to acknowledge the contribution of Incepta Pharmaceuticals Ltd. 40,
Shahid Tajuddin Ahmed Sarani, Tejgaon industrial area, Dhaka, Bangladesh, email: info@in-
ceptapharma.com, for donating colchicine and placebo for our participants. We would also
like to thank Editage (www.editage.com) for English language editing.
Author Contributions
Conceptualization: Motlabur Rahman, Ponkaj K. Datta, Pratyay Hasan, Manjurul Haque,
Khan Abul Kalam Azad, Titu Miah, Md. Mujibur Rahman.
Data curation: Khairul Islam, Mahfuzul Haque, Pratyay Hasan, Manjurul Haque, Imtiaz
Faruq, Mohiuddin Sharif, Rifat H. Ratul.
Formal analysis: Motlabur Rahman, Ponkaj K. Datta, Reaz Mahmud, Pratyay Hasan.
Funding acquisition: Motlabur Rahman, Khan Abul Kalam Azad.
Investigation: Motlabur Rahman, Ponkaj K. Datta, Khairul Islam, Rifat H. Ratul.
Methodology: Motlabur Rahman, Ponkaj K. Datta, Khairul Islam, Mahfuzul Haque, Pratyay
Hasan, Mohiuddin Sharif, Titu Miah, Md. Mujibur Rahman.
Project administration: Motlabur Rahman, Ponkaj K. Datta, Khan Abul Kalam Azad, Titu
Miah, Md. Mujibur Rahman.
Resources: Motlabur Rahman, Ponkaj K. Datta, Uzzwal Mallik, Imtiaz Faruq, Mohiuddin Sha-
rif, Khan Abul Kalam Azad, Md. Mujibur Rahman.
Software: Motlabur Rahman, Reaz Mahmud, Mohiuddin Sharif.
Supervision: Motlabur Rahman, Ponkaj K. Datta, Khairul Islam, Mahfuzul Haque, Uzzwal
Mallik, Pratyay Hasan, Manjurul Haque, Imtiaz Faruq, Rifat H. Ratul, Khan Abul Kalam
Azad, Md. Mujibur Rahman.
Visualization: Ponkaj K. Datta.
Writing – original draft: Motlabur Rahman, Ponkaj K. Datta.
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Colchicine in moderate COVID-19: A double-blinded, randomized, placebo-controlled trial
PLOS ONE | https://doi.org/10.1371/journal.pone.0277790 November 16, 2022 13 / 15
Writing – review & editing: Motlabur Rahman, Ponkaj K. Datta, Khairul Islam, Mahfuzul
Haque, Reaz Mahmud, Uzzwal Mallik, Pratyay Hasan, Manjurul Haque, Imtiaz Faruq,
Rifat H. Ratul, Khan Abul Kalam Azad, Titu Miah, Md. Mujibur Rahman.
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