Colchicine

Mild infection

• Symptomatic (any acute COVID-19 related symptoms
• AND respiratory rate <24/min
• WITHOUT pneumonia or hypoxia

Mild or moderate illness without hypoxia

• Pneumonia (clinical or radiological)
• AND respiratory rate ≤30/min
• AND SpO2 ≥94% on room air

Moderate illness with hypoxia

NO features of severe or critical illness (see below).

• Hypoxia (SpO2 <94% on room air)
• AND respiratory rate ≤30/min
• AND SpO2 ≥90% on room air

Severe infection

Pneumonia with ANY ONE of the following:

• respiratory rate >30/min
• severe respiratory distress
• SpO2 <90% on room air
• NO invasive or non-invasive respiratory support needed

Critical infection

• Requirement for high-level respiratory support: non-invasive ventilation, high-flow oxygen (≥20 litres per minute) or invasive mechanical ventilation
• OR acute respiratory distress syndrome (PaO2/FiO2 ratio of <300)
• OR sepsis
• OR shock

Colchicine has been used as an anti-inflammatory drug in the past and in COVID-19, it has been thought to reduce vascular endothelial inflammation by targeting the “inflammasome”. There is extensive experience with the use of Colchicine in diseases like Gout and the mechanism of action here is believed to be due to impairment of neutrophil function, prevention of macrophage activation and degranulation of mast cells and thus prevention of inflammation. The evidence from RCTs indicates that in hospitalized patients with COVID-19 with non-severe or severe to critical illness, colchicine use was not associated with reduction in hospital stay, progression to invasive mechanical ventilation or mortality suggesting that there was no benefit to using Colchicine for this group of patients. In the single randomized control study conducted in outpatients with COVID-19, there was a slight reduction to hospital admission in those given Colchicine, however the other critical outcomes like mortality or progression to invasive mechanical ventilation were not convincingly reduced. The confidence intervals were wide and event rates were low in both the placebo and colchicine groups and hence since it was a single trial the evidence was deemed insufficient to come to a robust conclusion. In addition, in all the subgroups studies, Colchicine was found to cause significant adverse events and diarrhea as compared to the control groups again leading to a fair bit of uncertainty regarding implementation of this drug. Further trials are essential to be confident of effects produced by Colchicine and frame a recommendation for this sub group of patients. Overall, there seems to be no benefit of Colchicine over standard of care in hospitalized severe or non-severe COVID-19 illness, and the data available in outpatients with COVID-19 so far is inconclusive.

Date of latest search: 15^th July 2021.

Date of completion & presentation to Expert Working Group: 22^nd July 2021.

Date of planned review: 15^th January 2022

Evidence synthesis team: Padmanaban Venkatesan, Divya Deodhar, Richard Kirubakaran and Priscilla Rupali.

The Anti-inflammatory Expert Working Group met on 22^nd July 2021 to consider Colchicine as a treatment for COVID-19. Conflict of interest declarations were reviewed by the Steering Committee; none were found to be relevant to Colchicine

A summary and then more detailed explanations of the Expert Working Group's judgements follow.

Problem

The COVID-19 pandemic in India with more than 30 million cases and over 0.39 million deaths has significantly impacted and stressed the health structure of the country. With a shortage of intensive care unit beds, oxygen and trained personnel the country is facing a major health crisis. This has prompted many irrational and experimental treatment interventions like Colchicine in all severity of patients across the country in patients hospitalized in Covid-19 without a clear indication or evidence in which subgroup of population or disease severity the drug is effective for. The group judged the problem to be of utmost priority.

Desirable effects

The group agreed that the evidence suggests that Colchicine does not have a clinically significant effect on mortality and progression to mechanical ventilation in all the sub groups of severity but may reduce admission to hospital in outpatients. This the group noted was significant but the evidence was from 1 trial with very few events in each of the arms suggesting we could not be confident of the effect of Colchicine for this outcome.

Undesirable effects

The group noted that the certainty of evidence for adverse events and gastrointestinal side effects especially diarrhea was of moderate significance in all subgroups. Comparatively higher number of patients with Colchicine experienced adverse events, especially diarrhea. Hence the group felt that diarrhea which is a well-known adverse effect of Colchicine based on experience with use in gout is an inconvenience to most patients when used for treatment in patients with mild COVID-19 infection.

Certainty of evidence

Using GRADE methodology, the evidence synthesis team rated certainty of evidence was found to be low for desirable effects and moderate for adverse events (diarrhea) for outpatients, whereas in hospitalized non-severe it was very low for critical outcomes of mortality, progression to invasive mechanical ventilation but it was moderate for diarrhea. In severe to critical hospitalized patients, evidence was judged to be moderate for all critical events including adverse events. The group agreed with these judgements and rated the overall certainty of evidence as moderate.

Values

The EWG felt that all the outcomes including those of admission to hospital, mortality and progression to mechanical ventilation were expressed variably in the studies. However, there is no important uncertainty or variability on how people would value the main outcomes.

Balance of effects

The group discussed at length regarding implementation of Colchicine. There was a slight effect in reducing admission to hospital but otherwise other critical outcomes were not impacted significantly by Colchicine for a categoric routine implementation in any of subgroups. Even in the out-patients, though there was a reduction in admission to hospital there were significantly higher side effects noted in this subgroup of patients with diarrhea being particularly significant. This was also in keeping with the group’s experiences with the use of Colchicine in the past for other indications. Hence since the marginal benefit if at all was noted in the outpatient group with mild COVID-19 infection which is the sub group with the lowest mortality and morbidity anyway and hence the group felt that the balance of effects probably favors the comparison, rather than the intervention.

Resources required

The group felt that the costs were negligible to small. The group discussed and concluded that the requirement of resource is negligible cost and savings. The group includes clinicians in different types of Indian hospitals who have a good idea of drug and hospitalization costs.

Certainty of evidence of required resources

No studies reporting this were reviewed by the group but the clinicians in the group were aware of the cost and hence felt that there was high certainty of evidence for required resources to implement this intervention.

Cost effectiveness

The group discussed that even though there was no research evidence that evaluated cost effectiveness of Colchicine. It is a cheap drug in an Indian context, it would probably favor the intervention if found useful in outpatients, though with the limited evidence available from 1 trial the group did not favor its widespread implementation at this point. It does favor the comparison in inpatients, as this intervention did not provide any clinical benefit and in fact lead to an increased incidence of adverse events especially diarrhea.

Equity

At this point in time this intervention would probably increase equity as the cost is low, the drug is widely available and clinicians have prior experience in the use of this drug, if found useful.

Acceptability

The group felt that this intervention is likely to have wide acceptance by all the relevant stakeholders (policy-makers, patients and clinicians) as it is an oral drug that is probably quite safe, but taking evidence and cost into account a well-informed clinician would be unlikely to use it.

Feasibility

This is a feasible intervention if found efficacious as it is easy to deliver and available easily over the counter in the country.

Colchicine is not recommended for use in all hospitalized patients including those patients with severe disease as there are no beneficial effects on all-cause mortality and progression to mechanical ventilation. It also results in significant adverse effects especially diarrhea which can be debilitating in hospitalized patients. No recommendation can be made for the use of Colchicine in outpatients because of its uncertain effects in this group of patients even though the drug is cheap and easily accessible. The limited evidence available from 1 trial is unconvincing and does not impact critical outcomes suggesting that further trials are required to unequivocally suggest that this drug reduces hospital admission.

Clinicians may still choose to use Colchicine in outpatients though the effects are trivial with low certainty of evidence in the absence of other medications for this group of patients. Diarrhea has been noted as an undesirable side effect especially in outpatients and non-severe hospitalized patients. Other adverse events were increased in all groups.

The current recommendation is based on the evidence to date and will be updated as new evidence emerges.

Our recommendation against the use of colchicine applies to all sub-groups of COVID-19 patients. Colchicine use is relatively contra-indicated in pregnant and lactating women, children, patients with severe hepatic and renal impairment and those on concomitant strong CYP-3A4 or P-glycoprotein inhibitors. Such patients were not included in the analyzed trials of colchicine.

We evaluated Colchicine in various subgroups of severity. In out-patients with mild COVID-19 infection, Colchicine seemed to reduce admission to hospital but the evidence was of low certainty suggesting we were not confident of its effects. Other critical outcomes were suggested Colchicine made little to no difference in these outcomes. In hospitalized non-severe COVID-19 patients, evidence was of very low certainty for all critical outcomes as the number of patients and events evaluated for these outcomes were extremely small. In hospitalized severe to critical group of patients with COVID-19 we were able to determine with a moderate degree of certainty that Colchicine did not impact critical outcomes and thus would not be recommended in this subgroup of patients.

Colchicine commonly produces gastrointestinal toxicities like abdominal pain, diarrhea and vomiting. It usually produces rhabdomyolysis when given for a long duration >6 months when given along with other medications which can cause muscle injury like statins. Since cardiac muscle may also be affected, when medications like Digoxin are given caution needs to be exercised as it may result in arrhythmias. Some medications like antifungal azoles, protease inhibitors, antibiotics like Clarithromycin and Telithromycin and Nefazodone are also likely to cause an increase in level of Colchicine thus leading to adverse effects. Myopathy is not a concern in short course as would be used in covid 19; diarrhea is more common with doses above 2 mg /day, although again does not cause permanent damage and usually not of serious concern.

The recommendation against the use of Colchicine will be reviewed as and when new evidence emerges.

Colchicine was not found to be beneficial in any of the trials in hospitalized patients in severe or critical categories. There is still equipoise regarding the benefit of colchicine in mild out-patient category as the evidence was of low certainty and reduced admission to hospital. This benefit probably needs to be explored further in other large randomized controlled trials. This is a cheap drug albeit with a few side effects but if found to have a signal towards benefit should be definitely explored.

1. Tardif J-C, Bouabdallaoui N, L’Allier PL, et al. Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial. The Lancet Respiratory Medicine. 2021;0(0). doi:10.1016/S2213-2600(21)00222-8
2. Deftereos et al, Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized with Coronavirus Disease 2019The GRECCO-19 Randomized Clinical Trial
3. Lopes et.al, Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.
4. FarhadSalehzadeh, FarhadPourfarzi, SobhanAtaei et.al. The Impact of Colchicine on The COVID-19 Patients; A Clinical Trial Study. doi:10.21203/rs.3.rs-69374/v1
5. Horby et al. Colchicine in patients admitted to hospital with 3 COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. RECOVERY TRIAL

Covid Management Guidelines India Group – Anti-inflammatory working Group – Colchicine. Covid Guidelines India; Published online on September 03rd , 2021; URL: https://indiacovidguidelines.org/colchicine/  (accessed ).