Evidence review for colchicine (2024)

Study characteristics

Hospital setting

In this update we included data from RECOVERY (Horby) 2021 for the following outcomes:

• All-cause mortality within 21-28 days of starting treatment

• Mechanical ventilation within 21-28 days of starting treatment

• Discharge from hospital within 28 days

The following outcomes have not been updated:

• Serious adverse events within 21 days of starting treatment

• Adverse events within 21 days of starting treatment

• Discontinuation due to adverse events within 21 days of starting treatment

• Clinical progression (scale) within 21 days of starting treatment

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• ICU admission – follow-up timepoint was not provided

• Discharge from hospital by day 10

• Duration of hospital stay

Findings

There is no evidence that colchicine is more effective than placebo or standard care in treating hospitalised patients with COVID-19.

What is the evidence informing this conclusion?

This is a November 2021 update of the evidence review from May 2021 and includes 1 new study (RECOVERY 2021). Evidence comes from 4 randomised trials that compared colchicine with placebo or standard care in 11620 adults admitted to hospital with COVID-19 (Deftereos 2020, Lopes 2021, Salehzadeh 2020, RECOVERY 2021).

The colchicine arm of the RECOVERY trial stopped recruitment because of futility of the intervention – that is, no effect on mortality was seen for existing participants and recruitment of further participants was not expected to change this finding.

Publication status

Salehzadeh 2020 was only available as a preprint and has therefore not been peer reviewed.

Study characteristics

The median age ranged from 55 to 64 years and the proportion of women ranged from 42% to 59%. The severity of COVID-19 was not clearly reported across studies. In Deftereos 2020, an arterial oxygen partial pressure of lower than 95 mmHg on room air was a key inclusion criterion. Lopes 2021 specified moderate to severe COVID-19 as an inclusion criterion but did not report how many patients of each category of severity were recruited. Salehzadeh 2020 did not define disease severity other than specifying COVID-19 with confirmed lung involvement. In RECOVERY 2021, 15% of participants had no oxygen support or simple oxygen, 31-33% had non-invasive ventilation, and 45-46% had invasive mechanical ventilation.

The dosage of colchicine differed across the studies. Deftereos 2020, RECOVERY 2021, and Lopes 2021 used a higher initial dose (from 1,000 micrograms daily to 2,000 micrograms daily) for between 1 and 5 days before switching to a lower maintenance dose. The daily dose in the maintenance phase was 1,000 micrograms (Deftereos 2020, RECOVERY 2021, Lopes 2021, Salehzadeh 2020). Duration of treatment ranged from 6 days to 3 weeks across the studies.

Participants in 3 studies received hydroxychloroquine (or chloroquine) and azithromycin as part of standard care (Deftereos 2020, Lopes 2021, Salehzadeh 2020 ). Deftereos 2020 compared colchicine with standard care which included using hydroxychloroquine (or chloroquine) in 98% of participants and azithromycin in 92% of participants. RECOVERY 2021 compared colchicine with standard care which included using corticosteroids in 93% of participants and remdesivir in 22% of participants.

Follow-up ranged from 2 to 3 weeks; however Lopes 2021 did not clearly report the duration of follow-up.

Pregnant and breastfeeding women were excluded from all studies. No children were included.

What are the main results?

Critical outcomes

There was no statistically significant effect on mortality or need for mechanical ventilation within 21 to 28 days of starting colchicine treatment compared with placebo or standard care.

Important outcomes

There was a statistically significant increase in adverse events with colchicine compared with standard care.

No statistically significant differences were seen with colchicine compared with control for the other important outcomes reviewed. This includes duration of hospital stay.

Our confidence in the results

The certainty of evidence is moderate to very low for all outcomes. Reasons for downgrading evidence included: risk of bias (with all studies having some degree of risk of bias); inconsistency (for example, when point estimates varied widely between studies); indirectness (with, for example, standard care not including corticosteroids); and imprecision (with outcomes rated as having serious imprecision when the confidence interval crossed the line of no effect and outcomes further downgraded as having very serious imprecision when fewer than 300 people contributed to the outcome). One study was only available as a preprint.

Community setting

In this update we included data from PRINCIPLE 2021 for the following outcomes:

• All-cause mortality or hospitalisation (28 or 30 days)

• Mechanical ventilation within 28-30 days of starting treatment

• Serious adverse events within 28-30 days of starting treatment

• Alleviation of all symptoms, estimated treatment effect (median days) within 28 days of starting treatment

• Time to first reported recovery (days) within 28 days of starting treatment

The following outcomes have not been updated:

• All-cause mortality within 30 days of starting treatment

• Adverse events within 30 days of starting treatment

• Hospitalisation for COVID-19 within 30 days of starting treatment

• Hospitalisation due to any cause (30 days) within 30 days of starting treatment

Findings

There is no evidence that colchicine is more effective than placebo or standard care in treating patients in the community with COVID-19.

What is the evidence informing this conclusion?

This is a November 2021 update of an evidence review from May 2021 and includes 1 new study (PRINCIPLE 2021). Evidence comes from 2 randomised trials that compared colchicine with placebo or standard care in 4764 adults in the community with COVID-19 (Tardiff 2021 (COLCORONA trial), PRINCIPLE 2021).

Publication status

PRINCIPLE 2021 was only available as a preprint and has therefore not been peer reviewed.

Study characteristics

The age of participants ranged from 18 to over 65 years and the proportion of women ranged from 49 to 59%. The studies did not clearly define the severity of COVID-19.

For Tardif 2021, the dosage of colchicine was 500 micrograms twice daily for the first 3 days then once daily for 27 days. For PRINCIPLE 2021, participants received colchicine 500 micrograms daily for 14 days.

As standard care in PRINCIPLE 2021, participants received medications focused on managing symptoms with antipyretics. In Tardif 2021, small percentages of participants were given hydroxychloroquine, oral anticoagulants, aspirin, and/or other platelet agents.

Follow-up after starting treatment was 28 days for PRINCIPLE 2021 and 30 days for Tardif 2021.

Pregnant and breastfeeding women were excluded from all studies. No children were included.

What are the main results?

Critical outcomes

For the critical outcomes of hospitalisation for COVID-19, all-cause mortality, and need for mechanical ventilation, there was no statistically significant effect 28-30 days after starting colchicine treatment compared with control.

Important outcomes

There was a statistically significant increase in adverse events with colchicine compared with standard care. There was a statistically significant increase in serious adverse events with standard care compared with colchicine. This was potentially due to a greater number of cases of pneumonia in the standard care arm. No statistically significant differences were seen with colchicine compared with control for the other important outcomes reviewed. This includes time to reported recovery.

Our confidence in the results

The certainty of evidence is high to very low for all outcomes. Reasons for downgrading evidence included: risk of bias (with one study having some degree of risk of bias); inconsistency (for example, when point estimates varied widely between studies); and imprecision (with outcomes rated as having serious imprecision when the confidence interval crossed the line of no effect). One study was only available as a preprint.

Hospital settings

The panel considered that the results from studies of colchicine for COVID-19 in hospitals showed no benefit of effect on all-cause mortality, mechanical ventilation, discontinuation due to adverse events, clinical progression, ICU admission, or discharge from hospital within 28 days.

The evidence shows that people having colchicine plus standard care have statistically significantly more adverse events compared with people having standard care alone. Known adverse effects such as diarrhoea appear to have been under-reported in the identified evidence in hospital settings. The panel noted that colchicine commonly causes diarrhoea, which can lead to potassium deficiency (hypokalaemia). They advised that, because of the adverse events, colchicine tends to be used (for the treatment of gout) only for 3 to 4 days.

Although one study suggests that colchicine plus standard care reduces duration of hospital stay at a mean follow-up of 21 days compared with placebo plus standard care, this reduction of hospital stay is not statistically significant (a mean difference of 1.84 days (95% CI 0.78 to 2.90)).

Community settings

The panel considered that the results from studies of colchicine for COVID-19 in the community showed no benefit on hospitalisation for COVID-19, all-cause mortality, all-cause mortality or hospitalisation, mechanical ventilation, number of participants who experienced alleviation of all symptoms, or reported recovery time.

The evidence shows that people having colchicine plus standard care have a statistically significant reduction in serious adverse events compared with standard care alone or with placebo. This is possibly because pneumonia was reported less frequently in patients of the colchicine group compared with those in the placebo group. However, people having colchicine plus standard care have a statistically significant increase in adverse events compared with standard care plus placebo.

The adverse event diarrhoea was higher with colchicine than with placebo in Tardif 2021.

Certainty of evidence

The panel agreed that the certainty of evidence on colchicine for people with COVID-19 in hospital and in the community ranges from high to very low for all outcomes. Reasons for downgrading evidence included: risk of bias (with most studies having some degree of bias); inconsistency (for example, when point estimates varied widely between studies); indirectness (with, for example, standard care in hospitals not including corticosteroids); and imprecision (with outcomes rated as having serious imprecision when the confidence interval crossed the line of no effect and outcomes further downgraded as having very serious imprecision when fewer than 300 people contributed to the outcome). Two studies were only available as preprints.

Values and preferences

The panel were not aware of any systematically collected data on preferences and values.

The panel thought that people would not want to take a treatment with no known benefits but well-established side effects such as diarrhoea.

Resources

Cost effectiveness was not assessed as part of the evidence review.

Colchicine costs from £2.54 for 28 tablets (BNF, November 2021). The panel therefore expected a negligible effect on resources.

Equity

Colchicine should not be used in pregnancy and no studies in children were identified. However, because the overall recommendation is not to offer colchicine to anyone, it is not expected to cause inequity among any subgroups.

Acceptability

The panel were not aware of any systematically collected evidence about acceptability.

Colchicine is not licensed in the UK for treating COVID-19. The panel noted that its side effects are unlikely to be acceptable to patients or prescribers, especially diarrhoea and hypokalaemia. The panel noted that diarrhoea is particularly concerning in older people because frequent toilet visits and dehydration could be a risk factor for falls. They also noted that avoidable diarrhoea would not be acceptable in the intensive care setting.

Feasibility

The panel were not aware of any systematically collected evidence about feasibility.

Colchicine is not used for treating COVID-19 in the UK, so the recommendation supports current practice.

Appendix A. PICO table

PICO table (PDF, 128K)

Appendix B. Study flow diagram

Download PDF (111K)

Appendix C. Included studies

• DeftereosSG; GiannopoulosG; VrachatisDA; SiasosGD; GiotakiSG; GargalianosP; MetallidisS; SianosG; BaltagiannisS; PanagopoulosP; DolianitisK; RandouE; SyrigosK; KotanidouA; KoulourisNG; MilionisH; SipsasN; GogosC; TsoukalasG; OlympiosCD; TsagalouE; MigdalisI; GerakariS; AngelidisC; AlexopoulosD; DavlourosP; HahalisG; KanonidisI; KatritsisD; KolettisT; ManolisAS; MichalisL; NakaKK; PyrgakisVN; ToutouzasKP; TriposkiadisF; TsioufisK; VavouranakisE; Martinèz-DolzL; ReimersB; StefaniniGG; ClemanM; GoudevenosJ; TsiodrasS; TousoulisD; IliodromitisE; MehranR; DangasG; StefanadisC; ; Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial.; JAMA network open; vol. 3 (no. 6) [PMC free article: PMC7315286] [PubMed: 32579195]

• Horby Peter, W; Campbell, Mark; Spata, Enti; Emberson Jonathan, R; Staplin, Natalie; Amorim Guilherme, Pessoa-Amorim; Peto, Leon; Wiselka, Martin; Wiffen, Laura; Tiberi, Simon; Caplin, Ben; Wroe, Caroline; Green, Christopher; Hine, Paul; Prudon, Benjamin; George, Tina; Wight, Andrew; BaillieJ, Kenneth; Basnyat, Buddha; Buch Maya, H; Chappell Lucy, C; Day Jeremy, N; Faust Saul, N; Hamers Raph, L; Jaki, Thomas; Juszczak, Edmund; Jeffery, Katie; Lim Wei, Shen; Montgomery, Alan; Mumford, Andrew; Rowan, Kathryn; Thwaites, Guy; Mafham, Marion; Haynes, Richard; Landray Martin, J; Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial; Lancet

• LopesMI; BonjornoLP; GianniniMC; AmaralNB; MenezesPI; DibSM; GiganteSL; BenattiMN; RezekUC; Emrich-FilhoLL; SousaBAA; AlmeidaSCL; LuppinoAssad R; VerasFP; SchneiderA; RodriguesTS; LeiriaLOS; CunhaLD; Alves-FilhoJC; CunhaTM; ArrudaE; MirandaCH; Pazin-FilhoA; Auxiliadora-MartinsM; BorgesMC; FonsecaBAL; BollelaVR; Del-BenCM; CunhaFQ; ZamboniDS; SantanaRC; VilarFC; Louzada-JuniorP; OliveiraRDR; Beneficial effects of colchicine for moderate to severe COVID-19: a randomised, double-blinded, placebo-controlled clinical trial.; RMD open; 2021; vol. 7 (no. 1) [PMC free article: PMC7868202] [PubMed: 33542047]

• PRINCIPLE Trial Collaborative Group; Colchicine for COVID-19 in adults in the community (PRINCIPLE): a randomised, controlled, adaptive platform trial; medRxiv; 2021

• Salehzadeh, F. Pourfarzi, F. AtaeiS; The Impact of Colchicine on The COVID-19 Patients; A Clinical Trial Study; Research Square; 2021; 1–11 [PMC free article: PMC9450200] [PubMed: 36128202]

• Tardif, Jean-Claude; Bouabdallaoui, Nadia; L’Allier, Philippe L; Gaudet, Daniel; Shah, Binita; Pillinger, Michael H; Lopez-Sendon, Jose; da Luz, Protasio; Verret, Lucie; Audet, Sylvia; Dupuis, Jocelyn; Denault, Andre; Pelletier, Martin; Tessier, Philippe A; Samson, Sarah; Fortin, Denis; Tardif, Jean-Daniel; Busseuil, David; Goulet, Elisabeth; Lacoste, Chantal; Dubois, Anick; Joshi, Avni Y; Waters, David D; Hsue, Priscilla; Lepor, Norman E; Lesage, Frederic; Sainturet, Nicolas; Roy-Clavel, Eve; Bassevitch, Zohar; Orfanos, Andreas; Stamatescu, Gabriela; Gregoire, Jean C; Busque, Lambert; Lavallee, Christian; Hetu, Pierre-Olivier; Paquette, Jean-Sebastien; Deftereos, Spyridon G; Levesque, Sylvie; Cossette, Marieve; Nozza, Anna; Chabot-Blanchet, Malorie; Dube, Marie-Pierre; Guertin, Marie-Claude; Boivin, Guy; COLCORONA, Investigators; 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 [PMC free article: PMC8159193] [PubMed: 34051877]

Appendix D. Excluded studies at full text screening

Appendix E. Evidence tables

COLCORONA (Tardif) 2021 (PDF, 381K)

Appendix F. Forest plots

Hospital setting (PDF, 256K)

Appendix G. GRADE profiles

Colchicine compared to standard care for COVID-19: Hospitalised (PDF, 197K)