Study characteristics

Methods

Design: Pseudo‐randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 11 years

Participants

Number randomised: Total 52. 29 colchicine. 23 control

Condition: Ascitic cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age mean (SD) in years: colchicine 54.27 (14.27). control 54.21 (15.04)

Sex (women): 13%

Inclusion criteria: "The trial included 52 ascitic cirrhotic patients."

Exclusion criteria: "According to Kershenobich the patients were excluded if they had evidence of gastrointestinal bleeding or of encephalopathy during a period of two weeks before the trial."

Interventions

Colchicine:

• Dose: 1 mg/d 5d/week

• Duration: "Colchicine treatment, according to need, was given from 4 to 84 months on average 27.63±20.54 months, while the Placebo was given 0.75 to 36.25 months, on average 11.63±11.42 months."

Control:

• Dose: placebo

Outcomes

Primary outcome of the study:

• "the goal is to determine the role of colchicine in the survival of cirrhotic patients. This is thought to occur by decreasing hepatic fibrosis and decrease of portal hypertension."

Outcomes considered in this review:

• All‐cause mortality

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

High risk

Randomisation according to odd/even age

Allocation concealment (selection bias)

Low risk

Pharmacy supplied drugs and kept identity of drugs confidential

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"neither staff, nor the patients knew the drug used", double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

Analysis unclear; 13% missing data reported for control group ‐ imbalance to colchicine group might cause bias

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, multicentre (6 centres, 2 centres in substudy)

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 3 years

Participants

Number randomised: Total 90. 46 colchicine, 44 control. (Substudy: Total 44. colchicine 22, control 22)

Condition: Primary biliary cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Italy

Age mean (SD) in years: Colchicine 55.5 (10.9), control 53.3 (10.2). (Substudy: colchicine 55 (11), control 58 (10))

Sex (women): Colchicine 87%, control 93% (Substudy: colchicine 86, control 86)

Inclusion criteria: "The criteria for entry into the trial were: an established diagnosis of primary biliary cirrhosis according to Taal et al.; symptomatic disease as defined by presence of pruritus (severe enough to necessitate therapy); and/or serum bilirubin higher than 2 mg/dl; and/or histological or clinical diagnosis of cirrhosis. Patients were included regardless of the duration of symptoms or the stage."

Exclusion criteria: "Exclusion criteria were: advanced liver disease (ascites, encephalopathy, portal hypertensive bleeding, bilirubin >10 mg/dl); hepatocellular carcinoma; any concomitant immunosuppressive treatment; evidence of other major diseases unrelated to primary biliary cirrhosis; alcohol abuse; and low compliance. Treatment with cholestyramine, antihistamines, H₂‐blockers or proton‐pump inhibitors, calcium supplementation and liposoluble vitamins was allowed."

Interventions

Colchicine:

• Dose: 1 mg/d

• Plus 500 mg/d ursodeoxycholic acid

• Duration: 3 years

Control:

• Placebo plus ursodeoxycholic acid 500 mg/d

• Duration: 3 year

Outcomes

Primary outcome of the study:

• "In order to evaluate the efficacy of the two therapeutic regimens, we analysed clinical, biochemical and histological end‐points. We considered as ‘treatment failure’ the occurrence of any of the following events: death, liver transplantation, decompensation of cirrhosis, doubling of serum bilirubin"

Outcomes considered in this review:

• All‐cause mortality

Notes

Substudy results are reported from 2 of 6 centres (with separate randomisation) with longer follow‐up. We used the main study results for our analyses. Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"The randomization was performed by a central study unit using the same randomized blocks separately for each centre"

Allocation concealment (selection bias)

Low risk

Central randomization

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT; ≤ 10% missing data per group

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, multicentre (8 centres)

Blinding: Open‐label

Longest mean follow‐up period for a review‐relevant outcome: 25 months

Participants

Number randomised: Total 50. 18 colchicine, 32 control.

Condition: Idiopathic pulmonary fibrosis

Cardiovascular risk profile: Not reported

Setting: outpatient

Country: Greece

Age median (range) in years: Colchicine 69 (54 ‐ 85), control 66 (42 ‐ 82)

Sex (women): 16%

Inclusion criteria: "Eligible patients were aged 40–80 yrs, had shown clinical symptoms of IPF for ≥3 months, and had a forced vital capacity (FVC) of ≥55% and ≤90% of the predicted value, a transfer factor of the lung for carbon monoxide (TL,CO) of ≥35% pred and an arterial oxygen tension (Pa,O₂ ) of >7.3 kPa while breathing room air at rest."

Exclusion criteria: "Criteria for exclusion were a significant history of exposure to organic or inorganic dust or drugs known to cause pulmonary fibrosis and connective tissue disease or other chronic lung diseases causing pulmonary fibrosis, a ratio of the forced expiratory volume in one second to FVC of <0.6 after bronchodilator use, a residual volume of >120% pred, active infection within 1 week before enrolment, unstable cardiovascular or neurological disease, uncontrolled diabetes, pregnancy, lactation, any active malignancy likely to result in death or any condition other than IPF likely to result in death within 3 yrs."

Interventions

Colchicine:

• Dose: 1 mg/d

• Plus prednisolone 10 mg/d

• Duration: 15 months median duration (range 5 – 44 months), intended 24 months

Control:

• IFN‐c 1b 200 mg 3 x / week subcutaneously plus prednisolone 10 mg/d

• Duration: 20 months median duration (range 2 – 44 months), intended 24 months

Outcomes

Primary outcome of the study:

• "The study was originally designed to investigate the molecular perspective after both treatment regimens. [...] The study did not have prespecified end‐points. [...] The study objectives were to compare the clinical effects of the two treatment regimens after 6, 12 and 24 months of therapy using: pulmonary function tests (FVC, total lung capacity (TLC), TL,CO and Pa,O2 at rest), the extent of lung fibrosis on high‐resolution computed tomography (HRCT), quality of life (St George’s Respiratory Questionnaire (SGRQ)), treatment outcome (using the ATS/ERS criteria), and overall survival."

Outcomes considered in this review:

• All‐cause mortality, non‐scheduled hospitalisation

Notes

"supported by an unrestricted grant from Boehringer Ingelheim Hellas (Athens, Greece) and the Society for Pulmonary and Intensive Care Research in the district of East Macedonia and Thrace (Alexandrou´polis, Greece). The Greek National Health System supported both colchicine and interferon gamma‐1b."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Randomisation was performed using a random number table."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open trial

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Two readers, blinded to the clinical functional data and type of treatment, examined the HRCT images"; however, we do not measure the outcomes related to the HRCT images; no other blinding reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

In total, 17 (11 in the IFN‐c‐1b group and 6 in the colchicine group) of the 50 participants discontinued treatment before 24 months. Of the 11 participants in the IFN‐c‐1b group, 8 stopped because of an adverse event and/or disease progression and 3 for social reasons. Of the colchicine group, 6 participants withdrew; 2 stopped because of disease progression and 4 for social reasons. In addition, median follow‐up was longer (median 5 months) in control group than in colchicine group

Selective reporting (reporting bias)

Unclear risk

"The study was originally designed to investigate the molecular perspective after both treatment regimens. Owing to technical difficulties, this aim was only investigated in a subgroup of 10 patients (data not shown). The study did not have prespecified end‐points."

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 26 months

Participants

Number randomised: Total 57. Colchicine 28 control 29

Condition: Primary biliary cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: USA

Age mean (SD) in years: Colchicine 53 (not reported), control 51 (not reported)

Sex (women): Colchicine 93%, control 90%

Inclusion criteria: "History of chronic cholestatic liver disease and liver biopsy results compatible with PBC were entered into the study. Fifty‐one of our patients were followed at Mount Sinai Medical."

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: mean 33 months

Control:

• Placebo

• Duration: mean 33 months

Outcomes

Primary outcome of the study:

• To test the safety of long‐term colchicine administration

Outcomes considered in this review:

• All‐cause mortality

Notes

Endpoint mortality (extracted from Bodenheimer 1985) reported only for 26 months. Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"The liver histology was reviewed without knowledge of the clinical status or the drug the patient was receiving." However, we did not look into liver outcomes, so the blinding remains unclear

Incomplete outcome data (attrition bias)
All outcomes

High risk

Unbalanced attrition and missing reporting: in the abstract from 1985, Bodenheimer et al report 39% attrition in colchicine group and 24% in the control group at 26 weeks follow‐up. In their publication from 1988, they report 29% attrition in colchicine and 21% in the control group at a mean follow‐up of 33 months.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Not reported

Longest mean follow‐up period for a review‐relevant outcome: 36 months

Participants

Number randomised: Total 180. Colchicine 100, placebo 80

Condition: Liver cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age: Not reported

Sex (women): Not reported

Inclusion criteria: Liver cirrhosis

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 1.0 mg/d

• Duration: 6 ‐ 36 months. Mean 17.4 months

Control:

• "Conventional therapy"

• Duration: 6 ‐ 36 months. Mean 17.4 months

Outcomes

Primary outcome of the study:

• Clinical improvement of liver cirrhosis markers

Outcomes considered in this review:

• All‐cause mortality

Notes

This study is reported only as an abstract.
Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis unclear, no withdrawal reported

Selective reporting (reporting bias)

High risk

Only abstract, objectives unclear

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: mean 45 months

Participants

Number randomised: Total 129. Colchicine 63, control 66

Condition: Alcoholic cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age: Not reported

Sex (women): Not reported

Inclusion criteria: People with alcoholic cirrhosis

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 1 mg/d

• Duration: mean follow‐up 45.3 months (range 1 ‐ 106)

Control:

• Placebo

• Duration: mean follow‐up 45.3 months (range 1 ‐ 106)

Outcomes

Primary outcome of the study:

• Overall survival and liver‐related death

• Effect on the natural history of chronic alcoholic liver disease or liver‐related complications

Outcomes considered in this review:

• All‐cause mortality

Notes

This study is only reported as an abstract.
Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported specifically enough (sequential numbers)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not specified

Incomplete outcome data (attrition bias)
All outcomes

High risk

From initially 129 participants: 41 died, another 41 were withdrawn (26 did not comply, 10 had adverse events, 5 for geographic reasons)

Selective reporting (reporting bias)

High risk

Abstract only; no protocol reported

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Unclear

Longest mean follow‐up period for a review‐relevant outcome: 2 years

Participants

Number randomised: Total 555. Colchicine 269, control 286

Condition: HCV with advanced liver disease

Cardiovascular risk profile: Not reported

Setting: Not reported

Country: Unclear

Age mean (SD) in years: mean 51 (not reported)

Sex (women): 30%

Inclusion criteria: "IFN failures with Ishak stage 3−6" and "Study patients had no evidence of liver decompensation or HCV (liver cancer); Ishak Fibrosis stage 3 or more; HIV & HbeAg negative."

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: 4 years ("49% of patients discontinued medication over 4 years")

Control:

• Peg‐Interferon‐alpha 0.5 μg/kg/w

• Duration: 4 years ("49% of patients discontinued medication over 4 years")

Outcomes

Primary outcome of the study:

• All‐cause mortality, liver failure, transplant, variceal bleeding and HCC

Outcomes considered in this review:

• All‐cause mortality, adverse events (any) at 2 years follow‐up

Notes

This study was reported as an abstract only.
Outcomes from Afdhal 2008 not included in analysis because group assignment unclear. Funding not reported but 1 or more of the authors with pharmaceutical industry affiliation

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Not reported specifically enough (sequential numbers)

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

ITT; dropouts were censored; unclear how many dropouts

Selective reporting (reporting bias)

High risk

Abstract only; results from secondary endpoints not described

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Open‐label

Longest mean follow‐up period for a review‐relevant outcome: 20 months

Participants

Number randomised: Total 84. Colchicine 42, control 42

Condition: Recurrent pericarditis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Italy

Age mean (SD) in years: Colchicine 56.4 ± 16.9 control 51.2 ± 16.3

Sex (women): Colchicine 62%, control 69%

Inclusion criteria: "Inclusion criteria were a diagnosis of recurrent pericarditis (first episode); previous idiopathic, viral, and autoimmune etiologies (including postpericardiotomy syndromes and connective tissue diseases) of the first episode of acute pericarditis; 18 years or older; and informed consent."

Exclusion criteria: "Exclusion criteria were tuberculous, neoplastic, or purulent etiologies of the first episode; known severe liver disease or current transaminase levels greater than 1.5 times the upper limit of normal; a current serum creatinine level greater than 2.5 mg/dL (221 µmol/L); known myopathy or a current serum creatine kinase level greater than the upper limit of normal; known blood dyscrasias or gastrointestinal disease; pregnant and lactating women or women of child bearing potential not protected by a contraception method; known hypersensitivity to colchicine; and current treatment with colchicine for any indication."

Interventions

Colchicine:

• Dose: 1 ‐ 2 mg the first day, maintenance dose of 0.5 ‐ 1.0 mg/d

• < 70 kg or intolerant to higher dose: 1 x 1.0 mg then maintenance dose 1 x 0.5 mg/d; ≥ 70 kg: 2 x 1.0 mg then maintenance dose 2 x 0.5 mg/d

• Plus Aspirin, 800 mg every 6 or 8 hours for 7 ‐ 10 days, with gradual tapering for 3 ‐ 4 weeks

• Duration: 6 months

Control:

• Aspirin, 800 mg every 6 or 8 hours for 7 ‐ 10 days, with gradual tapering for 3 ‐ 4 weeks

• Duration: 6 months

Outcomes

Primary outcome of the study:

• "to verify the safety and efficacy of colchicine therapy as an adjunct to conventional therapy for the first episode of recurrence of pericarditis and to verify whether the natural history of the disease may change because of the early use of colchicine"

Outcomes considered in this review:

• Adverse events (any), serious adverse events

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified ("Randomization was based on permuted blocks, with a block size of 4.")

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"The validation of clinical events was ensured by an ad hoc committee of expert cardiologists blinded to patient treatment assignment", "data analyses were performed by an external data analysis committee masked to treatment assignment"

Incomplete outcome data (attrition bias)
All outcomes

High risk

ITT, but "clinical follow‐up data were available in all patients for a mean of 20 months (range, 8‐44 months)"

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, multicentre (4 centres)

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 2 years

Participants

Number randomised: Total 120. Colchicine 60, control 60

Condition: Recurrent pericarditis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Italy

Age mean (SD) in years: Colchicine 47.3 (14.4), control 47.9 (15.4)

Sex (women): Colchicine 57%, control 52%

Inclusion criteria: "Inclusion criteria were a definite diagnosis of recurrent pericarditis (first recurrence), age 18 years or older, and provision of informed consent. The relevant institutional review boards and ethics committees approved our research protocol, and all participants gave written informed consent"

Exclusion criteria: "Patients were excluded if they were having their first episode of acute pericarditis or their second or subsequent recurrence or had pericarditis with tuberculous, purulent, or neoplastic causes; known severe liver disease; current aminotransferase levels greater than 1.5 times the upper limit of normal, current serum creatinine level greater than 221 mol/L(2.5mg/dL); known myopathy; serum creatine kinase level above the upper limit of normal; known blood dyscrasias; gastrointestinal disease; or known hypersensitivity to colchicine. Also excluded were pregnant or lactating women (because of the contraindication to colchicine) and women in their childbearing years who were not using contraception. Finally, we excluded persons who were receiving or had previously received colchicine for any indication."

Interventions

Colchicine:

• Dose: colchicine 1 ‐ 2 mg on the first day, followed by maintenance dose of 0.5 ‐ 1.0 mg/d

• < 70 kg or intolerant to higher dose: 0.5 mg/12h, then maintenance dose 0.5 mg/d; ≥ 70 kg: 2 mg/d, then maintenance dose 1 mg/d

• Plus conventional treatment of 800 to 1000 mg aspirin (or ibuprofen, 600 mg) every 8 hours for 7 ‐ 10 days, with gradual tapering over 3 ‐ 4 weeks

• Duration: 6 months

Control:

• Placebo plus conventional treatment of 800 to 1000 mg Aspirin (or ibuprofen, 600 mg) per os every 8 hours for 7‐10 days, with gradual tapering over 3‐4 weeks

• Duration: 6 months

Outcomes

Primary outcome of the study:

• Pericarditis recurrence rate at 18 months

Outcomes considered in this review:

• Gastrointestinal adverse event, adverse event (any), serious adverse events

Notes

"Primary Funding Source: Maria Vittoria Hospital, Torino, Italy."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"central computer– based automated sequence Randomization was based on permuted blocks, with a block size of 4. The random allocation sequence was implemented by using sequentially numbered containers."

Allocation concealment (selection bias)

Low risk

"central computer–based automated sequence"

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"participants and trial investigators were blinded to randomized treatment"; double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"Data were collected by using case report and clinical events adjudication forms and were managed by investigators who were blinded to treatment assignments. A blinded clinical end point committee adjudicated all events."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT, 7% in the control and 8% in the colchicine group discontinued intervention

Selective reporting (reporting bias)

Unclear risk

"Study protocol: Available from Dr. Imazio (e‐mail, [email protected]). Statistical code and data set: available from Dr. Imazio (e‐mail, [email protected]) for personal use, with approval from the Steering Committee"

Study characteristics

Methods

Design: Randomised controlled trial, multicentre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 20 months

Participants

Number randomised: Total 240. Colchicine 120, control 120

Condition: Recurrent pericarditis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Italy

Age mean (SD) in years: Colchicine 48.6 (13.6), placebo 48.9 (15.5)

Sex (women): Colchicine 45%, control 55%

Inclusion criteria: "Consecutive patients aged 18 years or older with two or more recurrences of pericarditis (idiopathic, viral, post‐cardiac injury, or caused by connective tissue disease) were eligible for enrolment."

Exclusion criteria: "Patients with any of the following were ineligible: tuberculous, neoplastic, or purulent pericarditis; severe liver disease or current aminotransferase concentrations more than 1.5 times the upper limit of the normal; serum creatinine concentration more than 221.00 μmol/L; skeletal myopathy or serum creatine kinase concentration more than the upper limit of the normal; blood dyscrasia; inflammatory bowel disease; hypersensitivity to colchicine or other contraindication to colchicine; current treatment with colchicine; and life expectancy of 18 months or less. Pregnant or lactating women or women of childbearing potential not using contraception were also ineligible, as were patients with evidence of myopericarditis as indicated by any increase of serum troponin concentration."

Interventions

Colchicine:

• Dose: 0.5 or 1.0 mg daily

• < 70 kg or intolerant to higher dose: 0.5 mg/d; ≥ 70 kg: 2 x 0.5 mg/d

• Duration: 6 months

Control:

• Placebo

• "Colchicine and placebo tablets were identical"

• Duration: 6 months

Outcomes

Primary outcome of the study:

• Recurrent pericarditis

Outcomes considered in this review:

• Gastrointestinal adverse events, adverse events (any), serious adverse events

Notes

"supported by the former Azienda Sanitaria 3 of Torino (now ASLTO2) within the Italian National Health service. Acarpia (Madeira, Portugal) provided the study drug and placebo as an unrestricted grant."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"Participants were randomly assigned to receive colchicine or placebo (1:1) with a central computer‐based automated sequence."

Allocation concealment (selection bias)

Low risk

"The random allocation sequence was implemented with sequentially numbered study drug containers."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled, "All patients and investigators were masked to treatment allocation."

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"All patients and investigators were masked to treatment allocation."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT, 6% in the control and 7% in the colchicine group discontinued intervention

Selective reporting (reporting bias)

Low risk

Protocol available.

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 41 months

Participants

Number randomised: Total 62. Colchicine 31, control 31

Condition: Alcoholic cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age mean (SD) in years: Colchicine 53.2 (8.5), control 54.4 (9.1)

Sex (women): Colchicine 7%, control 15%

Inclusion criteria: "Ambulatory subjects aged 18‐65 years, with biopsy proven liver cirrhosis and a well‐documented history of previous daily alcohol intake exceeding 40 g of ethanol in women and 60 g in men for more than 5 years, in whom other causes of liver disease were excluded, were eligible for inclusion."

Exclusion criteria: "Exclusion criteria included the presence of other liver diseases, namely haemochromatosis, Wilson's disease, α₁‐antitrypsin deficiency, autoimmune hepatitis, primary biliary cirrhosis, or viral hepatitis, as evaluated by the latter tests. Child‐Pugh class C, serum bilirubin >10 mg/dl, gastrointestinal bleeding in the previous 15 days, refractory ascites, or serious illness, e.g. renal failure (creatinine >2.5 mg/dl), cardiac failure or neoplasia were also exclusion criteria."

Interventions

Colchicine:

• Dose: 1 mg/d, 5 d/week

• Duration: median 40.6 months (range 1.4 ‐ 126.3)

Control:

• Placebo

• Duration: median 42.4 months (range 5.7 ‐ 118.2)

Outcomes

Primary outcome of the study:

• "Clinical endpoints were death from any cause, episodes of gastrointestinal bleeding, ascites, encephalopathy or jaundice."

Outcomes considered in this review:

• All‐cause mortality, gastrointestinal adverse events, adverse events (any)

Notes

Maximum follow‐up 10 years. "supported in part by a grant from the Center of Nutrition and Metabolism (RUN 437)."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"computer‐generated randomization list (blocks of four)"

Allocation concealment (selection bias)

Low risk

"either 1 mg colchicine or a placebo identical in appearance, prepared at the hospital pharmacy. The study `drugs' were coded and distributed to the patient, by the hospital pharmacy, according to a computer‐generated randomization list (blocks of four)."

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, "At no time were the treatment codes disclosed for any patient, attending physicians or investigators."

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Unclear, although "investigators" are blinded

Incomplete outcome data (attrition bias)
All outcomes

High risk

"Two (6%) patients in the colchicine group and five (16%) in the placebo, who did not return for the first follow‐up visit, were not included in the analysis of data." ITT mentioned but not all randomised participants were analysed; "Patient dropouts were as follows: nine patients (16%) before 3 years, 14 patients (25%) before 5 years, and 33 patients (60%) before 10 years."

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 6 months

Participants

Number randomised: Total 222. Colchicine 112, control 110

Condition: PCI

Cardiovascular risk profile: Secondary prevention

Setting: Outpatient

Country: Not reported

Age mean (SD) in years: Colchicine 63.7 (6.9), control 63.5 (7.2)

Sex (women): Colchicine 37%, control 32%

Inclusion Criteria:

"Eligible patients were diabetic, 40 to 80 years of age, undergoing PCI in a coronary artery with a diameter of at least 2.5 mm with a BMS. Acceptable reasons for not implanting a drug‐eluting stent were: contraindication to long‐term dual antiplatelet treatment, need for triple antithrombotic therapy, planned or high probability of necessary surgery in the following 12 months, or the patient’s expressed wish in the context of the PCI informed consent procedure. Only 1 lesion per patient was included in the study. (If PCI was performed in >1 coronary site in a patient, the site with the greater artery diameter was included.) Diabetes mellitus had to be previously diagnosed by a specialist, with the patient treated with either oral medication or insulin."

Exclusion Criteria:

"Exclusion criteria were left main artery disease (>30% in angiography); PCI performed as primary treatment for ST‐segment elevation myocardial infarction, hepatic impairment (Child‐Pugh class B or C); target vessel segment presenting particular technical challenges for intravascular ultrasound (IVUS) (e.g., marked tortuosity, vessel with steep take‐off angle); severe or end‐stage renal failure (estimated glomerular filtration rate ≤20 ml/min/1.73 m² or requiring dialysis); history of intolerance to colchicine, myopathy, and statin hepatotoxicity or myotoxicity; women with child‐bearing potential; and inability or unwillingness to adhere to standard treatment or to provide consent."

Interventions

Colchicine:

• Dose: 2 x 0.5 mg/d

• Duration: 6 months

Control:

• Placebo

• Duration: 6 months

Outcomes

Primary Outcome of the Study:

• "The main outcome measures were angio‐ISR and IVUS‐ISR."

Outcomes considered in this review:

• Gastrointestinal adverse events, cardiovascular intervention, all‐cause mortality, stroke fatal; from author request: heart failure fatal and non‐fatal, stroke non‐fatal, cardiovascular mortality

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Method of randomisation not specified in publication; author reply: “This is not reported in the paper, but randomization was computer‐based, with the random number sequence being produced by a short script in R language.”

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Not reported in the publication; author reply: “Outcome assessment was completely blinded. It is stated in the published paper that 'Captured IVUS data, identified only by a serial number, were analyzed offline.' That means that assessors of IVUS‐defined restenosis were not in knowledge of the images‐patient correspondence (even if they had been they would not know the treatment allocation of each patient). The same was true for the QCA measurements (for angiographic restenosis).”

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Modified ITT: "All patients who received at least 1 dose of study treatment were included in the analysis"; "Of 222 eligible patients who consented to take part in the study, 26 (12%) were not available for follow‐up catheterization. As a result, 196 (100 in the colchicine and 96 in the placebo group) completed the study procedures and were available for analysis"; according to author reply, all randomised participants were analysed for outcomes pertinent to this review.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 6 months

Participants

Number randomised: Total 279. Colchicine 140, control 139

Condition: Chronic heart failure

Cardiovascular risk profile: Secondary prevention

Setting: Outpatient

Country: Not reported

Age mean (SD) in years: Colchicine 66.9 (5.8), control 66.4 (5.7)

Sex (women): Colchicine 33%, control 33%

Inclusion criteria: "Patients with stable symptomatic heart failure and systolic left ventricular dysfunction (ejection fraction ≤40%) were included."

Exclusion criteria: "Recently hospitalized patients (hospital stay for heart failure in the previous 3 months) were excluded. Other exclusion criteria were New York Heart Association (NYHA) class IV, recent (in the previous 6 months) implantation of a cardiac resynchronization treatment device, active inflammatory/infectious disease or malignancy, known autoimmune diseases, corticosteroid or other immunosuppressive or immunomodulatory therapy, moderate or severe hepatic impairment (Child‐Pugh class B or C), severe renal failure (estimated glomerular filtration rate <30 ml/min/1.73 m²), current participation in another research protocol, and inability or unwillingness to adhere to standard treatment or to provide consent."

Interventions

Colchicine:

• Dose: 0.5 mg/d if body weight < 60 kg. 2 x 0.5 mg/d if body weight ≥ 60 kg

• Duration: 6 months

Control:

• Placebo daily

• Duration: 6 months

Outcomes

Primary outcome of the study:

• "The primary endpoint was the proportion of patients achieving at least one‐grade improvement in New York Heart Association class for heart failure."

Outcomes considered in this review:

• All‐cause mortality, gastrointestinal adverse events

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Not reported specifically enough (sequential numbers); from author: "Randomization was computer‐based. Random numbers were produced by a short script written in R language.”

Allocation concealment (selection bias)

Unclear risk

Method of randomisation not specified

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

All personnel blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT and PP; 3 participants excluded from analysis (1%)

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Open‐label

Longest mean follow‐up period for a review‐relevant outcome: 30 months

Participants

Number randomised: Total 26. Colchicine 14, control 12

Condition: Idiopathic pulmonary fibrosis

Cardiovascular risk profile: Not reported

Setting: Not reported

Country: USA

Age mean (SD) in years: Colchicine 65.9 (12.3), control 69.9 (4.0)

Sex (women): Colchicine 17%, control 29%

Inclusion criteria: "Conforms to clinical plus either high‐resolution computed tomography (HRCT) or histopathologic criteria for the diagnosis of idiopathic UIP; baseline tests performed, including pulmonary function, chest radiograph, serum creatinine, liver function tests, and complete blood count; willing to return for follow‐up examination at 3 month intervals for 1 year; age 18 years or older; written informed consent given."

Exclusion criteria: "Exclusion criteria were as follows: history of allergy, intolerance, or unwillingness to take either study drug; pregnancy, lactation, or women capable of becoming pregnant who were without adequate birth control; history of chronic asthma and/or treated for asthma within the previous year; diabetes treated (including dietary therapy) within the previous year; active tuberculosis treated within the previous year; use of either study drug within the previous 2 months."

Interventions

Colchicine:

• Dose: 0.6 ‐ 1.2 mg/day as tolerated

• Duration: 12 months

Control:

• "The minimum dose of prednisone used was 60 mg/d for 1 mo, tapered to 40 mg/d over the second month, tapered to 40 mg every other day during the third month, with subsequent doses adjusted as clinically indicated"

• Duration: 12 months

Outcomes

Primary outcome of the study:

• "Death, significant deterioration of pulmonary function, intolerance or adverse event due to the study drug requiring cessation of therapy, addition of a second drug for treatment of UIP, and study dropout for any other reason."

Outcomes considered in this review:

• All‐cause mortality

Notes

"Funding was provided by Mayo Institute funds."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Method of randomisation not specified, but was done by biostatistician: "Randomization was accomplished by the Section of Biostatistics at Mayo Rochester." and "Within each stratum defined by the three stratification factors described previously, the randomization was done in blocks of four, ensuring that after every fourth subject was entered in a given stratum the number of subjects in the stratum assigned to prednisone was the same as the number of subjects in the strata assigned to colchicine."

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open study

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Not clear; missing data reported for baseline and various outcomes (e.g. baseline symptoms 7.1% vs 16.7% missing data)

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Not reported

Longest mean follow‐up period for a review‐relevant outcome: 2 years

Participants

Number randomised: Total 22. Colchicine 10, control 12

Condition: Primary biliary cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age mean (SE) in years: Colchicine 57 (3), control 64 (3)

Sex (women): Colchicine 90%, control 83%

Inclusion criteria: "The diagnosis of PBC was made based on the following observations: 1) elevation of alkaline phosphatase (ALP) over the upper limit of normal, 2) presence of antimitochondrial antibody in the serum, 3) compatible histological appearance of liver biopsy specimens, and 4) radiological or ultrasonographic evidence that the bile ducts were patent. Anti‐mitochondrial antibody titers were measured by the immunofluorescence technique. Histological staging of liver biopsy specimens was carried out as previously described."

Exclusion criteria: "None of them had a history of blood transfusion, ethanol addiction, or drug abuse, and none had anti‐HCV antibodies (second‐generation RIA assay), HBs antigen, or anti‐HBc antibody in the serum" and "No patients had taken any medicines known to be hepatotoxic nor had been treated with corticosteroids, immunosuppressive agents, colchicine, penicillamine, or UDCA in the previous 6 months."

Interventions

Colchicine:

• Dose: 1 mg/d

• Plus ursodeoxycholic acid 600 mg/d

• Duration: 2 years

Control:

• Ursodeoxycholic acid 600 mg/d

• Duration: 2 years

Outcomes

Primary outcome of the study:

• "The major pre‐defined parameters for the evaluation of UDCA treatment were serum levels of total bilirubin, ALP, y‐glutamyltranspeptidase (y‐GTP), aspartate aminotransferase (AST), and IgM. To evaluate the effectiveness of UDCA treatment in each patient, indices were calculated as weighted means of changes in these values (expressed as the ratio to baseline values) according to Battezzati et al. with slight modifications as follows"

Outcomes considered in this review:

• Gastrointestinal adverse events, adverse events (any)

Notes

Previous treatment with 600 mg/d ursodeoxycholic acid during 30 months before randomisation in 2 different groups, and continued for 2 years after randomisation. "supported by a grant from the Intractable Liver Diseases Research Committee, the Ministry of Health and Welfare, Japan."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

No blinding, no placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis unclear; missing data unclear

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 2 years

Participants

Number randomised: Total 60. Colchicine 30, control 30

Condition: Primary biliary cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age: 6 participants ≤ 50 years in colchicine group and 6 participants ≤ 50 years in control group (no further information provided in paper)

Sex (women): Colchicine 93%, control 97%

Inclusion criteria: "The criteria for entry into the trial included a clinical history and biochemical profile consistent with primary biliary cirrhosis, a positive test for antimitochondrial antibody, liver‐biopsy results consistent with or diagnostic of primary biliary cirrhosis, and radiologic or ultrasonographic evidence that the bile ducts were patent."

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: 2 years

Control:

• Placebo

• Duration: 2 years

Outcomes

Primary outcome of the study:

• "Each patient remained in the double‐blind phase of the study for 24 months unless clear evidence of progression of the disease was found, at which time treatment was considered to have failed in that patient. Treatment failure was defined as (1) doubling of both serum alkaline phospatase and bilirubin levels on at least two consecutive measurements at two‐month intervals, (2) tripling of either level ‐also at two consecutive two‐months intervals appearance, or (3) the appearance of a serious complications such as hepatic encephalopathy, intractable ascites, hemorrhage from esophageal varices."

Outcomes considered in this review:

• Fatal myocardial infarction, cardiovascular mortality, all‐cause mortality

Notes

Control group received colchicine after 2 years. "Supported by a Research Grant (AM‐28490), a Training Grant (AM‐07024). and a General Research Center Grant (M01‐RR00054) from the National institutes of Health."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not sufficiently specified ("randomization scheme in which the numbers […] tended to be kept equal")

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind until 24 months; placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Low risk

3 of 60 participants (5%) dropped out and were excluded from the analysis; the rest were included in analyses. 2 of them had early disease and did no tolerate medication, 1 had Stage 4 disease.

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 10 years

Participants

Number randomised: 87. Colchicine 43, control 42; (2 never received any drug, allocation not reported)

Condition: Primary biliary cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: USA

Age mean (SD) in years: Colchicine 51 (1.4), control 51 (1.5)

Sex (women): 94%

Inclusion criteria: "15 Patients were included provided they had (1) a medical history and blood test results consistent with chronic cholestatic liver disease; (2) a serum alkaline phosphatase that was at least twice that of the upper limit of normal; (3) a serum bilirubin that was not greater than 10 mg/dL; (4) a liver biopsy performed within 12 months of entry that was consistent with primary biliary cirrhosis, and (5) imaging tests that demonstrated that bile ducts were patent."

Exclusion criteria: "Patients were excluded if they had end‐stage liver disease, which was defined as: (1) a serum bilirubin level greater than 10 mg/dL or a serum albumin level less than 3.0 g/dL on two examinations two months apart; (2) hepatic encephalopathy; (3) hemorrhage from esophageal varices and/or portal gastropathy; (4) refractory ascites; or (5) signs of hypersplenism (i.e. a hematocrit less than 30, white blood cell count less than 2,500, and platelet count less than 100,000). Other reasons for exclusion were history of alcohol abuse, administration of drugs associated with chronic liver disease, contemplation of pregnancy, or any serious medical illness that might in itself cause liver dysfunction or shorten life expectancy."

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: 2 ‐ 10 years

Control:

• Methotrexate 15 mg/week

• Duration: 2 ‐ 10 years

Outcomes

Primary outcome of the study:

• "Initially, the study was designed such that each patient would remain in the double‐blind phase of the study for 6 years or until clear evidence of progression of disease or drug toxicity was detected and the patient was judged a treatment failure. Evidence of progression included: (1) an increase in serum bilirubin of 3 mg/dL or more to a level exceeding 4 mg/dL that was maintained for at least 3 months; (2) a decrease in serum albumin of 0.8 g/dL or more to a level below 3 g/dL that was maintained for at least 3 months; and 3) appearance of a serious complication, such as hepatic encephalopathy, intractable ascites, or hemorrhage from esophageal varices. Patients who developed toxicity attributable to a drug were also classified as treatment failures. Drug toxicity attributable to methotrexate included interstitial pneumonitis and persistent cytopenias that were not due to hypersplenism (determined after patients had undergone bone marrow biopsy). Drug toxicity attributable to colchicine included intractable diarrhea and cytopenias not due to hypersplenism. Patients classified as treatment failures were censored and then referred for liver transplantation if clinically indicated or followed outside of the study."

Outcomes considered in this review:

• All‐cause mortality

Notes

Ursodeoxycholic acid was administered to all participants after 2 years. "Supported in part by National Institutes of Health Center for Research Resources, General Clinical Research Center, grant RR 00054; by GRASP (Gastroenterologic Research in Absorptive and Secretory Processes) Digestive Disease Center grant NIH‐NIDDK P30 DK34928; and by a grant from Lederle Laboratories (Pearl River, New York)."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"randomly assigned, using a computer generated list in blocks of four"

Allocation concealment (selection bias)

Low risk

Active drug and placebo were kept in the hospital pharmacy and dispensed by a research pharmacist who was the only caregiver with access to the randomisation code.

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

"Patients and investigators were blinded"

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

ITT; high rate of withdrawals: 14% in both study groups at 2‐year follow‐up, 51% in colchicine group and 67% in control at 10‐year follow‐up

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 24 months

Participants

Number randomised: Total 28. Colchicine 14, control 14

Condition: Liver fibrosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age: Not reported

Sex (women): Not reported

Inclusion criteria: "Each patient had bilirubin below 1 mg%, prothrombin below 16/12 and pre‐trial histologic evidence of cirrhosis."

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 1 mg/d, 5 d/week

• Duration: 24 months

Control:

• Placebo

• Duration: 24 months

Outcomes

Primary outcome of the study:

• Liver biopsy, histological changes

Outcomes considered in this review:

• All‐cause mortality

Notes

This study was reported as an abstract only.
Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No missing data reported, 2 participants in group B (placebo) died

Selective reporting (reporting bias)

High risk

Abstract only

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 14 years

Participants

Number randomised: Total 100.Colchicine 54, control 46

Condition: Liver fibrosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Mexico

Age mean (SE) in years: Colchicine 49.7 (1.5), control 50.8 (1.7)

Sex (women): Colchicine 55%, control 46%

Inclusion criteria: "They had to have a definitive diagnosis of liver cirrhosis, as established by history, physical examination, and biochemical tests, histologic studies of the liver, or both. Second, they had to be at least 18 years of age."

Exclusion criteria: "Patients were excluded if they had an episode of gastrointestinal bleeding or encephalopathy within two weeks before entry into the trial, if they had a total serum bilirubin level above 171 µmol per liter (10 mg per deciliter) or a serum albumin level below 220 μmol per liter (1.5 g per deciliter), if they had a severe concomitant disease, or if they were unable to attend the clinic regularly for geographic or other reasons."

Interventions

Colchicine:

• Dose: 1 mg/d, 5 d/week

• Duration: up to 14 years, mean 4.7 years

Control:

• Placebo

• Duration: up to 14 years, mean 4.7 years

Outcomes

Primary outcome of the study:

• "Patients' survival and histologic manifestations of cirrhosis"

Outcomes considered in this review:

• Fatal myocardial infarction, all‐cause mortality, cardiovascular mortality, gastrointestinal adverse events, adverse events (any)

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not sufficiently specified ("Randomization was carried out by one of us […]")

Allocation concealment (selection bias)

Low risk

"At no time […] disclose the treatment code for any patients to the attending physicians"; person who conducted randomisation was in another institution

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

ITT; all randomised participants analysed, 19 participants lost to follow‐up (number of participants balanced between groups, but considerably unbalanced median follow‐up: colchicine 42 months vs control 12 months)

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Not reported

Longest mean follow‐up period for a review‐relevant outcome: 5 years

Participants

Number randomised: Total 101. Colchicine 52, control 49

Condition: Primary systemic amyloidosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: USA

Age median (SD) in years: Colchicine 62 (not reported), control 64 (not reported)

Sex (women): Colchicine 43%, control 40%

Inclusion criteria: "All patients had clinical or laboratory evidence of systemic amyloidosis."

Exclusion criteria: "Excluded from the study were patients with secondary, familial, or localized amyloidosis; patients with overt symptomatic multiple myeloma or diarrhea; patients who had received alkylating agents or colchicine; and patients with brittle diabetes, severe hypertension, or an active peptic ulcer that would prevent the use of prednisone as indicated in the protocol."

Interventions

Colchicine:

• Dose: 2 x 0.6 mg at beginning, then increased by 0.6 mg/d each week until abdominal cramps or diarrhoea developed. The use of colchicine was then discontinued and was resumed in the highest dose that did not produce side effects. Median dose was 1.5 mg.

• Duration: median 12 months (range 1 ‐ 56 months)

Control:

• "Dose: melphalan 0.15 mg/kg daily and prednisone 0.8 mg/kg daily for a 7‐day period. Melphalan/prednisone therapy was repeated every 6 weeks. The dose of melphalan was increased by 2 mg daily for each 6‐week course until mid‐cycle leukopenia or thrombocytopenia occurred. If severe leukopenia or thrombocytopenia occurred, the dose of melphalan was reduced accordingly."

• Duration: median 12 months (range 1 ‐ 30 months)

Outcomes

Primary outcome of the study:

• Time of death, or progression of disease

Outcomes considered in this review:

• Heart failure, all‐cause mortality

Notes

"Forty‐nine patients initially received melphalan/prednisone and eight subsequently had colchicine added to their regimen. Fifty‐two patients lnitially received colchicine and 35 subsequently required melphalan/prednisone because of progressive disease." "supported in part by Research Grant CA‐16835 from the National Institutes of Health, Public Health Service, Bethesda, Maryland, and by the Toor Myeloma Research Fund, West Palm Beach, Florida."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Not specified, but authors report that colchicine dosage was weekly increased until side effects occurred, thus no blinding

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis unclear; it seems all randomised participants were analysed

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Unclear

Longest mean follow‐up period for a review‐relevant outcome: 9 years

Participants

Number randomised: Total 148. Colchicine, melphalan and prednisone 71 (MPC), melphalan and prednisone 77 (MP)

Condition: Primary amyloidosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: USA

Age median (SD) in years: Colchicine 65 (not reported), control 63 (not reported)

Sex (women): Not reported

Inclusion criteria: "Amyloidosis was confirmed by biopsy in every patient."

Exclusion criteria: "Patients with secondary, familial, senile, or localized amyloidosis were not admitted to the study. Patients with overt symptomatic multiple myeloma or diarrhea were ineligible, as were patients who had previously received alkylating drugs or colchicine."

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Plus melphalan (0.15 mg per kilogram) and prednisone (0.8 mg per kilogram) daily for 7 d once every 6 weeks

• Duration: Not reported

Control:

• Melphalan (0.15 mg per kilogram) and prednisone (0.8 mg per kilogram) daily for 7 d once every 6 weeks

Outcomes

Primary outcome of the study:

• Survival

Outcomes considered in this review:

• All‐cause mortality

Notes

One‐third treatment group (colchicine without melphalan or prednisone, 72 participants) was not considered for analysis. "Supported in part by grants from the National Institutes of Health (CA62242) and the Quade Amyloidosis Research Fund."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis unclear; missing data unclear (14 participants "were removed from the study" = 6.4%)

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised trial, single‐centre

Blinding: Open‐label

Longest mean follow‐up period for a review‐relevant outcome: 4 years

Participants

Number randomised: Total 66. Colchicine 38, control 27. Exclusion of 1 participant after randomisation, assignment unclear

Condition: Chronic hepatitis B cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Taiwan

Age mean (SD) in years: Cochicine 40 (9), control 40 (13)

Sex (women): Colchicine 13%, control 11%

Inclusion criteria: "Patients with hepatic decompensation, bridging necrosis or an alpha‐fetoprotein level greater than 100 ng/ml during an exacerbation of hepatitis have a high risk of developing cirrhosis"

Exclusion criteria: "Patients under age 25, pregnant, with renal insufficiency (serum creatinine > 2.5mg/ml (normal < 1.0 mg/ml)), a history of idiosyncrasy or who refused the trial after careful explanation were excluded. (...)Those with clinical suspicions of cirrhosis, including spider angioma, palmar erythaema, an albumin <1.5 g m % (normal > 3.5 g m %), and endoscopy documented esophageal varices were also excluded."

Interventions

Colchicine:

• Dose: 1.0 mg/d, 5 d/week

• Duration: 4 years

Control:

• No treatment (no steroids, no antiviral agents)

Outcomes

Primary outcome of the study:

• Developing cirrhosis, episodes of acute exacerbation

Outcomes considered in this review:

• All‐cause mortality

Notes

"supported by grants from the National Science Council of the Republic of China: NSC‐79‐0419‐B18209, NSC‐80‐0412‐B‐182A‐32 and NSC‐82‐0412‐B‐182‐029."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"random table sequence"

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

12% participants were lost, unclear group allocation

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial

Blinding: Not reported

Longest mean follow‐up period for a review‐relevant outcome: Colchicine up to 2 years, control up to 7 years

Participants

Number randomised: Total 54. Colchicine 27, control 27

Condition: Renal amyloidosis

Cardiovascular risk profile: Not reported

Setting: Not reported

Country: Not reported

Age: Not reported

Sex: Not reported

Inclusion criteria: People with renal amyloidosis secondary to rheumatic diseases

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 1 ‐ 2 mg/d

• Duration: up to 2 years

Control:

• Dimethyl sulfoxide, 1 ‐ 2 g/d

• Duration: up to 7 years

Outcomes

Primary outcome of the study:

• "changes in glomerular filtration rate, serum creatinine level and fluid retention, in physician and patient global assessment and tolerability."

Outcomes considered in this review:

• Adverse events (any)

Notes

This study was reported as an abstract only.
Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported specifically enough (sequential numbers)

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

Follow‐up in the control group was 5 years longer

Selective reporting (reporting bias)

High risk

Abstract only

Study characteristics

Methods

Design: Randomised controlled trial, multicentre (13 centres)

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 6 years

Participants

Number randomised: Total 549. Colchicine 274, control 275

Condition: Alcoholic cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: USA

Age mean (SD) in years: Colchicine 55.2 (8.0), control 55.9 (7.6)

Sex (women): Colchicine 2.5%, control 1.4%

Inclusion criteria: "Outpatients were eligible for the study if they had a clinical diagnosis of alcoholic cirrhosis (based on a long history of alcohol use and the exclusion of other causes of liver disease and a modified Pugh 27 score of 7 or greater. Liver biopsy demonstrating cirrhosis was required unless contraindications to biopsy were present (eg. ascites, coagulopathy)."

Exclusion criteria: "Patients were excluded for the following reasons: gastrointestinal bleeding within the prior 28 days requiring transfusion; explicit drug use in the prior 12 months, human immunodeficiency virus infection; cancer in the prior 10 years; serum creatinine greater than 1.5 mg/dL; total white blood cell (WBC) count less than 3500/mL; age 70 years or greater; serious chronic disease interfering with adherence to the protocol follow‐up schedule; no home telephone; and refusal."

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: all participants at least 24 months, some up to 72 months

Control:

• Placebo

• Duration: all participants at least 24 months, some up to 72 months

Outcomes

Primary outcome of the study:

• All‐cause mortality

Outcomes (time points) considered in this review:

• All‐cause mortality, non‐scheduled hospitalisation

Notes

"Supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation scheme based on permuted bocks of random length separately for each study centre

Allocation concealment (selection bias)

Low risk

"Patient enrollment and random assignment to treatment was by telephone call to the data‐coordinating center" and matched placebo

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Neither participants nor study personnel were aware of treatment group assignment

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

"physicians assessing the outcomes were aware of the treatment group assignment until all data analysis was complete."

Incomplete outcome data (attrition bias)
All outcomes

Low risk

ITT, no losses to follow‐up for survival analysis

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 4 years

Participants

Number randomised: Total 74. Colchicine 37, control 37

Condition: Chronic liver disease

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Not reported

Age mean (SD) in years: 53 (13)

Sex (women): 38%

Inclusion criteria: Not reported. Diverse chronic liver diseases

Exclusion criteria: "Exclusion criteria were: age < 20 years or a known hypersensitivity to colchicine. Patients were recruited by referral from general practitioner or by self choice and gave informed consent to be assigned to intervention (colchicine) or control by using random allocation."

Interventions

Colchicine:

• Dose: 1 mg/d

• Duration: 4.4 years

Control:

• Standard treatment (diuretics, beta‐blockers, ursodeoxycholic acid, withdrawal of alcohol)

• Duration: 4.4 years

Outcomes

Primary outcome of the study:

• "To test whether colchicine would be an effective antifibrotic agent for treatment of chronic liver diseases in patients who could not be treated with α‐interferon."

Outcomes (time‐points) considered in this review:

• All‐cause mortality

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified ("using random allocation. Randomization was performed by giving 74 consecutive numbers to all patients coming to our clinic")

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Reported as double‐blind in the abstract, not placebo‐controlled

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

High risk

Analysis unclear; odd mentioning of ITT ("Inclusion criteria were on an intention‐to‐treat basis."); 12 (colchicine 9 and control 3; 16%) participants withdrew due to personal reasons, another 10 (colchicine 3 and control 7; 14%) died

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement.

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Open trial, observer‐blinded endpoint

Longest mean follow‐up period for a review‐relevant outcome: 3 years

Participants

Number randomised: Total 532. Colchicine 282, control 250

Condition: Stable coronary disease

Cardiovascular risk profile: Secondary prevention

Setting: Outpatient

Country: Australia

Age mean (SD) in years: Colchicine 66 (9.6), control 67 (9.2)

Sex (women): Colchicine 11%, control 11%

Inclusion criteria: "Patients were eligible for inclusion if they met each of the following criteria: 1) angiographically proven coronary disease; 2) age 35 to 85 years; 3) clinically stable for at least 6 months; 4) no major competing comorbidities or contraindication to colchicine therapy; 5) considered to be compliant with therapy and attending routine cardiology follow‐up appointments; and 6) willing to provide consent and be randomized into the study. Patients with a history of bypass surgery were only eligible if they had undergone bypass surgery more than 10 years before, had angiographic evidence of graft failure, or had undergone stenting since their bypass surgery."

Exclusion criteria: Not reported

Interventions

Colchicine:

• Dose: 0.5 mg/d

• Duration: 3 years

Control:

• No placebo

• Duration: 3 years

Outcomes

Primary outcome of the study:

• Composite incidence of acute coronary syndrome, out‐of‐hospital cardiac arrest, or noncardioembolic ischaemic stroke

Outcomes considered in this review:

• Fatal and non‐fatal myocardial infarction, cardiovascular mortality, fatal and non‐fatal stroke, all‐cause mortality

Notes

93% of the participants continued with aspirin and/or clopidogrel and 95% continued with statins;

"Patients (N=32) who were intolerant of therapy remained in the study, were followed in the usual manner, and were included in the primary ITT analysis"; Trial "conducted under the auspices of the Heart Research Institute of Western Australia." "There was no external funding source."

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation sequence was computer‐generated

Allocation concealment (selection bias)

Low risk

Concealed from the investigators

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open trial

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

Observer‐blinded outcome trial

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Modified ITT: "All patients who received at least 1 dose of study treatment were included in the analysis"; ≤ 10% missing data per group that were excluded from analysis

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Not reported

Longest mean follow‐up period for a review‐relevant outcome: 12 months

Participants

Number randomised: Total 38. Colchicine 21, control 17

Condition: Liver cirrhosis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Greece

Age median (SD) in years: Colchicine 49 (not reported), control 53 (not reported)

Sex (women): Colchicine 43%, control 35%

Inclusion criteria: Chronic liver disease

Exclusion criteria: "Patients were excluded from the study if they had: age <20 and >70 years, evidence of pregnancy, malignancies or renal, cardiopulmonary, hematological, neurological and collagen diseases, diabetes mellitus, hyper/hypothyroidism or Child C liver function."

Interventions

Colchicine:

• Dose: 1.0 mg/d, 5d/week

• Duration: at least 12 months

Control:

• No antifibrotic treatment

• Duration: at least 12 months

Outcomes

Primary outcome of the study:

• Biochemical parameters; PIIINP, IgA, IgG, IgM, CD4, CD 8, CD 4

Outcomes considered in this review:

• Adverse events (any), gastrointestinal adverse events

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Method of concealment not specified

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Not reported

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

"Liver tissue samples were evaluated by two pathologists (K.P., M.L.) who were blinded to the treatment groups and to response to treatment." However, we did not look into liver outcomes, so the blinding remains unclear

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Analysis unclear, no dropouts reported

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, single‐centre

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 6 months

Participants

Number randomised: Total 197. Colchicine 130, control 67

Condition: Coronary angioplasty

Cardiovascular risk profile: Secondary prevention

Setting: Outpatient

Country: USA

Age mean (SD) in years: Colchicine 59 (not reported), control 62 (not reported)

Sex (women): Colchicine 15%, control 13%

Inclusion criteria: "Elegibility criteria for entry into the trial were 1) successful elective coronary angioplasty; 2) single or multivessel angioplasty; 3) bypass graft angioplasty; 4) angioplasty of previously undiluted (new) and restenosed lesions; 5) angioplasty performed for silent ischemia and stable or unstable angina pectoris"

Exclusion criteria: "Exclusion criteria were 1) direct angioplasty for acute myocardial infarction; 2) unsuccessful coronary angioplasty; 3) premenopausal women; 4) baseline leukopenia; 5) active peptic ulcer disease; 6) active diarrhea; 7) creatinine ≥2.5 mg/dI at baseline; 8) known colchicine intolerance. Successful angioplasty was defined as the reduction of the dilated lesion to ≤50% lumen diameter stenosis without documented acute reocclusion during the hospital stay."

Interventions

Colchicine:

• Dose: 2 x 0.6 mg/d

• Duration: 6 months

Control:

• Placebo

• Duration: 6 months

Outcomes

Primary outcome of the study:

• Restenosis after coronary angioplasty

Outcomes considered in this review:

• All‐cause mortality

Notes

Funding not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method of randomisation not specified

Allocation concealment (selection bias)

Unclear risk

Not reported

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Not reported

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No ITT analysis reported, incomplete outcome measures (angiographic follow‐up rate 74%) mainly due to refusal of catheterisation, reported dropout rate due to adverse events, Colchicine 6.9% vs control 1.5%

Selective reporting (reporting bias)

Unclear risk

Insufficient information to permit judgement

Study characteristics

Methods

Design: Randomised controlled trial, multicentre (7 centres)

Blinding: Double‐blind

Longest mean follow‐up period for a review‐relevant outcome: 3 years

Participants

Number randomised: Total 84. Colchicine 44, control 40

Condition: Primary sclerosing cholangitis

Cardiovascular risk profile: Not reported

Setting: Outpatient

Country: Sweden

Age mean (95% CI) in years: Colchicine 39.5 (36.2 to 42.7), control 43.7 (40.1 to 47.3)

Sex (women): Colchicine 39%, control 28%