Combes 1995.

Methods	Multicenter double‐blind, placebo controlled randomised clinical trial with parallel group design (two interventions groups). Trial duration 2 years. Follow‐up: 2 patients from the ursodeoxycholic acid and 3 patients from the placebo groups withdrew from the trial during the placebo controlled period (0 to 2 year).
Participants	Country: USA Number of patients randomised: 151, from six centres, mean age 49.2 years (89% females), histological stage I‐II 32.5%, III‐IV 67.5%. Inclusion criteria: ‐ cholestatic liver disease for at least six months; ‐ serum alkaline phosphatase > 1.5 times upper normal limit; ‐ positive AMA; ‐ no biliary obstruction; ‐ liver biopsy compatible with PBC. Exclusion criteria: ‐ PBC treatment during the last three months; ‐ recurrent bleeds from varices; ‐ spontaneous encephalopathy; ‐ diuretic‐resistant ascites; ‐ serum bilirubin ≥ 20 mg/dl; ‐ pregnancy; ‐ age < 19 years; ‐ other cause of liver disease.
Interventions	Patients were randomly assigned to receive: Intervention group 1: ursodeoxycholic acid 10 to 12 mg/kg/day once at bedtime (Ciba‐Geigy Corporation), n = 77; Intervention group 2: placebo (2 years) and open‐label ursodeoxycholic acid (4 years), n = 74.
Outcomes	Mortality free of liver transplantation. Liver transplantation. Symptoms. Liver biochemistry. Liver histology. ursodeoxycholic acid enrichment in bile.
Notes	Three patients randomised to receive placebo had high bile‐ursodeoxycholic acid concentrations, suggesting ursodeoxycholic acid intake. All patients were offered open label ursodeoxycholic acid following completion of the first 2‐year of the trial.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	The trial is described as randomised, but the method of sequence generation was not specified.
Allocation concealment (selection bias)	Unclear risk	The trial was described as randomised but the method used to conceal the allocation was not described, so that intervention allocations may have been foreseen in advance of, or during enrolment.
Blinding (performance bias and detection bias) All outcomes	Low risk	Described as double‐blind, placebo described as 'comparable‐appearing' and it was reported that 'coded medications were provided'. All investigators remained blinded throughout the trial to the treatment allocation for each patient.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)	Low risk	Pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
Other bias	Low risk	The trial appears to be free of information that could put it at risk of bias.