Madejon 1994

Methods	Sample size: calculated. Generation of allocation schedule: by computer. Allocation concealment: not used. Intention‐to‐treat analysis: yes. Interim analyses: no.
Participants	Patients with chronic hepatitis D (n =32) from Spain. Inclusion criteria: positive HDV antibody, presence of serum HDV RNA documented in the last six months, elevated ALT for six months, histological evidence of chronic hepatitis or cirrhosis. Six patients (18%) had anti‐HCV and 2 (6%) anti‐HIV antibodies. Exclusion criteria were: antiviral or immunosuppressive therapy within one year, decompensated cirrhosis (Child B or C), concomitant severe illness, proven active drug abuse, prothrombin time less than 50% of normal valve, platelets < 75,000/cmm.
Interventions	Experimental 1: interferon alfa‐2a 18 million units (MU) thrice a week for 6 months, 9 MU thrice a week for 1 month, 6 MU t.i.w. for 1 month, 3 MU thrice a week for 4 months (n =16) . Experimental 2: interferon alfa‐2a 3 million units daily for 3 months then 1.5 MU daily for 9 months (n =16). Duration : 1 year. Follow‐up: 18 months post treatment. Liver biopsy at enrolment and second month of post‐treatment follow‐up.
Outcomes	Loss of HDV RNA. Normalisation of ALT. Improvement in liver histology.
Notes	Drop outs/withdrawals = 7; 3 from low dose and 4 from high dose. Reasons were: return to active drug abuse (n =2), neuropsychiatric disorder (n =2), thrombocytopoenia (n =2), and voluntary withdrawal (n =1). Intention to treat analysis was done throughout. Histological improvement was less than 2 points. No end of treatment biopsy available. Liver biopsy was done after 18 months posttreatment follow‐up period.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote " The patients were randomly allocated into two groups by means of a computer random‐sample generation."
Allocation concealment (selection bias)	Unclear risk	Not mentioned.
Blinding (performance bias and detection bias) All outcomes	High risk	Unblinded trial design.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote "All but seven (three from group I and four from group II) finished the treatment period... All dropout patients had persistently increased ALT values and HDV RNA positivity when they left the study." Missing outcomes data balanced across groups.
Selective reporting (reporting bias)	Low risk	Outcome measures adequately reported.