Ellison 1989

Methods	Allocation: randomised (3 arms) ‐ blocks of 4 patients. Allocation masked: patient sequence was the order of presenting the initial prescription to the pharmacy. Blindness: double. Design: parallel group. Duration: 3 years treatment/follow‐up. Intention to treat analysis: performed.
Participants	MS patients in progressive phase N=65 (31 azathioprine and placebo; 34 placebo). N= 54 (83%) included in analysis (26 azathioprine and placebo; 28 placebo). Sex: 32 females, 22 males. Age at onset: mean 31 years (azathioprine); mean 33 years (placebo). Disease duration: mean 16.7 years (azathioprine); mean 12.6 years (placebo). DSS: mean 5.6 (1.3) (azathioprine); mean 5.5 (1.0) (placebo). Exclusion criteria: pregnancy or pregnancy planned within the next 3 years; men wishing to father offpring during the next 3 years. Infections not under treatment. Pressure ulcers. Active coccidiomycosis, past or present neiplastic diseases, diseases that compromise neurological assessment ( deformimg arthritis, major amputations, psycoses) Cytotoxic therapy within the preceding 6 months, steroids within the preceding 3 months, relapses within the 3 months before. USA 1 centre
Interventions	1. Azathioprine started at 2.2 mg/kg/day (to the nearest 25 mg) up to above 4.4 mg/kg/day until the white blood cell count was mantained between 3000 to 4000 or adverse effects were encountered . Placebo i.v. preparation was added. 2. Placebo
Outcomes	Mean difference DSS score at 3 years (ending minus baseline). Number of patients who worsened defined as a change in DSS over 3 years Number of relapses for patient at 1, 2 and 3 years. Frequency of adverse events.
Notes	13 (19%) people were lost to 3 years follow‐up (7 azathioprine, 6 placebo); reasons ‐ 3 persons (1 azathioprine, 2 placebo) died by drowing, suicide, and ruptured abdominal aneurysm respectively ; 7 persons dropped out (3 azathioprine, 4 placebo); 3 persons (azathioprine) withdrew for causes unrelated to MS. Drop‐outs/withdrawals: 25 (13 azathioprine, 12 placebo). People who dropped‐out were included in analysis. Blindness: 47% of patients, 37% of neurologists (who performed neurological examinations and recorded the results at 3‐months intervals and when a relapse was suspected), and 90% of monitoring neurologists (who assessed patients for non‐MS problems including adverse effects and provided standard care) guessed the assigned treatment. Supported by USPHS grants and University grants. Wellcome Company supplied AZA and appropriate placebo; Upjohn Company provided methylprednisolone and placebo.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment?	Low risk	A ‐ Adequate