Edan 1997.

Methods	Randomised controlled trial. Central randomisation. Intention to treat used, even if not specified in the paper. Double blinded: but in discussion it is specified that blinding of patients is difficult for MX side effects and blinding of the physicians is difficult for the decrease in white cell count. Treatment period: 6 months. No follow‐up. Withdrawn criteria: not pre‐specified. Withdrawals: 5 "due to pronounced clinical worsening" (all in MP group). Lost to follow‐up: no follow‐up.
Participants	42 patients: 21 MX + MetylP; 21 MetylP. 6 Centres. Sex: both. Included: CDMS with a RR (at least 2 exacerbations with sequelae within the previous 12 months) or SP course (progression of 2 points on EDSS scale within the previous 12 months); disease duration < 10 years; age between 18 and 65 years; EDSS ≤ 6.0; at least 1 MRI enhancing lesion during the baseline period (defined as the period between 2 months before the baseline visit and the baseline visit, during which all the patients received 1 g MetylP once a month). Excluded: coexistence of other severe illnesses; pregnancy; immunosuppressant drugs use 3 months before entry; corticotropin or corticosteroids use 1 month before entry. Baseline characteristics: Sex: MX+MetylP 71,4% female; MetylP 52,3 % female. Mean Age (SD): MX+MetylP 31,4 years (8,3); MetylP 32,2 years (8,1). Mean EDSS (SD): MX+MetylP 4.5 (1.6), MetylP 4.6 (1.7). Mean disease duration (SD): MX+MetylP 6,9 years (3,6), MetylP 5,7 years (4). Age at onset of MS (SD): MX+MetylP 25,1 (7); MetylP 26,6 (6,5). Number of relapses 1 year before the inclusion (SD): MX+MetylP 3,1 (1,8); MetylP 2,4 (1,7). Course of disease: MX+MetylP (80,9% RR; 19,1% SP); MetylP (71,4% RR; 28,6% SP).
Interventions	Rx: 20 mg MX + 1 g. MetylP i.v. Placebo: 1 g. MetylP i.v. (Between Month ‐2 and baseline: MetylP 1 g. i.v. for either groups). Administration: once a month. Total dosage: MX 120 mg over 6 months.
Outcomes	Primary outcomes: (1) Proportion of patients who develop new T1 enhancing lesions on serial gadolinium MRI scans during trial. Secondary outcomes: (1) Mean number of new enhanced lesions per month per patient; (2) Mean number of new T2 lesions between baseline and end of trial; (3) Mean EDSS difference between baseline and end of trial; (4) Mean number of exacerbations between baseline and end of trial.
Notes	Definitions: Progression of disability: Confirmed increase of 1.0 EDSS point if baseline EDSS <= 5,5, or of a 0.5 EDSS point if baseline EDSS >= 6.0, between month 0 and the end of the study (measured for two months running at the end of the study). Relapse: occurrence of symptoms of neurological disfunction lasting more than 48 hours and preceded by stability or improvement for at least 30 days.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Not reported.
Allocation concealment (selection bias)	Low risk	"The allocation of the treatment at month 0 was done after inclusion by a central randomisation service by fax." Page 113
Blinding (performance bias and detection bias) For investigator e patients	High risk	"In the present study, although the allocation of treatment was performed using an unbiased randomisation service, neither the patients nor the clinical investigators were blinded during the study. Blinding of patients was not possible in this trial, as obvious side effects of mitoxantrone were experienced in almost all cases. Blinding of the physician was made difficult by the fall in white cell count that always accompanies mitoxantrone treatment. Blind clinical observers might have been appointed, but this could not be done for economic reasons. The clinical efficacy suggested in this study must therefore be regarded with caution as it was acquired unblinded.” (Page 116) Only the two MRI observers were blinded to patients’ clinical status.
Incomplete outcome data (attrition bias) All outcomes	High risk	5 withdrawals "due to pronounced clinical worsening" (all in the methylprednisolone group) were not included in the 6 months follow‐up analysis. Bias is toward a reduced efficacy of the drug, on the reduction of the disability progression since all excluded patients in the control group worsened during the study.
Selective reporting (reporting bias)	Low risk	Protocol not available. Outcomes were reported completely, even if the total number of relapses in the two arms was reported, but not the distribution in patients. Moreover, the two arms were not matched for baseline number of enhancing lesions.
Other bias	High risk	Sustained disability progression confirmed every 2 months. Possibility that part of the benefit reported in the mitoxantrone group came from the addition of methylprednisolone to the treatment regimen. Notes: It's unclear if this study was sponsored.