Methods

The randomisation sequence was generated for each centre by the trial statistician and the packs of trial tablets were issued to individual pharmacies labelled with a code. The aza and placebo tablets were identical.
Blindness: double.
Design: parallel group.
Duration: 3 years treatment/follow‐up.
Intention to treat analysis: performed.

Participants

RRMS N= 236 (67%); SPMS N= 67 (18%) ; PPMS N= 51 (15%) .
N= 354 (azathioprine 174; placebo 180).
N= 332 followed patients at 3 years (azathioprine 161; placebo 171).
Sex: 207 females, 147 males.
Age: mean 39 years (azathioprine); mean 38 years (placebo).
Disease duration: mean 9 years.
EDSS: mean 3.7(1.5) (azathioprine); mean 3.7 (1.6) (placebo).
Exclusion criteria: patients on other immunomodulatory drugs or hyperbaric oxygen treatment, or patients with concomitant systemic disease and mental deficit.
UK and Holland. 20 Centers.

Interventions

1. Azathioprine 2.5 mg/kg/day (to the nearest 25 mg). Control: placebo.
2. PLacebo

Outcomes

Mean change in EDSS score, Kurtzke functional scales and ambulation Index at 1, 2 and 3 years.
Mean (SE) number of relapse per patient per year at 1, 2 and 3 years.

Notes

23 (6.5%) people were lost to 3 years follow‐up (14 azathioprine, 9 placebo); reasons ‐ 3 persons (azathioprine) died of a cause unrelated to MS; 16 persons (11 azathioprine, 5 placebo) declined to attend; 2 persons (placebo) emigrated; reasons not reported for 2 persons (placebo).
Drop‐outs/withdrawals: 1st year 47 (35 azathioprine, 12 placebo); 2nd year 16 (6 azathioprine, 10 placebo); 3rd year 11 (5 azathioprine, 6 placebo).
People who dropped‐out were included in analysis.
Supported by the Medical Research Council. Wellcome Research laboratories supplied AZA and placebo tablets.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate

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

Methods

Allocation: randomised‐ no further information.
Blindness: single.
Design: parallel group.
Intention to treat not done.
Duration: 18 months treatment/follow‐up.

Participants

RRMS N= 74 (40%); SPMS N= 111 (60%).
N= 185 (azathioprine 93; placebo 92).
N= 135 (73%) included in analysis (azathioprine 69; placebo 66).
Baseline characteristics available for 135 patients:
Sex: 88 females, 47 males.
Age at onset: mean 26 years (RRMS); mean 30 years (SPMS).
Disease duration: mean 5 years (RRMS); mean 7 years (SPMS).
EDSS: mean 2.1 (range 1‐5) (RRMS); mean 3.7 (range 1‐7) (SPMS).
Exclusion criteria: disease duration lower than 1 year and concomitant diseases controindicating immunosuppression.

Interventions

1. Azathioprine 2.5 mg/kg/daily.
2. No treatment.

Outcomes

Mean number of relapses in the two groups at 18 months.
Patients defined worsened in relation to the difference between final and initial Kurtzke EDSS score.

Notes

50 (27%) people were lost to 18 monhs follow‐up (24 azathioprine, 26 placebo); reasons ‐ 13 persons (azathioprine) had adverse effects and 1 person (unclear about the treatment status) had surgical operation. No other data available.
People who dropped‐out were not included in analysis.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear

Methods

Allocation: randomised; random number tables used ‐ no further information.
Blindness: double.
Design: parallel group.
Intention to treat not done.
Duration: 2 years treatment/follow‐up.

Participants

Diagnosis: RRMS N= 59 (100%)
N= 54 (azathioprine 29; placebo 25).
N= 52 (96%) included in analysis (azathioprine 27; placebo 25).
Sex: 40 females,19 males.
Age at onset: mean 30 years.
Disease duration: mean 6 years.
EDSS: mean 3.2 (1.2) (azathioprine); mean 3.7 (1.6) (placebo).
Exclusion criteria: immunosuppressive therapy for 1 year prior to the study, total lymphoid irradiation at any time. Pregnancy, unwilling to practice birth control, systemic ilnesses, unable to give informed consent.
USA 1 centre.

Interventions

1. Azathioprine 3 mg/kg/daily
2. Placebo

Outcomes

Primary outcomes: mean relapse rate at 1 and 2 years.
Mean change in EDSS score at 2 years.
Secondary outcomes: time to first relapse, percentage of patients with at least one relapse at 1, 2 years, time to EDSS deterioration sustained for > 2 months, change in mean ambulation index score, time to deterioration of at least 1 point on ambulation index score > 2 months, time to deterioration of 20% or more in baseline nine‐hole‐peg test (9HPT) or in box‐and‐block test (BBT) for > 2 months, percentage of groups experiencing such deterioration in 9HPT or BBT, patient's subjective assessment of treatment, examining physician's assessment.
* EDSS deterioration: worseniing of 0.5 or more if EDSS at entry > 5; of 1 or more if baseline EDSS < 5.5.

Notes

7 (12%) people were lost to 2 years follow‐up (3 azathioprine, 4 placebo); reasons ‐ 4 persons (1 azathioprine, 3 placebo) denied entry; 1 person (placebo) developed severe relapse before entry; 1 person (azathioprine) refused follow‐up; and 1 person (azathioprine) was a protocol breach.
People who did not enter the study or who dropped‐out were not included in analysis.
Blinding: at the end of follow‐up, 56% of patients and 85% of the psysicians did not guess therapy.
Supported by National Multiple Sclerosis Society. Drugs supplied by Wellcome Company.
Recruitment period: 1983 to 1989.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Unclear risk

B ‐ Unclear

Methods

Allocation: randomised‐ central randomisation, provided by Wellcome Italia, with random code numbers. Masking of allocation unclear.
Blindness: double.
Design: parallel group.
Intention to treat: performed.
Duration: 3 years treatment/follow‐up.

Participants

Diagnosis: RRMS N=19 (47.5%); SPMS N=10 (25%); PPMS N=11 (27.5%).
N= 40 (azathioprine 19; placebo 21).
N= 33 followed patients at 3 years (azahioprine 14; placebo 19). All included in survival analysis.
Sex: not reported
Mean age: at onset: azathioprine 29.5 years (6.5 SD); Placebo 29.6 (8.6 SD).
Mean disease duration: azathioprine 92.2 months ( 50.4 SD); placebo 87.8 (44.9 SD).
EDSS: mean 3.4 ( 1.7) (azathioprine); 3.1 ( 1.1) (placebo) .
Relapse rate: azathioprine 0.69 (0.77 SD); placebo 0.5 ( 0.58 SD).
Exclusion criteria: immunoprogressive treatment in the year preceding the study.
Italy 1 Centre.

Interventions

1. Azahioprine 2 mg/kg/die (no more than 2.5 mg/kg/die).
2. Placebo (lactose) in identical form ( 50 mg tablets).

Outcomes

Annual relapse rate.
Number of patients experiencing at least one relapse at 1, 2, and 3 years.
Mean change in EDSS at 1 and 2 and 3 years.
Number of patient remaining stable (no deterioration by 1 EDSS point or more if EDSS at entry was 5 or less or by 0.5 point or more if initial EDSS was >5).

Notes

7 (17.5%) people were lost to 3 years follow‐up (5 azathioprine, 2 placebo); reasons ‐ not reported.
Drop‐outs/withdrawals: 21 people (12 azathioprine, 9 placebo); reasons ‐ 5 persons (4 azathioprine, 1 placebo) had adverse events; 13 persons (7 azathioprine, 6 placebo) required the double‐blind regimen to be interruped but reasons were not reported; 2 persons(1 azahioprine, 1 placebo) had change of residence; and 1 person (placebo) due to wife's pregnancy.
People who dropped‐out were included in analysis.
AZA and placebo tablets in identical form were supplied by Wellcome Company.

Risk of bias

Bias

Authors' judgement

Support for judgement

Allocation concealment?

Low risk

A ‐ Adequate