Score

0‐Normal neurologic examination

1.0‐No disability, minimal signs on one Functional System (FS)*

1.5‐No disability, minimal signs on >1 FS

2.0‐Minimal disability in 1 FS

2.5‐Minimal disability in 2 FS

3.0‐Moderate disability in 1 FS; or mild disability in 3‐4 FS, though fully ambulatory

3.5‐Fully ambulatory but with moderate disability in 3‐4 FS

4.0‐Fully ambulatory without aid, up and about 12hrs./day despite relatively severe disability. Able to walk without aid 500meters

4.5‐Fully ambulatory without aid, up and about much of day, able to work a full day, may otherwise have some limitations of full activity or require minimal assistance. Relatively severe disability. Able to walk without aid 300meters

5.0‐Ambulatory without aid for about 200m. Disability impairs full daily activities

5.5‐Ambulatory for 100m, disability precludes full daily activities

6.0‐Intermittent or unilateral constant assistance required to walk 100m with or without resting

6.5‐Constant bilateral support required to walk 20m. without resting

7.0‐Unable to walk beyond 5m even with aid, essentially restricted to wheelchair, wheels self, transfers alone

7.5‐Unable to take more than a few steps, restricted to wheelchair, any need aid in transfer, wheels self but may require motorized chair for full day's activities

8.0‐Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed much of day, retains self care functions, generally effective use of arms

8.5‐Essentially restricted to bed much of day,some effective use of arms, some self care functions

8.5‐Essentially restricted to bed much of day,some effective use of arms, some self care functions

9.0‐Helpless bed patient, can communicate and eat

9.5‐Unable to communicate effectively or eat/swallow

10.0‐Death

* Functional Systems are eight scales representing different functions of the Central Nervous System (Kurtzke 1961). Each system is rated on a five‐point (three systems) or six‐point (four systems) response scale except 'Other Functions' which is rated dichotomously (0 = none, 1 = any other neurological findings attributed to multiple sclerosis)

Study

Withdrawals

Losses to follow‐up

Total

% of patients

MSCRG (1996)

23 (included in analysis)

129 (premature study termination)

129

43

Myhr (1999)

3

3

6

9

Durelli (1994)

0

0

0

0

Knobler (1993)

1

4

5

38

OWIMS (1999)

8

8

16

8

PRISMS (1998)

20

16

36

10

IFNB MS Group (1993)

unreported

unreported

48

19

Polman (2003)

2

4

6

7

Study

Data in the articles

IFNB MS Study Group (1993)

Abnormal laboratory values: 1) Increased aspartate aminotransferase (AST) = above upper limit of normal; 2) Increased alanine aminotransferase (ALT) = above upper limit of normal; 3) Leukopenia = white blood cells < 2,999 per mm3; 4) Lymphopenia = lymphocytes < 1,499 per mm3; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Clinical side effects = no definition. Neutralizing antibodies against interferon (NAB) = neutralizing titres were expressed relative to the National Institute of Health (NIH) standard, with the limit of detection at 20 neutralizing units per milliliter

Knobler (1993)

Abnormal laboratory values: 1) Increased AST = no definition; 2) Increased ALT = no definition; 3) Leukopenia = no definition; 4) Lymphopenia = lymphocytes < 1,000 per mm3; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Clinical side effects = no definition. NAB = neutralizing titres were expressed relative to the NIH standard, with the limit of detection at 20 neutralizing units per milliliter

Durelli (1994)

Abnormal laboratory values: 1) Increased AST = mild elevation: 2 x normal value and moderate elevation: 3 x normal value; 2) Increased AST and ALT = mild elevation: 2 x normal value and moderate elevation: 3 x normal value; 3) Neutropenia = cell number between 1,000 and 2,000 per mm3; 4) Lymphopenia = no definition; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Depression = tested with the Hamilton Depression Scale; Flu‐like syndrome = contemporary presence of fever, headache, arthralgias and myalgias; Other clinical outcomes = no definition. NAB = neutralizing titres were not defined

The MSCRG (1995)

Abnormal laboratory values: 1) Increased AST; 2) Increased ALT; 3) Leukopenia; 4) Lymphopenia; 5) Decreased haemoglobin values; 6) Thrombocytopenia. The Authors reported "Adverse events and current laboratory data were monitored and recorded according to the Food and Drug Administration (FDA) phase III requirements". Moreover, they reported "FDA, HHS 21 CFR, Chapt. 1, 312.32, part c, 4/1/90". Depression = tested with the Beck Depression Inventory and Functional Assessment: using several scales = The MS Functional Disability Assessment, The Functional Indipendence Measure, The Barthel Index, The Incapacity Status Scale, and The Brief Symptom Inventory. NAB = neutralizing titres were expressed relative to the NIH standard, with the limit of detection at 20 neutralizing units per milliliter

The PRISMS (1998)

Abnormal laboratory values: 1) Increased AST = no definition; 2) Increased ALT = no definition; 3) Leukopenia = no definition; 4) Lymphopenia = lymphocytes < 1,000 per mm3; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Depression = tested with the Beck Depression Inventory, The Centre for Epidemiologic Studies' Depression Mood Scale, and the General Health Questionnaire. Other clinical outcomes = no definition. NAB = neutralizing titres were expressed relative to the NIH standard, with the limit of detection at 20 neutralizing units per milliliter. The Authors used the four grades of the World Health Organization about toxic effects

Myhr (1999)

Abnormal laboratory values: 1) Increased AST = no definition; 2) Increased ALT = no definition; 3) Leukopenia = no definition; 4) Lymphopenia = no definition; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Clinical side effects = no definition. NAB = the Authors reported that "they were analyzed by F. Hoffmann‐La Roche according to standardized protocols"

The OWIMS (1999)

Abnormal laboratory values: 1) Increased AST = no definition; 2) Increased ALT = no definition; 3) Leukopenia = no definition; 4) Lymphopenia = no definition; 5) Decreased haemoglobin values = no definition; 6) Thrombocytopenia = no definition. Clinical side effects = no definition. NAB: no definition

Study

MRI

Year(s) of follow‐up

Control group

Treated group

IFNB (1993)

Mean [standard error (SE)] and median annual % change of total lesion area.

1 and 2 years from randomisation

At 1st year: mean 110.6; median 6.7 (SE 96.3). At 2nd year: mean 43.8; median 11.9 (SE 14.0). N. of patients 72

At 1st year: mean 5.4; median ‐4.9 (5.1). Number of patients 77. At 2nd year: mean 9.4; median ‐ 5.6 (SE 8.5). Number of patients 73

Knobler (1993)

No MRI outcome

Durelli (1994)

Number of patients who had active lesions. Total number of enlarging lesions and new lesions in the two groups. Mean (SE)number of active lesions per patient

6 months from randomisation.

Number of patients with active scans: 6 of 8 patients (enlarging lesions: 12 of 6; new lesions: 15 of 6). Mean number of active lesions per patient 3.37 (1.03)

Number with active scans: 1 of 12 patients (enlarging lesions: 1; new lesions: 0). Mean number of active lesions per patient 0.08 (0.08)

MSCRG (1995)

Number of patients who had active lesions. Mean (SE) number and volume of active lesions per patient. Median % change of total lesion volume (mm3).

1 and 2 years from randomisation

At 1st year: number of patients with active scans: 52 of 123 patients. Mean number of active lesions per patient 1.59 (0.31). Mean volume per patient 96.5 (21.2) mm3. Median change ‐3.3%. At 2nd year: number of patients with active scans: 35 of 82 patients. Mean number of active lesions per patient 1.65 (0.48). Mean volume per patient 122.4 (48.5) mm3. Median change ‐6.5%.

At 1st year: number of patients with active scans: 40 of 134 patients. Mean number of active lesions per patient 1.04 (0.28). Mean volume per patient 70.0 (24.9) mm3. Median change ‐13.1%. At 2nd year: number of patients with active scans: 24 of 83 patients. Mean number of active lesions per patient 0.80 (0.22). Mean volume per patient 74.1 (38.3) mm3. Median change ‐13.2%.

PRISMS (1998)

Median % change of total lesion burden (area or volume?). Difference (%) of the number of active lesions between treated and control groups.

2 years from randomisation

Median 10.9 (N. 187 patients).

Median ‐3.8 (N. 184). Difference of active lesions ‐ 78% than placebo group

Myhr (1999)

Mean (no SE) and median of new active lesions per patient. Number of patients with new active lesions. Mean (no SE) and median of total number of lesions per patient (number of T1‐weighted active lesions plus unactive T2‐weighted lesions)

6 months and 1 year from randomisation

At 6th month: mean 7.3 and median 2.5 new active lesions per patient ; 24 of 32 patients with new active lesions; mean 1.6 and median 1.0 total number of lesions per patient. At 1st year: mean 1.6 and median 0.0 total number of lesions per patient. (N. 32 patients)

At 6th month: mean 1.4 and median 0.0 new active lesions per patient; 9 of 28 patients with new active lesions; mean 0.3 and median 0.0 total number of lesions per patient. At 1st year: mean 0.7 and median 0.0 total number of lesions per patient (N. 28 patients)

OWIMS (1999)

Mean [standard deviation (SD)] and median number of active lesions (measured by different MRI techniques). The proportion of scans showing active lesions. Mean (no SE) and median % change of total lesion area.

24 and 48 weeks from randomisation

At 24th week: mean and median number of combined unique active lesions 1.7 (2.7) and 0.7 per patient; median number of proton density/T2 unique active lesions 0.3 per patient; median number of T1‐Gadolinium unique active lesions 0.7 per patient; 50% of scans with combined active lesions. At 48th week: mean 15.5 % and median 5.9% change of total lesion area (N. of patients at 24th and 48th week = unknown).

At 24th week: mean and median number of combined unique active lesions 0.8 (1.1) and 0.3 per patient; median number of proton density/T2 unique active lesions 0.2 per patient; median number of T1‐Gadolinium unique active lesions 0.3 per patient; 33% of scans with combined active lesions. At 48th week: mean 0.8% and median ‐1.4% change of total lesion area (N. of patients at 24th and 48th week = unknown).

Polman (2003)

Cumulative number of newly active lesions over 6 months.

6 months from randomisation.

Median and quartiles (Q1; Q3): 4.0 (2.7; 10.0)

Median and quartiles (Q1; Q3): 9.0 (1.0; 16.0)

Outcomes

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Patients who continued to experience exacerbations during the first year

37 (22:333)

19 (11:177)

12 (7:111)

9 (6:83)

7 (4:67)

6 (4:56)

5 (3:48)

5 (3:42)

4 (2:37)

Patients who continued to experience exacerbations during the first 2 years

Patients who continued to experience exacerbations during the first 2 yrs (base case)
Patients who continued to experience exacerbations during the first 2 yrs (base case)

50 (37:83)

25 (19:42)

17 (12:28)

13 (9:21)

10 (7:17)

8 (6:14)

7 (5:12)

6 (5:10)

6 (4:9)

Patients who progressed during the first 2 years

32 (22:77)

16 (11:38)

11 (7:26)

8 (6:19)

6 (4:15)

5 (4:13)

5 (3:11)

4 (3:10)

4 (2:9)