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Comparison 1 interferon versus placebo: primary outcomes, Outcome 1 Patients with at least one exacerbation until 1 yr.
Figures and Tables -
Analysis 1.1

Comparison 1 interferon versus placebo: primary outcomes, Outcome 1 Patients with at least one exacerbation until 1 yr.

Comparison 1 interferon versus placebo: primary outcomes, Outcome 2 Patients with at least one exacerbation until 1 year: subgroup analysis.
Figures and Tables -
Analysis 1.2

Comparison 1 interferon versus placebo: primary outcomes, Outcome 2 Patients with at least one exacerbation until 1 year: subgroup analysis.

Comparison 1 interferon versus placebo: primary outcomes, Outcome 3 Patients with at least one exacerbation at 2 yrs.
Figures and Tables -
Analysis 1.3

Comparison 1 interferon versus placebo: primary outcomes, Outcome 3 Patients with at least one exacerbation at 2 yrs.

Comparison 1 interferon versus placebo: primary outcomes, Outcome 4 Patients with at least one exacerbation at 2 yrs (best scenario).
Figures and Tables -
Analysis 1.4

Comparison 1 interferon versus placebo: primary outcomes, Outcome 4 Patients with at least one exacerbation at 2 yrs (best scenario).

Comparison 1 interferon versus placebo: primary outcomes, Outcome 5 Patients with at least one exacerbation at 2 yrs (worst scenario).
Figures and Tables -
Analysis 1.5

Comparison 1 interferon versus placebo: primary outcomes, Outcome 5 Patients with at least one exacerbation at 2 yrs (worst scenario).

Comparison 1 interferon versus placebo: primary outcomes, Outcome 6 Patients who progressed at 2 yrs.
Figures and Tables -
Analysis 1.6

Comparison 1 interferon versus placebo: primary outcomes, Outcome 6 Patients who progressed at 2 yrs.

Comparison 1 interferon versus placebo: primary outcomes, Outcome 7 Patients who progressed at 2 yrs (best scenario).
Figures and Tables -
Analysis 1.7

Comparison 1 interferon versus placebo: primary outcomes, Outcome 7 Patients who progressed at 2 yrs (best scenario).

Comparison 1 interferon versus placebo: primary outcomes, Outcome 8 Patients who progressed at 2 yrs (worst scenario).
Figures and Tables -
Analysis 1.8

Comparison 1 interferon versus placebo: primary outcomes, Outcome 8 Patients who progressed at 2 yrs (worst scenario).

Comparison 1 interferon versus placebo: primary outcomes, Outcome 9 Mean change in disability (EDSS) at 2 yrs.
Figures and Tables -
Analysis 1.9

Comparison 1 interferon versus placebo: primary outcomes, Outcome 9 Mean change in disability (EDSS) at 2 yrs.

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 1 Patients who required steroid treatment until first year.
Figures and Tables -
Analysis 2.1

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 1 Patients who required steroid treatment until first year.

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 2 Patients who required steroid treatment until 2 years.
Figures and Tables -
Analysis 2.2

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 2 Patients who required steroid treatment until 2 years.

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 3 Patients with at least one hospital admission until 2 years.
Figures and Tables -
Analysis 2.3

Comparison 2 Interferon versus placebo: secondary outcomes, Outcome 3 Patients with at least one hospital admission until 2 years.

Comparison 3 interferon versus placebo: adverse events, Outcome 1 Patients who had clinical adverse events during treatment.
Figures and Tables -
Analysis 3.1

Comparison 3 interferon versus placebo: adverse events, Outcome 1 Patients who had clinical adverse events during treatment.

Comparison 3 interferon versus placebo: adverse events, Outcome 2 Patients who had abnormal laboratory values during treatment.
Figures and Tables -
Analysis 3.2

Comparison 3 interferon versus placebo: adverse events, Outcome 2 Patients who had abnormal laboratory values during treatment.

Table 1. Kurtzke Expanded Disability Status Scale (EDSS)

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)

Figures and Tables -
Table 1. Kurtzke Expanded Disability Status Scale (EDSS)
Table 2. Withdrawals and losses to follow‐up in the included studies

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

Figures and Tables -
Table 2. Withdrawals and losses to follow‐up in the included studies
Table 3. Side effects or adverse events: definitions as reported in the original articles

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

Figures and Tables -
Table 3. Side effects or adverse events: definitions as reported in the original articles
Table 4. Magnetic Resonance Imaging (MRI) as reported in the original articles

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)

Figures and Tables -
Table 4. Magnetic Resonance Imaging (MRI) as reported in the original articles
Table 5. Number (95% CI) needed to treat according to different values of patient baselin

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)

Figures and Tables -
Table 5. Number (95% CI) needed to treat according to different values of patient baselin
Comparison 1. interferon versus placebo: primary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Patients with at least one exacerbation until 1 yr Show forest plot

5

667

Risk Ratio (M‐H, Random, 95% CI)

0.73 [0.55, 0.97]

2 Patients with at least one exacerbation until 1 year: subgroup analysis Show forest plot

5

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 duration of treatment: 6 months

3

283

Risk Ratio (M‐H, Random, 95% CI)

0.65 [0.33, 1.29]

2.2 duration of treatment: 12 months

2

384

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.14, 1.92]

3 Patients with at least one exacerbation at 2 yrs Show forest plot

3

919

Risk Ratio (M‐H, Fixed, 95% CI)

0.80 [0.73, 0.88]

4 Patients with at least one exacerbation at 2 yrs (best scenario) Show forest plot

3

919

Risk Ratio (M‐H, Random, 95% CI)

0.62 [0.44, 0.87]

5 Patients with at least one exacerbation at 2 yrs (worst scenario) Show forest plot

3

919

Risk Ratio (M‐H, Random, 95% CI)

1.11 [0.73, 1.68]

6 Patients who progressed at 2 yrs Show forest plot

3

919

Risk Ratio (M‐H, Fixed, 95% CI)

0.69 [0.55, 0.87]

7 Patients who progressed at 2 yrs (best scenario) Show forest plot

3

919

Risk Ratio (M‐H, Fixed, 95% CI)

0.43 [0.35, 0.53]

8 Patients who progressed at 2 yrs (worst scenario) Show forest plot

3

919

Risk Ratio (M‐H, Random, 95% CI)

1.31 [0.60, 2.89]

9 Mean change in disability (EDSS) at 2 yrs Show forest plot

2

618

Mean Difference (IV, Fixed, 95% CI)

‐0.25 [‐0.46, ‐0.05]

Figures and Tables -
Comparison 1. interferon versus placebo: primary outcomes
Comparison 2. Interferon versus placebo: secondary outcomes

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Patients who required steroid treatment until first year Show forest plot

2

85

Risk Ratio (M‐H, Random, 95% CI)

0.52 [0.04, 7.31]

2 Patients who required steroid treatment until 2 years Show forest plot

1

371

Risk Ratio (M‐H, Fixed, 95% CI)

0.70 [0.56, 0.87]

3 Patients with at least one hospital admission until 2 years Show forest plot

2

391

Risk Ratio (M‐H, Random, 95% CI)

0.44 [0.08, 2.36]

Figures and Tables -
Comparison 2. Interferon versus placebo: secondary outcomes
Comparison 3. interferon versus placebo: adverse events

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Patients who had clinical adverse events during treatment Show forest plot

6

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Flu‐like symptoms

4

1117

Risk Ratio (M‐H, Random, 95% CI)

1.70 [1.23, 2.37]

1.2 Fever

6

1199

Risk Ratio (M‐H, Random, 95% CI)

1.92 [1.52, 2.43]

1.3 Myalgias/arthralgias

6

1199

Risk Ratio (M‐H, Random, 95% CI)

1.90 [1.50, 2.42]

1.4 Fatigue

5

952

Risk Ratio (M‐H, Random, 95% CI)

1.37 [1.01, 1.88]

1.5 Nausea and vomiting

2

363

Risk Ratio (M‐H, Random, 95% CI)

2.00 [0.75, 5.31]

1.6 Headache

5

952

Risk Ratio (M‐H, Random, 95% CI)

1.17 [1.03, 1.33]

1.7 Injection site‐reactions by subcutaneous route

4

878

Risk Ratio (M‐H, Random, 95% CI)

5.57 [2.33, 13.29]

1.8 Hair loss

2

82

Risk Ratio (M‐H, Random, 95% CI)

9.32 [1.84, 47.23]

1.9 Major psichic disorders

6

1199

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.75, 1.24]

1.10 Committed or attempted suicide

3

919

Risk Ratio (M‐H, Random, 95% CI)

1.98 [0.41, 9.56]

2 Patients who had abnormal laboratory values during treatment Show forest plot

5

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

2.1 Decreased hemoglobin values

3

383

Risk Ratio (M‐H, Fixed, 95% CI)

2.84 [0.69, 11.59]

2.2 Leukopenia

5

1004

Risk Ratio (M‐H, Fixed, 95% CI)

6.47 [2.43, 17.20]

2.3 Lymphopenia

2

618

Risk Ratio (M‐H, Fixed, 95% CI)

1.90 [1.39, 2.60]

2.4 Thrombocytopenia

3

383

Risk Ratio (M‐H, Fixed, 95% CI)

7.47 [0.98, 57.15]

2.5 Increased aspartate aminotransferase

3

919

Risk Ratio (M‐H, Fixed, 95% CI)

2.83 [1.14, 7.06]

2.6 Increased alanine aminotransferase

4

981

Risk Ratio (M‐H, Fixed, 95% CI)

3.57 [1.98, 6.43]

Figures and Tables -
Comparison 3. interferon versus placebo: adverse events