Interferon beta for secondary progressive multiple sclerosis

Loredana La Mantia; Laura Vacchi; Carlo Di Pietrantonj; George Ebers; Marco Rovaris; Sten Fredrikson; Graziella Filippini

doi:10.1002/14651858.CD005181.pub3

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Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Analysis 1.1

Comparison 1 Disability progression, Outcome 1 Sustained (6 months) EDSS increase after 3 years.

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Analysis 1.2

Comparison 1 Disability progression, Outcome 2 Sustained (3 or 6 months) EDSS increase at 3 years in patients with or without pre‐study relapses.

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Analysis 1.3

Comparison 1 Disability progression, Outcome 3 Sustained (3 months) EDSS increase.

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Analysis 1.4

Comparison 1 Disability progression, Outcome 4 Sustained (3 or 6 months') EDSS increase according to pre‐study clinical characteristics of patients.

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Analysis 2.1

Comparison 2 Adverse Events, Outcome 1 Total number of patients with Serious AEs.

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Analysis 2.2

Comparison 2 Adverse Events, Outcome 2 Patients who had discontinuated for AEs (including SAEs) *.

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Analysis 2.3

Comparison 2 Adverse Events, Outcome 3 Deaths.

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Analysis 2.4

Comparison 2 Adverse Events, Outcome 4 Patients who done or attempted suicide.

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Analysis 2.5

Comparison 2 Adverse Events, Outcome 5 Allergy/Rash (number of events).

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Analysis 2.6

Comparison 2 Adverse Events, Outcome 6 Cutaneous necrosis *.

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Analysis 2.7

Comparison 2 Adverse Events, Outcome 7 Injection site reactions *.

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Analysis 2.8

Comparison 2 Adverse Events, Outcome 8 Patients with psychiatric disorders.

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Analysis 2.9

Comparison 2 Adverse Events, Outcome 9 Patients with headache.

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Analysis 2.10

Comparison 2 Adverse Events, Outcome 10 Patients with influenza like syndrome *.

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Analysis 2.11

Comparison 2 Adverse Events, Outcome 11 Patients with myalgia.

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Analysis 2.12

Comparison 2 Adverse Events, Outcome 12 Patients with fatigue/asthenia.

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Analysis 2.13

Comparison 2 Adverse Events, Outcome 13 Patients with leucopenia *.

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Analysis 2.14

Comparison 2 Adverse Events, Outcome 14 Patients with liver dysfunction.

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Analysis 3.1

Comparison 3 Relapses' outcomes, Outcome 1 Number of patients with at least one relapse during follow.

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Analysis 3.2

Comparison 3 Relapses' outcomes, Outcome 2 Relapse rate.

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Analysis 4.1

Comparison 4 MRI: role of treatment, Outcome 1 Number of patients with combined lesions at different times (6, 9 and 24 months).

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Analysis 4.2

Comparison 4 MRI: role of treatment, Outcome 2 Mean absolute change of T2 lesion load.

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Summary of findings for the main comparison. INTERFERONS for secondary progressive multiple sclerosis

INTERFERONS for secondary progressive multiple sclerosis
Patient or population: patients with secondary progressive multiple sclerosis Settings: Intervention: INTERFERONS
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	INTERFERONS
Sustained (6 months) EDSS increase after 3 years	Study population		RR 0.98 (0.82 to 1.16)	2026 (3)	HIGH	RCTs low risk of bias Heterogeneity probably due to different clinical characteristics of patients
	410 per 1000	402 per 1000 (336 to 475)
	Moderate
	372 per 1000	365 per 1000 (305 to 432)
Sustained (3 months) EDSS increase after 3 years	Study population		RR 0.88 (0.8 to 0.97)	1336 (2)	HIGH
	579 per 1000	510 per 1000 (463 to 562)
	Moderate
	594 per 1000	523 per 1000 (475 to 576)
Sustained (3 or 6 months) EDSS increase at 3 years in patients with pre study relapses	Study population		RR 0.9 (0.75 to 1.09)	1106 (3)	HIGH
	465 per 1000	419 per 1000 (349 to 507)
	Moderate
	388 per 1000	349 per 1000 (291 to 423)
Number of patients with at least one relapse during follow‐up ‐ after 3 years	Study population		RR 0.91 (0.84 to 0.97)	2639 (4)	HIGH
	530 per 1000	482 per 1000 (445 to 514)
	Moderate
	509 per 1000	463 per 1000 (428 to 494)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Summary of findings for the main comparison. INTERFERONS for secondary progressive multiple sclerosis

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Table 1. Summary of baseline characteristics of included studies

Study Name	Intervention	Number of patients	% of female	Age ‐ mean (SD)	Baseline EDSS ‐ mean (SD)	Disease duration ‐ mean (SD)	Pre‐study change* in EDSS ‐ mean (SD)	Pre‐study progression duration* ‐ mean (SD)	Pre‐study number of relapses* ‐ mean (SD)	Pre‐study % of patients without relapse*
Andersen 2004 (Nordic)	Rebif 22µg weekly	188	60	45.1 (nr)	4.7 (nr)	14.2 (nr)	nr	4.8 (nr)	1.7 (0.4)	40
	Placebo	183	60	46.4 (nr)	5.0 (nr)	.14.4 (nr)	nr	6.1 (nr)	1.6 (0.4)	34
Cohen 2002 (IMPACT)	Avonex 60µg weekly	217	64	47.2 (8.2)	5.2 (1.1)	16.2 (9.0)	nr	nr	1.5 (2.1)	37
	Placebo	219	64	47.9 (7.7)	5.2 (1.1)	16.7 (9.0)	nr	nr	1.3 (2.1)	44
North American SG 2004	Betaferon 250µg, every other day	317	66	46.1 (8.0)	5.2 (1.1)	14.6 (7.8)	1.7 (0.9)	4.0 (3.3)	0.8 (1.1)	54
	Betaferon 160µg/m^2, every other day	314	61	46.8 (8.3)	5.1 (1.2)	14.5 (8.7)	1.7 (0.9)	4.1 (3.5)	0.9 (1.6)	55
	Placebo	308	60	47.6 (8.2)	5.1 +1.1	14.9 (8.3)	1.7 (0.9)	4.1 (3.5)	0.8 (1.2)	56
SPECTRIMS 2001	Rebif 44µg, three times weekly	204	67	42.6 (7.3)	5.3 + 1.1	12.9 (6.9)	1.5 (0.8)	3.7 (2.7)	0.9 (1.3)	52
	Rebif 22µg, three times weekly	209	62	43.1 (7.2)	5.5 (1.1)	13.3 (7.4)	1.6 (0.9)	4.2 (3.1)	0.9 (1.4)	54
	Placebo	205	60	42.7 (6.8)	5.4 (1.1)	13.7 (7.2)	1.7 (1.0)	4.1 (3.2)	0.9 (1.2)	52
The European SG 1998	Betaferon 250µg, every other day	360	58·1	41·1 (7·2)	5·1 (1·1)	12.8 (6.6)	1.5 (nr)	3·8 (2·7)	1.7 (0.85)	32
	Placebo	358	64·2	40·9 (7·2)	5·2 (1·1)	13.4 (7.5)	1.5 (nr)	3·8 (3·4)	1.7 (0.85)	28
* Pre‐study length of observation: 4 years (Andersen 2004 (Nordic)) ; 3 years (Cohen 2002 (IMPACT) ; 2 years (North American SG 2004 ; SPECTRIMS 2001 ; The European SG 1998)

Table 1. Summary of baseline characteristics of included studies

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Comparison 1. Disability progression

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Sustained (6 months) EDSS increase after 3 years Show forest plot	3	2026	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.82, 1.16]

2 Sustained (3 or 6 months) EDSS increase at 3 years in patients with or without pre‐study relapses Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 In patients with pre study relapses	3	1106	Risk Ratio (M‐H, Random, 95% CI)	0.90 [0.75, 1.09]
2.2 In patients without pre‐study relapses	3	903	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.83, 1.33]
3 Sustained (3 months) EDSS increase Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 After 2 years	2	1054	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.81, 1.08]
3.2 After 3 years	2	1336	Risk Ratio (M‐H, Random, 95% CI)	0.88 [0.80, 0.97]
4 Sustained (3 or 6 months') EDSS increase according to pre‐study clinical characteristics of patients Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 low age and disease duration	2	1336	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.83, 1.02]
4.2 high age and disease duration	3	1739	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.90, 1.18]

Comparison 1. Disability progression

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Comparison 2. Adverse Events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Total number of patients with Serious AEs Show forest plot	5	3082	Risk Ratio (M‐H, Random, 95% CI)	1.00 [0.83, 1.19]

2 Patients who had discontinuated for AEs (including SAEs) * Show forest plot	5	3082	Risk Ratio (M‐H, Random, 95% CI)	2.62 [1.92, 3.57]

3 Deaths Show forest plot	5	3082	Risk Ratio (M‐H, Random, 95% CI)	1.41 [0.58, 3.42]

4 Patients who done or attempted suicide Show forest plot	4	2441	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.36, 1.95]

5 Allergy/Rash (number of events) Show forest plot	2	1657	Risk Ratio (M‐H, Random, 95% CI)	1.57 [0.99, 2.48]

6 Cutaneous necrosis * Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6.1 Number of events	2	1336	Risk Ratio (M‐H, Random, 95% CI)	33.02 [4.57, 238.79]
6.2 Number of patients	2	1557	Risk Ratio (M‐H, Random, 95% CI)	18.76 [3.72, 94.61]
7 Injection site reactions * Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7.1 Number of events	2	1657	Risk Ratio (M‐H, Random, 95% CI)	3.84 [3.11, 4.74]
7.2 Number of patients	3	1425	Risk Ratio (M‐H, Random, 95% CI)	1.60 [0.84, 3.07]
8 Patients with psychiatric disorders Show forest plot	5	3082	Risk Ratio (M‐H, Random, 95% CI)	1.05 [0.94, 1.18]

9 Patients with headache Show forest plot	3	1746	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.97, 1.60]

10 Patients with influenza like syndrome * Show forest plot	4	2364	Risk Ratio (M‐H, Random, 95% CI)	1.45 [1.01, 2.07]

11 Patients with myalgia Show forest plot	3	1746	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.93, 1.83]

12 Patients with fatigue/asthenia Show forest plot	3	1746	Risk Ratio (M‐H, Random, 95% CI)	1.09 [0.98, 1.22]

13 Patients with leucopenia * Show forest plot	3	1921	Risk Ratio (M‐H, Random, 95% CI)	2.25 [1.06, 4.75]

14 Patients with liver dysfunction Show forest plot	2	1310	Risk Ratio (M‐H, Random, 95% CI)	1.69 [0.97, 2.95]

Comparison 2. Adverse Events

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Comparison 3. Relapses' outcomes

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of patients with at least one relapse during follow Show forest plot	5		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 After 2 years	1	436	Risk Ratio (M‐H, Random, 95% CI)	0.72 [0.54, 0.95]
1.2 After 3 years	4	2639	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.84, 0.97]
2 Relapse rate Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 After 2 years	1	436	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.20, ‐0.04]
2.2 After 3 years	3	1752	Mean Difference (IV, Random, 95% CI)	‐0.16 [‐0.21, ‐0.10]

Comparison 3. Relapses' outcomes

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Comparison 4. MRI: role of treatment

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of patients with combined lesions at different times (6, 9 and 24 months) Show forest plot	2		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 6 months	1	125	Risk Ratio (M‐H, Random, 95% CI)	0.70 [0.52, 0.95]
1.2 9 months	1	264	Risk Ratio (M‐H, Random, 95% CI)	0.51 [0.42, 0.62]
1.3 24 months	1	109	Risk Ratio (M‐H, Random, 95% CI)	0.52 [0.33, 0.80]
2 Mean absolute change of T2 lesion load Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

2.1 1 year	2	1022	Mean Difference (IV, Random, 95% CI)	‐1.74 [‐3.25, ‐0.23]
2.2 2 years	2	956	Mean Difference (IV, Random, 95% CI)	‐2.56 [‐5.08, ‐0.05]
2.3 3 years	1	567	Mean Difference (IV, Random, 95% CI)	‐4.87 [‐6.22, ‐3.52]

Comparison 4. MRI: role of treatment

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