alemtuzumab versus interferon beta 1a for relapsing‐remitting multiple sclerosis

Jian Zhang; Shengliang Shi; Yueling Zhang; Jiefeng Luo; Yousheng Xiao; Lian Meng; Xiaobo Yang

doi:10.1002/14651858.CD010968.pub2

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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 Number of participants experiencing at least one relapse at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 1.2

Comparison 1 Number of participants experiencing at least one relapse at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Analysis 2.1

Comparison 2 Number of participants whose disease progressed at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 2.2

Comparison 2 Number of participants whose disease progressed at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Analysis 3.1

Comparison 3 Number of participants with at least one adverse event at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 3.2

Comparison 3 Number of participants with at least one adverse event at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Analysis 4.1

Comparison 4 Number of participants with severe adverse events at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 4.2

Comparison 4 Number of participants with severe adverse events at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Analysis 5.1

Comparison 5 Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 5.2

Comparison 5 Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Analysis 6.1

Comparison 6 Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging at 24 and 36 months, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 7.1

Comparison 7 Number of participants experiencing treatment discontinuation caused by adverse events, Outcome 1 Alemtuzumab 12 mg vs interferon beta 1a.

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Analysis 7.2

Comparison 7 Number of participants experiencing treatment discontinuation caused by adverse events, Outcome 2 Alemtuzumab 24 mg vs interferon beta 1a.

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Summary of findings for the main comparison. Alemtuzumab 12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis

alemtuzumab12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis
Patient or population: patients with relapsing‐remitting multiple sclerosis Settings: Intervention: alemtuzumab 12 mg Comparison: interferon beta 1a
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Interferon beta 1a	alemtuzumab12 mg
Number of participants experiencing at least one relapse Follow‐up: 24‐36 months	448 per 1000	269 per 1000 (233 to 314)	RR 0.6 (0.52 to 0.70)	1414 (3 studies)	⊕⊕⊕⊝ moderate¹
Number of participants whose disability worsened Follow‐up: 24‐36 months	168 per 1000	101 per 1000 (76 to 133)	RR 0.6 (0.45 to 0.79)	1414 (3 studies)	⊕⊕⊝⊝ low^1,2
Number of participants with at least one adverse event Follow‐up: 24‐36 months	948 per 1000	976 per 1000 (929 to 1000)	RR 1.03 (0.98 to 1.08)	1415 (3 studies)	⊕⊕⊝⊝ low^1,3
Number of participants with serious adverse events Follow‐up: 24‐36 months	192 per 1000	197 per 1000 (157 to 247)	RR 1.03 (0.82 to 1.29)	1415 (3 studies)	⊕⊕⊕⊝ moderate¹
Mean Expanded Disability Status Scale score change from baseline Follow‐up: 24‐36 months	The mean EDSS score in the control groups ranged from ‐0.14 to 0.38	Mean EDSS score in the intervention groups was 0.35 lower (0.73 lower to 0.03 higher)		1414 (3 studies)	⊕⊕⊝⊝ low^1,4
Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging Follow‐up: 24 months	630 per 1000	472 per 1000 (384 to 585)	RR 0.75 (0.61 to 0.93)	1125 (2 studies)	⊕⊕⊝⊝ low^1,5
Number of participants experiencing treatment discontinuation caused by adverse events Follow‐up: 24‐36 months	76 per 1000	25 per 1000 (14 to 43)	RR 0.33 (0.19 to 0.56)	1414 (3 studies)	⊕⊕⊝⊝ low^1,6
*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). The assumed risk in the comparison group is the median control group risk across studies. 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.
¹ Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). ² Downgraded for one level due to inconsistency (I² = 66%) ³ Downgraded for one level due to inconsistency (I² = 85%) ⁴ Downgraded one level due to inconsistency (high heterogeneity, I² = 88%) ⁵ Downgraded one level due to inconsistency (high heterogeneity, I² = 73%). ⁶Downgraded one level due to imprecision (low number of events).

Summary of findings for the main comparison. Alemtuzumab 12 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis

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Summary of findings 2. Alemtuzumab 24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis

alemtuzumab24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis
Patient or population: patients with relapsing‐remitting multiple sclerosis Settings: Intervention: alemtuzumab 24 mg Comparison: interferon beta 1a
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Interferon beta 1a	alemtuzumab24 mg
Number of participants experiencing at least one relapse Follow‐up: 36 months	405 per 1000	154 per 1000 (93 to 251)	RR 0.38 (0.23 to 0.62)	221 (1 study)	⊕⊕⊝⊝ low^1,2	Single study estimate
Number of participants whose disability worsened Follow‐up: 36 months	216 per 1000	91 per 1000 (45 to 182)	RR 0.42 (0.21 to 0.84)	221 (1 study)	⊕⊕⊝⊝ low^1,2	Single study estimate
Number of participants with at least one adverse event Follow‐up: 24‐36 months	964 per 1000	984 per 1000 (926 to 1000)	RR 1.02 (0.96 to 1.08)	578 (2 studies)	⊕⊕⊝⊝ low^1,3
Number of participants with serious adverse events Follow‐up: 24‐36 months	220 per 1000	209 per 1000 (154 to 288)	RR 0.95 (0.7 to 1.31)	578 (2 studies)	⊕⊕⊕⊝ moderate¹
Mean Expanded Disability Status Scale score change from baseline Follow‐up: 36 months	Mean EDSS score in the control group was 0.38 higher	Mean EDSS score in the intervention group was 0.45 lower		221 (1 study)	⊕⊝⊝⊝ very low^1,4	Single study estimate
Number of participants experiencing treatment discontinuation caused by adverse events Follow‐up: 24‐36 months	89 per 1000	30 per 1000 (9 to 14)	RR 0.34 (0.10 to 1.16)	593 (2 studies)	⊕⊝⊝⊝ very low^1,2,3
*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). The assumed risk in the comparison group is the median control group risk across studies. 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.
¹ Downgraded one level due to study limitation (blinding of participants and personnel could not be well performed). ² Downgraded one level due to imprecision (low number of events). ³ Downgraded one level due to inconsistency (high heterogeneity, I² = 86%.) ⁴ Imprecision (‐2): In view of the low number of participants and the wide confidence intervals, we downgraded by two points.

Summary of findings 2. Alemtuzumab 24 mg compared to interferon beta 1a for relapsing‐remitting multiple sclerosis

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Comparison 1. Number of participants experiencing at least one relapse at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1414	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.52, 0.70]

1.1 At 24 months	2	1191	Risk Ratio (M‐H, Fixed, 95% CI)	0.62 [0.53, 0.72]
1.2 At 36 months	1	223	Risk Ratio (M‐H, Fixed, 95% CI)	0.53 [0.35, 0.80]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.23, 0.62]

2.1 At 36 months	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.38 [0.23, 0.62]

Comparison 1. Number of participants experiencing at least one relapse at 24 and 36 months

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Comparison 2. Number of participants whose disease progressed at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1414	Risk Ratio (M‐H, Fixed, 95% CI)	0.60 [0.45, 0.79]

1.1 At 24 months	2	1191	Risk Ratio (M‐H, Fixed, 95% CI)	0.68 [0.50, 0.92]
1.2 At 36 months	1	223	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.16, 0.70]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.21, 0.84]

2.1 At 36 months	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	0.42 [0.21, 0.84]

Comparison 2. Number of participants whose disease progressed at 24 and 36 months

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Comparison 3. Number of participants with at least one adverse event at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1415	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.98, 1.08]

1.1 At 24 months	2	1200	Risk Ratio (M‐H, Random, 95% CI)	1.04 [1.01, 1.07]
1.2 At 36 months	1	215	Risk Ratio (M‐H, Random, 95% CI)	1.0 [0.98, 1.02]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	2	578	Risk Ratio (M‐H, Random, 95% CI)	1.02 [0.96, 1.08]

2.1 At 24 months	1	363	Risk Ratio (M‐H, Random, 95% CI)	1.04 [1.01, 1.08]
2.2 At 36 months	1	215	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.97, 1.02]

Comparison 3. Number of participants with at least one adverse event at 24 and 36 months

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Comparison 4. Number of participants with severe adverse events at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1415	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.82, 1.29]

1.1 At 24 months	2	1200	Risk Ratio (M‐H, Fixed, 95% CI)	1.04 [0.81, 1.34]
1.2 At 36 months	1	215	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.60, 1.63]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	2	578	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.70, 1.31]

2.1 At 24 months	1	363	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.56, 1.30]
2.2 At 36 months	1	215	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.69, 1.80]

Comparison 4. Number of participants with severe adverse events at 24 and 36 months

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Comparison 5. Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1414	Mean Difference (IV, Random, 95% CI)	‐0.35 [‐0.73, 0.03]

1.1 At 24 months	2	1191	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.60, 0.20]
1.2 At 36 months	1	223	Mean Difference (IV, Random, 95% CI)	‐0.7 [‐1.04, ‐0.36]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	1	221	Mean Difference (IV, Random, 95% CI)	‐0.83 [‐1.17, ‐0.49]

2.1 At 36 months	1	221	Mean Difference (IV, Random, 95% CI)	‐0.83 [‐1.17, ‐0.49]

Comparison 5. Mean Expanded Disability Status Scale score change from baseline at 24 and 36 months

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Comparison 6. Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging at 24 and 36 months

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	2	1125	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.61, 0.93]

1.1 At 24 months	2	1125	Risk Ratio (M‐H, Random, 95% CI)	0.75 [0.61, 0.93]

Comparison 6. Number of participants with new T2‐hyperintense lesions on magnetic resonance imaging at 24 and 36 months

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Comparison 7. Number of participants experiencing treatment discontinuation caused by adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Alemtuzumab 12 mg vs interferon beta 1a Show forest plot	3	1414	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.19, 0.56]

1.1 At 24 months	2	1191	Risk Ratio (M‐H, Fixed, 95% CI)	0.37 [0.20, 0.66]
1.2 At 36 months	1	223	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.07, 0.78]
2 Alemtuzumab 24 mg vs interferon beta 1a Show forest plot	2	593	Risk Ratio (M‐H, Random, 95% CI)	0.34 [0.10, 1.16]

2.1 At 24 months	1	372	Risk Ratio (M‐H, Random, 95% CI)	0.55 [0.23, 1.33]
2.2 At 36 months	1	221	Risk Ratio (M‐H, Random, 95% CI)	0.16 [0.04, 0.67]

Comparison 7. Number of participants experiencing treatment discontinuation caused by adverse events

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