Interferons‐beta versus glatiramer acetate for relapsing‐remitting multiple sclerosis

Loredana La Mantia; Carlo Di Pietrantonj; Marco Rovaris; Giulio Rigon; Serena Frau; Francesco Berardo; Anna Gandini; Anna Longobardi; Bianca Weinstock‐Guttman; Alberto Vaona

doi:10.1002/14651858.CD009333.pub3

Cochrane Database of Systematic Reviews

Interferones beta versus acetato de glatirámero para la esclerosis múltiple recurrente remitente

Información

DOI:

https://doi.org/10.1002/14651858.CD009333.pub3 Copiar DOI

Base de datos:

Cochrane Database of Systematic Reviews

Versión publicada:

24 noviembre 2016see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Esclerosis múltiple y enfermedades raras del sistema nervioso central

Copyright:

Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Loredana La Mantia

Unit of Neurorehabilitation ‐ Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente ‐ Fondazione Don Gnocchi, Milano, Italy
Carlo Di Pietrantonj

Regional Epidemiology Unit SeREMI, Local Health Unit Alessandria‐ ASL AL, Alessandria, Italy
Marco Rovaris

Unit of Neurorehabilitation ‐ Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente ‐ Fondazione Don Gnocchi, Milano, Italy
Giulio Rigon

Primary Care, Azienda ULSS 20 ‐ Verona, Verona, Italy
Serena Frau

Brighton and Hove, UK
Francesco Berardo

Drug Efficacy Evaluation Unit (UVEF) ‐ Veneto Regional Drug Information Center, Azienda Ospedaliera di Verona ‐ Department of Pharmacy, Verona, Italy
Anna Gandini

Regional Health Service, Azienda ULSS 21 ‐ Legnago, Legnago, Italy
Anna Longobardi

Primary Care, Azienda ULSS 20 ‐ Verona, Verona, Italy
Bianca Weinstock‐Guttman

Director, Jacobs MS Center and Pediatric MS Center of Excellence, SUNY University of Buffalo, Buffalo, USA
Alberto Vaona

Correspondencia a: Primary Care, Azienda ULSS 20 ‐ Verona, Verona, Italy

[email protected]

Contributions of authors

Roles and responsibilities
Drafting the protocol	All review authors
Selecting which studies to include	LLM, SF, AG
Planning data sheet for study data extraction	LLM, AV, GR, CDP
Planning data sheet for MRI data extraction	LLM, AV, MR, CDP
Extracting data from studies, double‐checking data and resolving discrepancies	LLM, AV, MR, FB, SF, AL, GR
Assessing risk of bias of included studies	LLM, AV, SF
Entering data into RevMan	LLM, AV, CDP
Planning the strategy analysis	LLM, AV, MR, CDP
Carrying out statistical analysis, interpreting statistical results	CDP, AV, LLM
Carrying out and interpreting the results and drafting the final review	LLM, AV, MR, CDP, BWG
Providing review control, according to Standards for the Reporting of New Cochrane Intervention Reviews	LLM, AV
Updating the review	LLM, AV, AL, SF

Sources of support

Internal sources

Cochrane Multiple Sclerosis Group, The Cochrane Collaboration, Other.

Cochrane MS Review Group, Neuroepidemiology Unit. Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20133 Milan, Italy

External sources

No sources of support supplied

Declarations of interest

This Cochrane review has no commercial sponsorship.

MR and BWG have participated in meetings and trials sponsored by large pharmaceutical companies.

LLM, SF, AG, FB, GR, AL, CDP, and AV have no conflicts of interest.

Acknowledgements

We thank Dirk Pleimes, MD, Global Medical Lead Neurology (Bayer Healthcare Pharmaceuticals, Global Medical Affairs Specialized Therapeutics, Montville, M100, USA), for providing data from the primary studies (BEYOND).

We thank Andrea Fittipaldo, Trials Search Co‐ordinator, for support provided in paper retrieval. We are grateful to Liliana Coco for valuable and helpful technical assistance provided, as well as for support in drawing up the paper.

Version history

Published

Title

Stage

Authors

Version

2016 Nov 24

Interferons‐beta versus glatiramer acetate for relapsing‐remitting multiple sclerosis

Review

Loredana La Mantia, Carlo Di Pietrantonj, Marco Rovaris, Giulio Rigon, Serena Frau, Francesco Berardo, Anna Gandini, Anna Longobardi, Bianca Weinstock‐Guttman, Alberto Vaona

https://doi.org/10.1002/14651858.CD009333.pub3

2014 Jul 26

Interferons‐beta versus glatiramer acetate for relapsing‐remitting multiple sclerosis

Review

Loredana La Mantia, Carlo Di Pietrantonj, Marco Rovaris, Giulio Rigon, Serena Frau, Francesco Berardo, Anna Gandini, Anna Longobardi, Bianca Weinstock‐Guttman, Alberto Vaona

https://doi.org/10.1002/14651858.CD009333.pub2

2011 Sep 07

Interferon beta versus glatiramer acetate for relapsing‐remitting multiple sclerosis

Protocol

Loredana La Mantia, Alberto Vaona, Marco Rovaris, Francesco Berardo, Serena Frau, Anna Gandini, Anna Longobardi, Giulio Rigon, Carlo Di Pietrantonj, Bianca Weinstock‐Guttman

https://doi.org/10.1002/14651858.CD009333

Differences between protocol and review

Outcomes

The secondary clinical outcome "Mean change in EDSS disability score" was deleted because it was considered not relevant.

The secondary clinical outcomes "Mean number of active (new or enlarged) T2‐hyperintense lesions per participant" and "Mean number of new contrast‐enhancing T1 lesions per participant" at 3 months were not evaluated because considered not relevant

The definition of outcome "Number of relapse free" was changed to "Number of participants who experienced a relapse" for consistency.

Analysis

Treatment schedules not approved in RRMS treatment and not used in clinical practice were not included in the analysis.

Scoring of overall quality of the study was better defined.

Sensitivity analysis exploring the impact of loss to follow‐up was performed using a likely scenario because that is more understandable.

We used risk ratio instead of odds ratio because this measure is suitable for the design of included studies, as studies provided neither infrequent events nor unbalanced groups.

The summary of findings Table for the main comparison was added.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

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 who experienced at least 1 relapse at 24 months and at end of follow‐up, Outcome 1 At the end of follow‐up (24 ‐ 36 months).

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Analysis 1.2

Comparison 1 Number of participants who experienced at least 1 relapse at 24 months and at end of follow‐up, Outcome 2 During follow‐up likely scenario.

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Analysis 2.1

Comparison 2 Number of participants who worsened during the study (EDSS progression) at 24 months and at the end of follow‐up, Outcome 1 At the end of follow‐up (24‐36 months).

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Analysis 2.2

Comparison 2 Number of participants who worsened during the study (EDSS progression) at 24 months and at the end of follow‐up, Outcome 2 During follow‐up likely scenario.

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Analysis 3.1

Comparison 3 Number of participants who withdrew or dropped out of the study because of adverse events, Outcome 1 Number of participants who dropped out for AE.

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Analysis 3.2

Comparison 3 Number of participants who withdrew or dropped out of the study because of adverse events, Outcome 2 Number of participants who dropped out for SAE.

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Analysis 4.1

Comparison 4 Frequency of relapse (ARR), Outcome 1 Relapse frequency.

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Analysis 5.1

Comparison 5 Time to first relapse, Outcome 1 Time to first relapse (HR).

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Analysis 7.1

Comparison 7 Number of participants treated with steroids for MS relapse, Outcome 1 Patients Treated with Steroids.

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Analysis 9.1

Comparison 9 Mean number of active (new or enlarged) T2‐hyperintense lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period, Outcome 1 During follow‐up.

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Analysis 10.1

Comparison 10 Mean number of new contrast‐enhancing T1 lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period, Outcome 1 Mean number.

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Analysis 11.1

Comparison 11 Mean change in total T2‐hyperintense lesion load at 12‐24 months and at end of follow‐up period, Outcome 1 Mean absolute change.

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Analysis 12.1

Comparison 12 Mean change in total T1‐hypointense lesion load at 12‐24 months and at end of follow‐up, Outcome 1 Mean absolute change.

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Analysis 13.1

Comparison 13 Mean change in total brain volume (as a measure of atrophy) at 12‐24 months and at end of follow‐up, Outcome 1 Mean absolute change.

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Summary of findings for the main comparison. Interferons compared with glatiramer acetate for participants with relapsing‐remitting multiple sclerosis

interferons compared with glatiramer acetate for participants with relapsing‐remitting multiple sclerosis
Patient or population: people with relapsing‐remitting multiple sclerosis Settings: secondary care Intervention: interferons Comparison: glatiramer acetate
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk (control)	Corresponding risk (intervention)
	Glatiramer acetate	Interferons
Number of participants with relapse Risk ratio (M‐H, random, 95% CI) Follow‐up: 24 months	Study population		RR 1.04 (0.87 to 1.24)	2184 (3 studies)	⊕⊕⊕⊝ moderate^a	Detection bias risk for clinical outcomes was judged as high for 1 study and low for the other 2 RCTs
	36 per 100	38 per 100 (31 to 45)
	Moderate
	35 per 100	36 per 100 (30 to 43)
Number of participants with confirmed progression Risk ratio (M‐H, random, 95% CI) Follow‐up: 24 months	Study population		RR 1.11 (0.91 to 1.35)	2169 (3 studies)	⊕⊕⊕⊝ moderate^a	Detection bias risk for clinical outcomes was judged as high for 1 study and low for the other 2 RCTs
	15 per 100	16 per 100 (13 to 20)
	Moderate
	15 per 100	17 per 100 (14 to 21)
Number of participants who dropped out for AEs Risk ratio (M‐H, random, 95% CI) Follow‐up: 24 months	Study population		RR 0.95 (0.64 to 1.4)	2685 (4 studies)	⊕⊕⊝⊝ low^a,b
	4 per 100	4 per 100 (3 to 6)
	Moderate
	5 per 100	5 per 100 (3 to 7)
Mean number of active T2 lesions Mean difference (IV, random, 95% CI) Follow‐up: 24 months		0.15 lower in IFN versus GA groups (0.68 lower to 0.39 higher)		1790 (3 studies)	⊕⊕⊝⊝ low^b,c	Detection bias risk for MRI outcomes was judged as low for all studies
Mean number of new enhancing lesions Mean difference (IV, random, 95% CI) Follow‐up: 24 months		0.14 lower in IFN versus GA groups (0.3 lower to 0.02 higher)		1734 (3 studies)	⊕⊕⊕⊝ moderate^d	Detection bias risk for MRI outcomes was judged as low for all studies
Mean change in total T2‐hyperintense lesion load Mean difference (IV, random, 95% CI) Follow‐up: 24 months		0.58 lower in IFN versus GA groups (0.99 to 0.18 lower)		1608 (2 studies)	⊕⊕⊕⊝ moderate^d	Detection bias risk for MRI outcomes was judged as low for both studies
Mean change in total T1‐hypointense lesion load Follow‐up: 24 months		−0.20 lower in IFN versus GA groups (−0.33 to −0.07)		1602 (2 studies)	⊕⊕⊕⊝ moderate^d	Detection bias risk for MRI outcomes was judged as low for both studies
The basis for the assumed risk* (e.g. median control group risk (GA) across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group (IFNs) 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.
^aHigh risk of attrition bias. ^bWide 95% confidence intervals. ^cSignificant heterogeneity of results. ^dEffect size of uncertain value.

Summary of findings for the main comparison. Interferons compared with glatiramer acetate for participants with relapsing‐remitting multiple sclerosis

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Table 1. Baseline characteristics of the population included in the RCTs

Study name	Drugs	Number of participants	% female	Age, years, mean (SD)	Mean EDSS score (SD)	Disease duration, years,mean (SD)	Previous number of relapses, mean (SD)	Number of participants with MRI Gad+ lesions (%)
Cadavid 2009a	IFN‐beta 1b	36	75	36 (7.75)	2.0* (0 to 5)	0.9* (0.1 to 24)	1.8* (0 to 7.5)	26 (72)
Cadavid 2009a	GA	39	64	36 (8.25)	2.0* (0 to 5.5)	1.2* (0.2 to 34)	1,9* (0.13 to 7.0)	27 (69)
Calabrese 2012	IFN‐beta 1a 44	55	69.5	35.9 (9.1)	1.9 (1.0)	5.7 (4.9)	1,2 (0.6)	ND
	IFN‐beta 1a 30 μg	55	68.0	34.8 (9.6)	1.9 (0.8)	5.3 (5.1)	1,2 (0.7)	ND
	GA	55	72.9	38.9 (10.2)	2.1 (1.1)	5.5 (6.1)	1,3 (0.7)	ND
Lublin 2013a	IFN‐beta 1a 30 μg	250	69.2	37.6 (10.2)	2.0 (1.2)	1.4 (4.0)	1.7° (0.9)	187 (74.8)
Lublin 2013a	GA	259	71.4	39.0 (9.5)	1.9 (1.2)	1.0 (2.9)	1.6° (0.7)	215 (83.01)
Mikol 2008	IFN‐beta 1a 44 μg	386	69	36.7 (9.8)	2.35 (1.28)	5.93 (6.25)	0.97** (0.42)	150 (39)
Mikol 2008	GA	378	72	36.8 (9.5)	2.33 (1.31)	6.55 (7.10)	1.01** (0.35)	156 (41)
O'Connor 2009a	IFN‐beta 1b	897	70	35.8** (11.13)	2.35 (2)	5.3** (4.45)	1.6° (0.74)	ND
O'Connor 2009a	GA	448	68	35.2** (11.87)	2.28 (2)	5.1** (4.45)	1.6° (0.74)	ND
ND (no data available). Median (range); mean not reported. *SD or weighted mean was calculated. °Pre‐1‐year.

Table 1. Baseline characteristics of the population included in the RCTs

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Table 2. Dropout data

Study	Arm	N° participants			N° dropout		Reasons for missing
Study	Arm	At randomisation	24 months	36 months	n°	%	Lost to follow‐up	Did not receive drug	Switched treatment	Withdrew	Deviated from protocol	Had adverse events	Died	Became pregnant	Other reasons
Cadavid 2009a¹	IFN‐beta 1a 44 μg	36	25	ND	11⁶	30.6	7	0	0	0	0	1	0	0	3⁸
Cadavid 2009a¹	GA	39	31	ND	8⁷	20.5	4	0	0	0	0	0	0	0	4⁸
Calabrese 2012²	IFN‐beta 1a 44 μg	55	46	ND	9	16.4	9	ND
	IFN‐beta 1a 30 μg	55	47	^ND	8	14.5	8
	GA	55	48	^ND	7	12.7	7
Lublin 2013a³	IFN‐beta 1a 30 μg	250	^ND	194	56	22.4	13	0	0	0	0	17¹¹	1	0	25¹³
Lublin 2013a³	GA	259	^ND	223	36	13.9	9	0	0	0	0	11¹²	1	0	15¹⁴
Mikol 2008⁴	IFN‐beta 1a 44 μg	386	301	^ND	85	22.0	17	3	0	0	2	23	0	8	32⁹
Mikol 2008⁴	GA	378	324	^ND	54	14.3	2	3	0	0	2	19	0	5	23¹⁰
O'Connor 2009a⁵	IFN‐beta 1b 250	897	784	^ND	113	12.6	12	9	10	38	3	13		1	27
O'Connor 2009a⁵	GA	448	374	^ND	74	16.5	12	3	5	18	2	8	1	1	24
^{ND (no data available)} ^{Source of data are described as follow.} ^{1] pg 1977; 2] pg 3; 3] pg 33; 4] pg 904; 5] pg 890; 6] 7 lost to follow‐up + 4 discontinued intervention (see pg 1977); 7] 4 lost to follow‐up + 4 discontinued intervention (see pg 1977); 8] treatment failure; 9] 4 had disease progression + 28 for other reasons; 10] 7 had disease progression + 16 for other reasons; 11] 4 AE/SAE + 13 side effects; 12] 6 AE/SAE + 5 side effects; 13] 14 non‐medical reason + 11 other medical reason; 14] 8 non‐medical reason + 7 other medical reason}

Table 2. Dropout data

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Table 3. Sensitivity analysis (OUTCOME: N° of participants with at least 1 relapse)

Study	Arm	N° participants			N° dropout		Lost to follow‐up
Study	Arm	Randomised available for the outcome	24 months	36 months	n°	%	Lost to follow‐up
Cadavid 2009a	IFN‐beta 1a 44	36	25		11	30.6	7
Cadavid 2009a	GA	39	31		8	20.5	4
Calabrese 2012	IFN‐beta 1a 44	55	46		9	16.4	9
	IFN‐beta 1a 30	55	47		8	14.5	8
	GA	55	48		7	12.7	7
Lublin 2013a	IFN‐beta 1a 30	250		194	56	22.4	13
Lublin 2013a	GA	259		223	36	13.9	9
Mikol 2008	IFN‐beta 1a 44	386	301		85	22.0	17
Mikol 2008	GA	378	324		54	14.3	2
O'Connor 2009a	IFN‐beta 1b	897	784		113	12.6	57*
O'Connor 2009a	GA	448	374		74	16.5	31*
^*Data provided by Bayer (Pleimes 2013).

Table 3. Sensitivity analysis (OUTCOME: N° of participants with at least 1 relapse)

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Table 4. Sensitivity analysis (OUTCOME: N° participants with EDSS progression)

Study	Arm	N° participants at			N° dropout		Lost to follow‐up
Study	Arm	Randomised available for the outcome	24 months	36 months	n°	%	Lost to follow‐up
Cadavid 2009a	IFN‐beta 1a 44	36	25		11	30.6	7
Cadavid 2009a	GA	39	31		8	20.5	4
Calabrese 2012	IFN‐beta 1a 44	55	46		9	16.4	9
	IFN‐beta 1a 30	55	47		8	14.5	8
	GA	55	48		7	12.7	7
Lublin 2013a	IFN‐beta 1a 30	241		194	47	19.5	13
Lublin 2013a	GA	246		223	23	9.3	9
Mikol 2008	IFN‐beta 1a 44	386	301		85	22.0	17
Mikol 2008	GA	378	324		54	14.3	2
O'Connor 2009a	IFN‐beta 1b	886	784		102	11.5	80^*
O'Connor 2009a	GA	444	374		70	15.8	58^*
^*Data provided by Bayer (Pleimes 2013).

Table 4. Sensitivity analysis (OUTCOME: N° participants with EDSS progression)

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Comparison 1. Number of participants who experienced at least 1 relapse at 24 months and at end of follow‐up

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At the end of follow‐up (24 ‐ 36 months) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At 24 months	3	2184	Risk Ratio (M‐H, Random, 95% CI)	1.04 [0.87, 1.24]
1.2 At 36 months	1	509	Risk Ratio (M‐H, Random, 95% CI)	1.27 [0.92, 1.75]
2 During follow‐up likely scenario Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 At 24 months	3	2184	Risk Ratio (M‐H, Random, 95% CI)	1.10 [0.91, 1.34]
2.2 At 36 months	1	509	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.98, 1.73]

Comparison 1. Number of participants who experienced at least 1 relapse at 24 months and at end of follow‐up

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Comparison 2. Number of participants who worsened during the study (EDSS progression) at 24 months and at the end of follow‐up

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 At the end of follow‐up (24‐36 months) Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 At 24 months	3	2169	Risk Ratio (M‐H, Random, 95% CI)	1.11 [0.91, 1.35]
1.2 At 36 months	1	487	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.63, 1.20]
2 During follow‐up likely scenario Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2.1 At 24 months	3	2169	Risk Ratio (M‐H, Random, 95% CI)	1.24 [0.81, 1.90]
2.2 At 36 months	1	487	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.71, 1.26]

Comparison 2. Number of participants who worsened during the study (EDSS progression) at 24 months and at the end of follow‐up

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Comparison 3. Number of participants who withdrew or dropped out of the study because of adverse events

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Number of participants who dropped out for AE Show forest plot	4	2685	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.64, 1.40]

2 Number of participants who dropped out for SAE Show forest plot	3	2610	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.63, 1.56]

Comparison 3. Number of participants who withdrew or dropped out of the study because of adverse events

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Comparison 4. Frequency of relapse (ARR)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse frequency Show forest plot	5		Rate Ratio (Random, 95% CI)	Subtotals only

1.1 At 24 months	4		Rate Ratio (Random, 95% CI)	1.06 [0.95, 1.18]
1.2 At 36 months	1		Rate Ratio (Random, 95% CI)	1.40 [1.13, 1.74]

Comparison 4. Frequency of relapse (ARR)

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Comparison 5. Time to first relapse

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Time to first relapse (HR) Show forest plot	3		Hazard Ratio (Random, 95% CI)	1.01 [0.87, 1.16]

Comparison 5. Time to first relapse

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Comparison 7. Number of participants treated with steroids for MS relapse

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Patients Treated with Steroids Show forest plot	2	1420	Risk Ratio (M‐H, Random, 95% CI)	1.30 [0.76, 2.24]

Comparison 7. Number of participants treated with steroids for MS relapse

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Comparison 9. Mean number of active (new or enlarged) T2‐hyperintense lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 During follow‐up Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 6 months	1	396	Mean Difference (IV, Random, 95% CI)	‐0.86 [‐1.32, ‐0.40]
1.2 At 12 months	2	1722	Mean Difference (IV, Random, 95% CI)	‐0.52 [‐1.12, 0.09]
1.3 At 24 months	3	1790	Mean Difference (IV, Random, 95% CI)	‐0.15 [‐0.68, 0.39]

Comparison 9. Mean number of active (new or enlarged) T2‐hyperintense lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period

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Comparison 10. Mean number of new contrast‐enhancing T1 lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean number Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 6 months	0	0	Mean Difference (IV, Random, 95% CI)	0.0 [0.0, 0.0]
1.2 At 12 months	1	1233	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.26, 0.06]
1.3 At 24 months	3	1734	Mean Difference (IV, Random, 95% CI)	‐0.14 [‐0.30, 0.02]

Comparison 10. Mean number of new contrast‐enhancing T1 lesions per participant at 6 ‐ 12 ‐ 24 months and at end of follow‐up period

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Comparison 11. Mean change in total T2‐hyperintense lesion load at 12‐24 months and at end of follow‐up period

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean absolute change Show forest plot	3		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 12 months	1	1221	Mean Difference (IV, Random, 95% CI)	‐0.4 [‐0.59, ‐0.21]
1.2 At 24 months	2	1608	Mean Difference (IV, Random, 95% CI)	‐0.58 [‐0.99, ‐0.18]
1.3 At 36 months	1	509	Mean Difference (IV, Random, 95% CI)	‐0.26 [‐1.04, 0.52]

Comparison 11. Mean change in total T2‐hyperintense lesion load at 12‐24 months and at end of follow‐up period

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Comparison 12. Mean change in total T1‐hypointense lesion load at 12‐24 months and at end of follow‐up

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean absolute change Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 12 months	1	1207	Mean Difference (IV, Random, 95% CI)	‐0.06 [‐0.18, 0.07]
1.2 At 24 months	2	1602	Mean Difference (IV, Random, 95% CI)	‐0.20 [‐0.33, ‐0.07]

Comparison 12. Mean change in total T1‐hypointense lesion load at 12‐24 months and at end of follow‐up

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Comparison 13. Mean change in total brain volume (as a measure of atrophy) at 12‐24 months and at end of follow‐up

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mean absolute change Show forest plot	2		Mean Difference (IV, Random, 95% CI)	Subtotals only

1.1 At 12 months	1	1137	Mean Difference (IV, Random, 95% CI)	‐0.10 [‐0.22, 0.02]
1.2 At 24 months	2	1552	Mean Difference (IV, Random, 95% CI)	‐0.12 [‐0.23, ‐0.01]

Comparison 13. Mean change in total brain volume (as a measure of atrophy) at 12‐24 months and at end of follow‐up

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