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JNNP Online First, published on December 30, 2014 as 10.1136/jnnp-2014-309243 Multiple sclerosis
REVIEW
Comparative efficacy of interferon β versus glatiramer acetate for relapsing-remitting multiple sclerosis Loredana La Mantia,1,2 Carlo Di Pietrantonj,3 Marco Rovaris,1 Giulio Rigon,4 Serena Frau,5 Francesco Berardo,6 Anna Gandini,7 Anna Longobardi,4 Bianca Weinstock-Guttman,8 Alberto Vaona4 For numbered affiliations see end of article. Correspondence to Dr Alberto Vaona, Primary Care, Azienda ULSS 20 Verona, Ospedale di Marzana, Piazzale Ruggero Lambranzi 1, Verona 37142, Italy; [email protected] Received 15 August 2014 Revised 4 November 2014 Accepted 25 November 2014
ABSTRACT Interferon β (INFβ) and glatiramer acetate (GA) are widely used in patients with relapsing–remitting multiple sclerosis (RRMS). However, it is still unclear whether they have different efficacy. We performed a systematic search of head-to-head trials for gaining objective reliable data to compare the two drugs, using the Cochrane Collaboration methodology. We identified five randomised-controlled trials (RCTs) (2858 participants) comparing directly INFβ versus GA in RRMS. All studies were at high risk for attrition bias. Both therapies showed similar efficacy at 24 months, considering clinical ( patients with relapse or progression) and one MRI activity (enhancing lesions) measure. At 3 years, evidence from a single study showed that the relapse rate was higher in the INFβ group than in the GA group (risk ratio 1.40, 95% CI 1.13 to 1.74, p 0.002). However, the average reduction in T2-weighted and T1-weighted lesion volume was significantly greater in the INFβ group than in the GA group (mean difference (MD) −0.58, 95% CI −0.99 to −0.18, p 0.004, and MD −0.20, 95% CI −0.33 to −0.07, p 0.003, respectively). The number of participants who dropped out of the studies because of adverse events was similar in the two groups. These data support clinicians in the use of these therapies, based on their similar safety and efficacy in the prevention of disease activity, although the different effect on MRI measures and the different tolerability might have a role in the therapeutic choice at the individual level.
BACKGROUND Glatiramer acetate (GA) and recombinant interferon β (INFβ) are used worldwide as treatments for relapsing–remitting multiple sclerosis (RRMS). Currently, there is no clear evidence to support physicians’ preferences regarding INFβ or GA treatment for their patients.
OBJECTIVE To cite: La Mantia L, Di Pietrantonj C, Rovaris M, et al. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/ jnnp-2014-309243
To determine, through a systematic review of head-to-head trials, whether INFβ and GA in RRMS have different efficacy and safety.
METHODS The review group used the Cochrane Collaboration methodology to identify all randomised active-
controlled trials (RCTs) directly comparing INFβ with GA in RRMS. The primary outcomes were: (1) number of participants who experienced at least one relapse; (2) number of participants who experienced worsening of at least a 0.5-point increase from starting Expanded Disability Status Scale (EDSS) score ≥5.5 or a 1-point increase from starting EDSS ≤5.0, confirmed at 6 months and (3) number of participants who withdrew from or dropped out of the study because of adverse events (AEs). The secondary outcomes included: frequency of relapses, changes in quality of life (QOL) and MRI measures of disease activity (number of new or enlarged T2-hyperintense lesions, of contrast-enhancing T1 lesions, mean change of total T2-hyperintense lesion load) and measures of disease progression (mean change of T1-hypointense lesion volume and total brain volume). The risk of bias in included studies was assessed independently by the review authors. A statistical analysis was performed using Review Manager (RevMan) software. For dichotomous data, the study results were summarised as risk ratios (RR), with 95% CIs, according to Mantel-Haenszel method and tested for overall effect Z. For continuous outcomes, weighted mean difference (MD) was assessed, using inverse variance methods and SE. Count outcomes were assessed by estimating log-RR and log-HR, using generic inverse variance of log estimates and SE. A between-study heterogeneity of findings was assessed using the I2 statistic. The results have been presented using the random effect model.
RESULTS Five RCTs have met our selection criteria: BECOME,1 BEYOND,2 REGARD,3 Calabrese4 and COMBIRX.5 All RCTs have included patients with RRMS with low disability (EDSS at entry 1.9–2.35) and active disease (frequency of relapse ≥1/year less marked for REGARD’s study)1–5 possibly related to slightly different inclusion criteria (table 1). The overall population considered in our analysis was 2.858 (1.679 patients treated with INFβ and 1.179 with GA). The drugs analysed in comparison with GA were INFβ-1b (2 trials, 933 participants),1 2 subcutaneous INFβ-1a 44 mg (2 trials, 441 participants)3 4 and intramuscular INFβ-1a 30 mg (2 trials,
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
2
Characteristics of included trials
Study, year, countries (centres)
BEYOND (2009)2 USA, Europe, Australia (198)
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
REGARD (2008)3 Europa, USA, UK, Ireland Russia (81) Calabrese (2012)4 Italy (1)
COMBIRX 20135 US, Canada (68)
INFβ-1b 250 μg SC every other day GA 20 mg SC every day
36
INFβ-1b* 500 μg SC every other day INFβ-1b 250 μg SC every other day GA 20 mg SC every day INFβ-1a 44 μg SC 3 times/week GA 20 mg SC every day INFβ-1a 44 μg SC 3 times/week INFβ-1a 30 μg IM 1 time/week GA 20 mg SC every day INFβ-1a 30 μg IM 1 time/week GA 20 mg SC every day INF+GA* 30 μg IM 1 time/week +20 mg SC every day
899
39
897
Accrual period
Follow-up duration (months)
Not reported
24
Mean combined active lesion counts in the first year
November 2003–June 2005
24
Relapse risk
Age 18–60 at least one relapse in the year before entry EDSS 0–5.5 Naive patients
February– December 2004
24
Time to first relapse
New or worsening neurological symptoms, without fever, lasted ≥48 h, with change in FS score
Age 18–55 RRMS EDSS ≤5.0
January 2007–June 2008
24
Number of new cortical lesions
NR
Age 18–60 at least 2 exacerbations in the 3 years before entry, one exacerbation could be an MRI change EDSS 0–5.5
January 2005–April 2009
36
Annualised relapse rate
New symptom or worsening of an old symptom, attributable to MS, preceded by stability or improvement for at least 30 day and confirmed by the examining physician within 7 days of onset, without fever, lasted ≥24 h with decrease by ≥7 points in SNRS score or increase: A. in EDSS by ≥0.5 point or B. in 1 FS by ≥2 points or C. in ≥2 FS by ≥1 point
Inclusion criteria Age 18–55 at least one relapse in the 6 months before entry CIS with onset within 6 months plus evidence of dissemination EDSS 0–5.5 Age 18–55 at least one relapse in the year before entry EDSS 0–5 Naive patients
Primary Outcome
Relapse Definition New or worsening neurological symptoms , without fever or infection, lasted ≥24 h, with decrease by ≥7 points in SNRS score or increase: A. in EDSS by ≥0.5 point or B. in 1 FS by ≥2 points or C. in ≥2 FS by ≥1 point New or recurrent neurological abnormalities, separated by at least 30 days from the onset of the preceding event, without fever or infection, lasted ≥24 h, with increase in EDSS or FS scores appropriate to the symptoms
Disability Progression Definition
Sponsor
Increase of 1 EDSS point, or ≥0.2 SD in MSFC, sustained at 6 months
Bayer
Increase of 1 EDSS point, sustained at 3 months
Bayer
Increase of EDSS points, ≥1.5 (if basal EDSS=0) ≥1.0 (if basal EDSS=0.5−4.5) ≥0·5 (if basal EDSS ≥5) sustained at 6 months NR
Merck Serono
448
386
378
55
Merck Serono
55
55
250
259
499
Increase of EDSS points, ≥1.0 (if basal EDSS ≤5.0) ≥0·5 (if basal EDSS ≥5.5), sustained at 6 months
National Institutes of Health, National Institute of Neurological Disorders and Stroke
*This arm was not included in the analysis because the treatment schedule is not used in the clinical practice. CIS, Clinically Isolated Syndrome; EDSS, Expanded Disability Status Scale; FS, Functional System; GA, glatiramer acetate; INFβ, interferonsβ; IM, intramuscular; MSFC, Multiple Sclerosis Functional Composite; NR, not reported; RRMS, relapsing–remitting multiple sclerosis; SC, subcutaneous; SNRS, Scripps Neurological Rating Scale.
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BECOME (2009)1 US (2)
Interventions
No of Patients
Multiple sclerosis
Table 1
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Multiple sclerosis Table 2
Baseline characteristics of patients in the included trials
Study
Interventions
Age (years) Mean (SD)
BECOME1
INFβ-1b 250 μg GA 20 mg INFβ-1b 250 μg GA 20 mg INFβ-1a 44 μg GA 20 mg INFβ-1a 44 μg INFβ-1a 30 μg GA 20 mg INFβ-1a 30 μg GA 20 mg
36 (7.7) 36 (8.2) 35.8 (11.1) 35.2 (11.9) 36.7 (9.8) 36.8 (9.5) 35.9 (9.1) 34.8 (9.6) 38.9 (10.2) 37.6 (10.2) 39.0 (9.5)
BEYOND2 REGARD3 Calabrese4
COMBIRX5
Baseline EDSS Mean (SD)
Disease Duration (years) Mean (SD)
Prestudy Relapses Mean (SD)
2.0 2.0 2.3 2.3 2.3 2.3 1.9 1.9 2.1 2.0 1.9
0.9 (NR) 1.2 (NR) 5.3 (4.45) 5.1 (4.45) 5·9 (6·2) 6·5 (7·1) 5.7 (4.9) 5.3 (5.1) 5.5 (6.1) 1.4 (4.0) 1.0 (2.9)
1.8 (NR) 1.9 (NR) 1.6 (0.74) 1.6 (0.74) 0.97* (0.42) 1.01* (0.35) 1.2 (0.6) 1.2 (0.7) 1.3 (0.7) 1.7 (0.9) 1.6 (0.7)
(NR) (NR) (2) (2) (1.3) (1.3) (1.0) (0.8) (1.1) (1.2) (1.2)
*Pre two years. EDSS, Expanded Disability Status Scale; GA, glatiramer acetate; INFβ, interferonβ; NR, not reported.
305 participants).4 5 The treatment duration and follow-up were 3 years for the COMBIRX’s study and 2 years for the other four RCTs. Table 2 shows the characteristics of patients in the included trials. The attrition bias was the main biased dimension of all RCTs. The patients who dropped out were 13–30%, with higher proportion for IFNs group in four RCTs; the reasons for incompleteness were different and poorly described (table 3). The effects of interventions in terms of primary clinical efficacy outcomes were the following: 1) the number of patients who experienced at least one relapse was assessed in three trials at 24 months (2184 patients, 76% of participants) and in one trial5 at 36 months (509 patients, 18% participants). At 24 months, 38% and 36% of patients relapsed in the INFβ and GA groups, respectively. There were no significant differences in the effect at 24 months (RR 1.04, 95% CI 0.87 to 1.24) and 36 months (RR 1.27, 95% CI 0.92 to 1.75; figure 1A). (2) The number of patients with confirmed worsening was assessed by three trials at 24 months (2169 patients, 76% of participants). At 24 months, 16% and 15% of patients worsened in the INFβ and GA groups, respectively. No differences were found when confirmed progression was analysed either at 24 months (RR
1.11, 95% CI 0.91 to 1.35) or at 36 months (RR 0.87, 95% CI 0.63 to 1.20) (figure 1B). (3) The number of patients who withdrew from the study because of adverse events was 3% for IFNs and 4% for GA; the RR was 0.95 (95% CI 0.65 to 1.39), without significant differences between the two treatment groups. The relapse frequency (clinical secondary outcome) was similar at 24 months (RR 1.06, 95% CI 0.94 to 1.18), while at 36 months it was significantly higher in the INFβ group, thereby favouring GA (RR 1.40, 95% CI 1.13 to 1.74; figure 2A). Considering MRI outcome measures, mean T2 lesion volume increase was significantly lower in INFβ-treated than in GA-treated patients at 12 months as well as 24 months; the same difference was also present in 36-month data from a single study, but it did not reach statistical significance (figure 2B). No significant differences between INFβ and GA were found for number of contrast-enhancing T1 lesions, at 12 (MD −0.10, −0.26 to 0.06) as well as 24 months (MD −0.14, −0.30 to 0.02). Mean T1 lesion volume increase was significantly lower in INFβ-treated than in GA-treated patients at month 24 (MD −0.20, −0.33 to −0.07, p 0.003), while the mean brain volume reduction at 24 months was significantly higher in INFβ-treated than in
Table 3 Patients with incomplete outcome data Patients
Randomised N
Number of drop-out with reasons Drop-out
Lost to follow-up
N
N
Did not receive drug
Studyref
Interventions
BECOME1
INFβ-1b 250 μg GA 20 mg
36 39
11 8
30.6 20.5
7 4
19.4 10.3
BEYOND2
INFβ-1b 250 μg GA 20 mg
897 448
113 74
12.6 16.5
12 12
1.3 2.7
9 3
REGARD3
INFβ-1a 44 μg GA 20 mg
386 378
85 54
22.0 14.3
17 2
4.4 0.0
3 3
Calabrese4
INFβ-1a 44 μg INFβ-1a 30 μg GA 20 mg
55 55 55
9 8 7
16.4 14.5 12.7
9 8 7
16.4 14.5 12.7
COMBIRX5
INFβ-1a 30 μg GA 20 mg
250 259
56 36
22.4 13.9
13 9
5.2 3.5
Per cent*
Per cent*
Drug switches
Withdrawn
Protocol deviation
Adverse events
Died
Pregnancy
1 10 5
38 18
3 2
13 8
2 2
23 19
Other reasons 3 4
1
1 1
27 24
8 5
32 23
Not described
17 11
1 1
25 15
*On randomised population. GA, glatiramer acetate; INFβ, interferonsβ.
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
3
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Multiple sclerosis Figure 1 Number of patients who experienced (A) at least one relapse at the end of follow-up and (B) Expanded Disability Status Scale (EDSS) progression at the end of follow-up (24–36 months; GA, glatiramer acetate; IFNs, interferons).
GA-treated patients (MD −0.12, −0.23 to −0.01, p 0.04); the heterogeneity was significant (I2=83%; data not shown).
DISCUSSION The aim of this systematic review was to evaluate whether treatment with INFβ and GA in patients with RRMS differs in terms of efficacy and safety. We selected outcome measures evaluating changes in clinical and MRI activity, as well as in disability progression and disease burden accrual. The main conclusion is that the two therapies do not seem to differ in terms of clinical efficacy and safety, although IFNs were found to limit the increase of MRI lesion burden more than GA. All RCTs were at high risk for attrition bias: the percentage of drop-outs was higher in the INFβ group versus the GA group and related to different reasons (side effects, nonconsent, tolerability), although full details were not always provided. This aspect might have a role in the final assessment of effectiveness of these drugs. The results of this systematic review have several limitations: 1. We cannot exclude that non-homogeneous criteria for relapse definition and count as well as different inclusion criteria might constitute a bias in the outcome assessment; 2. The main comparison of this review was between GA and IFNs at high frequency and dosages; the evaluation of the 4
comparative effect of low versus high INFβ dosages and GA was limited by different time points assessment available; 3. The analysis of the safety profile was restricted to the number of participants who withdrew from or dropped out of the study; drug-related side effects were not considered because they had already been widely reported; 4. The main outcome measure not available for analysis was QOL, impairing the possibility to compare the drugs in terms of patient needs.
RECOMMENDATIONS These data support clinicians in the use of these therapies based on their similarities in safety and efficacy in the prevention of disease activity, although the different effects on some MRI measures and the different levels of tolerability might have a role in therapeutic choice at the individual level. The assessment of patient-related outcomes is warranted to take into account the needs of patients in the treatment choice. Concerning the quality of evidence, standardised sets of outcome measures, clear presentation of data and comparable MRI protocols for image acquisition and analysis may allow more accurate interpretation of trial results.
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
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Multiple sclerosis Figure 2 Clinical and MRI disease activity outcome measures. (A) Relapse rate at the end of follow-up (24–36 months). (B) Mean change of total T2-hyperintense lesion load at 12–2436 months.
Author affiliations 1 Unit of Neurorehabilitation—Multiple Sclerosis Center, IRCCS Santa Maria Nascente—Fondazione Don Gnocchi, Milano, Italy 2 Department of Neurosciences—Multiple Sclerosis Centre, AO Ospedale Niguarda Ca’ Granda, Milano, Italy 3 Regional Epidemiology Unit SeREMI- CochraneVaccines Field, Local Health Unit Alessandria—ASL AL, Alessandria, Italy 4 Primary Care, Azienda ULSS 20 Verona, Verona, Italy 5 Dialogo sui Farmaci Srl, Verona, Italy 6 Drug Efficacy Evaluation Unit (UVEF)—Veneto Regional Drug Information Center, Azienda Opsedaliera di Verona—Department of Pharmacy, Verona, Italy 7 Regional Health Service, Azienda ULSS 21—Legnago, Legnago, Italy 8 Director Jacobs MS Center and Pediatric MS Center of Excellence, SUNY University of Buffalo, Buffalo, New York, USA Contributors The study protocol was designed by all the authors; study selection was performed by AG, SF and LLM; analyses and interpretation of the results were carried out by LLM, CDP, AV and MR; and LLM wrote the paper and its revision was performed by AV. All the authors approved the final version of this paper. Competing interests MR received travel grants and compensations for consultancies from TEVA Italia, Biogen Italia, Novartis, Genzyme-Sanofi, Almirall and Bayer Schering.BW-G has participated in speaker’s bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Mylan Inc, and Acorda Therapeutics, Inc and has received grant/research support from the agencies listed in the previous sentence as well as Questcor
Pharmaceuticals Inc, and Shire. She serves in the editorial board for BMJ Neurology, Journal of International MS and Journal of Multiple Sclerosis. Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES 1
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3
4
5 6
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
Cadavid D, Wolansky LJ, Skurnick J, et al. Efficacy of treatment of MS with INFβ-1b or glatiramer acetate by monthly brain MRI in the BECOME study. Neurology 2009;72:1976–83. O’Connor P, Filippi M, Arnason B, et al. 250 microg or 500 microg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study. Lancet Neurol 2009;8:889–97. Mikol DD, Barkhof F, Chang P, et al. Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial. Lancet Neurol 2008;7:903–14. Calabrese M, Bernardi V, Atzori M, et al. Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing–remitting multiple sclerosis. Mult Scler J 2012;18:418–24. Lublin FD, Cofield SS, Cutter GR, et al. Randomized study combining interferon and glatiramer acetate in multiple sclerosis. Ann Neurol 2013;73:327–40. La Mantia L, Vaona A, Rovaris M, et al. Interferon beta versus glatiramer acetate for relapsing-remitting multiple sclerosis. Cochrane Database of Syst Rev 2011;(9): CD009333.
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Comparative efficacy of interferon β 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 and Alberto Vaona J Neurol Neurosurg Psychiatry published online December 30, 2014
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JNNP Online First, published on December 30, 2014 as 10.1136/jnnp-2014-309243 Multiple sclerosis
REVIEW
Comparative efficacy of interferon β versus glatiramer acetate for relapsing-remitting multiple sclerosis Loredana La Mantia,1,2 Carlo Di Pietrantonj,3 Marco Rovaris,1 Giulio Rigon,4 Serena Frau,5 Francesco Berardo,6 Anna Gandini,7 Anna Longobardi,4 Bianca Weinstock-Guttman,8 Alberto Vaona4 For numbered affiliations see end of article. Correspondence to Dr Alberto Vaona, Primary Care, Azienda ULSS 20 Verona, Ospedale di Marzana, Piazzale Ruggero Lambranzi 1, Verona 37142, Italy; [email protected] Received 15 August 2014 Revised 4 November 2014 Accepted 25 November 2014
ABSTRACT Interferon β (INFβ) and glatiramer acetate (GA) are widely used in patients with relapsing–remitting multiple sclerosis (RRMS). However, it is still unclear whether they have different efficacy. We performed a systematic search of head-to-head trials for gaining objective reliable data to compare the two drugs, using the Cochrane Collaboration methodology. We identified five randomised-controlled trials (RCTs) (2858 participants) comparing directly INFβ versus GA in RRMS. All studies were at high risk for attrition bias. Both therapies showed similar efficacy at 24 months, considering clinical ( patients with relapse or progression) and one MRI activity (enhancing lesions) measure. At 3 years, evidence from a single study showed that the relapse rate was higher in the INFβ group than in the GA group (risk ratio 1.40, 95% CI 1.13 to 1.74, p 0.002). However, the average reduction in T2-weighted and T1-weighted lesion volume was significantly greater in the INFβ group than in the GA group (mean difference (MD) −0.58, 95% CI −0.99 to −0.18, p 0.004, and MD −0.20, 95% CI −0.33 to −0.07, p 0.003, respectively). The number of participants who dropped out of the studies because of adverse events was similar in the two groups. These data support clinicians in the use of these therapies, based on their similar safety and efficacy in the prevention of disease activity, although the different effect on MRI measures and the different tolerability might have a role in the therapeutic choice at the individual level.
BACKGROUND Glatiramer acetate (GA) and recombinant interferon β (INFβ) are used worldwide as treatments for relapsing–remitting multiple sclerosis (RRMS). Currently, there is no clear evidence to support physicians’ preferences regarding INFβ or GA treatment for their patients.
OBJECTIVE To cite: La Mantia L, Di Pietrantonj C, Rovaris M, et al. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/ jnnp-2014-309243
To determine, through a systematic review of head-to-head trials, whether INFβ and GA in RRMS have different efficacy and safety.
METHODS The review group used the Cochrane Collaboration methodology to identify all randomised active-
controlled trials (RCTs) directly comparing INFβ with GA in RRMS. The primary outcomes were: (1) number of participants who experienced at least one relapse; (2) number of participants who experienced worsening of at least a 0.5-point increase from starting Expanded Disability Status Scale (EDSS) score ≥5.5 or a 1-point increase from starting EDSS ≤5.0, confirmed at 6 months and (3) number of participants who withdrew from or dropped out of the study because of adverse events (AEs). The secondary outcomes included: frequency of relapses, changes in quality of life (QOL) and MRI measures of disease activity (number of new or enlarged T2-hyperintense lesions, of contrast-enhancing T1 lesions, mean change of total T2-hyperintense lesion load) and measures of disease progression (mean change of T1-hypointense lesion volume and total brain volume). The risk of bias in included studies was assessed independently by the review authors. A statistical analysis was performed using Review Manager (RevMan) software. For dichotomous data, the study results were summarised as risk ratios (RR), with 95% CIs, according to Mantel-Haenszel method and tested for overall effect Z. For continuous outcomes, weighted mean difference (MD) was assessed, using inverse variance methods and SE. Count outcomes were assessed by estimating log-RR and log-HR, using generic inverse variance of log estimates and SE. A between-study heterogeneity of findings was assessed using the I2 statistic. The results have been presented using the random effect model.
RESULTS Five RCTs have met our selection criteria: BECOME,1 BEYOND,2 REGARD,3 Calabrese4 and COMBIRX.5 All RCTs have included patients with RRMS with low disability (EDSS at entry 1.9–2.35) and active disease (frequency of relapse ≥1/year less marked for REGARD’s study)1–5 possibly related to slightly different inclusion criteria (table 1). The overall population considered in our analysis was 2.858 (1.679 patients treated with INFβ and 1.179 with GA). The drugs analysed in comparison with GA were INFβ-1b (2 trials, 933 participants),1 2 subcutaneous INFβ-1a 44 mg (2 trials, 441 participants)3 4 and intramuscular INFβ-1a 30 mg (2 trials,
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.
1
2
Characteristics of included trials
Study, year, countries (centres)
BEYOND (2009)2 USA, Europe, Australia (198)
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
REGARD (2008)3 Europa, USA, UK, Ireland Russia (81) Calabrese (2012)4 Italy (1)
COMBIRX 20135 US, Canada (68)
INFβ-1b 250 μg SC every other day GA 20 mg SC every day
36
INFβ-1b* 500 μg SC every other day INFβ-1b 250 μg SC every other day GA 20 mg SC every day INFβ-1a 44 μg SC 3 times/week GA 20 mg SC every day INFβ-1a 44 μg SC 3 times/week INFβ-1a 30 μg IM 1 time/week GA 20 mg SC every day INFβ-1a 30 μg IM 1 time/week GA 20 mg SC every day INF+GA* 30 μg IM 1 time/week +20 mg SC every day
899
39
897
Accrual period
Follow-up duration (months)
Not reported
24
Mean combined active lesion counts in the first year
November 2003–June 2005
24
Relapse risk
Age 18–60 at least one relapse in the year before entry EDSS 0–5.5 Naive patients
February– December 2004
24
Time to first relapse
New or worsening neurological symptoms, without fever, lasted ≥48 h, with change in FS score
Age 18–55 RRMS EDSS ≤5.0
January 2007–June 2008
24
Number of new cortical lesions
NR
Age 18–60 at least 2 exacerbations in the 3 years before entry, one exacerbation could be an MRI change EDSS 0–5.5
January 2005–April 2009
36
Annualised relapse rate
New symptom or worsening of an old symptom, attributable to MS, preceded by stability or improvement for at least 30 day and confirmed by the examining physician within 7 days of onset, without fever, lasted ≥24 h with decrease by ≥7 points in SNRS score or increase: A. in EDSS by ≥0.5 point or B. in 1 FS by ≥2 points or C. in ≥2 FS by ≥1 point
Inclusion criteria Age 18–55 at least one relapse in the 6 months before entry CIS with onset within 6 months plus evidence of dissemination EDSS 0–5.5 Age 18–55 at least one relapse in the year before entry EDSS 0–5 Naive patients
Primary Outcome
Relapse Definition New or worsening neurological symptoms , without fever or infection, lasted ≥24 h, with decrease by ≥7 points in SNRS score or increase: A. in EDSS by ≥0.5 point or B. in 1 FS by ≥2 points or C. in ≥2 FS by ≥1 point New or recurrent neurological abnormalities, separated by at least 30 days from the onset of the preceding event, without fever or infection, lasted ≥24 h, with increase in EDSS or FS scores appropriate to the symptoms
Disability Progression Definition
Sponsor
Increase of 1 EDSS point, or ≥0.2 SD in MSFC, sustained at 6 months
Bayer
Increase of 1 EDSS point, sustained at 3 months
Bayer
Increase of EDSS points, ≥1.5 (if basal EDSS=0) ≥1.0 (if basal EDSS=0.5−4.5) ≥0·5 (if basal EDSS ≥5) sustained at 6 months NR
Merck Serono
448
386
378
55
Merck Serono
55
55
250
259
499
Increase of EDSS points, ≥1.0 (if basal EDSS ≤5.0) ≥0·5 (if basal EDSS ≥5.5), sustained at 6 months
National Institutes of Health, National Institute of Neurological Disorders and Stroke
*This arm was not included in the analysis because the treatment schedule is not used in the clinical practice. CIS, Clinically Isolated Syndrome; EDSS, Expanded Disability Status Scale; FS, Functional System; GA, glatiramer acetate; INFβ, interferonsβ; IM, intramuscular; MSFC, Multiple Sclerosis Functional Composite; NR, not reported; RRMS, relapsing–remitting multiple sclerosis; SC, subcutaneous; SNRS, Scripps Neurological Rating Scale.
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BECOME (2009)1 US (2)
Interventions
No of Patients
Multiple sclerosis
Table 1
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Multiple sclerosis Table 2
Baseline characteristics of patients in the included trials
Study
Interventions
Age (years) Mean (SD)
BECOME1
INFβ-1b 250 μg GA 20 mg INFβ-1b 250 μg GA 20 mg INFβ-1a 44 μg GA 20 mg INFβ-1a 44 μg INFβ-1a 30 μg GA 20 mg INFβ-1a 30 μg GA 20 mg
36 (7.7) 36 (8.2) 35.8 (11.1) 35.2 (11.9) 36.7 (9.8) 36.8 (9.5) 35.9 (9.1) 34.8 (9.6) 38.9 (10.2) 37.6 (10.2) 39.0 (9.5)
BEYOND2 REGARD3 Calabrese4
COMBIRX5
Baseline EDSS Mean (SD)
Disease Duration (years) Mean (SD)
Prestudy Relapses Mean (SD)
2.0 2.0 2.3 2.3 2.3 2.3 1.9 1.9 2.1 2.0 1.9
0.9 (NR) 1.2 (NR) 5.3 (4.45) 5.1 (4.45) 5·9 (6·2) 6·5 (7·1) 5.7 (4.9) 5.3 (5.1) 5.5 (6.1) 1.4 (4.0) 1.0 (2.9)
1.8 (NR) 1.9 (NR) 1.6 (0.74) 1.6 (0.74) 0.97* (0.42) 1.01* (0.35) 1.2 (0.6) 1.2 (0.7) 1.3 (0.7) 1.7 (0.9) 1.6 (0.7)
(NR) (NR) (2) (2) (1.3) (1.3) (1.0) (0.8) (1.1) (1.2) (1.2)
*Pre two years. EDSS, Expanded Disability Status Scale; GA, glatiramer acetate; INFβ, interferonβ; NR, not reported.
305 participants).4 5 The treatment duration and follow-up were 3 years for the COMBIRX’s study and 2 years for the other four RCTs. Table 2 shows the characteristics of patients in the included trials. The attrition bias was the main biased dimension of all RCTs. The patients who dropped out were 13–30%, with higher proportion for IFNs group in four RCTs; the reasons for incompleteness were different and poorly described (table 3). The effects of interventions in terms of primary clinical efficacy outcomes were the following: 1) the number of patients who experienced at least one relapse was assessed in three trials at 24 months (2184 patients, 76% of participants) and in one trial5 at 36 months (509 patients, 18% participants). At 24 months, 38% and 36% of patients relapsed in the INFβ and GA groups, respectively. There were no significant differences in the effect at 24 months (RR 1.04, 95% CI 0.87 to 1.24) and 36 months (RR 1.27, 95% CI 0.92 to 1.75; figure 1A). (2) The number of patients with confirmed worsening was assessed by three trials at 24 months (2169 patients, 76% of participants). At 24 months, 16% and 15% of patients worsened in the INFβ and GA groups, respectively. No differences were found when confirmed progression was analysed either at 24 months (RR
1.11, 95% CI 0.91 to 1.35) or at 36 months (RR 0.87, 95% CI 0.63 to 1.20) (figure 1B). (3) The number of patients who withdrew from the study because of adverse events was 3% for IFNs and 4% for GA; the RR was 0.95 (95% CI 0.65 to 1.39), without significant differences between the two treatment groups. The relapse frequency (clinical secondary outcome) was similar at 24 months (RR 1.06, 95% CI 0.94 to 1.18), while at 36 months it was significantly higher in the INFβ group, thereby favouring GA (RR 1.40, 95% CI 1.13 to 1.74; figure 2A). Considering MRI outcome measures, mean T2 lesion volume increase was significantly lower in INFβ-treated than in GA-treated patients at 12 months as well as 24 months; the same difference was also present in 36-month data from a single study, but it did not reach statistical significance (figure 2B). No significant differences between INFβ and GA were found for number of contrast-enhancing T1 lesions, at 12 (MD −0.10, −0.26 to 0.06) as well as 24 months (MD −0.14, −0.30 to 0.02). Mean T1 lesion volume increase was significantly lower in INFβ-treated than in GA-treated patients at month 24 (MD −0.20, −0.33 to −0.07, p 0.003), while the mean brain volume reduction at 24 months was significantly higher in INFβ-treated than in
Table 3 Patients with incomplete outcome data Patients
Randomised N
Number of drop-out with reasons Drop-out
Lost to follow-up
N
N
Did not receive drug
Studyref
Interventions
BECOME1
INFβ-1b 250 μg GA 20 mg
36 39
11 8
30.6 20.5
7 4
19.4 10.3
BEYOND2
INFβ-1b 250 μg GA 20 mg
897 448
113 74
12.6 16.5
12 12
1.3 2.7
9 3
REGARD3
INFβ-1a 44 μg GA 20 mg
386 378
85 54
22.0 14.3
17 2
4.4 0.0
3 3
Calabrese4
INFβ-1a 44 μg INFβ-1a 30 μg GA 20 mg
55 55 55
9 8 7
16.4 14.5 12.7
9 8 7
16.4 14.5 12.7
COMBIRX5
INFβ-1a 30 μg GA 20 mg
250 259
56 36
22.4 13.9
13 9
5.2 3.5
Per cent*
Per cent*
Drug switches
Withdrawn
Protocol deviation
Adverse events
Died
Pregnancy
1 10 5
38 18
3 2
13 8
2 2
23 19
Other reasons 3 4
1
1 1
27 24
8 5
32 23
Not described
17 11
1 1
25 15
*On randomised population. GA, glatiramer acetate; INFβ, interferonsβ.
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
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Multiple sclerosis Figure 1 Number of patients who experienced (A) at least one relapse at the end of follow-up and (B) Expanded Disability Status Scale (EDSS) progression at the end of follow-up (24–36 months; GA, glatiramer acetate; IFNs, interferons).
GA-treated patients (MD −0.12, −0.23 to −0.01, p 0.04); the heterogeneity was significant (I2=83%; data not shown).
DISCUSSION The aim of this systematic review was to evaluate whether treatment with INFβ and GA in patients with RRMS differs in terms of efficacy and safety. We selected outcome measures evaluating changes in clinical and MRI activity, as well as in disability progression and disease burden accrual. The main conclusion is that the two therapies do not seem to differ in terms of clinical efficacy and safety, although IFNs were found to limit the increase of MRI lesion burden more than GA. All RCTs were at high risk for attrition bias: the percentage of drop-outs was higher in the INFβ group versus the GA group and related to different reasons (side effects, nonconsent, tolerability), although full details were not always provided. This aspect might have a role in the final assessment of effectiveness of these drugs. The results of this systematic review have several limitations: 1. We cannot exclude that non-homogeneous criteria for relapse definition and count as well as different inclusion criteria might constitute a bias in the outcome assessment; 2. The main comparison of this review was between GA and IFNs at high frequency and dosages; the evaluation of the 4
comparative effect of low versus high INFβ dosages and GA was limited by different time points assessment available; 3. The analysis of the safety profile was restricted to the number of participants who withdrew from or dropped out of the study; drug-related side effects were not considered because they had already been widely reported; 4. The main outcome measure not available for analysis was QOL, impairing the possibility to compare the drugs in terms of patient needs.
RECOMMENDATIONS These data support clinicians in the use of these therapies based on their similarities in safety and efficacy in the prevention of disease activity, although the different effects on some MRI measures and the different levels of tolerability might have a role in therapeutic choice at the individual level. The assessment of patient-related outcomes is warranted to take into account the needs of patients in the treatment choice. Concerning the quality of evidence, standardised sets of outcome measures, clear presentation of data and comparable MRI protocols for image acquisition and analysis may allow more accurate interpretation of trial results.
La Mantia L, et al. J Neurol Neurosurg Psychiatry 2014;0:1–5. doi:10.1136/jnnp-2014-309243
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Multiple sclerosis Figure 2 Clinical and MRI disease activity outcome measures. (A) Relapse rate at the end of follow-up (24–36 months). (B) Mean change of total T2-hyperintense lesion load at 12–2436 months.
Author affiliations 1 Unit of Neurorehabilitation—Multiple Sclerosis Center, IRCCS Santa Maria Nascente—Fondazione Don Gnocchi, Milano, Italy 2 Department of Neurosciences—Multiple Sclerosis Centre, AO Ospedale Niguarda Ca’ Granda, Milano, Italy 3 Regional Epidemiology Unit SeREMI- CochraneVaccines Field, Local Health Unit Alessandria—ASL AL, Alessandria, Italy 4 Primary Care, Azienda ULSS 20 Verona, Verona, Italy 5 Dialogo sui Farmaci Srl, Verona, Italy 6 Drug Efficacy Evaluation Unit (UVEF)—Veneto Regional Drug Information Center, Azienda Opsedaliera di Verona—Department of Pharmacy, Verona, Italy 7 Regional Health Service, Azienda ULSS 21—Legnago, Legnago, Italy 8 Director Jacobs MS Center and Pediatric MS Center of Excellence, SUNY University of Buffalo, Buffalo, New York, USA Contributors The study protocol was designed by all the authors; study selection was performed by AG, SF and LLM; analyses and interpretation of the results were carried out by LLM, CDP, AV and MR; and LLM wrote the paper and its revision was performed by AV. All the authors approved the final version of this paper. Competing interests MR received travel grants and compensations for consultancies from TEVA Italia, Biogen Italia, Novartis, Genzyme-Sanofi, Almirall and Bayer Schering.BW-G has participated in speaker’s bureaus and served as a consultant for Biogen Idec, Teva Neuroscience, EMD Serono, Novartis, Genzyme & Sanofi, Mylan Inc, and Acorda Therapeutics, Inc and has received grant/research support from the agencies listed in the previous sentence as well as Questcor
Pharmaceuticals Inc, and Shire. She serves in the editorial board for BMJ Neurology, Journal of International MS and Journal of Multiple Sclerosis. Provenance and peer review Not commissioned; externally peer reviewed.
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Comparative efficacy of interferon β 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 and Alberto Vaona J Neurol Neurosurg Psychiatry published online December 30, 2014
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