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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.
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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 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).
Characteristics of included trials
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 µg (2 trials, 441 participants)3 ,4 and intramuscular INFβ-1a 30 µg (2 trials, 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.
Baseline 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).
Patients with incomplete outcome data
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.
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).
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).
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 12–24-36 months.
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 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, non-consent, 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:
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;
The main comparison of this review was between GA and IFNs at high frequency and dosages; the evaluation of the comparative effect of low versus high INFβ dosages and GA was limited by different time points assessment available;
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;
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.
Footnotes
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.