Application of Interferon Beta-1b in Multiple Sclerosis • •


each patient serves as his/her own control, thus minimising the effect of inter-patient variability in measuring drug effect; and it generally requires a smaller number of subjects.


However, at the same time BVT studies eliminate the blinding component of the RCT, thus potentially introducing the so-called Pygmalion type of bias. In MS, studies of this led to the initial identification of IFNβ-1b’s efficacy in decreasing the number of active lesions or CELs within individual patients.


Presently, in patients with MS, placebo-controlled trials can still ethically be prepared, but with restrictions. Specifically, for MS patients for whom established effective therapies exist, placebo- controlled trials should only be offered with rigorous informed consent if the patients refuse any of the existing therapies, have not responded to them, or if these treatments are not available for other reasons, such as cost.19


Interferon Beta-1b Effects on Clinical and Imaging Disease Parameters This section discusses the effects of IFNβ-1b on clinical and imaging measures of disease seen in the main clinical trials. Clinical and imaging findings will be presented separately. For each type of finding, evidence obtained in each patient subgroup, i.e. CIS, RRMS and SPMS with and without superimposed relapses and PPMS, is discussed.


In the majority of clinical trials and post-marketing studies, IFNβ-1b has been administered at a dosage of 8 million international units, equivalent to 250µg, subcutaneously every other day (EOD). For the purpose of this review, this dosage is always referred to as the as standard dose unless otherwise indicated. In addition, when specifying that the effects of the drug were found to be significant, a p-value ≤0.05 is always referred to. Readers are advised to consult the individual papers referred to for additional details regarding the magnitude of alpha error of each study.


Clinical Measures Frequency and Severity of Clinical Relapses


When looking at differences in clinical relapse rate between patients treated with IFNβ-1b and patients in the placebo group, a statistically significant reduction was seen and maintained over the course of two-year observational periods in patients with CIS,20 and SPMS with superimposed relapses.22 every seven RRMS21


RRMS21 or one in every nine CIS20


On average, one in patients will remain


relapse-free for two years if treated with 250µg IFNβ-1b. It is important to highlight that when a greater proportion of CIS patients remain relapse-free, ultimately a greater proportion have a delay in time to conversion to MS.20


Such reductions, to some extent dose-dependent,21 are attributable to


an average two-fold decrease in the frequency of moderate and severe attacks in treated versus untreated patients. Subcutaneous administrations of 250µg IFNβ-1b EOD had greater efficacy than 50µg EOD.21


On clinical relapse, 250µg IFNβ-1b was not inferior to:


• 500µg subcutaneous IFNβ-1b EOD;23 • 22µg IFNβ-1a subcutaneously once weekly;24 • 44µg IFNβ-1a subcutaneously three times per week; or25 •


20mg subcutaneous glatimerar acetate (GA) daily23 EUROPEAN NEUROLOGICAL REVIEW


The greater efficacy of standard doses of IFNβ-1b over 30µg IFNβ-1a given intramuscularly once weekly has been proven.25,27


In SPMS


patients without superimposed relapses, IFNβ-1b 250µg or 160µg/m2 body surface area administered EOD significantly decreased the number of clinical attacks over a time period of up to two years.28


Observational periods longer than two years have provided controversial results. In CIS patients, early treatment with 250µg IFNβ-1b maintained a reduced annualised relapse rate for only one additional year, but not from year four of therapy onwards versus patients starting therapy two years later.29


In RRMS patients, a


one-third reduction in exacerbation rate was maintained for up to five years versus placebo.30


Differences in mean yearly exacerbation rate


between patients treated with a standard dose of IFNβ-1b and those treated with either 50µg subcutaneous IFNβ-1b EOD or placebo only remained statistically significant until the end of the second year of therapy.30


Conversely, a lower rate of severe versus moderate relapses was seen throughout five years in the standard-dose group.30 In SPMS patients with superimposed relapses, a statistically relevant decrease in mean relapse rate was sustained for up to four years in treated patients.31


Disability Progression


When one looks at the effect of a given drug in reducing disability progression, two important considerations need be kept in mind. First, disability changes during therapy might be linked to the indirect effect of a given drug in reducing the number and severity of clinical relapses, thereby leading to slower or lower accumulation of disability over time. Second, changes in disability might be due to a direct effect of the drug in promoting faster and more efficient remyelination or relenting demyelination. This will favor slower and less pronounced disability accumulation independently from the effect of reducing clinical relapse.


Compared with placebo, 250μg subcutaneous IFNβ-1b EoD over a two-year time period significantly reduced the proportion of patients experiencing a sustained progression in disability among those with CIS, RRMS and SPMS with superimposed relapses.20,21,22 with relapse rate, 250µg was superior to 50µg administered EOD21


As seen but


was not inferior to the following subcutaneous regimens for remaining free from disability progression or having relevant beneficial changes in EDSS during therapy: 500µg IFNβ-1b EOD,23 weekly24


and 44µg IFNβ-1a three times per week.25 or EOD26


22µg IFNβ-1a once Interestingly, on


measures of disability progression by EDSS scores, 250µg subcutaneous IFNβ-1b EOD was superior to 20mg subuctaneous GA daily23


and 30µg intramuscular IFNβ-1a weekly.24,27 None of the


effects of IFNβ-1b on physical disability were seen in patients with SPMS without superimposed relapses28


or in those with PPMS.32 It is


important to highlight that although IFNβ-1b keeps a higher number of patients free from disability progression, it does not necessarily imply that the EDSS scores of treated versus untreated patients or patients before and after therapy are statistically different.


Few studies have looked at the effect of IFNβ-1b on MSFC score. Over a two-year observational period, a significant improvement in MSFC score was seen in patients with PPMS treated with IFNβ-1b compared with those taking placebo.32


or EOD.26


This improvement was not


maintained beyond three months after drug discontinuation. Nor was MSFC score paralleled by improvement in other cognitive tests evaluating verbal fluency and processing speed. Conversely, in


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