[Show abstract][Hide abstract] ABSTRACT: To expand current knowledge, we examined the safety and tolerability of subcutaneous interferon β-1a in patients with pediatric-onset multiple sclerosis. Records from 307 patients who had received at least 1 injection of subcutaneous interferon β-1a for demyelinating events when aged younger than 18 years were reviewed. Overall, 168 (54.7%) patients had at least 1 prespecified medical event related to or under close monitoring with subcutaneous interferon β-1a or specific to pediatric patients, 184 (59.9%) had nonserious medical events related to treatment or of unknown causality, and 12 (3.9%) had serious medical events irrespective of causality. The most common laboratory abnormalities were increased alanine (74/195; 37.9%) and aspartate aminotransferase levels (59/194; 30.4%). Annualized relapse rates were 1.79 before treatment and 0.47 during treatment. In conclusion, adult doses of subcutaneous interferon β-1a (44 and 22 μg, 3 times weekly) were well tolerated in pediatric patients and were associated with reduced relapse rates.
[Show abstract][Hide abstract] ABSTRACT: In patients presenting with a first clinical demyelinating event that is suggestive of multiple sclerosis (MS), treatment with interferon beta can delay the occurrence of further attacks and the onset of MS. We investigated the effects of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event.
We undertook a multicentre phase 3 study (REbif FLEXible dosing in early MS [REFLEX]) that included patients (aged 18-50 years) with a single clinical event suggestive of MS, and at least two clinically silent T2 lesions on brain MRI. Participants were randomly assigned in a 1:1:1 ratio by use of a centralised interactive voice response system to receive the serum-free formulation of subcutaneous interferon beta-1a 44 μg three times a week or once a week (plus placebo twice a week for masking), or placebo three times a week for up to 24 months. Patients and physicians were masked to group allocation. The primary endpoint was time to a diagnosis of MS as defined by the 2005 McDonald criteria and the main secondary endpoint was time to clinically definite MS (CDMS) as defined by the Poser criteria. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00404352.
517 patients were randomly assigned (171 to subcutaneous interferon beta-1a three times a week, 175 to subcutaneous interferon beta-1a once a week, and 171 to placebo) and 515 were treated. The 2-year cumulative probability of McDonald MS was significantly lower in patients treated with subcutaneous interferon beta-1a (three times a week 62·5%, p<0·0001, hazard ratio [HR] 0·49 [95% CI 0·38-0·64]; once a week 75·5%, p=0·008, HR 0·69 [0·54-0·87]) versus placebo (85·8%). 2-year rates of conversion to CDMS were lower for both interferon beta-1a dosing regimens (three times a week 20·6%, p=0·0004, HR 0·48 [0·31-0·73]; once a week 21·6%, p=0·0023, HR 0·53 [0·35-0·79]) than for placebo (37·5%). Adverse events were within the established profile for subcutaneous interferon beta-1a.
Both regimens of subcutaneous interferon beta-1a delayed clinical relapses and subclinical disease activity. The potential differences between the regimens warrant longer-term study.
Merck Serono SA, Geneva, Switzerland.
The Lancet Neurology 12/2011; 11(1):33-41. DOI:10.1016/S1474-4422(11)70262-9 · 21.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In multiple sclerosis (MS), the aim of therapies is to prevent the accumulation of irreversible disability. This is difficult to assess given the short time course of clinical trials. MRI markers and relapses are often used as surrogate of disability in MS studies, but their validity remains controversial. We sought to validate, at the individual patient level, MRI lesions and relapses as surrogates for disability progression over the course of MS trials.
Individual patient data from a large, placebo-controlled trial of interferon β-1a in relapsing-remitting MS (RRMS) were analyzed. The Prentice criteria were applied to evaluate surrogacy of 1-year MRI active lesions and relapses for disability worsening (Expanded Disability Status Scale [EDSS]) over the 2-year follow-up.
All Prentice criteria were satisfied. Treatment reduced by 31% the odds of having EDSS worsening over 2 years, reducing the mean number of MRI lesions by 61% and the mean number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on 2-year EDSS worsening. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years.
A combined measure of 1-year changes in MRI lesions and relapses after interferon therapy fully estimated the corresponding effect on 2-year EDSS worsening. This short-term combined measure appears to be a surrogate for disability progression over a longer term when evaluating the effect of interferon in RRMS.
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
In multiple sclerosis (MS), the ultimate aim of therapies is to prevent the accumulation of irreversible disability. This may be difficult to assess given the short time course of clinical trials. Magnetic resonance imaging (MRI) outcomes and relapses are often used as surrogates of disability progression in MS studies, but their validity remains controversial.We sought to validate, at the individual-patient level, the number of MRI active lesions and clinical relapses as surrogate endpoints for worsening of disability measured over the course of MS clinical trials.Individual-patient data from a large placebo-controlled clinical trial of subcutaneous interferon beta-1a in patients with relapsing–remitting (RR) MS (the PRISMS [Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis] study) were analysed. The four Prentice criteria were applied to evaluate surrogacy of MRI active lesions and relapses assessed in the shorter term (1 year) for disability worsening (measured as Expanded Disability Status Scale, EDSS) over the follow-up (2 years).
All Prentice criteria were satisfied. Treatment reduced by 31% the proportion of patients with EDSS worsening over 2 years, reducing the number of MRI active lesions by 61%, and the number of relapses by 36% over 1 year. Both 1-year MRI lesion activity and relapses, when considered independently, accounted for more than 60% of the treatment effect on EDSS worsening over 2 years. A combination of 1-year MRI lesion activity and relapses explained 100% of the treatment effect on EDSS worsening over 2 years.A combined measure of shorter-term changes in MRI active lesions and relapses over the first year of interferon therapy fully estimated the corresponding effect on worsening of disability over 2 years in patients with RRMS, and appears to be a perfect surrogate for clinical disability progression over a longer term when evaluating the therapeutic effect of interferon.
21st Meeting of the European Neurological Society 2011; 07/2011
[Show abstract][Hide abstract] ABSTRACT: Use of quantitative magnetic resonance imaging (MRI) metrics as surrogates for clinical outcomes in multiple sclerosis (MS) trials is controversial.
We sought to validate, at the individual-patient level, the number of MRI active lesions, as a surrogate marker for relapses in MS.
Individual-patient data from two large, placebo-controlled clinical trials of subcutaneous interferon β-1a in patients with relapsing-remitting or secondary progressive (SP) MS were analysed separately and as pooled data. The four Prentice criteria were applied to assess surrogacy for the number of new T2 MRI lesions. The predictive value of short-term treatment effects on this MRI marker for longer-term clinical relapses was also assessed.
All Prentice criteria were satisfied. The number of new T2 MRI lesions correlated with the number of relapses over the follow-up period. The proportion of treatment effect on relapses accounted for by the effect of treatment on new T2 MRI lesions over 2 years was 53% in patients with relapsing-remitting MS, 67% in patients with secondary progressive MS, and 62% in pooled data. In the pooled data, treatment effects on new lesions over 1 year mediated a good proportion (70%) of effects on relapses over the subsequent year.
This study provides evidence that new T2 MRI lesion count is a surrogate for relapses in patients with MS treated with interferon or drugs with a similar mechanism of action. Short-term treatment effects on this MRI measure can predict longer-term effects on relapses.