Interferon Treatments In Multiple Sclerosis 2g2

Background
Interferon-beta-1a (IFN-ß-1a; Avonex) is effective for the treatment of Relapsing MS; however, the optimal dose of IFN-ß-1a is not known.

Objective
To determine whether IFN-ß-1a 60 micro g IM once weekly is more effective than IFN-ß-1a 30 micro g IM once weekly in reducing disability progression in Relapsing MS.

Methods
In a double-blind, parallel-group, dose-comparison study, 802 patients with Relapsing MS from 38 centers in Europe were randomized to IFN-ß-1a 30 micro g (n = 402) or 60 micro g (n = 400) IM once weekly for >/=36 months.

The primary endpoint was disability progression, defined as time to a sustained increase of >/=1.0 point on the Expanded Disability Status Scale (EDSS) persisting for 6 months.

Additional endpoints included relapses, MRI, safety, immunogenicity, and subgroup analyzes of disability progression.

Results
Both groups showed equal rates of disability progression (hazard ratio, 0.96; 95% CI, 0.77 to 1.20; p = 0.73).

In both groups the proportion of subjects with progression of disability by 36 months estimated from Kaplan-Meier curves was 37%. No dose effects were observed on any of the secondary clinical endpoints.

Only one MRI measure at one time point, number of new or enlarging T₂ lesions at month 36 compared with month 24, showed a difference favoring the 60- micro g dose.

Both doses were well tolerated; however, slightly higher incidences of Flulike symptoms and muscle weakness were observed in the 60- micro g group.

The incidences of Neutralizing AntiBodies (titers >/= 20) were 2.3% in the 30- micro g group and 5.8% in the 60- micro g group.

Conclusion
There was no difference between (Avonex) IFN-ß-1a 30 micro g and 60 micro g IM in clinical or MRI measures.

Background
Interferon-beta (IFN-ß) reduces relapses and MRI activity in Relapsing/Remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial.

Methods
This randomized, controlled, multicenter trial compared the efficacy and safety of IFN-ß-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFN-ß-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS.

Assessors blinded to treatment performed Neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks.

Results
After 24 weeks, 74.9% (254/339) of patients receiving IFN-ß-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw.

The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw.

Patients receiving 44 micro g tiw (Rebif) had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw (Avonex).

Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of Liver Enzymes (18% vs 9%, p = 0.002) and altered Leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage.

Neutralizing AntiBodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw.

Conclusions
Rebif (44 micro g subcutaneously tiw) was more effective than Avonex (30 micro g qw) on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.

Recent advances in therapy for Multiple Sclerosis (MS) have centred on the use of the disease-modifying drugs Glatiramer Acetate (GA) and Interferon-beta (Interferon-ß).

Several large-scale clinical trials have been carried out on the use of these compounds, but there have been few studies that have directly compared their efficacy in MS.

Furthermore, there has been controversy and confusion over the IFN-ß therapy regimen that will achieve the best possible clinical outcome for MS patients.

This review focuses principally on clinical trials of IFN-ß-1a, where data that allow direct comparison of different treatment regimens are now available.

Current data indicate that IFN-ß, and in particular IFN-ß-1a, has important advantages over GA in the treatment of Relapsing/Remitting MS (RRMS).

Additionally, IFN-ß-1a (Rebif, Serono), 44 microg administered subcutaneously (s.c.) three times weekly (t.i.w.), is significantly more effective than IFN-ß-1a (Avonex, Biogen), 30 microg administered intramuscularly once weekly.

For optimal management of RRMS, treatment with (Rebif) IFN-ß-1a, 44 microg s.c. t.i.w., should begin as early as possible after diagnosis.

The objectives were twofold to:
1. Explore a possible association between Major Depression and treatment with Interferon-ß-1b in patients with Multiple Sclerosis; and
2. Investigate whether putative antecedent risk factors such as a previous Psychiatric history and a family history of affective illness influence the prevalence of Major Depression post-treatment with Interferon-ß-1b.

Forty-two patients with Relapsing/Remitting MS underwent Neurological Examination and were interviewed with the Structured Clinical Interview for Axis 1 DSM-IV Disorders prior to starting Interferon-ß-1b and thereafter at 3, 6 and 12 months.

Ethical considerations dictated that patients diagnosed with Major Depression received anti-depressant medication.

At index assessment, 21.4 % of the sample were diagnosed with a Major Depression, the figures falling to 17.5 %, 11.4 % and 6.3 % at 3, 6 and 12 months respectively. The majority of subjects with a Major Depression had a history of Psychiatric illness prior to treatment with Interferon-ß-1b.

A family history of Affective Disorder was not associated with a significantly increased rate of major depression either before or after treatment with Interferon-ß-1b.

While the study's methodology did not address causality, the data demonstrate that Major Depression post-treatment with Interferon-ß-1b is linked to a history of Psychiatric illness prior to starting treatment.

The threefold decline in prevalence rates for Major Depression over the course of a year demonstrates a good response to AntiDepressant medication and possible beneficial effects of Interferon-ß-1b on mood.

The objective of this work was to assess the effect of Interferon-beta-1a (Avonex) on the rate of development of Clinically Definite Multiple Sclerosis and Brain Magnetic Resonance Imaging changes in subgroups.

Based on type of presenting event, baseline Brain Magnetic Resonance Imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial.

After the onset of a first DeMyelinating event, 383 patients with Brain Magnetic Resonance Imaging evidence of SubClinical DeMyelination were treated with CorticoSteroids and randomly assigned to receive weekly intramuscular injections of 30 microg Interferon-ß-1a or placebo.

The treatment effect within subgroups was assessed in proportional hazards models both for the development of Clinically Definite Multiple Sclerosis and for a combined outcome of development of Clinically Definite Multiple Sclerosis or >1 new or enlarging T₂ lesions on Brain Magnetic Resonance Imaging.

A beneficial effect of treatment was noted in all subgroups evaluated.

Adjusted rate ratios for the development of Clinically Definite Multiple Sclerosis in the Optic Neuritis, BrainStem-Cerebellar, and Spinal Cord Syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01).

And, for the development of the combined Clinically Definite Multiple Sclerosis/Magnetic Resonance Imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively.

A treatment benefit on both outcome measures also was seen in subgroups based on baseline Brain Magnetic Resonance Imaging parameters, gender, and age.

Interferon-ß-1a is beneficial when initiated at the first clinical DeMyelinating event (CIS) in patients with Brain Magnetic Resonance Imaging evidence of SubClinical DeMyelination.

The beneficial effect is present for Optic Neuritis, BrainStem-Cerebellar Syndromes, and Spinal Cord Syndromes.

Objective
To examine MRI changes resulting from treatment of Secondary/Progressive MS (SPMS) with two doses of Interferon-ß-1a (Rebif).

Background
Interferon-beta (IFN-ß) reduces relapses and delays progression in Relapsing/Remitting MS, but there are conflicting results on its clinical benefit in SPMS.

Methods
In a double-blind, randomized, multicenter, placebo-controlled study (SPECTRIMS), 618 patients received IFN-ß-1a 22 microg, 44 microg, or placebo subcutaneously three times weekly for 3 years.

T₂ activity and Burden Of Disease (BOD) were measured in 617 patients by using semiannual Proton Density/T₂-weighted (PD/T₂) MRI scans.

A cohort of 283 patients also had 11 monthly PD/T₂ and T₁-weighted Gadolinium-enhanced (T₁-Gd) scans at study start.

Results
Treatment reduced median numbers of active lesions per patient per scan (semiannual T₂ activity: 0.17, 0.20 and 0.67 for the high dose, low dose, and placebo, p < 0.0001.

Monthly combined unique activity [T₁+T₂]: 0.11, 0.22, and 1.00, p < 0.0001) and accumulation of BOD (percent change from baseline to month 36: -1.3, -0.5, and 10.0 for the high dose, low dose, and placebo, respectively; p = 0.0001).

MRI benefit was most evident in the subgroup of patients who reported relapses in the 2 years before the study.

Neutrailzing AntiBody development was associated with reduction in treatment effect: AntiBody-positive patients did not show significant differences from placebo at either dose.

Conclusions
Interferon-ß-1a (Rebif) used in SPMS showed significant effects on all MRI measures, particularly in patients with relapses in the 2 years before the study.

Background
The beneficial effect of Interferon-ß on exacerbations in Relapsing/Remitting MS has been demonstrated repeatedly, but results concerning disability vary.

Objective
This multicenter, randomized, parallel-group, placebo-controlled study tested two doses of Interferon-ß-1a in patients with Secondary/Progressive MS (SPMS), which may include relapses but is dominated by accumulating disability.

Methods
A total of 618 patients received subcutaneous placebo or Interferon-ß-1a, 22 or 44 microg (Ribif) three times weekly for 3 years. Patients were assessed every 3 months.

Results
The primary outcome, time to confirmed progression in disability, was not significantly affected by treatment (hazard ratio, 0.83; 95% CI, 0.65 to 1.07; p = 0.146 for 44 microg versus placebo).

Relapse rate was reduced from 0.71 per year with placebo to 0.50 per year with treatment (p < 0.001 for both doses).

Significant treatment effects were seen on other exacerbation-related outcomes and on a composite measure incorporating five separate clinical and MRI outcomes.

The hazard ratio for time to progression for the combined Interferon-ß-1a groups compared with placebo was 0.74 among patients reporting relapses in the 2 years before study (p = 0.055).

And, 1.01 for those without prestudy relapses (p = 0.934). An unexpected treatment-by-sex interaction favored women. The drug was well tolerated.

Conclusions
Treatment with Interferon-ß-1a did not significantly affect disability progression in this cohort, although significant treatment benefit was observed on exacerbation-related outcomes.

Exploratory post hoc analyzes suggested greater benefit in women and in patients who had reported at least one relapse in the 2 years before the study.

Background
The PRISMS study demonstrated significant clinical and MRI benefit at 2 years for Interferon-ß-1a, 22 and 44 mcg thrice weekly (tiw), compared with placebo in Relapsing/Remitting MS.

Years 3 and 4 extension study results are reported.

Methods
Patients initially receiving placebo were randomized to blinded Interferon-ß-1a, 22 or 44 mcg tiw (n = 172; crossover group); others continued blinded treatment with their originally assigned dose, 22 mcg (Rx22 group) or 44 mcg (Rx44 group) tiw (n = 167 per group).

Patients had 3- to 6-month clinical and annual MRI assessments.

Results
Relapse rates for 4 years were 1.02 (crossover), 0.80 (Rx22, p < 0.001), and 0.72 (Rx44, p < 0.001); the dose effect approached significance (p = 0.069; risk ratio, 0.88; 95% CI, 0.76-1.01).

Crossover groups showed reductions in relapse count, MRI activity, and lesion-burden accumulation with Interferon-ß-1a compared with their placebo period (p < 0.001 both doses).

Time to sustained disability progression was prolonged by 18 months in the Rx44 group compared with the crossover group (p = 0.047).

Rx22 and Rx44 reduced new T₂ lesion number and lesion burden compared with crossover (p < 0.001); Rx44 was superior to Rx22 on several clinical and MRI outcomes.

Persistent Neutralizing AntiBodies developed in 14.3% (Rx44) and 23.7% (Rx22) of patients and were associated with reduced efficacy.

Conclusions
Clinical and MRI benefit continued for both doses up to 4 years, with evidence of dose response.

Outcomes were consistently better for patients treated for 4 years than for patients in crossover groups. Efficacy decreased with Neutrailzing AntiBody formation.

Background
Interferon-ß reduces activity in Multiple Sclerosis as measured clinically and by Magnetic Resonance Imaging (MRI).

We assessed the effect of Interferon-ß-1a (Rebif) on the occurrence of relapses in patients after first presentation with Neurological events, who are at high risk of conversion to Clinically Definite Multiple Sclerosis.

Methods
Eligible patients had had a first episode of Neurological dysfunction suggesting Multiple Sclerosis (CIS) within the previous 3 months and had strongly suggestive Brain MRI findings.

Patients were randomly assigned Interferon-ß-1a 22 microg (Ribif) or placebo subcutaneously once weekly for 2 years.

Neurological and Clinical assessments were done every 6 months and Brain MRI every 12 months. Analyzes excluded one patient assigned placebo who received no study injections.

Findings
241 (78%) of 308 randomized patients received study treatment for 2 years; 278 (90%) remained in the study until termination.

57 (85%) of 67 who stopped therapy did so after conversion to Clinically Definite Multiple Sclerosis. Fewer patients developed Clinically Definite Multiple Sclerosis in the Interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047).

The time at which 30% of patients had converted to Clinically Definite Multiple Sclerosis was 569 days in the Interferon group and 252 in the placebo group (p=0.034).

The annual relapse rates were 0.33 and 0.43 (p=0.045). The number of new T₂-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment.

Interpretation
Interferon-ß-1a (Rebif) treatment at an early stage of Multiple Sclerosis had significant positive effects on clinical and MRI outcomes.

In a survey of disease course, the efficacy and tolerability of 24-month Interferon-ß-1b (Betaferon) therapy for Relapsing/Remitting Multiple Sclerosis (RRMS) were evaluated in 410 patients.

The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions.

In the 241 patients still on therapy, efficacy was rated after 24 months as "good" or "very good" in 75% of cases.

After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%). Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year.

In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the Extended Disability Status Scale (EDSS). This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials.

This postmarketing survey supports data from the published controlled (Betaferon) Interferon-ß-1b studies and confirms the main effects of this therapy under routine conditions in general practice.

Objective
To compare efficacy of (Rebif) Interferon-ß-1a, 22 microg or 44 microg weekly, with placebo in Relapsing MS.

Background
Uncertainty exists concerning the optimal dose regimen for Interferon-ß in Relapsing/Remitting MS.

Many patients and physicians prefer the convenience and lesser side effects of an injection given once weekly (qw) as opposed to three times weekly. Pharmacokinetic data and information on biologic markers suggest that this frequency may be suboptimal.

Methods
Randomized, double-blind study of Interferon-ß-1a 22 microg, 44 microg, or placebo administered by weekly subcutaneous injection for 48 weeks.

Proton density (PD)/T₂-weighted and T₁-weighted-Gadolinium MRI scans during 24 weeks of therapy were analyzed for the number of Combined Unique (CU) lesions (primary outcome).

Biannual PD/T₂ scans were analyzed for T₂ activity and Burden Of Disease (BOD).

Results
CU lesions at 24 weeks had a median of 0.71/scan with placebo, 0.50/scan with 22 microg (not significant), and 0.33/scan with 44 microg (p = 0.002).

T₂ new lesion count/scan (mean/median) at 48 weeks was 3.2/1.5 for placebo, 2.4/1.0 for 22 microg (p = 0.03), and 1.5/1.0 for 44 microg (p = 0.0005).

BOD at 48 weeks showed a median increase of 5.9% for placebo compared with a decrease of 1.4% in the 44 microg group (p = 0.0058) and 2% in the 22 microg group (p = 0.0018).

No clinical variable, apart from Steroid use in the 44 microg qw group (p = 0.014), showed significance.

Conclusions
These data confirm an MRI benefit of Interferon-ß-1a at low dose in MS, but highlight the limited clinical effect.

Taken together with other studies, the data demonstrate a dose-effect relationship for both clinical and MRI variables.

Interferon-beta (IFN-ß) reduces exacerbation rates in patients with Relapsing/Remitting Multiple Sclerosis (MS), but some patients do not respond to treatment.

Recent studies have shown a clear dose-response effect on the reduction of exacerbation rates, and on burden of disease accumulation and active lesion frequency seen on MRI.

During treatment with 8 MIU IFN-ß we noticed a 30% rate of treatment failure.

We then treated non-responders with 12 MIU IFN-ß and observed significant improvement in the clinical signs of disease activity.

In order to compare the efficacy of two different doses of IFN-ß-1b, a multicenter study for the optimization of Interferon for MS (OPTIMS) has been organized. The design of the study is presented here.