A Retrospective, Observational Study Comparing The Four Available ImmunoModulatory Treatments For Relapsing/Remitting Multiple Sclerosis
Carra A, Onaha P, Sinay V, Alvarez F, Luetic G, Bettinelli R, San Pedro E, Rodriguez L
Eur J Neurol 2003 Nov;10(6):671-6
Hospital Britanico Buenos Aires, Argentina
We performed an observational, retrospective analysis of outcome in a sequential cohort of patients with Relapsing/Remitting Multiple Sclerosis (RRMS) in Argentina.
Patients treated for 16 months with Interferon-ß-1a (Avonex; 30 micrograms intramuscularly, once a week), Interferon-ß-1a (Rebif); 44 micrograms subcutaneously, thrice weekly), Interferon-beta-1b (Betaferon; 250 micrograms subcutaneously, every other day) or Glatiramer Acetate (Copaxone; 20 mg subcutaneously daily) were compared with a non-treated group of patients.
The different treatment groups were similar in baseline demographic and clinical variables.
A significant fall in the annual relapse rate was observed for all four treatments, with the largest effect observed with Glatiramer Acetate (81% reduction in relapse rate, compared with pre-treatment values).
The proportion of patients remaining relapse-free for the entire 16-month treatment period varied from 37% in untreated patients to 83% in the Glatiramer Acetate treated group. No statistically significant changes in disability scores were observed over the treatment period.
This first such comparative study in Latin America shows that treatment of Multiple Sclerosis patients with ImmunoModulatory therapies in the context of current standards of care in Argentina provides clinically important benefit, and suggest that some of these therapies may be better than others.
Oral Interferon-beta-1a In Relapsing/Remitting Multiple Sclerosis: A Double-Blind Randomized Study
European Oral Interferon-beta-1a in Relapsing/Remitting MS Study Group
Polman C, Barkhof F, Kappos L, Pozzilli C, Sandbrink R, Dahlke F, Jakobs P, Lorenz A
Mult Scler 2003 Aug;9(4):342-8
Free University Medical Center, Department of Neurology, de Boelelaan 1117, NL-1007 MB Amsterdam, The Netherlands
Interferon-beta (IFN-ß) is available in parenteral formulations for treatment of Multiple Sclerosis (MS).
The purpose of this study was to evaluate safety, tolerability and effects on MRI lesions of three different doses of oral IFN-ß-1a compared with placebo over six months in Relapsing/Remitting (RR) MS patients.
In this multicenter; double-blind randomized trial, RR-MS patients received 0.06, 0.6 or 6 million international units (MIU) IFN-ß-1a or placebo every other day for up to six months.
Gadolinium DTPA-enhanced Brain MRI scans were performed at screening and monthly during treatment.
The primary variable was the cumulative number of newly active lesions. Secondary variables included volume of enhancing lesions on T1-weighted images each month and lesion volume on T2-weighted images at months three and six.
Safety measures included adverse events, laboratory variables, vital signs, ECG, physical examination, EDSS and number of relapses. Neopterin was measured in 21 patients and Neutralizing AntiBodies in 24 patients.
Of 194 screened patients, 173 were randomized (42-44 patients per group) in 15 centers.
Median cumulative numbers of newly active lesions over six months were 4.0 in the placebo and 0.6 MIU groups, compared with 7.5 and 9.0 in the 0.06 and 6 MIU groups (no significant differences).
Secondary efficacy endpoints showed small and inconsistent differences between groups. Adverse events showed no notable group differences.
Approximately two-thirds of patients in each group remained relapse free. No patients showed Neutralizing AntiBodies. Neopterin levels were comparable between groups.
Oral IFN-ß-1a showed neither beneficial effects in RRMS nor any systemic biological effects. Treatment was safe and well tolerated.
Management Of Multiple Sclerosis: Current Trials And Future Options
Curr Opin Neurol 2003 Jun;16(3):289-97
Mayo Medical School, Clinic and Foundation, Department of Neurology, Rochester, Minnesota 55905, USA
Purpose Of The Review
The present review of Multiple Sclerosis (MS) therapeutic trials published in 2002 is intended to assist the reader in understanding the most current advances in the care of their patients.
A substantial number of pivotal and preliminary reports continue to demonstrate encouraging new evidence that advances are being made in the care of patients with MS.
Several short-term studies in Relapsing/Remitting MS have demonstrated that it is possible to complete head-to-head comparison trials of active agents in MS (e.g. without a placebo control group).
The findings of these trials remain open to interpretation and have generated considerable controversy, as expected.
A phase 3 trial [the International MS Secondary/Progressive Avonex Controlled Trial (IMPACT)] became the fourth study of the beta-Interferons (Interferon-beta-1a, in this case) to demonstrate a partial effect on disease activity in Secondary/Progressive MS.
Two trials demonstrated apparent partial efficacy for the anthrecenedione Mitoxantrone in active and Progressive MS.
Disappointing results were announced for a number of large pivotal trials, although those results have not yet been published (e.g. oral Glatiramer Acetate in Relapsing/Remitting MS, Glatiramer Acetate in Primary/Progressive MS, and IntraVenous ImmunoGlobulin in Secondary/Progressive MS).
The MS research community needs to determine how best to address two key unanswered questions. Is late clinical deterioration often or invariably tied to the initial Inflammatory/DeMyelinating phase of the disease?
What is the optimal research design to address whether current and future experimental strategies affect the later phases of MS (e.g. does early treatment delay or prevent clinical disability)?
Beta-Interferon Treatment Does Not Always Slow The Progression Of Axonal Injury In Multiple Sclerosis
A. Parry, R. Corkill, A. M. Blamire, J. Palace, S. Narayanan, D. Arnold, P. Styles, P. M. Matthews
J Neurol 2003 Feb;250(2):171-8
Centre for Functional Magnetic Resonance Imaging of the Brain, The John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
Progression of disability in Multiple Sclerosis (MS) appears related to Axonal damage, which is at least in part associated with White Matter lesions.
Beta-Interferon (BIFN) substantially reduces new inflammatory activity in MS and a recent report suggested that it may reverse a component of Axonal injury.
To test the feasibility of this conclusion, particularly in a population with relatively active disease, we used Magnetic Resonance Spectroscopy measures, to test whether BIFN can reverse or arrest progression of Axonal injury in patients with MS.
Eleven patients with a history of active (median, 1.5 relapses/year) Relapsing/Remitting MS were treated with BIFN and responses to treatment were monitored with serial MRI and single voxel Magnetic Resonance Spectroscopic measurements of relative concentrations of Brain N-AcetylAspartate (NAA).
A measure of Axonal integrity from a Central, predominantly White Matter Brain region. BIFN treatment was associated with a significant reduction in relapse rate (p = 0.007) and White Matter water T2 relaxation time (p = 0.047) over 12 months.
Also consistent with a treatment effect, White Matter T2-HyperIntense lesion loads did not increase.
However, the Central White Matter NAA/Creatine ratio (NAA/Cr, which was reduced over 16 % in patients relative to healthy controls at the start of treatment), continued to decrease in the patients over the period of observation (mean 6.2 % decrease, p = 0.02).
For individual patients the magnitude of the NAA/Cr decrease was correlated with the frequency of relapses over the two years prior to treatment (r = -0.76, p = 0.006).
These data suggest that reduction of new inflammatory activity with BIFN does not invariably halt progression of Axonal injury.
Nonetheless, there appears to be a relationship between the rate of progression of Axonal Injury and relapse rate over the previous two years.
The consequences of reduced inflammation on pathological progression relevant to disability therefore may be present, but substantially delayed. Alternatively, distinct mechanisms may contribute to the two processes.
Interferon-beta-1a For Secondary/Progressive Multiple Sclerosis
J Neurol Sci 2003 Feb 15;206(2):199-202
Guy's, King's and St. Thomas School of Medicine, Guy's Hospital, Department of NeuroImmunology, London SE1 1 UL, UK
This non-systematic review identified four randomized trials that have tested the efficacy of Interferon-beta in Secondary/Progressive Multiple Sclerosis (SPMS). Two were trials of Interferon-beta-1a (IFN-ß-1a) and two of Interferon-beta 1b (IFN-ß-1b).
All have shown significant reductions in relapse rates and accumulation of new Magnetic Resonance Imaging (MRI) lesions, but only one trial (of IFN-ß-1b) showed significant slowing of disability progression.
Post hoc analyzes of these trials suggest that the differences in outcomes might be partly explained by the differences between the trials in the proportions of patients with Relapsing disease.
In one of the trials of IFN-ß-1a (the SPECTRIMS trial), the hazard ratio for progression in the treated Relapsing patients with relapses in the two pre-study years was 0.74 compared to placebo patients with pre-study relapses and 1.01 in the treated patients compared to the placebo patients without pre-study relapses.
In the same trial, the treatment effects on MRI parameters were more marked in the patients who had recent pre-study relapses compared with those who had not.
These observations have led to the recommendation in national guidelines that prescribing of IFN-ß in SPMS be limited to those patients who have had disabling relapses in the last 2 years.
These conclusions should be reviewed when the full results of all four trials have been published.
Comparative Tolerance Of IFN-ß-1a Regimens In Patients With Relapsing Multiple Sclerosis The EVIDENCE Study
Sandberg-Wollheim M, Bever C, Carter J, Farkkila M, Hurwitz B, Lapierre Y, Chang P, Francis GS
J Neurol 2005 Jan;252(1):8-13
University Hospital, Department of Neurology, 221 85, Lund, Sweden
The EVIDENCE study was a direct comparative study of two dose regimens of Interferon-beta-1a (IFN-ß-1a) used in the treatment of Relapsing/Remitting Multiple Sclerosis (RRMS): 30 mcg IntraMuscularly once weekly (qw; n=338) and 44 mcg SubCutaneously three times weekly (tiw; n=339).
The study continued for an average of 64 weeks. The safety population consisted of all patients receiving at least one dose of study drug.
Clinical assessments occurred every 4 weeks for 24 weeks and then every 12 weeks. Blood tests for safety were taken at baseline and at weeks 4 and 12, and every 12 weeks thereafter.
Overall adverse events were more common with the 44 mcg tiw regimen (p=0.007), and were due predominantly to differences in injection-site reactions. The majority of adverse events were rated mild by investigators.
Hepatic and Haematological adverse events and asymptomatic laboratory abnormalities were more common with 44 mcg tiw (p < 0.001),with no difference seen for severe events.
Flu-like symptoms were more common with 30 mcg qw (p=0.031), were more severe and persisted for longer. Serious adverse events were comparable for both groups, as were drug discontinuations.
In conclusion, although adverse events were more common with high-dose, high-frequency IFN-ß therapy, differences were primarily for mild events and did not affect treatment adherence.
Based on superior clinical and Magnetic Resonance Imaging outcomes over an average of 64 weeks, coupled with modest safety differences, the risk-benefit ratio for IFN-ß therapy in RRMS favours the 44 mcg tiw regimen over this period of time.
Clinical Benefits Of Interferon-beta-1a In (Avonex) Relapsing/Remitting MS: A Phase IV Study
Fernandez O, Arbizu T, Izquierdo G, Martinez-Yelamos A, Gata JM, Luque G, de Ramon E
Acta Neurol Scand 2003 Jan;107(1):7-11
Hospital Regional Universitario Carlos Haya, Department of Neurology, Malaga, Spain
To evaluate the efficacy and safety of IFN-ß-1a (Avonex, Biogen, Inc., Cambridge, MA, USA) in patients with Relapsing/Remitting Multiple Sclerosis (MS).
In this multicenter, open-label, prospective clinical trial, 96 patients with Relapsing/Remitting MS received IFN-ß-1a 30 mcg intramuscularly once weekly for 2 years.
Outcome variables included: change from baseline in mean number of exacerbations, proportion of exacerbation-free patients, and mean Expanded Disability Status Scale (EDSS) scores at Years 1 and 2.
IFN-ß-1a significantly (P < 0.0001) reduced exacerbation rate at Years 1 and 2 of treatment. The percentage of exacerbation-free patients was 53% during Year 1 and 33% during Year 2.
Mean EDSS scores were 2.96 +/- 1.26 at baseline, 2.89 +/- 1.42 at Year 1, and 3.00 +/- 1.62 at Year 2 (P = 0.116). EDSS scores improved in 35.4%, remained stable in 28.1%, and worsened in 36.5% of patients. IFN-ß-1a treatment was well tolerated.
This study confirms and extends the beneficial clinical profile for IFN-ß-1a (Avonex) in Relapsing MS.
An Examination Of The Results Of The EVIDENCE, INCOMIN, And Phase III Studies Of Interferon-beta Products In The Treatment Of Multiple Sclerosis
Clin Ther 2003 Jan;25(1):105-18
Beth Israel Deaconess Medical Center, Department of Neurology, Boston, Massachusetts 02115, USA
Three Interferon-beta (IFN-ß) products are currently available for the treatment of Relapsing Multiple Sclerosis (MS).
Each of these agents showed effectiveness in the treatment of MS in the respective randomized, double-blind, placebo controlled Phase III trials.
However, there have been no randomized, double-blind, placebo-controlled trials directly comparing the efficacy and safety of these formulations.
The objective of this article was to compare the results of available comparative studies with the results of the pivotal Phase III trials of each IFN-ß product.
BIOSIS, Current Contents/Clinical Medicine, and MEDLINE were searched for English-language articles published from 1996 to the present comparing the efficacy and safety of IFN-ß formulations in the treatment of MS.
Search terms included Interferon-beta-1a, Interferon-beta-1b, and Multiple Sclerosis.
Articles or abstracts that reported the results of Phase III trials or studies directly comparing IFN-ß formulations in the treatment of Relapsing or Relapsing/Remitting MS were included in the review.
Seven head-to-head studies were identified that directly compared the efficacy of IFN-ß products in the treatment of MS.
Two of these studies- INCOMIN (Independent Comparison of Interferon) and EVIDENCE (Evidence for Interferon Dose-Effect: European-North American Comparative Efficacy) - found significant differences in clinical efficacy between IFN-ß products, whereas the remaining studies showed equal clinical efficacy between products.
Inconsistencies within and between the results of the reviewed studies suggest that clinicians should use caution in interpreting the findings of the INCOMIN and EVIDENCE comparative trials.