Impact Of Interferon-ß-1a On Neurologic Disability In Relapsing Multiple Sclerosis
The Multiple Sclerosis Collaborative Research Group (MSCRG)
Rudick RA, Goodkin DE, Jacobs LD, Cookfair DL, Herndon RM, Richert JR, Salazar AM, Fischer JS, Granger CV, Simon JH, Alam JJ, Simonian NA, Campion MK, Bartoszak DM, Bourdette DN, Braiman J, Brownscheidle CM, Coats ME, Cohan SL, Dougherty DS, Kinkel RP, Mass MK, Munschauer FE, Priore RL, Whitham RH, et al
Neurology 1997 Aug;49(2):358-63
Mellen Center for Multiple Sclerosis Treatment and Research, Dept of Neurology, Cleveland Clinic Foundation, Cleveland, OH 44195-5244, USA
PMID# 9270562; UI# 97416612
Background And Objective
A Phase III double-blind, placebo-controlled clinical trial demonstrated that Interferon-ß-1a (IFN-ß-1a) (Avonex, Biogen) significantly delayed progression of Disability in Relapsing MS patients.
The primary clinical outcome was time from study entry until Disability progression, defined as > or = 1.0 point worsening from baseline Kurtzke Expanded Disability Status Scale (EDSS) score persisting for at least two consecutive scheduled visits separated by 6 months.
The objective of this study was to examine the magnitude of benefit on EDSS and its clinical significance.
Post hoc analyzes related to Disability outcomes using data collected during the double-blind, placebo-controlled Phase III clinical trial.
- Clinical efficacy related to Disability did not depend on the definition of Disability progression.
- A significant benefit in favor of IFN-ß-1a was observed:
- When > or = 2.0 point worsening from baseline EDSS was required, Or
- When worsening was required to persist for > or = 1.0 year.
- Placebo recipients who reached the primary clinical outcome worsened by a larger amount from baseline EDSS than did IFN-ß-1a recipients who reached the primary study outcome.
- Significantly fewer IFN-ß-1a recipients progressed to EDSS milestones of:
- 4.0 (relatively severe impairment), Or
- 6.0 (unilateral assistance needed to walk)
- Cox proportional hazards models demonstrated that the only baseline characteristic strongly correlated with longer time to Disability progression was IFN-ß-1a treatment.
The primary clinical outcome for the IFN-ß-1a clinical trial underestimated clinical benefits of treatment.
Results in this report demonstrate that IFN-ß-1a treatment is associated with robust, clinically important beneficial effects on Disability progression in Relapsing MS patients.
Effect Of Weekly Intramuscular Interferon-ß-1a On MRI Lesions In
Relapsing Multiple Sclerosis
Waubant E, Sloan R, Andersson PB, Goodkin D
Rev Neurol (Paris) 1999;155 Suppl 2:S20-3
UCSF/Mt Zion Multiple Sclerosis Center, San Francisco, CA 94115, USA
PMID# 10367321; UI# 99295397
We compared the number of new Gadolinium-enhancing (Gd+) and T2-weighted (T2W) lesions on 6-monthly MRI scans before and after initiating weekly intramuscular injections of Interferon-ß-1a (Avonex) 30 mcg.
The mean number of new focal Gd+ lesions detected during the 6 monthly on-treatment scanning sessions was:
- 58 per cent less per MRI scan
- 62.5 per cent less per patient than during the 6 monthly pre-treatment scanning sessions (p = 0.016, Wilcoxon signed rank test)
The results are similar for new focal Gd+ and T2W lesions.
The reduction in disease activity detected by monthly Gd+ enhanced MRI scans after initiating weekly intramuscular IFN-ß-1a 30 mcg is consistent with benefits observed with:
- thrice weekly subcutaneous IFN-ß-1a 10 mcg
- thrice weekly subcutaneous IFN-ß-1a 30 mcg
- alternate day subcutaneous IFN-ß-1b 8.0 MIU
Multicenter, Randomized, Double Blind, Placebo Controlled, Phase III Study Of Weekly, Low Dose, Subcutaneous Interferon-ß-1a In Secondary/Progressive Multiple Sclerosis
Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Myhr KM, Sandberg-Wollheim M, Soelberg Sorensen P
J Neurol NeuroSurg Psychiatry 2004 May;75(5):706-10
Sahlgrenska University Hospital, University of Goteborg, Institute of Clinical NeuroScience, Goteborg, Sweden
Interferon-beta (IFN-ß) has repeatedly shown benefit in Multiple Sclerosis (MS) in reducing the rate of relapse, the disease activity as shown with Magnetic Resonance Imaging and, to some degree, the progression of disability;
However, it is unknown how much the therapeutic response depends on the dose, the subgroup involved, and the disease stage.
This multicenter, double blind, placebo controlled study explored the dose-response curve by examining the clinical benefit of low dose IFN-ß-1a (Rebif), 22 micro g subcutaneously once weekly, in patients with Secondary/Progressive MS.
A total of 371 patients with Clinically Definite SPMS were randomized to receive either placebo or subcutaneous IFN-ß-1a, 22 micro g once weekly, for 3 years. Clinical assessments were performed every 6 months.
The primary outcome was time to sustained disability, as defined by time to first confirmed 1.0 point increase on the Expanded Disability Status Scale (EDSS). Secondary outcomes included a sensitive disability measure and relapse rate.
Treatment had no beneficial effect on time to confirmed progression on either the EDSS (hazard ratio (HR) = 1.13; 95% confidence interval (CI) 0.82 to 1.57; p = 0.45 for 22 micro g v placebo) or the Regional Functional Status Scale (HR = 0.93; 95% CI 0.68 to 1.28; p = 0.67).
Other disability measures were also not significantly affected by treatment.
Annual relapse rate was 0.27 with placebo and 0.25 with IFN (rate ratio = 0.90; 95% CI 0.64 to 1.27; p = 0.55). The drug was well tolerated with no new safety concerns identified. No significant gender differences were noted.
This patient population was less clinically active than SPMS populations studied in other trials.
Treatment with low dose, IFN-ß-1a (Rebif) once weekly did not show any benefit in this study for either disability or relapse outcomes, including a subgroup with preceding relapses.
These results add a point at one extreme of the dose-response spectrum of IFN-ß therapy in MS, indicating that relapses in this phase may need treatment with higher doses than in the initial phases.
Benefit of Interferon-ß-1a on MSFC progression in Secondary/Progressive MS
Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, Sandrock AW, Rudick RA, Simon JH, Simonian NA, Tsao EC, Whitaker JN
Neurology 2002 Sep 10;59(5):679-87
The Mellen Center for Multiple Sclerosis Treatment and Research, Department of Neurology (Drs. Cohen, Fischer, and Rudick), Cleveland Clinic Foundation, OH
PMID# 12221157; UI# 22209794
Interferon-beta-1a (IFN-ß-1a), Avonex is efficacious in Relapsing forms of MS. Studies of other IFN-ß preparations in Secondary/Progressive MS (SPMS) yielded conflicting results.
This study was undertaken to determine whether IFN-ß-1a slowed disease progression in SP-MS.
A total of 436 subjects with SPMS and Expanded Disability Status Scale (EDSS) score 3.5 to 6.5 were randomized to receive IFN-ß-1a (60 micro g) or placebo by weekly intramuscular injection for 2 years.
The primary outcome measure, used for the first time in a large-scale MS trial, was baseline to month 24 change in the MS Functional Composite (MSFC), comprising quantitative tests of Ambulation (Timed 25-Foot Walk), Arm Function (Nine-Hole Peg Test [9HPT]), and Cognition (Paced Auditory Serial Addition Test [PASAT]).
Median MSFC Z-score change was reduced 40.4% in IFN-ß-1a subjects (-0.096 vs -0.161 in placebo subjects, p = 0.033), an effect driven mainly by the 9HPT and PASAT.
There was no discernible benefit on the EDSS, which in this range principally reflects walking ability. IFN-ß-1a subjects had 33% fewer relapses (p = 0.008).
There was significant benefit on eight of 11 MS Quality of Life Inventory subscales. New or enlarging T2-HyperIntense Brain MRI lesions and Gadolinium-enhancing lesions were reduced at months 12 and 24 (both p < 0.001).
IFN-ß-1a was well tolerated by the majority of subjects. Neutralizing AntiBodies developed in 3.3% of IFN-ß-1a-treated subjects.
IFN-ß-1a demonstrated benefit on MSFC progression, relapses, quality of life, and MRI activity in SPMS.