Interferon beta for secondary progressive multiple sclerosis (Review)

Transcription

1 Interferon beta for secondary progressive multiple sclerosis (Review) La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2012, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Disability progression, Outcome 1 Sustained (6 months) EDSS increase after 3 years.. 34 Analysis 1.2. Comparison 1 Disability progression, Outcome 2 Sustained (3 or 6 months) EDSS increase at 3 years in patients with or without pre-study relapses Analysis 1.3. Comparison 1 Disability progression, Outcome 3 Sustained (3 months) EDSS increase Analysis 1.4. Comparison 1 Disability progression, Outcome 4 Sustained (3 or 6 months ) EDSS increase according to prestudy clinical characteristics of patients Analysis 2.1. Comparison 2 Adverse Events, Outcome 1 Total number of patients with Serious AEs Analysis 2.2. Comparison 2 Adverse Events, Outcome 2 Patients who had discontinuated for AEs (including SAEs) *. 39 Analysis 2.3. Comparison 2 Adverse Events, Outcome 3 Deaths Analysis 2.4. Comparison 2 Adverse Events, Outcome 4 Patients who done or attempted suicide Analysis 2.5. Comparison 2 Adverse Events, Outcome 5 Allergy/Rash (number of events) Analysis 2.6. Comparison 2 Adverse Events, Outcome 6 Cutaneous necrosis * Analysis 2.7. Comparison 2 Adverse Events, Outcome 7 Injection site reactions * Analysis 2.8. Comparison 2 Adverse Events, Outcome 8 Patients with psychiatric disorders Analysis 2.9. Comparison 2 Adverse Events, Outcome 9 Patients with headache Analysis Comparison 2 Adverse Events, Outcome 10 Patients with influenza like syndrome * Analysis Comparison 2 Adverse Events, Outcome 11 Patients with myalgia Analysis Comparison 2 Adverse Events, Outcome 12 Patients with fatigue/asthenia Analysis Comparison 2 Adverse Events, Outcome 13 Patients with leucopenia * Analysis Comparison 2 Adverse Events, Outcome 14 Patients with liver dysfunction Analysis 3.1. Comparison 3 Relapses outcomes, Outcome 1 Number of patients with at least one relapse during follow. 51 Analysis 3.2. Comparison 3 Relapses outcomes, Outcome 2 Relapse rate Analysis 4.1. Comparison 4 MRI: role of treatment, Outcome 1 Number of patients with combined lesions at different times (6, 9 and 24 months) Analysis 4.2. Comparison 4 MRI: role of treatment, Outcome 2 Mean absolute change of T2 lesion load ADDITIONAL TABLES APPENDICES HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Interferon beta for secondary progressive multiple sclerosis Loredana La Mantia 1, Laura Vacchi 2, Carlo Di Pietrantonj 3, George Ebers 4, Marco Rovaris 5, Sten Fredrikson 6, Graziella Filippini 2 1 Unit of Neurology - Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente Fondazione Don Gnocchi, Milano, Italy. 2 Neuroepidemiology Unit, Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta, Milano, Italy. 3 Servizio Regionale di Riferimento per l Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Azienda Sanitaria Locale ASL AL, Alessandria, Italy. 4 Clinical Neurology, University of Oxford, Oxford, UK. 5 U.O. Sclerosi Multipla, I.R.C.S.S. S. Maria Nascente - Fondazione Don Gnocchi, Milano, Italy. 6 Division of Neurology R54 - Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden Contact address: Loredana La Mantia, Unit of Neurology - Multiple Sclerosis Center, I.R.C.C.S. Santa Maria Nascente Fondazione Don Gnocchi, Via Capecelatro 66, Milano, 20148, Italy. lamantialore@gmail.com. Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group. Publication status and date: New, published in Issue 1, Review content assessed as up-to-date: 8 August Citation: La Mantia L, Vacchi L, Di Pietrantonj C, Ebers G, Rovaris M, Fredrikson S, Filippini G. Interferon beta for secondary progressive multiple sclerosis. Cochrane Database of Systematic Reviews 2012, Issue 1. Art. No.: CD DOI: / CD pub3. Background A B S T R A C T Therapy with either recombinant beta-1a or beta-1b interferons (IFNs) is worldwide approved for Relapsing Remitting Multiple Sclerosis (RRMS). A major unanswered question is whether this treatment is able to safely reverse or retard the progressive phase of the disease. Objectives The main objective was to verify whether IFNs treatment in Secondary Progressive Multiple Sclerosis (SPMS) is more effective than placebo in reducing the number of patients who experience disability progression. Search methods We searched the Cochrane Multiple Sclerosis Group s Trials Register (1995 to 15 February 2011), the reference lists of relevant articles and conference proceedings. Regulatory agencies were used as additional sources of information. Selection criteria We included all randomised, double or single blind, placebo-controlled trials (RCTs) evaluating the efficacy of IFNs versus placebo in SPMS patients. Data collection and analysis Two review authors independently assessed all reports retrieved from the search. They independently extracted clinical, safety and MRI data, using a predefined data extraction form, resolving disagreements after discussion with a third reviewer. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using Risk Ratio (RR) with 95% confidence intervals () for the binary outcomes and Standard Mean Difference with 95% for the continuous outcomes. 1

4 Main results Five RCTs met the inclusion criteria, from which 3122 (1829 IFN and 1293 placebo) treated patients contributed to the analysis. Included population was heterogeneous in terms of baseline clinical characteristics of the disease, in particular the percentage of patients affected by secondary progression with superimposed relapse ranging from 72% to 44%. IFN beta 1a and 1b did not decrease the risk of progression sustained at 6 months (RR, 95% : 0.98, [ ]) after three years of treatment. A significant decrease of the risk of progression sustained at 3 months (RR, 95% : 0.88 [0.80, 0.97]) and of the risk of developing new relapses at three years (RR 0.91, [ ]) were found. The risk of developing new active brain lesions decreased over time but this data was obtained from single studies on Magnetic Resonance Imaging (MRI), performed in subgroups of patients; in spite of no effect on progression, the radiological data supported an effect on MRI parameters. The safety profile reflects what is commonly reported in MS IFN-treated patients. Authors conclusions Well designed RCTs, evaluating a high number of patients were included in the review. Recombinant IFN beta does not prevent the development of permanent physical disability in SPMS. We were unable to verify the effect on cognitive function for the lack of comparable data. This treatment significantly reduces the risk of relapse and of short -term relapse-related disability. Overall, these results show that IFNs anti-inflammatory effect is unable to retard progression, when established. In the future, no new RCTs for IFNs versus placebo in SPMS will probably be undertaken, because research is now focusing on innovative drugs. We believe that this review gives conclusive evidence on the clinical efficacy of IFNs versus placebo in SPMS. P L A I N L A N G U A G E S U M M A R Y Interferon beta for Secondary Progressive Multiple Sclerosis Interferon beta, an anti-inflammatory therapy for patients with Relapsing Remitting Multiple Sclerosis(RRMS), is also used for patients with the secondary progressive type. Although it remains unclear how either beta-1a or beta-1b interferons (IFNs) work in MS, these therapies have been well established in RRMS. Currently, IFNs therapies are also the first line treatment for Secondary Progressive Multiple Sclerosis (SPMS), since other drugs, such as mitoxantrone, have a worse risk/benefit profile. A major unanswered question is whether and to what extent IFNs are really effective in SPMS. The main objective of this review was to verify whether IFNs in patients with SPMS are more effective than placebo in reducing the number of patients who experience disability progression during the 2-3 years follow-up. Among the pertinent literature, only five studies met the criteria of the inclusion in the review, comprising a total of 3122 participants (1829 treated with IFN and 1293 with placebo). Overall, these results show that IFNs are unable to retard the progression once it is established, making INFs not useful in the secondary progressive phase of the disease. The well known adverse events related to IFNs treatment such as injection site reactions, influenza like syndrome, and leukopenia occurred frequently also in SPMS patients, while serious and life-threatening adverse events were not increased in the treated group of patients. Because this review has considered well designed studies with a high number of patients, the authors believe that its results give conclusive evidence on the clinical efficacy of IFN beta versus placebo in patients with SPMS. Research focused on innovative drugs is mandatory. 2

5 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] INTERFERONS for secondary progressive multiple sclerosis Patient or population: patients with secondary progressive multiple sclerosis Settings: Intervention: INTERFERONS Outcomes Illustrative comparative risks*(95% ) Relative effect (95% ) No of Participants (studies) Assumed risk Corresponding risk Control INTERFERONS Sustained (6 months) EDSS increase after 3 years Study population RR 0.98 (0.82 to 1.16) 410per per1000 (336to475) 2026 (3) Moderate 372per per1000 (305to432) Sustained (3 months) EDSS increase after 3 years Study population RR 0.88 (0.8 to 0.97) 579per per1000 (463to562) 1336 (2) Moderate 594per per1000 (475to576) Quality of the evidence (GRADE) Comments HIGH RCTs low risk of bias Heterogeneity probably due to different clinical characteristics of patients HIGH 3

6 Sustained (3 or 6 months) EDSS increase at 3 years in patients with pre study relapses Study population RR 0.9 (0.75 to 1.09) 465per per1000 (349to507) 1106 (3) HIGH Moderate 388per per1000 (291to423) Number of patients with at least one relapse during follow-up - after 3 years Study population RR 0.91 (0.84 to 0.97) 530per per1000 (445to514) 2639 (4) HIGH Moderate 509per per1000 (428to494) *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention(and its 95% ). : Confidence interval; RR: Risk ratio; GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. Very low quality: We are very uncertain about the estimate. 4

7 B A C K G R O U N D Description of the condition The natural history of multiple sclerosis (MS) evolves over 30 to 40 years (Paty 1998). A secondary progressive phase (SP) supervenes in more than 50% of relapsing-remitting (RR) patients within 15 years (Weinshenker 1989a); walking aid is needed about five years from its onset, the median rate of EDSS increase being DSS point per year (Weinshenker 1989a). Understanding when a RR course shifts to a progressive phase, which is characterised by a progressive physical or cognitive disability, is not an easy clinical task. Natural history studies show that at least one year is needed to confirm disease progression (Cottrell 1999; Kremenchutzky 2006; Ebers 2008). Progression may occur without a convincing link to clinical or magnetic resonance imaging (MRI) flares of the disease and in particular cognitive decline may indicate disease progression in the absence of worsening physical disability (Amato 2006; Duque 2008). It remains uncertain how the first phases of immune-mediated inflammation correlate with the development of progression and if immunological events are primarily or secondarily related to the progression of the disease (Compston 2002). What is the relationship between relapse frequency and progression? Progression in SPMS is strongly influenced by prior relapses in the first years after disease onset, but it is uncertain if this mechanism is causal (Ebers 2000; Weinshenker 1989). In patients with SPMS, superimposed relapses seem to be associated with a slower rate of progression (Confavreux 2000). The results of more recent studies with a mean follow-up over 20 years demonstrate that the progressive course is independent from relapses either preceding or subsequent to progression (Kremenchutzky 2006). Relapses during SPMS had no measurable impact on time to EDSS 6 (Tremlett 2009). Epidemiological studies show that the shift from RRMS to SPMS follows the achievement of EDSS 4 (Confavreux 2006) when clinical predictors are no longer influent for prognosis (Confavreux 2003). The physiopathological factors which underlie progression of MS are not completely understood, but it is widely believed that they include axonal and neuronal injury and loss, oligodendrocyte damage and extensive lesions of the white matter (WM) (Glass 2010; Frisher 2009; Noseworthy 2000). Diffuse abnormalities in the WM, i.e. the so-called diffusely abnormal WM, may contribute to the development of clinical disability (Seewann 2009; Lassmann 2009). A significant association between inflammation and axonal injury has been reported, showing that active progressive MS has a more aggressive course compared with inactive disease (Frisher 2009). MRI studies have showed that cortical lesions and tissue loss in RRMS and SPMS (Tekok-Kilic 2007; Calabrese 2009) as well as diffuse brain lesions, T1-T2 -lesion load in progressive MS (Ukkonen 2009) are associated with cognitive impairment. Description of the intervention Recombinant IFN-beta (rifnb) products licensed for MS treatment are IFN beta-1b (Betaferon-Bayer or Extavia-Novartis ) and two IFN beta-1a preparations (Avonex-Biogen Dompé and Rebif-Serono ). IFN beta-1b is a lyophilised protein produced by DNA recombinant technology using E. Coli. The approved dose is 250 mcg every other day by subcutaneous injection. IFN beta 1-a is a lyophilised glycoprotein produced in mammalian cells using the natural human gene sequence. Two preparations are licensed for the treatment of MS, i.e. 30 mcg (Avonex ) once a week administered by intramuscular injection, and 22 or 44 mcg (Rebif ) administered three times a week by subcutaneous injections. How the intervention might work It remains unclear how rifnb works in MS. The suggested mechanisms include inhibition of T-cell proliferation, regulation of many cytokines and blocking of blood-brain barrier opening by interference with cell adhesion molecules. Therapy with either beta-1a or beta-1b interferons is now established in RRMS, although their medium and long term effect has been challenged by a previous systematic review (Rice 2001). A major unanswered question is whether pharmacological inhibition of in ammation pathways is able to safely reverse or delay the course of the disease (Rice 2001; Filippini 2003; Glass 2010). Why it is important to do this review Interferon beta-1b was approved for SPMS treatment on 1999 by EMEA 2000 and by the FDA In 2006 it was confirmed that Betaferon was indicated for SPMS patients with active disease, evidenced by relapses (EMEA 2006). Extavia, which is the same interferon beta-1b product as Betaferon, was approved with the same indications (EMEA 2008; FDA 2009). This therapy is currently the first line treatment for SPMS, as mitoxantrone shows a worse risk/benefit profile (FDA 2000). A meta-analysis of Interferon-Beta in Multiple Sclerosis (Nikfar 2010), showed that the effectiveness of IFNs depends on the type of IFNs used and the subtype of MS treated; the results did not confirm the efficacy of IFN in SPMS. A systematic review is warranted to verify rifnb use in clinical practice for SPMS. O B J E C T I V E S Our primary questions were: 5

8 Are rifnbs more effective than placebo in reduction of disability progression or cognitive impairment in SPMS patients? What is the incidence and severity of adverse events during this treatment in this form of disease? Our secondary objectives were to assess the effect of rifnb on the reduction of clinical relapses, on the quality of life and on depression/other psychological aspects. Finally, MRI data were also considered to verify the effect of interferons on cerebral lesions. M E T H O D S Criteria for considering studies for this review Types of studies We assessed only randomised, double or single blind, placebo-controlled trials of recombinant interferon beta for SPMS patients. Randomised crossover trials were included if results were available for all phases. Uncontrolled or non-randomised trials were excluded. Trials in which the comparisons of interest were confounded by other treatments, such as immunosuppressive drugs, were excluded. Types of participants Patients diagnosed as having clinically definite MS according to Poser (Poser 1983), Mc Donald (McDonald 2001) or Polman (Polman 2005) criteria were included. According to accepted criteria (Lublin 1996), SPMS was defined as a clinical course, characterised by an initial relapsing-remitting phase followed by progression with or without superimposed relapses, minor remissions and plateaus. We excluded patients with primary progressive MS. Types of interventions Beta recombinant interferons (rifnb) versus placebo. Trials were not excluded on the basis of dose, treatment duration, administration route. Length of follow-up of at least one year was required. For trials in which treatment effects were reported for more than one dose, we considered the treated groups together. Types of outcome measures Primary outcomes The primary outcome measures were the proportion of patients who had disability progression or cognitive impairment after two and three years. Progression of disability, was defined as a 6 month sustained increase in Expanded Disability Status Scale (EDSS) (Kurtzke 1983) of at least one point (0.5 point if baseline EDSS 5.5) recorded in a period without relapses. Less stringent criteria (sustained disability at 3 months without mention of intercurrent relapses) have been accepted. Diagnostic criteria of cognitive impairment were taken from articles, provided they had been validated. Safety was evaluated in terms of: 1. patients with serious adverse events (SAE), defined as any untoward medical occurrence at any dose that results in death, requires patients hospitalisation (excluding hospitalisation for relapses), results in persistent or significant disability/incapacity or is life-threatening (WHO 2. proportion of patients who withdrew or dropped out from the study because of adverse events (AE), i.e. an adverse event for which the causal relation between treatment and the event is at least a reasonable possibility; 3. number of patients with any AE. Secondary outcomes We evaluated the proportion of patients who had one or more relapses during the treatment and follow-up periods. Relapses were defined as newly developed or recently worsened neurological dysfunction symptoms that lasted more than 24 hours, with or without objective confirmation, and that stabilised or resolved either partially or completely. We also assessed relapse rate, quality of life (QOL) measured by validated questionnaires such as the Multiple Sclerosis Quality of Life-54 (MSQOL-54), activities of daily living (ADL), psychological aspects measured by validated scales or other instruments for depression or anxiety, and the effect of treatment on cerebral MRI findings, i.e. number and/or volume of enhancing T1 and new T2 lesions, and cerebral atrophy. Search methods for identification of studies No language restrictions were applied to the search. Electronic searches The first search for this review covers the years 1995 to 2009 and the details of the search methods are listed in Appendix 1. For the most recent search the Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis Group s Specialised Register (2010 to 15 February 2011). The keywords used to search for this review are listed in Appendix 2. The Cochrane Multiple Sclerosis Trials Register is updated regularly and contains trials identified from: 1. The Cochrane Central Register of Controlled Trials (CENTRAL) (recent issue); 2. MEDLINE (PubMed) (1966 to date); 3. EMBASE (Embase.com) (1974 to date); 6

9 4. NAHL (Ebsco host) (1981 to Feb 2011); 5. LILACS (Bireme) (1982 to date); 6. PEDro; 7. Clinical trials registries. Information on the Cochrane Multiple Sclerosis Group s Trials Register and details of search strategies used to identify trials can be found in the Specialised Register section within the Cochrane Multiple Sclerosis Group s module. Searching other resources 1. US Food and Drug Administration (FDA) regulatory reports (1995 to 2011) 2. European Medicines Agency (EMEA) regulatory reports (1995 to 2011) 3. Reference lists of all available review articles and primary studies 4. Abstract books of ECTRIMS (European Committee for Treatment and Research in Multiple Sclerosis), ACTRIMS (Americas Committee for Treatment and Research in Multiple Sclerosis), EFNS (European Federation of Neurological Societies), ENS (European Neurological Society), AAN (American Academy of Neurology), ANA (American Neurological Association) international meetings (1995 to 2011); 5. Contact with authors or sponsor companies to obtain missing data. Data collection and analysis Selection of studies Two authors (LLM, LV) scrutinised all articles retrieved by the search and decided independently whether a trial met the criteria for inclusion in the review. Any disagreement about trial status was resolved by discussion among the two authors and a third reviewer (GF). Data extraction and management The two authors (LLM, LV) independently extracted trial data using an Excel sheet, focusing also on aspects of methodological quality in RCT. Study arms comparing different fixed doses of interferon within the therapeutic range were converted into a single arm by summing the number of events on the number of patients randomised. Other parameters were assessed, including patients baseline characteristics, duration and completeness of follow-up. Disagreements on extractions were resolved by discussion among three authors (LLM, LV and GF). Assessment of risk of bias in included studies Two authors (LLM, LV) independently judged trial quality according to the methods set out in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0) (Higgins 2009). Six recognised aspects of methodological quality in the RCTs were considered: (i) random sequence generation (selection bias); (ii) masking of patients allocation to comparison groups (allocation concealment); (iii) blinding of outcome assessment (detection bias); (iv) blinding of participants and personnel (performance bias); (v) how patients, withdrawn after randomisation or lost to followup, were treated in analysis (incomplete outcome data (attrition bias). We defined as high risk of bias lost to follow up more than 20%; (vi) other bias, such as early study termination, were also reported. Disagreements on trial quality were resolved by discussion among three authors (LLM, LV and GF). The results of trial quality assessment were included in the Risk of Bias Tables as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2009). Measures of treatment effect Binary outcomes were assessed by calculation of Risk Ratios (RRs) and 95% for each trial. Continuous outcomes were assessed by mean-differences between intervention and control groups. Unit of analysis issues No cross-over studies were found. For each trial the analysis was performed taking into account the original randomisation. For RCTs comparing different dosages of the same treatment we considered together the outcomes in the treated arms, summing the number of events (numerator) and the number of randomised patients (denominator). Dealing with missing data We attempted to retrieve missing data from the investigators and/ or sponsor companies for further details. Idec-Biogen and Ares Serono International SA provided the required supplementary information on clinical outcomes (sustained progression and relapse rate). Assessment of heterogeneity Heterogeneity among trials were examined using the I-squared statistic.the I-squared estimate greater than the 50% was interpreted as indicating heterogeneity. In this case, we used randomeffects estimates of the intervention effect (Der Simonian 1986). 7

10 Assessment of reporting biases The possibility of publication biases was investigated using a funnel plot, i.e. trial effect against trial size (Egger 1997). We have tried to avoid any possible publication bias, translating two Russian publications retrieved from the search. We evaluated whether or not there was a selective under-reporting of data in the included published articles and we searched FDA trial registration reports. We checked duplicate papers and/or ancillary studies, in order to find possible other relevant data not reported in the primary included RCTs. relapses, previous their comparison by statistical analysis (Anova test, post-hoc multiple comparison: mean difference significant at the level). Sensitivity analysis We performed a sensitivity analysis on primary outcomes, by including or excluding trials with high risk of bias. Data synthesis Data were processed using the total number of randomised patients. We calculated a weighted overall estimate of the RRs with 95% for binary outcomes, and weighted averages of differences between means for continuous outcomes. We used a random effects model to combine the study findings, except for subgroup analysis where we used a fixed-effect model because we didn t find heterogeneity between the included studies. When meta-analysis was not possible, we performed a qualitative description. Subgroup analysis and investigation of heterogeneity We performed two subgroup analyses regarding the outcome of sustained (3 or 6 months) disability progression. The first analysis considered for each of the included studies: (i) the number of patients with pre-study relapses and (ii) the number of patients without pre-study relapses. The second analysis considered each study according to baseline characteristics of the patients such as age, EDSS, disease duration, duration of progressive phase of the disease, and number of R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. Out of 2389 references identified by the search strategy from 1995 to 15 February 2011, 123 articles were provisionally selected as potentially fulfilling inclusion criteria Figure 1. A further sixty four articles were eliminated because they were non pertinent studies. Among the remaining 59 articles, 18 studies were excluded because they were performed in relapsing remitting (Buhse 2006; Smith 2005) or primary progressive MS patients (Leary 2003; Montalban 2009), or because evaluating the efficacy of treatments other than recombinant beta interferon (Goodkin 1997; Patti 1999; Arnason 1999; Tubridy 1999; Goodkin 2000a; Boiko2001; Skurkovich 2001; Hoogervorst 2002;,Zavalishin 2003; Christodoulou 2006; Bar-Or 2007). Trials that included active treatment comparisons (Baum 2006) or add-on therapies (Fernandez 2002) were excluded (see table Characteristics of excluded studies). One observational study was also excluded (Rio 2007). 8

11 Figure 1. Study flow diagram. 9

12 Five trials were eligible (Andersen 2004 (Nordic); Cohen 2002 (IMPACT); North American SG 2004; SPECTRIMS 2001;The European SG 1998 ) to which 36 other references were correlated. The studies methods, the characteristics of the participants, the interventions, the outcomes, along with risk of bias tables, are described in Characteristics of included studies table. In all included studies, secondary progression was defined as a period of deterioration sustained for at least 6 months, after a period of relapsing-remitting phase; one study did not define for how long sustained progression was observed (Cohen 2002 (IMPACT). Deterioration was quantified in terms of: at least two relapses or at least 1.0-point EDSS increase independent of relapses in the two years before the study (The European SG 1998); a history of at least one relapse and an increase in EDSS score of at least 1.0 point in the 2 years prior to screening (at least a 0.5-point increase for subjects with a screening EDSS score of 6.5 (North American SG 2004), an increase of at least 1 EDSS point over the last 2 years (or 0.5 point between EDSS score of 6.0 and 6.5), with or without superimposed exacerbations (SPECTRIMS 2001); not further defined in Andersen 2004 (Nordic) and Cohen 2002 (IMPACT) studies. Two studies (North American SG 2004; The European SG 1998) compared the effect of IFN beta-1b versus placebo, the first comparing two different dosages: 250 ug and 160 ug/ m 2 (corresponding to a mean administered dose of 220 ug). Three RCTs reported the effect of IFN beta-1a for different dosages and preparations: 60 ug intramuscular injections (i.m.)/ weekly (Avonex ) (Cohen 2002 (IMPACT), 22 mg subcutaneously/ weekly (Rebif ) (Andersen 2004 (Nordic) and 22 or 44 ug (two arms) subcutaneously/ three times weekly (Rebif ) (SPECTRIMS 2001). Treatment duration and follow-up were two years for one study (Cohen 2002 (IMPACT) and three years for the other four studies. The primary outcome was time to disability progression defined by EDSS measure for all of the trials, except for Cohen 2002 (IMPACT) study which used the MS Functional Composite (MSFC). Disability progression was defined as: 3 months sustained increase in EDSS of >1.0 point (0.5 for baseline EDSS >6) (The European SG FDA 2001); 3 months sustained increase in EDSS of >1.0 point (0.5 point for baseline EDSS >5.5) (SPECTRIMS 2001); 6 months sustained increase in EDSS of >1.0 point (0.5 for baseline EDSS>6) (North American SG 2004, FDA 2001); 6 months sustained increase in EDSS of >1.0 point (0.5 for baseline EDSS > 5.5) Andersen 2004 (Nordic). Disability progression measured by EDSS was a secondary outcome in Cohen 2002 (IMPACT) defined as a 3 months sustained increase in EDSS of > 1.0 point (0.5 for baseline EDSS 6). Results of 6 months sustained increase in EDSS in the The European SG 1998 were extracted from the FDA The summary of baseline clinical characteristics of included patients are reported in Table 1. The included patients were heterogeneous and significantly different for all the variables except for progression duration. Patients included in the The European SG 1998 and SPECTRIMS 2001 studies were younger and their disease duration was lower than that reported in other trials. SPECTRIMS 2001 population had higher baseline EDSS. The number of relapses was different ( ) and detected during a pre-study period of four years for Nordic (Andersen 2004 (Nordic)), three for Impact (Cohen 2002 (IMPACT)) and two years in the other three trials. Overall, 3122 (1829 IFN placebo) patients were included in this review. Risk of bias in included studies To assess risk of bias in the included studies, data from FDA reports were also considered (FDA 2001). Risk of bias are reported in the corresponding table of each included study and summarized in the figures (Figure 2 and Figure 3 ). Briefly, only one study was judged adequate for all aspects (SPECTRIMS 2001). The major concern refers to incomplete outcome reporting since only a proportion of the randomised patients were included into the primary studies analysis (74% in the The European SG 1998 study, 72% in the North American SG 2004 study, and 83% in the Andersen 2004 (Nordic) study). 10

13 Figure 2. Risk of bias graph: review authors judgements about each risk of bias item presented as percentages across all included studies. 11

14 Figure 3. Risk of bias summary: review authors judgements about each risk of bias item for each included study. 12

15 Effects of interventions See: Summary of findings for the main comparison INTERFERONS for secondary progressive multiple sclerosis Primary outcomes 1.The number of patients who had a sustained disability progression The number of patients who had 6 months s sustained progression assessed at 3 years was available for three trials (Andersen 2004 (Nordic); North American SG 2004; The European SG 1998) and 2026 (65%) patients (Analysis 1.1): 1177 (64%) patients in the interferon groups and 849 (69%) controls. From these data the RR was 0 98 ([0.82,1.16], p=0.79). However, a high level of heterogeneity was found (I 2 = 57%). One study (The European SG 1998) found a significant treatment effect while the other two studies did not confirm this. The number of patients who had 3 months sustained progression assessed at 3 years was available for two trials (SPECTRIMS 2001; The European SG 1998) and 1336 (43%) patients (Analysis 1.3): 773 (42%) patients in the interferon groups and 563 (43.5%) controls. From these data the RR was 0.88 ([0.80,0.97], p=0.01). The first subgroup analysis (Analysis 1.2) evaluating disability progression at 3 years for patients with (RR, (95% ): 0.90 [0.75,1.09], p=0.28) or without pre-study relapses (RR, (95% ): 1.05 [0.83,1.33], p=0.70) did not show any treatment effect in both groups of patients. However, a high level of heterogeneity was found (I 2 = 51%) for subgroup of patients without pre-study relapses. The second subgroup analysis was aimed to evaluate the role of baseline characteristics in the treatment response. We compared progression between SPECTRIMS 2001 and The European SG 1998 studies versus the other included studies, because of their relative similarity in term of age and disease duration (see Methods). A slight non-significant effect in patients with lower age and disease duration (RR, (95% ): 0.92 [0.83, 1.02] p=0.10) as compared with that in patients with higher age and disease duration ( 1.03 [0.90, 1.18] p=0.64) was found (Analysis 1.4). 2.The number of patients who had progression of cognitive impairment. Cognitive function was evaluated in two studies: North American SG 2004 used the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Cohen 2002 (IMPACT) used the Paced Auditory Serial Addition Task (PASAT, within the MSFC). It was not possible to give a synthesis due to differences in timepoint reporting, used tests and type of measures. In the first study (North American SG 2004), BRB-N s score decrease over time appeared to be similar between treatment groups (FDA 2001), while no significant changes in mean PASAT s score were found at the end of 24 month follow-up (Cohen 2002 (IMPACT)). 3. Safety AEs were extracted and analysed as number of patients who had any event, while only allergy/rash was reported as number of events. If results provided by the primary studies were unclear, data extraction was not performed. For similar AEs (such as increase of liver enzymes), we extracted the results with higher values. Details about AE risk are reported in Analysis 2 sections (Data and analyses). The risk of experiencing a Serious Adverse Event (SAE) (Analysis 2.1) was not significantly increased (RR, (95% ): 1.00 [0.83, 1.19]) in treatment group, while the number of patients withdrew or dropped out due to AEs (including SAEs, Analysis 2.2) were higher in the treated group (RR (95% ): 2.62 [1.92, 3.57]). Sixteen deaths occurred in the treated group (4 suicide, 3 pulmonary embolism, 3 cardiac arrest, 1 cancer, 1 intracerebral haemorrhage, 2 brainstem infarction and urosepsis, 2 unknown) and seven in the control groups (1 subarachnoid haemorrhage, 2 suicide, 1 arteriosclerosis, 1 pneumonia, 2 unknown) (Analysis 2.3). The following AEs were significantly related to the IFN treatment (marked in the corresponding Data and analyses table by an asterisk): injection site reactions (Analysis 2.7), cutaneous necrosis (Analysis 2.6), and influenza like syndrome (Analysis 2.10). Among haematological AEs, only leukopenia was significantly related to treatment (Analysis 2.13). Secondary outcomes 1. Number of patients experiencing at least one relapse during follow-up The number of patients who experienced at least one relapse at 3 years was available from four trials (Andersen 2004 (Nordic); North American SG 2004; The European SG 1998; SPECTRIMS 2001), accounting for 1590 patients in the interferon groups and 1049 controls. Results after two years were reported only by one study (Cohen 2002 (IMPACT)). IFN-beta significantly reduces the risk to have relapses during a three year follow-up: RR (95% ): 0.91 [0.84,0.97] (Analysis 3.1). 2. Relapse rate during follow-up This outcome was available at three years only for three studies (North American SG 2004; SPECTRIMS 2001 and The European SG 1998). We compared Betaseron 250 ug versus placebo for North American SG 2004 and The European SG 1998 and Rebif 44 ug versus placebo for SPECTRIMS From these data the Mean Difference was [-0.21, -0.10] (Analysis 3.2). 13

16 Results after two years were reported only for one study (Cohen 2002 (IMPACT)). 3. Quality of life (QOL) measured by validated questionnaires such as the Multiple Sclerosis Quality of Life-54 instrument (MSQOL-54) or activities of daily living (ADL) during follow-up Comparison among studies was not allowed because of differences in the scales used (Sickness Impact Profile in The European SG 1998, Multiple Sclerosis Quality of Life Inventory (MSQLI) in North American SG 2004 and Cohen 2002 (IMPACT), General Health Questionnaire in SPECTRIMS 2001, Nottingham Health Profile Part I (NHP-I) in Andersen 2004 (Nordic)), the time-point of assessment and the availability of appropriate published results. It may be described that a slight positive effect favouring the IFN group was found for the physical domain at 6 and 12 months and at last visit in The European SG To the contrary, no significant differences between treatment groups at any time point was found in health-related QOL measures in North American SG Significant benefit favouring IFNbeta-1a treatment was observed in MSQLI in the IMPACT study (Miller 2006). 4. Psychological aspects measured by validated scales or other instruments for depression or anxiety during follow-up This outcome was evaluated in three studies, with different scales: Montgomery Asberg Depression Rating Scale (MADRS) assessing mood changes and suicidal risk (The European SG 1998), changes in Beck Depression Index (BDI) score between baseline and the end of follow-up (North American SG 2004), the Center for Epidemiologic Studies Depression Rating Scale (CES-D) and Beck Hopelessness Scale (BHS) (SPECTRIMS 2001). Differences in scales, assessment time-points and availability of appropriate published results did not allow the comparison among studies. It may be described that patients on interferon beta 1b had no increased incidence of new or worsened depression, according to studies results (The European SG 1998; North American SG 2004; SPECTRIMS 2001). Depression was reported in 29% of patients receiving placebo, 32% receiving low-dose IFN, and 35% receiving high-dose IFN (SPECTRIMS 2001). 5. Change in MRI markers of disease activity. All studies, expect for Andersen 2004 (Nordic), provided MRI monitoring. Baseline MRI characteristics of the included patients were similar in IFN and placebo-treated groups in all included studies in terms of total T2 lesion volume (TLV). Gadolinium enhancing lesions were absent in about 60% of the patients for Cohen 2002 (IMPACT) and in 50% of patients for the other three RCTs. Different outcome measures were used at different time points: total lesion T2 volume or area, mean absolute or percentage change from baseline of total load volume (TLV) or area, number of new or enlarging T2-hyperintense lesions, number and/or percentage of patients with Gd-enhancing lesions, percentage of patients with new T2 or Gd-enhancing or enlarging lesions (the so called Combined Unique= CU), number of patients with enhancing lesions or number of enhancing lesions for patients. Furthermore, two studies have planned a frequent MRI studies (The European SG 1998; SPECTRIMS 2001) performed in subgroups of patients, corresponding to respectively 20% and 46% of the original population. In particular, a subgroup of 125 patients also underwent monthly Gd-enhanced and proton density/t2-weighted brain MRI from months 0 to 6 and 18 to 24, in order to determine the effect of treatment on the patterns of lesion activity, defined as new enhancing lesions and new/enlarging T2 lesions not Gd-enhancing (The European SG 1998, Miller 1999). In SPECTRIMS 2001 a cohort of 283 patients also had 11 monthly PD/T2 and Gd-enhanced scans at study start (Li 2001). Furthermore atrophy was evaluated only in one RCT (Molyneux 2000b). On the basis of available data, we decided to verify the MRI effect using only two outcome measures: the number of patients with CU and the absolute change of TVL. IFN reduces the risk to develop CU at 6 months (RR, (95% ): 0.70 [0.52,0.95]) and until 24 months (RR, (95% ): 0,52 [0.33,0.80]) as compared to placebo treatment (The European SG 1998; Analysis 4.1). The significance of these data is limited, because only single RCTs contributed to each analysis, involving subgroups of the original population (301 treated patients and 197 controls). The decrease of TLV in IFN-treated patients was significant at 1 year (-1.74, (95% ) [-3.25, -0.23]) and persisted at 3 years (-4.87, (95% ) [-6.22, -3.52]), but the heterogeneity of the results suggests that these data should be considered with caution (Analysis 4.2). D I S C U S S I O N Summary of main results Our systematic review was planned to evaluate the benefit rifns versus placebo in SPMS. The main result was the evidence of no effect of rifnbs in reducing the risk of sustained 6 months progression in SPMS patients. The main secondary results were a significant decrease of a) short -term (3 months) disability progression risk, reflecting relapse-related disability (Lublin 2003) and b) risk of having relapses during the treatment, although of limited size (9% and 12% respectively). Overall completeness and applicability of evidence The five RCTs selected were of good methodological quality as far as the selection and detection bias were concerned (Figure 2), although only one was free of bias risks (Figure 3). RCTs accounted for 3122 (1829 IFN and 1293 placebo) treated patients. 14

17 The objectives of this review were only partially satisfied, but the results allow us to properly define the profile of therapeutic effects of IFN in SPMS (Summary of findings for the main comparison). IFNs treatment is unable to prevent the risk of having sustained disability progression in these patients. On the contrary, significant results were detected on relapse-related outcomes. These findings suggest that IFNs have an anti-inflammatory effect on SPMS, the relapses-related outcomes might be independent from disability progression s evolution. It is known that the correlation between relapse rate and disability in MS patients changes over time; when milestones of disability are reached (EDSS 4), the clinical predictor of disability is no longer influent for prognosis (Confavreux 2006). A dissociation between the suppression of in ammation and the disease progression in SPMS patients has been already showed in patients treated with immunosuppressive drugs (Esposito 2010). A trend for a better response was found in patients with pre-study relapse, younger age and shorter disease duration, mainly related to the results of one study (The European SG 1998 ) (Analysis 1.2;.Analysis 1.4): these clinical baseline characteristics could be predictive factors of therapeutical response and should be taken into account in the selection of patients. It may be noticed that the included population (Table 1) seems to have a more marked progression of disability than that reported during natural evolution of the disease (Tremlett 2006; Koch 2010 ; Weinshenker 1989a); the The European SG 1998 s cases show the more active disease. According to Kappos 2004, a better response might be related to treatment in the early phase of disease. However, early treatment with interferon beta-1b after a first clinical event suggestive of MS reduced the risk of Clinically Defined MS, but the risk for confirmed disability progression was not significantly lower in the early treatment group (0.76, ; p=0.177) (Kappos 2009). A 16 year follow-up study in RR patients treated with IFN beta-1b found a decrease in the incidence of developing SP compared to those who discontinued treatment (28.6% vs. 44.4%) (not significant ) (Ebers 2009;Ebers 2010). Other observational studies showed that IFN beta treatment reduces the risk to conversion to SP: the percentage of patients that converted after 9 years of follow-up was 7.1% for treated vs. 21.7% for untreated (p = 0.022; RR = 0.32; 95% = ) in a study performed in Argentina (Patrucco 2009 ). Similar results were reported in an Italian population, after 7 years of follow-up (Troiano 2007). Unfortunately, in this review the analysis of MRI outcome measures were only descriptive due to the limitation of available data. Lack of comparable data did not allow analysis of IFNs effect in the prevention of neurodegenerative aspects of the disease, such as cognitive functions and atrophy. A comparative evaluation of different type of IFNs on disability progression was not the aim of our review. However, a possible role of different IFNs agents cannot be excluded, since different schedules of treatment have been adopted. Previous studies on RRMS have showed contradictory results. The annual relapse rates, the time to first relapse and the time to sustained progression were virtually equal in RRMS treated with different types of IFNs (Koch-Henriksen 2006). A recent meta-analysis of head-to-head and comparative trials of INFb agents in RRMS treatment has showed that high dose treatment demonstrated superior relapse reduction and MRI stability compared to low dose treatment; a trend favouring high dose treatment on disability progression (EDSS), was also suggested (Oliver 2011). We think that the results of this review are not related to IFN type or treatment schedules. Two RCTs analysed the role of the same interferon beta 1b (North American SG 2004;The European SG 1998) but with contradictory results, which have been already discussed (FDA 2001; Kappos 2004). Furthermore, the finding of relapse rate reduction was consistent for three out of four RCTs, using different types and dosages of IFNs. Safety profile reflected what is already known, the risk of developing injection site reactions, influenza like syndrome and leukopenia seemed to be similar or inferior to what is reported in the relapsing form of the disease (Rice 2001;Filippini 2003). Quality of the evidence The quality of evidence has been described in Summary of findings for the main comparison. The baseline characteristics of the studied population were heterogeneous in terms of age, percentage of patients with superimposed relapses, pre-study number of relapse and duration of the disease. Furthermore the adopted criteria for disability progression for patient inclusion and treatment effect were different (see section Description of studies ). We cannot exclude the fact that some patients classified as progressive might actually have experienced a prolonged relapse (transient treatment failure), since the adopted criterion was not able to capture permanent treatment failure, that is irreversible disability (Ebers 2008). Potential biases in the review process Study retrieval was not language restricted. Data collection was performed expanding the search to other sources, such as FDA reports, in particular for the North American SG 2004 study. The pharmaceutical companies (Serono, Biogen) kindly collaborated in providing missing data from the primary studies. Agreements and disagreements with other studies or reviews The results of this review are partially in agreement with those of a recent Meta-Analysis of the Efficacy and Tolerability of Interferon-Beta in Multiple Sclerosis (Nikfar 2010), because of some differences in the inclusion of studies and selected outcomes. The review included all MS subtypes (2639 with SPMS) and adopted 15

18 limited number of outcome measures. The key efficacy outcomes of interest were the number of patients with at least one relapse and the mean change in Expanded Disability Status Scale (EDSS) scores. Non significant results were found for the risk of at least one relapse (0.93, 95%, 0.75 to 1.14) in patients with SPMS receiving IFN-beta-1b (3 trials) (RR 1.11 (95%, 0.79 to 1.55)). The pooled effect sizes for the mean change in EDSS score were not significant. Implications for research The conclusions of this review are based on data from well designed RCTs which include a high number of participants. We think that it gives conclusive evidence of the clinical efficacy of IFN-beta versus placebo in SPMS. The licensure of Mitoxantrone has allowed a better control of refractory disease in selected patients, although at the expense of potentially life-threatening side effects. Studies focusing on innovative drugs aimed to evaluated motor, cognitive and degenerative MRI parameters of the disease are needed. A U T H O R S C O N C L U S I O N S Implications for practice This review defines the profile of therapeutic effects of IFN in SPMS; this therapy is able to prevent relapses, while the deterioration of the disease remains unresolved. The window of therapeutic opportunity for IFNs within the natural history of the disease is limited to the inflammatory phase, rifns not being useful in the secondary phase of the disease when the progression is established. These data give further support to EMEA s indication for active MS (EMEA 2006) and underline the need for careful clinical evaluation of responder patients. A C K N O W L E D G E M E N T S Phil You (Biogen Idec Wellesley, MA) (Cohen 2002 (IMPACT), Peter Cornelisse and Elisabetta Verdun di Cantogno (MerkSerono- Ginevra) (SPECTRIMS 2001) for providing data from the primary studies. Dr.Vasiliy Vlassov (Moscow Medical Academy) for his help in translation and analysis of Russian papers. Deirdre Beecher Trials Search Coordinator for her support on papers retrieval and Liliana Coco Managing Editor for her precious technical assistance and support in drawing up the paper. R E F E R E N C E S References to studies included in this review Andersen 2004 (Nordic) {published data only} Andersen O, Elovaara I, Farkkila M, Hansen HJ, Mellgren SI, Myhr KM, et al.multicentre, randomised, double blind, placebo controlled, phase III study of weekly, low dose, subcutaneous interferon beta-1a in secondary progressive multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry 2004;75(5): Beiske AG, Naess H, Aarseth JH, Andersen O, Elovaara I, Farkkila M, et al.health-related quality of life in secondary progressive multiple sclerosis. Multiple Sclerosis 2007;13(3): Wu X, Dastidar P, Kuusisto H, Ukkonen M, Huhtala H, Elovaara I. Increased disability and MRI lesions after discontinuation of IFN-b-1in secondary progressive MS. Acta Neurol Scand 2005;112: Wu X, Kuusisto H, Dastidar P, Huhtala H, Nikkari ST, Ukkonen M, et al.once-weekly 22lg subcutaneous IFN-b- 1a in secondary progressive MS: a 3-year follow-up study on brain MRI measurements and serum MMP-9 levels. Acta Neurol Scand 2007;116:43-8. Cohen 2002 (IMPACT) {published data only} Balcer LJ, Baier ML, Cohen JA, Kooijmans MF, Sandrock AW, Nano-Schiavi ML, et al.contrast letter acuity as a visual component for the Multiple Sclerosis Functional Composite. Neurology 2003;61(10): Cadavid D, Tang Y, O Neill G. Responsiveness of the Expanded Disability Status Scale (EDSS) to disease progression and therapeutic intervention in progressive forms of multiple sclerosis. Rev Neurol 2010;51(6): Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Jak AJ, et al.use of the Multiple Sclerosis Functional Composite as an Outcome Measure in a Phase 3 Clinical Trial. Archives of Neurology 2001;58(6): Cohen JA, Cutter GR, Fischer JS, Goodman AD, Heidenreich FR, Kooijmans MF, et al.benefit of interferon beta-1a on MSFC progression in secondary progressive MS. Neurology 2002;59(5): Masiello SA Director Office of Compliance and Biologics Quality Center for Biologics Evaluation and Research. CBER Warning Letter. Avonex (Interferon beta-1a) for SPMS. Biogen Inc; March 29, FDA 2001 Food and Drug Administration Center for Biologlcs Evaluation and Research (accessed 18 May 2010). Miller DM, Cohen JA, Kooijmans M, Tsao E, Cutter G, Baier M. Change in clinician-assessed measures of multiple sclerosis and subject-reported quality of life: results from the IMPACT study. Multiple Sclerosis 2006;12(2):

19 North American SG 2004 {published data only} FDA Unger, EF MD. Clinical Review of the June 28, 2000 Amendment to Supplemental BLA STN Chiron Corp.; Interferon β- 1b (Betaseron.Information covered in this review: June 28, major amendment to supplement June 14, Responses to FDA Complete Review Letter; Combined analyses of North American and European SPMS Studies. downloads/drugs/developmentapprovalprocess/ HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/ ucm pdf (accessed 6 June 2010). Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, et al.interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004;63(10): The North American Study Group on Interferon beta- 1b in Secondary Progressive MS. Interferon beta-1b in secondary progressive MS: Results from a 3-year controlled. Neurology 2004;63: SPECTRIMS 2001 {published data only} Li DK, Zhao GJ, Paty DW, The University of British Columbia, MS/MRI Analysis Research Group, The SPECTRIMS Study Group. Randomized controlled trial of interferon-beta-1a in secondary progressive MS: MRI results. Neurology 2001;56(11): Patten SB, Metz LM. Interferon beta1a and depression in secondary progressive MS: data from the SPECTRIMS Trial. Neurology 2002;59(5): Sandberg-Wollheim M, Hommes OR, Hughes RA, Paty DW, Abdul-Ahad AK. Recombinant human interferon beta in the treatment of relapsing-remitting and secondary progressive multiple sclerosis. Multiple sclerosis (Houndmills, Basingstoke, England) 1995;1 Suppl 1:S Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group*. Randomized controlled trial of interferonbeta-1a in secondary progressive MS Clinical results. Neurology 2001;56: Sormani, MP, Stubinski B, Cornelisse P, Rocak S, Li D, De Stefano N. Magnetic Resonance Active Lesions As Individual-Level Surrogate for Relapses in Multiple Sclerosis. Multiple Sclerosis 2010 Dec 9 [Epub ahead of print]. The European SG 1998 {published data only} Anonymous. Interferon beta 1b and secondary progressive multiple sclerosis. Rev Prescr 2000;20(205): Anonymous. Placebo-controlled multicentre randomised trial of interferon beta-1 b in treatment of secondary progressive multiple sclerosis. Mezhdunarodnyi Meditsinskii Zhurnal 2000;nr: Barkhof F, van Waesberghe JH, Filippi M, Yousry T, Miller DH, Hahn D, et al.t(1) hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment. Brain 2001;124((Pt 7)): Brex PA, Molyneux PD, Smiddy P, Barkhof F, Filippi M, Yousry TA, et al.the effect of IFNbeta-1b on the evolution of enhancing lesions in secondary progressive MS. Neurology 2001;57(12): Brex PA, Molyneux PD, Smiddy P, Moseley IF, Thompson AJ, Miller DH, et al.the effect of interferon beta-1b on the evolution of new enhancing lesions to hypointense T1 lesions in secondary progressive multiple sclerosis. Multiple Sclerosis 1999;5 Suppl 1:S9 [Abstract no: 31]. FDA. Clinical Review of the June 28, 2000 Amendment to Supplemental BLA STN Chiron Corp.; Interferon β-1b (Betaseron.Information covered in this review: June 28, major amendment to supplement June 14, Responses to FDA Complete Review Letter; Combined analyses of North American and European SPMS Studies. downloads/drugs/developmentapprovalprocess/ HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/ ucm pdf December 13, Freeman JA, Thompson AJ, Fitzpatrick R, Hutchinson M, Miltenburger C, Beckmann K, et al.interferon-beta1b in the treatment of secondary progressive MS: impact on quality of life. Neurology 2001;57(10): Goodin SD. Interferon b treatment for multiple sclerosis. Lancet 1999;353:496. Goodkin DE. Interferon b therapy for multiple sclerosis. Lancet 1998;352: Inglese M, van Waesberghe JH, Rovaris M, Beckmann K, Barkhof F, Hahn D, et al.the effect of interferon beta-1b on quantities derived from MT MRI in secondary progressive MS. Neurology 2003;60(5): Johnson KP, Panitch HS. Interferon b treatment for multiple sclerosis. The Lancet 1999;353:494. Kappos L, Polman C, Pozzilli C, Thompson A, Beckmann K, Dahlke F. Final analysis of the European multicenter trial on IFNbeta-1b in secondary-progressive MS. Neurology 2001;57(11): Kappos L, Weinshenker B, Pozzilli C, Thompson AJ, Dahlke F, Beckmann K, et al.interferon beta-1b in secondary progressive MS: a combined analysis of the two trials. Neurology 2004;63(10): Miller DH, Molyneux PD, Barker GJ, MacManus DG, Moseley IF, Wagner K. Effect of interferon-beta1b on magnetic resonance imaging outcomes in secondary progressive multiple sclerosis: results of a European multicenter, randomized, double-blind, placebo-controlled trial. European Study Group on Interferon-beta1b in secondary progressive multiple sclerosis. Annals of Neurology 1999;46(6): Miller DH, Molyneux PD, MacManus DG, Barker GJ, Wagner K. A double-blind, placebo-controlled trial of interferon A-1b in secondary progressive multiple sclerosis: magnetic resonance imaging results. Annals of Neurology 1998;44(3): Miller DH, Polman C, Pozzilli C, Kappos L, Thompson AJ, Wagner K, et al.mri protocol for the European trial of Beta interferon-1b in secondary progressive multiple sclerosis. 17

20 Journal of the Neurological Sciences 1997;150:S251. Molineux PD, Kappos L, Polman C, Pozzilli C, Barkhof F, Filippi M, et al.the effect of interferon beta 1 b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis. Brain 2000;123: Molyneux PD, Barker GJ, Barkhof F, Beckmann K, Dahlke F, Filippi M, et al.clinical-mri correlations in a European trial of interferon beta-1b in secondary progressive MS. Neurology 2001;57(12): Molyneux PD, Brex PA, Fogg C, Lewis S, Middleditch C, Barkhof F, et al.the precision of T1 hypointense lesion volume quantification in multiple sclerosis treatment trials: a multicenter study. Multiple Sclerosis 2000;6(4): Polman C, Kappos L, White R, Dahlke F, Beckmann K, Pozzilli C, et al.neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology 2003;60(1): Polman CH, Dahlke F, Thompson AJ, Ghazi M, Kappos L, Miltenburger C, et al.interferon beta-1b in secondary progressive multiple sclerosis--outline of the clinical trial. Multiple Sclerosis 1995;1 Suppl 1:S51 4. Polman CH, Kappos L, Dahlke F, Graf R, Beckmann K, Bogumil T, et al.interferon beta-1b treatment does not induce autoantibodies. Neurology 2005;64(6): Sormani MP, Rovaris M, Comi G, Filippi M. A reassessment of the plateauing relationship between T2 lesion load and disability in MS. Neurology 2009;73: The European Study Group on Interferon beta. Placebocontrolled multicentre randomised trial of interferon beta- 1b in treatment of secondary progressive multiple sclerosis. Lancet 1998;352(9139): Thompson AJ, Kappos L, Polman CH, Pozzilli C, Dahlke E, The European Study Group on Interferon beta. Interferon beta-1b delays progression of disability in secondary progressive multiple sclerosis: final results of the European multicentre study. Multiple Sclerosis 1998;4(4):392. Zimmermann C, Walther EU, Goebels N, Lienert C, Kappos L, Hartung HP, et al.interferon beta-1b for treatment of secondary chronic progressive multiple sclerosis. Nervenarzt 1999;70(8): References to studies excluded from this review Arnason 1999 {published data only} Arnason, BGW, Jacobs G, Hanlon M, Harding B, Noronha A.B.C, Auty A, et al.tnf neutralization in MS: Results of a randomized, placebo-controlled multicenter study. Neurology 1999;53(3): Bar-Or 2007 {published data only} Bar-Or A, Vollmer T, Antel J, Arnold DL, Bodner CA, Campagnolo D, et al.induction of Antigen-Specific Tolerance in Multiple Sclerosis after Immunization With DNA Encoding Myelin Basic Protein in a Randomized, Placebo-Controlled Phase 1/2 Trial. Archives of Neurology 2007;64(10): Baum 2006 {published data only} Baum K, Mannitol Formulation Study Group. Safety and tolerability of a refrigeration-free formulation of interferon beta-1b--results of a double-blind, multicentre, comparative study in patients with relapsing-remitting or secondary progressive multiple sclerosis. The Journal of international medical research 2006;34(1):1 12. Boiko2001 {published data only} Boiko A, Skurkovich S, Buglak A, Alekseeva, T, Smirnova N, Skurkovich B, et al.randomized, placebo-controlled trial comparing short course of anti-ifn? And anti-tnfa showed only anti-ifn? Effective in secondary progressive ms. Journal of Neurosurgery 2001;187 (suppl 1):S456. Buhse 2006 {published data only} Buhse M. Efficacy of EMLA cream to reduce fear and pain associated with interferon beta-1a injection in patients with multiple sclerosis. The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses 2006;38(4): Christodoulou 2006 {published data only} Christodoulou C, Melville P, Scherl WF, MacAllister WS, Elkins LE, Krupp LB. Effects of donepezil on memory and cognition in multiple sclerosis. Journal of the neurological sciences. 2006;245(1-2): Fernandez 2002 {published data only} Fernandez O, Guerrero M, Mayorga C, Munoz L, Lean A, Luque G, et al.combination therapy with interferon beta-1b and azathioprine in secondary progressive multiple sclerosis. A two-year pilot study. Journal of Neurology 2002; 249(8): Goodkin 1997 {published data only} Goodkin DE, Kinkel RP, Weinstock-Guttman B, Medendorp VanderBurg, Gogol DM, Perryman JE, et al.a randomized, double-masked, dose-comparison, phase II study of bimonthly intravenous methyprednisolone (IVMP) to modify progression of disability in patients with secondary progressive multiple sclerosis (SPMS). Neurology 1997;48 Suppl 2(3):A Goodkin 2000a {published data only} Goodkin DE, Shulman M, Winkelhake J, Waubant E, Andersson P, Stewart T, et al.a phase I trial of solubilized DR2:MBP (AG284) in multiple sclerosis. Neurology 2000;54 (7):1414. Hoogervorst 2002 {published data only} Hoogervorst EL, Polman CH, Barkhof F. Cerebral volume changes in multiple sclerosis patients treated with high-dose intravenous methylprednisolone. Multiple Sclerosis 2002;8 (5): Leary 2003 {published data only} Leary SM, Miller DH, Stevenson VL, Brex PA, Chard DT, Thompson AJ. Interferon beta-1a in primary progressive MS: an exploratory, randomized, controlled trial. Neurology 2003;60(1): Montalban 2009 {published data only} Montalban X, Sastre-Garriga J, Tintoré M, Brieva L, Aymerich FX, Río J, et al.progressive and transitional multiple sclerosisa single-center, randomized, double-blind, placebo-controlled study of interferon beta-1b on primary. Multiple Sclerosis 2009;15(10):