Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis(protocol)

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1 Cochrane Database of Systematic Reviews Alemtuzumab versus interferon beta 1a for relapsingremitting multiple sclerosis(protocol) ZhangJ,XiaoY,MengL,YangX,ShiS ZhangJ,XiaoY,MengL,YangX,ShiS. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD DOI: / CD Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis(protocol) Copyright 2014 The Cochrane Collaboration. Published by John Wiley& Sons, Ltd.

2 T A B L E O F C O N T E N T S HEADER ABSTRACT BACKGROUND OBJECTIVES METHODS ACKNOWLEDGEMENTS REFERENCES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST i

3 [Intervention Protocol] Alemtuzumab versus interferon beta 1a for relapsingremitting multiple sclerosis Jian Zhang 1, Yousheng Xiao 1, Lian Meng 1, Xiaobo Yang 2, Shengliang Shi 1 1 Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, Nanning, China. 2 Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, China Contact address: Shengliang Shi, Department of Neurology, The First Affiliated Hospital, Guangxi Medical University, No. 22, Shuang Yong Road, Nanning, Guangxi, , China. ssl_1964@163.com. sslno1@yahoo.com.cn. Editorial group: Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group. Publication status and date: New, published in Issue 2, Citation: Zhang J, Xiao Y, Meng L, Yang X, Shi S. Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD DOI: / CD A B S T R A C T This is the protocol for a review and there is no abstract. The objectives are as follows: To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of patients with relapsingremitting multiple sclerosis to prevent disease activity. B A C K G R O U N D Description of the condition Multiple sclerosis (MS) is an autoimmune disease of the central nervous system which is characterised by disseminated inflammatory demyelination. It mainly affects young adults, and leads to disability (Montalban 2010). It has high prevalence in western Europe and North America, (> 100 people per 100,000), lower prevalence in central and eastern Europe, the Balkans, Australia and New Zealand (50 per 100,000), and lowest prevalence in Asia, the Middle East, Africa, and South America (about 10 to 20 per 100,000) (Koch-Henriksen 2010). Women have approximately a two-fold increased risk of developing MS than men. After the first attack, known as clinically isolated syndromes, which refers to a first episode of largely reversible neurological dysfunction with features suggestive of MS, 51% of patients develop MS within six years (Chard 2011; Miller 2012). Most patients have a relapsing-remitting course, but after 10 years over half of MS patients convert to a secondary progressive phase which is characterised by continuing deterioration without remission (Weinshenker 1989). Magnetic resonance imaging (MRI) provides a reflection of the underlying pathology. The MRI measures of disease activity (enhancing demyelinating lesions) and severity (T2-T1- weighted lesion burden) are used to monitor the natural evolution of the disease and treatment effects. They have been integrated with clinical data into diagnostic criteria for MS (McDonald 2001; Polman 2005; Polman 2011). Considering the autoimmune pathogenesis of the disease, the mainstay of treatment is immunomodulatory therapy with interferon beta (IFN) and glatiramer acetate (GA), which are the current standard first-line treatments for MS. They reduce relapse frequency by around 30% (Brown 2013). Natalizumab, and more recently fingolimod, have been introduced for patients with highlyactive disease; they are more efficacious but have a more problematic safety profile than IFN and GA (Pucci 2011; Brown 2013). 1

4 The social costs associated with MS are high because of its long duration, the early loss of productivity, the need for assistance in activities of daily living and the use of immunomodulatory treatments and multi-disciplinary health care (Koutsouraki 2010). Description of the intervention Interferon beta 1a (IFN 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: 30 µg once a week administered by intramuscular injection (Avonex) and 22 or 44 µg administered three times a week by subcutaneous injections (Rebif). Their efficacy on disease activity is partial (Brown 2013). IFN therapy has been associated with a high frequency of treatment-related adverse events, mainly flu-like reactions and injection site reactions; most patients treated with interferon had leukopenia, lymphopenia, thrombocytopenia and increased plasma hepatic enzymes (Rice 2001). These data suggest the need for alternative MS treatments with less invasive routes of administration and new modes of action to expand the current treatment repertoire, increase patient satisfaction and adherence, and thereby improve efcacy. Alemtuzumab is a humanised monoclonal antibody, approved by the US Food and Drug Administration (FDA) for the treatment of B-cell chronic lymphocytic leukemia (FDA 2000). It binds to CD52, a 12-amino acid cell surface protein (Hale 2001) that is expressed at high levels on T cells and B cells, and at lower levels on monocytes, macrophages, and eosinophils. Cells of the innate immune system are unaffected (Coles 2013). Alemtuzumab alters the circulating lymphocyte pool (Cuker 2011), causing prolonged lymphopenia (Thompson 2010). The therapeutic effect of alemtuzumab is mediated by the remolding of the immune repertoire that accompanies homeostatic lymphocyte reconstitution (Coles 2013). Recovery of B- and T-lymphocytes to the lower limit of normal after a single course of alemtuzumab takes eight months and three years, respectively (Hill-Cawthorne 2012). Alemtuzumab is given as an intravenous infusion of 12 mg/day on 5 consecutive days during the first month (first cycle) and on 3 consecutive days at months 12 (second cycle) and 24 (third cycle). For patients with secondary progressive MS, it has been demonstrated that alemtuzumab significantly reduces the mean relapse rate and the risk of new MRI lesions. However, the patient s disability continues to deteriorate as their cerebral atrophy progresses. For patients with relapsing-remitting MS, unlike the progressive cohort, mean disability scores decrease after alemtuzumab (Coles 2013). In a unique program of drug development in MS, alemtuzumab has been compared in one phase 2 trial and two phase 3 trials with the active comparator IFN 1-a. In these trials alemtuzumab was more effective in suppressing relapses compared to IFN 1-a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy (Coles 2013). However, alemtuzumab use was associated with an increased occurrence of autoimmune disorders, such as immune thrombocytopenia, thyroid disease, and antiglomerular basement membrane disease (Cuker 2011). Moreover, in 2005, three MS patients developed severe idiopathic thrombocytopenic purpura while participating in a clinical study of alemtuzumab (Campath) (FDA 2005). One of these patients died. How the intervention might work The pathology of MS suggests an autoimmune etiology and includes infiltration of T cells, B cells, and macrophages in active MS brain lesions (Omar 2012). Alemtuzumab causes rapid and prolonged lymphocyte depletion, finally resulting in immunosuppression and decreased central nervous system immunosurveillance (Bielekova 2010). After alemtuzumab therapy, the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells (Coles 2013). In theory, these repertoire changes induced by alemtuzumab may improve longterm efficacy, but it could also underlie development of antibodymediated autoimmune complications (Bielekova 2010). Previous studies have demonstrated the efficacy of IFN 1-a in patients with relapsing-remitting MS (PRISMS 1998; Panitch 2002; Schwid 2007), and it has been commonly used in clinical practice. The mechanism of action of these therapeutic agents remains undefined. Several modes of action have been proposed, including: inhibition of T-cell activation and proliferation; apoptosis of autoreactive T cells; induction of regulatory T cells; inhibition of leukocyte migration across the blood-brain barrier; cytokine modulation; and potential antiviral activity. Endogenously-produced IFN in the injured brain is also now believed to contribute to mediation of anti-inflammatory and regenerative effects (Dhib-Jalbut 2002; Dhib-Jalbut 2010). Why it is important to do this review Monoclonal antibodies (mabs) have gained relevance in the treatment of MS. Available trials show that alemtuzumab is more effective than IFN 1-a, significantly reducing the relapse rate, risk for sustained accumulation of disability, and mean Expanded Disability Status Scale (EDSS) score at month 36 after treatment. However, 30% of patients develop autoimmunity (Thompson 2010). Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of adverse events, such as infusion-associated reactions, mild-tomoderate infections and autoimmunity (Ali 2013, Coles 2013). While the European Medicines Agency (EMA) has already approved it for relapsing-remitting MS (EMA 2013), it has not been approved by the FDA (FDA 2013; Thompson 2013). 2

5 A systematic review is warranted to assess the efficacy, tolerability and safety profile of alemtuzumab versus IFN 1-a. O B J E C T I V E S To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of patients with relapsing-remitting multiple sclerosis to prevent disease activity. M E T H O D S Criteria for considering studies for this review Types of studies Double-blind, randomised, controlled trials (RCTs). We will exclude uncontrolled, non-randomised and quasi-randomised trials. Types of participants Patients of any gender and age with relapsing-remitting multiple sclerosis (MS) fulfilling Poser criteria (Poser 1983), or original or revised McDonald criteria (McDonald 2001; Polman 2005; Polman 2011). We will exclude people with: a progressive disease course; previous MS disease therapy (apart from corticosteroids); previous immunosuppressive, investigational, or monoclonal antibody therapy; and clinically-significant autoimmune disorder other than MS. hours or more, and that were accompanied by a change in Functional Score on Kurtzke s EDSS scale shown by the examining physician. One or more of the following changes compared with baseline will be required for relapse confirmation: i) an increase in total EDSS by 0.5 point; ii) an increase of at least one point in two functional-systems scores, or of at least two points in one functional-system score. Other less stringent criteria will be accepted. 2. The number of patients whose disease progressed at 24 and 36 months. Progression is defined as an increase of at least 1.5 points on the EDSS scale for patients with a baseline score of 0, of at least 1.0 point for patients with a baseline score of 1.0 or more, and of at least 0.5 point for patients with a baseline score of 5.5 or more (Kurtzke 1983). 3. The total number of relapses at 24 and 36 months. Safety: The number of patients with at least one of any adverse events, including serious adverse events. Secondary outcomes 1. The mean EDSS score changed from baseline at 24 and 36 months. 2. Number of patients with new T2-hyperintense lesions on MRI at 24 and 36 months. 3. Number of patients experiencing treatment discontinuation caused by adverse events. Search methods for identification of studies We will conduct a systematic search without language restrictions to identify all relevant published and unpublished randomised controlled trials. Types of interventions Experimental intervention: Intravenous alemtuzumab 12 mg or 24 mg mg per day on 5 consecutive days during the first month and on 3 consecutive days at months 12 and 24. Control intervention: Subcutaneous interferon beta 1a 22 or 44 µg three times per week (Rebif) or intramuscular injection 30 µg once a week (Avonex). Types of outcome measures Primary outcomes Efficacy: 1. The number of patients experiencing at least one relapse at 24 and 36 months. Relapse is dened as new, or worsening, preexisting neurological symptoms, without fever, that lasted for 48 Electronic searches The Review Group s Trials Search Co-ordinator will search the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register which, among other sources, contains records from the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EM- BASE, CINAHL, LILACS, PEDRO and Clinical trials registries ( and the WHO International Clinical Trials Registry Platform (ICTRP) search portal ( trialsearch/default.aspx) for all prospectively registered and ongoing trials. Information on the 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 and Rare Diseases of the Central Nervous System Group s module. The keywords that we will use to search for trials for this review are listed in Appendix 1. 3

6 In addition we will handsearch congress reports and conference proceedings (from 1994 to date) from the most important neurological associations and MS Societies (e.g. American Academy of Neurology, American Neurological Association, American Committee for Treatment and Research in MS, the European Committee for Treatment and Research in MS) and contact pharmaceutical companies. The review authors will search the following three Chinese databases using the search terms (duofaxingyinghua) AND (alundankang) AND (β-ganraosu) (Appendix 2): 1. China Biological Medicine Database (CBM-disc) at sinomed.imicams.ac.cn/zh/ (1979 to date); 2. Chinese National Knowledge Infrastructure Database (CNKI) at (1979 to date); 3. VIP Chinese Science and Technique Journals Database at (1979 to date). Searching other resources To identify other relevant study data we will: 1. contact authors of published studies if data reported are incomplete; 2. screen reference lists of relevant review articles and primary studies found; 3. contact authors of unpublished manuscripts to ask if they are willing to disclose their unpublished data; and 4. contact experts in the field to identify further published or unpublished trials. Data collection and analysis Methods: study design, randomisation method, allocation concealment method, blinding methods of participants, personnel and outcome assessors. Interventions: details of alemtuzumab and interferon beta 1a (IFN 1-a), such as administration method, dosage and duration, treatment period, co-intervention(s). Outcomes: primary and secondary outcomes. Other: country and setting, publication year, sources of funding, intention-to-treat analysis. We will contact principal investigators of included studies to obtain additional data or confirmation of methodological aspects of the study. Any disagreements will be resolved by discussion among both review authors. Assessment of risk of bias in included studies Two review authors (Zhang J, Meng L) will independently assess the risk of bias (RoB) of the included studies using the checklist recommended by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The checklist for evaluating the risk of bias consists of seven specific domains: (1) sequence generation, (2) allocation concealment, (3) blinding of participants and personnel, (4) blinding of outcome assessment, (5) incomplete outcome data, (6) selective outcome reporting, and (7) other bias. Each domain will be classified as low, high, or unclear risk of bias (Higgins 2011a). Each study will be classified as high risk of bias in case of non -random sequence generation and inadequate allocation concealment, lack of blinded outcome assessor and/or lack of blinded participants/personnel. Any disagreements will be resolved by discussion among all review authors. Selection of studies Titles and abstracts of the citations retrieved by the literature search will be screened independently for inclusion/exclusion by two review authors (Zhang J, Xiao Y). We will select the full text of potentially-relevant studies for further assessment. We will evaluate independently the eligibility of these studies on the basis of information available in the published data. Papers that do not meet the inclusion criteria at this stage will be listed in the Characteristics of excluded studies table with the reason for exclusion. Any disagreement regarding inclusion will be resolved by discussion among all review authors. Data extraction and management Two review authors (Zhang J, Xiao Y) will independently extract the following data using a data extraction form: Participants: diagnostic criteria, number in each group, age, gender, baseline comparability between groups, length of followup, withdrawals or losses to follow-up. Measures of treatment effect All the data will be analysed following the intention-to-treat (ITT) principle. For dichotomous outcomes, risk ratios (RR) with 95% confidence intervals (CI) will be used to calculate the effect size. For continuous data, mean differences (MD) with 95% CI will be used to analyse the results. Unit of analysis issues We will assess trials with multiple observations for the same outcome according to randomisation and types of interventions, and perform separate analyses based on different periods. Dealing with missing data If data are insufficient or missing, we will attempt to obtain additional information from the authors of included studies by personal communication. If we do not receive a response, we will then analyse the available data. 4

7 Assessment of heterogeneity We will evaluate the clinical and methodological heterogeneity of included trials by comparing the characteristics of participants (diagnostic criteria, age, gender, disease duration), interventions (administration method, dosage and duration, control intervention, co-intervention(s)), and study designs (randomisation, allocation concealment, blinding methods). We will evaluate statistical heterogeneity among included studies using the Chi² test and the I² statistic. If the I² statistic is more than 50%, which indicates substantial heterogeneity (Higgins 2011), we will check the sources of potential clinical and methodological heterogeneity. Assessment of reporting biases Potential biases of reporting will be assessed using funnel plots and visual inspection for asymmetry according to the approach outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), if sufficient studies (at least 10) are identified. Data synthesis We will use Review Manager 5.2 software (Review Manager 2013) to conduct formal meta-analysis.the selection of a fixed-effect or random-effects model will be mainly based on the results of the Chi² test and I² statistic for heterogeneity (Higgins 2011). If the I² statistic indicates substantial statistical heterogeneity, we will explore potential causes of heterogeneity first, to determine whether a subgroup analyses is needed. If the substantial heterogeneity still cannot be explained, we will adopt a random-effects model. If the I² statistic indicates no significant statistical heterogeneity, we will use a fixed-effect model. 4. Different types of IFN 1-a. Sensitivity analysis The following sensitivity analyses will be performed if we identify a sufficient number of randomised trials: 1. Re-analysis excluding studies at high risk of bias, i.e. non - random sequence generation and inadequate allocation concealment, lack of blinded outcome assessor and/or lack of blinded participants/personnel 2. Re-analysis using a random-effects model if a fixed-effect model was used previously. Summary of findings table We will create a Summary of findings table reporting the following outcomes: the number of patients experiencing at least one relapse, the number of patients whose MS progressed, the total number of relapses, the number of patients with at least one of any adverse events and the number of patients experiencing treatment discontinuation caused by adverse events, the mean change in EDSS score, and the number of patients with new T2-hyperintense lesions on MRI. We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the metaanalyses for the prespecified outcomes. We will use methods and recommendations described in Section 8.5 (Higgins 2011a) and Chapter 12 (Schünemann 2011) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) using GRADEpro software. We will justify all decisions to down- or up-grade the quality of studies using footnotes and we will make comments to aid readers understanding of the review where necessary. Subgroup analysis and investigation of heterogeneity The following subgroups will be analysed if we identify a sufficient number of randomised trials: 1. Different dosages of alemtuzumab versus IFN 1-a. 2. Different duration of treatment. 3. Different co-interventions. A C K N O W L E D G E M E N T S We thank the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group and the peer reviewers for their help in developing this protocol. 5

8 R E F E R E N C E S Additional references Ali 2013 Ali R, Nicholas RS, Muraro PA. Drugs in development for relapsing multiple sclerosis. Drugs 2013;73(7): Bielekova 2010 Bielekova B, Becker BL. Monoclonal antibodies in MS: mechanisms of action. Neurology 2010;74 Suppl 1: Brown 2013 Brown JW, Coles AJ. Alemtuzumab: evidence for its potential in relapsing-remitting multiple sclerosis. Drug Design, Development and Therapy 2013;7: Chard 2011 Chard DT, Dalton CM, Swanton J, Fisniku LK, Miszkiel KA, Thompson AJ, et al. MRI only conversion to multiple sclerosis following a clinically isolated syndrome. Journal of Neurology, Neurosurgery & Psychiatry 2011;82(2): Coles 2013 Coles AJ. Alemtuzumab therapy for multiple sclerosis. Neurotherapeutics 2013;10(1): Cuker 2011 Cuker A, Coles AJ, Sullivan H, Fox E, Goldberg M, Oyuela P, et al. A distinctive form of immune thrombocytopenia in a phase 2 study of alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Blood 2011;118(24): Dhib-Jalbut 2002 Dhib-Jalbut S. Mechanisms of action of interferons and glatiramer acetate in multiple sclerosis. Neurology 2002;58 Suppl 4(8):3 9. Dhib-Jalbut 2010 Dhib-Jalbut S, Marks S. Interferon-beta mechanisms of action in multiple sclerosis. Neurology 2010;74 Suppl 1: EMA 2013 European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP)- Summary of opinion (initial authorisation)- -Lemtrada (Alemtuzumab). http: // Summary_of_opinion_-_Initial_authorisation/human/ /WC pdf (accessed January 2014). FDA 2000 US Food, Drug Administration. Compath (Alemtuzumab) Intravenous Product Approval Information - Licensing Action docs/nda/2000/103948s000_campathtoc.cfm (accessed October 2013). FDA 2005 US Food, Drug Administration. Alemtuzumab (marketed as Campath) Information. PostmarketDrugSafetyInformationforPatientsandProviders/ ucm htm (accessed October 2013). FDA 2013 US Food, Drug Administration. Peripheral and Central Nervous System Drugs Advisory Committee Meeting - Alemtuzumab (BLA \5139) Background Package. committeesmeetingmaterials/drugs/peripheralandcentralnervoussystemdrugsadvisorycommittee/ucm pdf (accessed January 2014). Hale 2001 Hale G. The CD52 antigen and development of the CAMPATH antibodies. Cytotherapy 2011;3(3): Higgins 2011 Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version [updated March 2011]. The Cochrane Collaboration Available from Higgins 2011a Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version (updated March 2011). The Cochrane Collaboration, Available from Hill-Cawthorne 2012 Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, et al. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry 2012;83(3): Koch-Henriksen 2010 Koch-Henriksen N, Sørensen PS. The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurology 2010 ;9(5): Koutsouraki 2010 Koutsouraki E, Costa V, Baloyannis S. Epidemiology of multiple sclerosis in Europe: a review. International Review of Psychiatry 2010;22(1):2 13. Kurtzke 1983 Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33: McDonald 2001 McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Annals of Neurology 2001;50(1): Miller 2012 Miller DH, Chard DT, Ciccarelli O. Clinically isolated syndromes. Lancet Neurology 2012;11(2): Montalban 2010 Montalban X, Tintoré M, Swanton J, Barkhof F, Fazekas F, Filippi M, et al. MRI criteria for MS in patients with 6

9 clinically isolated syndromes. Neurology 2010 ;74(5): Omar 2012 Jr Ode F, Moore CS, Kennedy TE, Antel JP, Bar-Or A, Dhaunchak AS. MicroRNA dysregulation in multiple sclerosis. Frontiers in Genetics 2012;3:311. Panitch 2002 Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O Connor P, et al. Randomized, comparative study of interferon beta-1a treatment regimens in MS: The EVIDENCE Trial. Neurology 2002;59(10): Polman 2005 Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the McDonald Criteria. Annals of Neurology 2005;58(6): Polman 2011 Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Annals of Neurology 2011;69(2): Poser 1983 Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Annals of Neurology 1983;13(3): PRISMS 1998 PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group. Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 1998;352(9139): Pucci 2011 Pucci E, Giuliani G, Solari A, Simi S, Minozzi S, Di Pietrantonj C, et al. Natalizumab for relapsing remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2011, Issue 10. [DOI: / CD007621] Review Manager 2013 [Computer program] The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.2. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, Rice 2001 Rice GP, Incorvaia B, Munari L, Ebers G, Polman C, D Amico R, et al. Interferon in relapsing-remitting multiple sclerosis. Cochrane Database of Systematic Reviews 2001, Issue 4. [DOI: / CD002002] Schwid 2007 Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clinical Therapeutics 2007; 29(9): Schünemann 2011 Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version (updated March 2011). The Cochrane Collaboration, Available from Thompson 2010 Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. Journal of Clinical Immunology 2010;30(1): Thompson 2013 Thompson AJ, Giovannoni G. Removal of access to alemtuzumab for patients with aggressive multiple sclerosis. BMJ 2013 Jan 18;346:275. Weinshenker 1989 Weinshenker BG, Bass B, Rice GP, Noseworthy J, Carriere W, Baskerville J, et al. The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability. Brain 1989 ;112: Indicates the major publication for the study 7

10 A P P E N D I C E S Appendix 1. Keywords for English databases {interferon beta-1a} OR {Avonex} OR {Biogen brand of Interferon beta 1a} OR {Rebif} OR {Serono brand of interferon beta 1a} OR {Betaseron} AND {alemtuzumab} OR {Campath 1G} OR {Campath-1G} OR {Campath-1-G} OR {Campath 1M} OR {Campath-1M} OR {MabCampath} OR {Schering brand of alemtuzumab} OR {Campath} OR {Berlex brand of alemtuzumab} OR {Campath 1H} OR {monoclonal antibody Campath-1H} OR {Campath-1H} OR {monoclonal antibod*} OR {Antibodies, Monoclonal} AND {relapsing remitting multiple sclerosis} OR {relapsing-remitting multiple sclerosis} OR {remitting-relapsing multiple sclerosis} OR {remitting relapsing multiple sclerosis} Appendix 2. Keywords for Chinese databases #1 #2 β #3 β- #4 -β #5 #6 #7 #8 #2 OR #3 OR #4 OR #5 #9 #6 OR #7 #10 #1 AND #8 AND #9 C O N T R I B U T I O N S O F A U T H O R S All authors contributed to developing the protocol. D E C L A R A T I O N S O F None known I N T E R E S T 8